diff --git a/2016-09-17-lecture01.md b/2016-09-17-lecture01.md index 391332e..b564802 100644 --- a/2016-09-17-lecture01.md +++ b/2016-09-17-lecture01.md @@ -577,6 +577,35 @@ They are the direct decendents of the mother stem cells that give rise to the ne Devasting diseases of astrocyte function include brain cancer with gliomas like glioblastomas typicaly being comprised of astrocytes gone wild. It is also thought that some childhoold epilepsies may originate from altered astrocyte function. +blood brain barrier-- control entry of neurotransmitters and hormones into the brain + +areas of the brain without a blood-brain barrier (from Table 32-2 Basic Neurochemistry 6e): + +Pituitary gland +Median eminence +Area postrema +Preoptic recess +Paraphysis +Pineal gland +Endothelium of the choroid plexus + +There is a positive relationship between lipid solubility and brain uptake of chemical compounds + +- permeability of lipid soluble compounds is rapid (ethanol, nicotine, diazepam, THC) +- polar molecules (e.g. glycine and catecholamines) enter slowly across BBB +- gases and volatile anesthetics diffuse rapidly into the brain + + blood—brain barrier permeability of CO2 greatly exceeds that of H+ thus pH of brain interstitial fluid reflect pCO2 rather than blood pH. Therefore a patient with metabolic acidosis may be brain alkalotic at teh same time. + + glucose is primary energy substrate of the brain. Nearly all oxygen consumption for the brain. GLUT-1 glucose transporters highly enriched in brain capillary endothelial cells. Since glucose is a polar substrate, this transporter facilitates its transport across the BBB. + +Neutral L-amino acids enter the brain as rapidly as glucose (Phenylalanine, leucine, tyrosine, isoleucine, valine, tryptophan, methionine, histidine and l-dihydroxy- phenylalanine (l-DOPA)) + +water enters rapidly through diffusion. + +
+ + -- ## Oligodendrocytes diff --git a/2016-10-16-lecture07.md b/2016-10-16-lecture07.md index 57a437e..221eb2c 100644 --- a/2016-10-16-lecture07.md +++ b/2016-10-16-lecture07.md @@ -450,6 +450,9 @@ Amphetamine also inhibits DAT as well as a transporter for norepinephrine * L-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline) collectively known as catecholamines. * it is converted into dopamine by the enzyme aromatic L-amino acid decarboxylase, also known as DOPA decarboxylase. +*Parkinson's treatment: LDOPA + enzyme inhibitors info* +*blood brain barrier info* + *Encephalitis lethargica, sleeping sickness, 40 yrs later Oliver Sacks in NYC treats them with L-DOPA* * neostriatum diff --git a/2016-10-16-lecture08.md b/2016-10-16-lecture08.md index 139fa54..8d5e3e4 100644 --- a/2016-10-16-lecture08.md +++ b/2016-10-16-lecture08.md @@ -185,7 +185,7 @@ A postsynaptic muscle fiber is voltage clamped to control the muscle fiber’s m ## Hypothetical ion channel selectivities and the reversal potential -
Current-voltage relationships for different ion selectivities
Neuroscience 3e 2001
+
Current-voltage relationships for different ion selectivities
Neuroscience 2e 2001
Note: @@ -530,7 +530,7 @@ The alpha subunits bind ACh. * ACh, nicotine, curare, and bungarotoxin binding sites are on the α1 subunits * Pore diameter 10x bigger than Na⁺ channels (3 nm vs 0.3 nm) -
Neuroscience 3e 2001
+
Neuroscience 2e 2001
Note: @@ -549,7 +549,7 @@ curare is a competitive antagonist. * Each monomer contributes properties * Mixing and matching from a large pool of monomer isoforms creates receptors with different properties -
Neuroscience 3e 2001
+
Neuroscience 2e 2001
Note: diff --git a/2016-10-16-lecture09.md b/2016-10-16-lecture09.md index 8cae6ff..8ca1d54 100644 --- a/2016-10-16-lecture09.md +++ b/2016-10-16-lecture09.md @@ -1,143 +1,460 @@ -## Signal transduction +## Somatic sensory system -* Neurons can change their state (e.g. which receptors, channels, neurotransmitters are opened, modulated, or expressed) depending on what is going on in their local environment -* They receive signals from other neurons (neurotransmitters) and other cells (hormones, growth factors, and trophic factors) -* They have specialized machinery that can transduce these signals to changes in their physiological state. +* Touch, vibration, pressure, position of limbs (sense of self), pain, temperature +* Monitors the external and internal forces acting on the body at any moment +* Leads to the ability to identify shapes and textures of objects +* Detects potentially harmful circumstances Note: -Today we take a broad overview of signal transduction pathways that work to change the physiological state of neurons. Many of the pathways and second messengers should be familiar to you from basic cell biology. +Today we will focus on the somatic sensory system also called the somatosensory system. -* hormones, estradiol, testosterone & (LH, FSH, progesterone) +Responsible for a bunch of fairly important things including touch or tactile discrimination, vibration, pressure, limb positioning or proprioception, pain, temperature. ---- +Monitors external and internal forces acting on the body— e.g. touch is external, proprioception/self positioning is internal. -## Different types of cell-cell communication +Gives rise to our ability to identify objects, also called stereognosis. -* Synaptic signaling -* Paracrine signaling– acts over a short range -* Endocrine signaling– secretion of hormones into the blood stream -* Membrane protein signaling– two cells next to each other signal through closely associated membrane proteins +And of course helps us become alarmed to potentially dangerous environments. -Note: +soma +: the parts of an organism other than the reproductive cells +: the body as distinct from the soul, mind, psyche -What types of cell-cell communication underly signaling? The answer is familiar ones like… +-- ---- +## Sensory systems -## Synaptic, paracrine, and endocrine signaling - -
Neuroscience 5e Fig. 7.1
+* The nervous system consists of discrete systems for each of the sensory modalities (touch, vision, hearing, taste, smell) +* Each functional system involves several CNS regions that carry out different types of information processing +* Identifiable pathways link the components of a functional system +* Each part of the brain projects in an orderly fashion onto the next, creating sensory (e.g. topographic) maps. Neural maps not only reflect the position of receptors on a sensory surface, but also their density +* Functional systems on one side of the body generally respond/control the other side of the body Note: +Parallel processing of sensory information + + +Totally fascinating to think out how all this works. Talk about which ones we will go over, common principles, all can get linked together. + --- -## Components of signaling -* Signal (the message) -* Receptor (signal detection) -* Effector/target molecules (mediate the cellular response) -* Intracellular signal transduction refers to the events between the receptor and the effector targets -* Signal amplification often occurs during signal transduction +## Overview of somatic sensory system + +* Specific receptor neurons located in skin or joints receive stimuli +* Information is carried to brain via the spinal cord, brainstem, thalamus, to the post central gyrus of the parietal lobe, which in turn project to higher order cortical areas +* Projections are topographic with respect to body region, and the amount of cortical space allocated to various body parts is proportional to the density of sensory receptors in that area Note: + --- -## Signal amplification +## Somatosensory pathway– from somatic sensory neuron to cortex -* results in a tremendous increase in the potency of the initial signal -* permits precise control of cell behavior +
Touch and pain have different routes to the brain
Neuroscience 5e Fig. 9.1
-
Neuroscience 5e Fig. 7.2
Note: +We’ve already become aware that the dorsal root ganglia contain sensory neurons that act as sensory receptors for the body with the cell body located in the ganglion and processes extending to the sensory periphery— e.g. this mechanosensory afferent fiber connected to your index finger, or a proprioceptive neuron sensing internal muscle stretch connected to your knee joint for the myotactic reflex that we’ve discussed previously. + +In this inset you see both mechanosensory and pain sensitive fibers connected to the finger— notice that these are coming from two different neurons (red and blue) and the ascending process from the DRG neurons course through the spinal cord to higher brain regions through different routes. *anterolateral tract vs dorsal column*. More on this later. --- -## Types of receptors +## There are many types of somatic sensory receptors + +* Different functions– pain, temperature, touch, and proprioception +* Different morphologies– free nerve endings or encapsulated +* Different conduction velocities– fast vs. slow +* Differ locations– skin, muscle, tendon, hair +* Different rates of adaptation– slow vs. fast + +Note: + +Variety of somatosensory receptors. + +--- + +## Types of somatosensory afferents
-* Ligand gated ion channels (channel linked receptors/ionotropic receptors)– e.g. nAChR, AMPA receptors -* Enzyme linked receptors– typically have extracellular binding site for signals. Has intracellular domain with catalytic activity regulated by signal. Most are protein kinases that phosphorylate intracellular proteins. e.g. tyrosine kinase -* G-protein coupled receptors– 7-transmembrane spanning receptors that signal through trimeric G-proteins intracellularly. The proteins can alter the function of many downstream proteins. e.g. muscarinic AChR, metabotropic glutamate receptors -* Intracellular receptors– activated by cell permeant or lipophilic signaling molecules like steroid hormones. Signal binds directly to an intracellular protein which then activates transcription +sensory function | receptor type | afferent axon type | axon diameter (µm) | conduction velocity (m/s) +--- | --- | --- | --- | --- +proprioception | muscle spindle | Ia, II (**myelinated**) | 13–20 | 80–120 +touch | Merkel, Meissner, Pacinian, and Ruffini cells | A𝛽 (**myelinated**) | 6–12 | 35–75 +pain, temperature | free nerve endings | Aδ (**myelinated**) | 1–5 | 5–30 +pain, temperature, itch | free nerve endings | C (**unmyelinated**) | 0.2–1.5 | 0.5–2
+ + Note: +This table summarizes the somatosensory afferents types, and variety in their functions, morphologies, and AP conduction velocities. +The fastest ones are… + +The slowest ones are… + +Tab. 1 after Rosenzweig 2005 --- -## Categories of cellular receptors +## Proprioception -
Neuroscience 5e Fig. 7.4
+* The function of some sensory receptors is to relay information about **self**. Where are my limbs and other body parts? +* Muscle spindles– are located in most muscles. Contain specialized muscle fibers encapsulated by connective tissue +* Axons from sensory neurons wrap around this connective tissue and fire depending on muscle length +* Feeds back to γ motor neurons that change spindle length to compensate as needed +* Golgi tendon organs do a similar thing but with tendons + +Note: + +Proprioception are stimuli that are produced and perceived within an organism, such as the positioning and movement of the body + +proprioceptive and vestibular system input is integrated within the brain to cause a perception of body position, movement, and acceleration + +-- + +## Proprioceptors provide information about the position of body parts + +
Neuroscience 5e Fig. 9.7
Note: -We already know how ion channels work. - -For enzyme linked receptors the signal binds extracellularly, which activates the intracellular enzymatic domain of the same protein catalyzing the production of a product from a substrate. +We will discuss proprioception in more detail during our motor system lectures later on in this class --- -## Categories of cellular receptors +## General properties of sensory receptors -
Neuroscience 5e Fig. 7.4
+* Stimuli applied to skin, deforms or changes the nerve endings, produces a receptor potential that triggers an action potential +* Quality of stimulus (what it represents and where it is) is determined by the relevant receptor and the afferent neuron’s targets in the brain +* Quantity or strength of stimulus is determined by the rate of action potential discharge + +Note: + +--- + +## Somatosensory receptors + +
Neuroscience 5e Fig. 9.2
+ +Note: + +The sensation of touch, pain, or temperature all starts with specialized receptors and nerve endings in the skin. In all cases ion channels open on the receptor neuron ending that can depolarize and initiate an AP with a sufficiently strong stimulus. + +[from: http://www.ncbi.nlm.nih.gov/gene/63895](http://www.ncbi.nlm.nih.gov/gene/63895) + +- example in this fig looks like a pacinian corpuscle + +-piezo type mechanosensitive ion channel component 2 + +-protein encoded by this gene contains more than thirty transmembrane domains and likely functions as part of mechanically-activated (MA) cation channels + +-channels serve to connect mechanical forces to biological signals + +piezo +: greek for push + +Piezoelectric Effect +: ability of some materials to generate an electric charge in response to applied mechanical stress +: reversible: mechanical stress <–> electricity +: gas stoves, cigarette lighters +: piezoelectric ceramics (Lead zirconate titanate or PZT Pb[Zr~x Ti~1-x ]O~3 ) and single crystal materials (gallium phosphate, quartz, tourmaline) + +--- + +## Slowly adapting and rapidly adapting mechanoreceptors respond differently to stimulation + +
Neuroscience 5e Fig. 9.4
Note: -For g protein coupled receptors, the signal binds to the receptor, then the g-protein binds and becomes activated. - -For intracellular receptors, the signaling molecule passes through lipid membrane, binds to the intracellular receptor and activates the receptors which can then enter the nucleus to regulate transcription. - +Another type of somatosensory afferent variability I mentioned was rate of adaptation– this figure highlights this difference where if we were performing extracellular electrode recordings close to somatic sensory we find that some types adapt slowly, with sustained spiking as a stimulus stays on, whereas others adapt rapidly with their spiking activity strong at the beginning of the stimulus but quiet as the stimulus is maintained. --- -## Downstream of activated receptors: G-proteins -* G-proteins– GTP binding proteins -* G-proteins generally couple the active receptor to downstream targets. Called G-proteins because they hydrolyze GTP -* Two types of G-proteins: - * Heterotrimeric G- proteins, composed of an α,β, γ subunits. Multiple members of each class. α subunit binds and hydrolyses GTP - * Small G-proteins– monomeric GTPases (e.g. ras) -* Active when bound to GTP, inactive when bound to GDP +## Skin harbors morphologically distinct mechanoreceptors + +
Neuroscience 5e Fig. 9.5
Note: -G proteins couple receptor activation to downstream effects for G-protein coupled receptors. - -They hydrolyze guanine triphosphate to guanine diphosphate so that downstream proteins can become phosphorylated and activated. - -There are two types… - -heterotrimeric composed of three distinct subunits. It is the alpha subunit that binds to the guanine nucleotides GDP and GTP. - -binding of GDP allows the alpha subunit to bind to the beta and gamma subunits to form an inactive trimer. Binding of the extracellular signal to the receptor allows the g-protein to bind the receptor and GDP to be replaced with GTP. Then the alpha subunit with GTP is free to dissociate from the trimer and bind downstream effector molecules to mediate a host of responses inside the cell. - -The monomeric GTPases also relay signals from membrane receptors to intracellular targes like the cytoskeleton. Ras is the first small G protein discovered (rat sarcoma tumors). Helps regulated cell differentiation and proliferation, relaying signals from receptor kinases. - -Rate of GTP hydrolysis is important property of G-protein mediated signaling and can be regulated by proteins like GAPs (or GTPase activating proteins) that replace GTP with GDP to return G proteins to their inactive form. - -* - Guanosine-5'-triphosphate (GTP) is a purine nucleoside triphosphate. -* - Effector enzymes for activated G-proteins include adenylyl cyclase, guanylyl cyclase, phospholipase C, and others. -* - In some cases G-proteins can directly modulate ion channels. mAChR that slow heart rate from vagus nerve stimulation are thought to be due to beta/gamma G protein subunits binding to and modulating K channels. Alpha subunits of g proteins can lead to rapid closing of voltage-gated Ca and Na channels. +So here are 5 types of morphologically different somatic sensory receptors— --- -## Types of GTP-binding proteins +## Low threshold (or high sensitivity) mechanoreceptors -
Neuroscience 5e Fig. 7.5
+* Provide information about touch, pressure, vibration, and cutaneous tension +* Four major types of encapsulated mechanoreceptors: + * Merkel’s disks + * Meissner’s corpuscles + * Ruffini’s corpuscles + * Pacinian corpuscles +* Called low-threshold mechanoreceptors because even weak stimulation causes them to fire action potentials. Innervated by large myelinated axons (type Aβ fast) + +Note: + +--- + +## Properties of mechanoreceptor afferents + +
+
+ +| type | Merkel | Meissner | Ruffini | Pacinian | +| --- | --- | --- | --- | --- | +| location | tip of epidermal sweat ridges | dermal papillae (close to skin surface) | dermis | dermis and deeper tissues | +| axon diameter | 7-11 µm | 6-12 µm | 6-12 µm | 6-12 µm | +| conduction velocity |40-65 m/s | 35-70 m/s | 35-70 m/s | 35-70 m/s | +| sensory function | form and texture perception | motion detection, grip control | tangential force, hand shape, motion direction | perception of distant events through transmitted vibrations, tool use | +| effective stimuli | edges, points, corners, curvature | skin motion | skin stretch | vibration | +| receptive field area | 9 mm^2 | 22 mm^2 | 60 mm^2 | entire finger or hand | +| innervation density (finger tip) | 100/cm^2 | 150/cm^2 | 10/cm^2 | 20/cm^2 | +| spatial acuity | 0.5 mm | 3 mm | 7+ mm | 10+ mm | +| response to sustained indentation | sustained (slow adaptation) | none (rapid adaptation) | sustained (slow adaptation) | none (rapid adaptation) | +| frequency range | 0-100 Hz | 1-300 Hz | 0-? Hz | 5-1000 Hz | +| peak sensitivity | 5 Hz | 50 Hz | 0.5 Hz | 200 Hz | +| best threshold for rapid indentation | 8 µm | 2 µm | 40 µm | 0.01 µm | +| mean threshold for rapid indentation | 30 µm | 6 µm | 300 µm | 0.08 µm | + +
+ + + +Note: + +Two broad classes based on receptive field area, innervation density-- both classes (ones with small receptive fields vs large receptive fields) have subtypes that have either sustained activity upon depression or transient activity just at when the stimulus is changin + +- receptive fields as measured with rapid 0.5 mm indentation +- table after K.O. Johnson 2002 + +Work +: *W* = *Fs*, force*displacement (N-M) +: joules newton-meters, N–M +: force over time +: no displacment, no work +: no work in direction orthongonal to displacement + +--- + +## Cutaneous mechanoreceptors + +
Neuroscience 2e, Mechanoreceptor types
+ +Note: + +-- + +## Merkel’s disks + +* Located in epidermis, precisely aligned with the ridges (finger print part of fingers) +* 25% of the mechanoreceptors in the hand +* Are particularly dense in finger tips, lips, and genitalia +* Slow adapting, selective stimulation leads to the feeling of light pressure +* Have small receptive fields + +Note: + +[from: http://www.ncbi.nlm.nih.gov/gene/63895](http://www.ncbi.nlm.nih.gov/gene/63895) + +-piezo type mechanosensitive ion channel component 2 + +-protein encoded by this gene contains more than thirty transmembrane domains and likely functions as part of mechanically-activated (MA) cation channels + +-channels serve to connect mechanical forces to biological signals + +[-http://www.nature.com/nature/journal/v509/n7502/full/nature13251.html 2014](http://www.nature.com/nature/journal/v509/n7502/full/nature13251.html) + +[-http://www.ncbi.nlm.nih.gov/pubmed/25471886 2014](http://www.ncbi.nlm.nih.gov/pubmed/25471886) + +-- + +## Meissner corpuscle + +* Located in the superficial layers of the skin, between the dermal papillae just beneath the epidermis +* Generate rapidly adapting action potentials after minimal stimulation. Adapt fast +* Have small receptive fields +* Account for 40% of the sensory innervation of the human hand. Particularly good in transducing info about low-frequency vibrations +* Detects movement of textures across the skin + +Note: + +-- + +## Ruffini’s corpuscles + +* Lie parallel to the skin +* Large receptive fields +* Detect cutaneous stretching produced by digit or limb movements +* 20% of receptors in hand +* Slow adapting + +Note: + +-- + +## Pacinian corpuscles + +* Have large encapsulated endings located in subcutaneous tissue +* The onion-like capsule acts like a filter allowing in only high frequency stimulation +* Adapts more rapidly than Meissner’s and has a lower response threshold +* Has large receptive fields +* Stimulation induces a sense of vibration or tickle +* Involved in the discrimination of fine surface textures +* 10-15% of cutaneous receptors in the hand + +Note: + +pacinian corpuscle + +: 'Lamellar' corpuscle +: 1 mm length +: surrounding capsule comprised of fibroblasts and fibrous connective tissue (Type IV and Type II collagen) +: 20 to 60 concentric lamellae +: lamellae comprised very thin, flat, epithelial cells inside the capsule and modified Schwann cells +: center contains a single afferent, unmyelinated at the receptive region + + +--- + +## Activity patterns in different mechanosensory afferents as Braille is read + +
Neuroscience 5e Fig. 9.6
+ +Note: + +Each dot represents an action potential recorded in a single mechanosensory afferent fiber. + +Horizontal line of dots in the raster plot represents the pattern of activity in the afferent when moving the pattern across the finger. The pattern position is then displaced slightly by a small distance and then the pattern is moved again and the spike pattern is displayed on the next row. + +Individual Braille dots can be distinguished in the pattern of Merkel afferent neural activity + +--- + +## Differences in mechanosensory discrimination across the body surface + +* The accuracy of our sense of touch is not the same all over the body +* Can use two-point discrimination tests to show this +* Fingers can distinguish things 2 mm apart, forearms 40 mm apart +* Mechanosensory receptors are more numerous in finger tips and have smaller receptive fields +* Doesn't explain everything about ability to discriminate two points. The CNS is also involved with discrimination. Two point thresholds vary with practice, and depend on the stimulus + +Note: + + +--- + +## Receptive field size across the body surface + +* Receptive field (RF)– the area in the periphery within which sensory stimulus can modulate the firing of the sensory neuron +* Spatial resolution of the RF: + * Size– smaller RF, higher resolution + * Density– higher density, higher resolution + * "Two-point discrimination test" + +
Neuroscience 5e Fig. 9.3
+
Neuroscience 5e Fig. 9.3
+ + + + +Note: + + + +--- + +## Pathways for sensory information + +* The cell somas of mechanosensory axons are located in the dorsal root ganglion (DRG). One on each side of the spinal cord, one for each segmental spinal nerve +* DRG neurons called first-order because they initiate the sensory process +* All sensory axons cross the midline once +* All map to primary somatic sensory cortex, located in the postcentral gyrus +* Mechanoreceptors and proprioception receptors use the dorsal-column-medial lemniscus pathway to get to brain +* Pain and temperature use spinothalamic (anterolateral pathway) + +Note: + + +--- + +## Dorsal column-medial lemniscus system + +* Dorsal root ganglion neurons– first order, initiate process +* Contains info from mechanoreceptors concerned with tactile discrimination or proprioception +* Upon entering spinal cord, axons bifurcate into ascending and descending branches, which in turn send out collateral branches to several spinal segments +* Some branches go to ventral horn of the cord and synapse on neurons that are part of the reflex system + +Note: + + +-- + +## Dorsal column-medial lemniscus system + +
Note: @@ -145,15 +462,51 @@ Note: --- -## Trimeric G-protein signaling +## Second order mechanosensory neurons -* Ligand binds receptor -* α subunit binds activated receptor -* GTP exchanged for GDP -* Dissociates complex and activates -* α and βγ subunits +* The major branches of dorsal root ganglion neurons are ascending and go up the dorsal columns of the spinal cord ipsilaterally +* They terminate in the gracile and cuneate nuclei (dorsal column nuclei) in the caudal (posterior) medulla +* Axons are organized such that lower limbs are mapped medially (gracile nucleus) and the upper limbs, trunk, and neck in the cuneate nucleus +* Axons from both nuclei cross the midline in the medulla and send projections to the somatic sensory portion of the thalamus, the ventral posterior lateral nucleus (VPL). Cuneate axons terminate in medial VPL, gracile projections terminate in lateral VPL -
Molecular Biology of the Cell 4e Fig. 15.28
+Note: + + + +--- + +## Mechanosensory pathways (body) + +
+Upper and lower body use slightly different pathways. +**Cross in the medulla** +
Neuroscience 5e Fig. 9.8
+ + +Note: + + +--- + +## Trigeminal tract + +* Information about the face takes a different route to the thalamus +* Trigeminal nerve (cranial nerve V, three subdivisions: ophthalmic, maxillary, and mandibular) +* Enters the brainstem at the level of the pons and terminates in the trigeminal brainstem complex. This complex has two main components, the principal nucleus (mechanosensory stimuli) and the spinal nucleus (pain and temp) +* Crosses midline in the pons and ascends to thalamus + +Note: + + + +--- + +## Trigeminal pathway (face) + +
+Info from head and face. +**Crosses in pons midbrain** +
Neuroscience 5e Fig. 9.8
Note: @@ -162,109 +515,99 @@ Note: --- -## Downstream targets of G-proteins +## The somatic sensory components of the thalamus -* Ion channels– can be directly-activated by both the βγ subunits (can gate some types of K⁺ channels) or by α subunits (can cause closing of voltage sensitive Na⁺ and Ca²⁺ channels) -* Enzymes that produce 2nd messengers– e.g. adenylyl cyclase, guanylyl cyclase, and phosopholipases -* Each 2nd messenger does different things -* Wide diversity of physiological responses +* Ventral posterior complex (VPC)– + * Ventral posterior lateral nucleus (VPL) receives projections from the medial lemniscus carrying all somatic sensory information from the body and posterior head + * Ventral posterior medial nucleus (VPM) receives axons from the trigeminal info from the face +* VPC contains a complete representation of the body Note: -In some cases G-proteins can directly modulate ion channels. mAChR that slow heart rate from vagus nerve stimulation are thought to be due to beta/gamma G protein subunits binding to and modulating K channels. Alpha subunits of g proteins can lead to rapid closing of voltage-gated Ca and Na channels. +-- -Effector enzymes for activated G-proteins include adenylyl cyclase, guanylyl cyclase, phospholipase C, and others. +## Thalamus– gateway to the cerebral cortex +
Thalamus (brown), ventricles (blue)
[C. Krebs CC BY-NC-SA, Univ. British Columbia](http://www.neuroanatomy.ca/3D_files/3D_index.html?id=1)
---- - -## Effector pathways associated with G-protein coupled receptors - -
Neuroscience 5e Fig. 7.6
- +
Fiber stain
[Brain Biodiversity Bank MSU, NSF](https://msu.edu/~brains/brains/human/coronal/montage.html)
Note: -There are many types of alpha, beta, and gamma g-protein subunits allowing a specific and diverse range of downstream responses. +The thalamus is located in the middle of the brain… -This shows three examples of different heterotrimeric g proteins bound to 3 types of receptors with 3 different cellular responses. +*red nucleus is part of midbrain, without a corticospinal tract it controls gait. Baby crawling controlled by red nucleus. Arm swinging while walking* +-- ---- +## Thalamus subdivisions -## Second messengers: calcium - -* Maintained at low concentrations inside cytosol -* Binds to many proteins and regulates their activity -* Calmodulin– binds Ca²⁺ and then can activate calmodulin dependent protein kinases -* IP3 receptors– channel that lets calcium out of ER +
Neuroscience 3/4e (5e Box A)
Note: - -Maybe the most common intracellular messenger in neurons. - -One target of calcium is calmodulin, a calcium binding protein abundant in the cytosol of all cells. Calcium binding to this protein initiates downstream effects by binding to targets like protein kinases. - +…and is the gateway for routing information into the cerebral cortex. It contains a number of different nuclei and subdivision that take information from other brain regions including the brain stem and sends to appropriate primary sensory or higher order regions of the cerebral cortex. --- -## Proteins involved in delivering and removing calcium to the cytoplasm +## Somatic sensory cortex -
Neuroscience 5e Fig. 7.7
- - -Note: - -ATPase called the calcium pump (Ca-proton pump). Works on cell membrane and also pumps calcium into intracellular organelles like ER and mitochondria. - -Na/Ca exchanger that replaces intracellular Ca with extracellular sodium ions. - -VGCCs - -calcium binding effector proteins like calmodulin mediate downstream effectors of calcium. - -calcium binding buffer proteins serve as calcium buffers (calbindin, common in strongly expressed in some neuron subtypes). Can blunt the magnitude and kinetics of calcium signals. - -Channels that allow Ca to be released from the the interior of the ER like the inositol trisphosphate receptors (IP3). These are regulated by IP3, a second messenger. - -Another one intracellular releasing channel is the ryanodine receptor. These are activated by cytoplasmic Ca and for at least muscle cells, membrane depolarization. - - ---- - -## Calcium activates calmodulin - -
Molecular Biology of the Cell 4e Fig. 15.40
+* All axons from ventral posterior complex project primarily to layer IV of the somatic sensory cortex +* Located in parietal lobe, post-central gyrus +* Divided into regions, Broadmann’s areas 3a, 3b, 1 and 2 that together comprise the primary somatosensory cortex, SI Note: --- -## Calcium second messaging video summary +## Brodmann areas -
Neuroscience 5e Animation 7.2
+
Brodmann 1909
+
Brodmann 1909 color
+ + +Note: + +Note areas 4 (primary motor cortex), 1,2,3 (primary somatosensory cortex), area 17 (primary visual cortex), area 18 (secondary visual cortex), area 41,42 (primary auditory cortex, also part of 22) + +*Comparative localization teachings of the cerebral cortex in their principles, illustrated on the basis of Zellenbaues. Leipzig, Johann Ambrosius Barth Verlag, 1909 . 2nd edition, 1925. English translation by Laurence J. Garey: Localisation in the Cerebral Cortex by Korbinian Brodmann. Smith-Gordon, 1994; new impression: Imperial College Press., 1999* + +*area 44,45 Broca's areas* +*area 39,40,22 wernicke's areas* +*area 43 gustatory cortex* +*area 22 superior temporal gyrus* + +--- + +## Somatic sensory portions of the thalamus and cortical targets + +
Neuroscience 5e Fig. 9.10
+ + +Note: + +Cross section view shows that there are really 4 subdivisions of primary somatosensory cortex + +In VP complex, Upper body medial, Lower body lateral + +--- + +## Receptive fields of somatosensory cortical neurons + +* Area 3b and 1– cutaneous stimuli +* 3a– proprioceptive stimuli +* 2– tactile and proprioceptive stimuli +* SI is organized in columns, by receptive field, and modality. Stick an electrode vertically, all neurons share same region of body Note: --- -## Second messengers: cyclic nucleotides +## Somatotopic order in the human primary somatosensory cortex -* cAMP and cGMP– derivatives of ATP and GTP. Made by adenylyl cyclase and guanylyl cyclase -* Bind to many targets– cAMP to protein kinase A, cGMP to protein kinase G -* Phosphodiesterases cleave cAMP and cGMP to inactivate them - -Note: - - ---- - -## cAMP formation and destruction - -
Molecular Biology of the Cell 4e Fig. 15.31
+
Neuroscience 5e Fig. 9.11
Note: @@ -273,116 +616,48 @@ Note: --- -## Second messengers: diacylglycerol and IP3 +## Somatotopic order in the primary somatosensory cortex -* Formed from the cleavage of lipids (phosphatidylinositols) by phospholipase C -* Diacylglycerol (DAG) activates protein kinase C -* IP3 opens calcium channels +* somatotopy– topographic representation of the body surface +* areas of high receptor density get more cortical space -Note: - - - ---- - -## Diacylglycerol and IP3 - -
Molecular Biology of the Cell 4e Fig. 15.35
+
Neuroscience 5e Fig. 9.11
+
Neuroscience 5e Fig. 9.11
Note: -Phosphatidylinositol 4,5-bisphosphate: PIP2 +More cortical space for body areas with higher somatic receptor density +-- ---- +## The ‘homunculus’ reflects sensory receptor density -## Neuronal second messengers - -
Neuroscience 5e Fig. 7.7
- - -Note: - -This table summarizes neuronal second messengers, their sources, targets, and inactivation mechanisms. - - ---- - -## Second messenger life cycles - -
cyclic nucleotides
Neuroscience 5e Fig. 7.7
- -
lipid signals
Neuroscience 5e Fig. 7.7
- - -Note: - -And this depicts the mechanisms involved in production and degradation or removal of cyclic nucleotides and DAG and IP3. - - ---- - -## 2nd messengers target protein kinases and phosphatases - -* Phosphorylation can rapidly alter a protein’s activity -* Phosphorylation is carried out by protein kinases and usually occurs on Ser/thr and tyr residues -* Dephosphorylation is carried out by protein phosphatases -* 2nd messengers typically activate Ser/Thr kinases -* Extracellular signals (e.g. growth factors) activate Tyr kinases - -Note: - -Second messengers regulate neuronal functions by modulating the phosphorylation of intracellular proteins. This addition and removal of phosphate groups rapidly and reversibly modulates protein function. - -Phosphorylation is carried out by protein kinases. - -Phosphate groups are removed by phosphatases. - -Protein substrates of kinases and phosphataes include enzymes, neurotransmitter receptors, ion channels, structural proteins. - - ---- - -## Regulation of cellular proteins by phosphorylation - -
Neuroscience 5e Fig. 7.8
+
Note: +-- ---- +## Magnified cortical representations of sensory apparatus -## Ser/thr kinases +
Krubitzer PNAS 2012 Fig. 3
-* PKA– cAMP dependent protein kinase. Ser/thr kinase. Tetramer of 2 regulatory and 2 catalytic subunits. cAMP binds the regulatory subunits causing the release of catalytic subunits -* CaMKII– Ca²⁺/calmodulin-dependent protein kinase. Ser/thr kinase, very abundant in brain. 12 or so subunits. Downstream targets: many ion channels, other signal transduction proteins, tyrosine hydroxylase. Thought to be involved in learning/memory -* PKC– Ser/thr kinase activated by DAG and Ca²⁺. DAG causes PKC to move from the cytosol to the membrane where it binds Ca²⁺ and gets activated - -Note: - - - ---- - -## Mechanism of activation of protein kinases - -
binding of cAMP to regulatory subunits free up the catalytic subunits
Neuroscience 5e Fig. 7.9
-
binding of calmodulin opens up protein to activate catalytic domain
Neuroscience 5e Fig. 7.9
-
DAG causes PKC to change its localization which leads it to be active
Neuroscience 5e Fig. 7.9
+
star-nosed mole
Note: +[http://www.pnas.org/content/109/Supplement_1/10647/F3.expansion.html](http://www.pnas.org/content/109/Supplement_1/10647/F3.expansion.html) + +-- ---- +## Whisker 'barrels' in rodent cortex -## Protein kinase A activation - -
Molecular Biology of the Cell 4e Fig. 15.32
+
Note: @@ -390,157 +665,231 @@ Note: --- -## Other kinases - -* Protein tyrosine kinases– Two types receptor tyrosine kinases (Eph receptors, growth factor receptors) and cytoplasmic kinases (many oncogenes). Cytoplasmic tyrosine kinases are particularly important for cell growth and differentiation -* MAP kinases– mitogen activated kinases. Are often intermediate kinases, become activated by kinases and kinase other proteins. Often found downstream of receptor tyrosine kinases - -Note: - -Mitogen activated protein kinases (MAP kinases) - -* first identified as having a role in cell growth -* also called extracellular signal regulated kinases (ERKs). -* normally inactive in neurons, but activated when phosphorylated by other kinases -* part of kinase cascades. -* activation can be triggered by extracellular growth factors that bind receptor tyrosine kinases that activate monomeric G proteins like ras. -* can phosphorylate transcription factors - ---- - -## MAP kinase cascade - -
Molecular Biology of the Cell 4e Fig. 15-56
- -Note: - - ---- - -## Nuclear signaling - -* Sometimes 2nd messengers (e.g. cAMP) can go into the nucleus where they can change the transcription of genes -* Transcription factors are proteins that interface with RNA polymerase to select promoter regions of genes -* These transcription factors can be regulated by phosphorylation - -Note: - -CREB is an important nuclear signal - -* [from https://en.wikipedia.org/wiki/Estrogen_receptor:](https://en.wikipedia.org/wiki/Estrogen_receptor) -* >estrogen receptors are largely located in the cytosol. Hormone binding to the receptor triggers a number of events starting with migration of the receptor from the cytosol into the nucleus, dimerization of the receptor, and subsequent binding of the receptor dimer to specific sequences of DNA known as hormone response elements. - - ---- - -## Steps involved in transcription of DNA to RNA - -
Neuroscience 5e Fig. 7.10
- -Note: - -uas: upstream activator sequence - -[from https://en.wikipedia.org/wiki/Upstream_activating_sequence:](https://en.wikipedia.org/wiki/Upstream_activating_sequence) - ->upstream activating sequence or upstream activation sequence (UAS) is a cis-acting regulatory sequence. It is distinct from the promoter and increases the expression of a neighbouring gene. - --upstream from minimal promoter TATA box, binding site for transactivators --a cis acting regulatory sequence (like IRES) - ---- - -## CREB - -* CREB (cAMP response element binding protein). An important transcription factor -* Normally bound to DNA but not active. Phosphorylation activates it and it activates transcription. CREB is important for transcription of tyrosine hydroxylase, neuropeptides, neurotrophins and channel proteins -* Important for learning and memory, mothering instincts, synaptic plasticity - -Note: - ---- - -## Transcriptional regulation by CREB - -
Neuroscience 5e Fig. 7.11
- - -Note: - - ---- - -## Chemical signaling mechanisms video summary - -
Neuroscience 5e Animation 5.2
- -Note: - - ---- - -## Mechanism of action of NGF - -
Neuroscience 5e Fig. 7.12
- - -Note: - - -nerve growth factor, binds to tyrosine kinase receptor (TrkA) leading to… - ---- - -## Signaling at cerebellar parallel fiber synapses +## Higher order processing
-* Glutamate released from presynaptic cell binds ionotropic and metabotropic glutamate receptors -* AMPA receptor opens and excites cell -* mGluR receptor activates a signal transduction pathway that feeds back and decreases AMPA receptor activity -* Called long term depression because now the same stimulus will lead to less depolarization than before (weakened synapse) +* SI sends out projections to other areas of cortex +* SII, adjacent to SI. Receives info from all 4 SI areas and sends it to amygdala and hippocampus. Plays roles in fear conditioning and tactile learning and memory
-
Neuroscience 5e Fig. 7.13
- +
Neuroscience 5e Fig. 9.12
Note: -Can result from strong synaptic stimulation at cerebellar purkinje neurons or from weak synaptic stimulation in the hippocampus. +--- -* Both parallel fibers and climbing fibers must be simultaneously activated for LTD to occur. With respect to calcium release however, it is best if the parallel fibers are activated a few hundred milliseconds before the climbing fibres. +## Pain -LTD is thought to result mainly from a decrease in postsynaptic receptor density, +* Submodality of the sense of touch, warns of injury and things that should be avoided +* More subjective than the other senses. The same stimulus can produce different responses in different individuals, or in the same individual in different circumstances -likely from phosphorylation of AMPA receptors by PKC and their elimination from the synapse and involves mapk cascade +
Congenital insensitivity to pain
-* Hippocampal/cortical LTD can be dependent on NMDA receptors, metabotropic glutamate receptors (mGluR), or endocannabinoids.[4] -* LTP involves +Note: + +Congenital insensitivity to pain + +[from: http://ghr.nlm.nih.gov/condition/congenital-insensitivity-to-pain](http://ghr.nlm.nih.gov/condition/congenital-insensitivity-to-pain) + +>20 cases have been reported in the scientific literature + +>Mutations in the SCN9A gene cause congenital insensitivity to pain. The SCN9A gene provides instructions for making one part (the alpha subunit) of a sodium channel called NaV1.7. + +>NaV1.7 sodium channels are found in nerve cells called nociceptors that transmit pain signals to the spinal cord and brain. The NaV1.7 channel is also found in olfactory sensory neurons, which are nerve cells in the nasal cavity that transmit smell-related signals to the brain. + +>The SCN9A gene mutations that cause congenital insensitivity to pain result in the production of nonfunctional alpha subunits that cannot be incorporated into NaV1.7 channels. As a result, the channels cannot be formed. + +>autosomal recessive pattern --- -## Regulation of tyrosine hydroxylase by protein phosphorylation +## Pain involves specialized neurons not just extrastimulation of touch receptors -
+* Scheme for transcutaneous nerve recording +* Nociceptor doesn’t fire until pain is felt. Other thermoreceptors fire at all temps and at about the same frequency + +
Neuroscience 5e Fig. 10.1
+ + +Note: + + + +--- + +## How do we detect pain? + +* A family of ion channel receptors have been found that open in response to heat as well as capsaicin called TRP (transient receptor potential) channels +* Structurally resemble voltage-gated K⁺ channels, having 6 transmembrane domains that make a pore +* When open allows Ca²⁺ and Na⁺ across membrane to generate a receptor potential + +Note: + + + +--- + +## Heat gated ion channels + +* Capsaicin receptors are nonselective cation channels opened by heat, low pH, and capsaicin (the hot in hot peppers) +* Mice without TRPV1 (VR1) have impaired sensitivity to pain. Can drink capsaicin as if it were water + +
Neuroscience 5e Box10A
+
Neuroscience 5e Box10A
+ + +Note: + +transient receptor potential cation channel subfamily V member 1 (TrpV1), also known as the capsaicin receptor or the vanilloid receptor 1 (VR1) + +function of TRPV1 is detection and regulation of body temperature. In addition, TRPV1 provides a sensation of scalding heat and pain (nociception). + +43ºC threshold (110ºF) + +*There is recent evidence for endovanilloids that are released by other cells that can stimulate TRPV1 and contribute to nociception* + +receptors for transduction of mechanical and chemical forms of nociceptive stimulation are not well understood, candidate include + +- TRP family (TRPV2 and TRPA1) +- ASIC acid sensing family (ASIC3 cardiac pain) +- TRPV3 TRPV4 warm temperatures +- TRPM8 cold temperatures + +*repeated applications of capsaicin desensitize pain fibers, preventing neuromodulatiors like sub P, VIP, and somatostatin from being released by PNS and CNS nerve terminals* + +NAV 1.7 and NAV 1.8 are sodium channels especially important for transmission of nociceptive information + + + + + +--- + +## Nociceptors + +
-* AP invades axon terminal -* Voltage-gated Ca²⁺ channels open -* Intracellular Ca²⁺ does two things: -* Short term causes vesicle fusion -* Long term activates protein kinases -* Activation of protein kinases -* Phosphorylation of tyrosine hydroxylase -* Increased catecholamine synthesis -* Increase in transmitter release -* Increase in post-synaptic response +* Transfer information about pain +* Three major classes of nociceptors: Aδ mechanosensitive nociceptors, Aδ thermal nociceptors, and polymodal nociceptors +* Aδ mechanosensitive nociceptors-activated by intense pressure, are lightly myelinated and have speeds of 5-30 m/s +* Aδ thermal nociceptors are activated by very hot or very cold temperatures. Are lightly myelinated +* Polymodal nociceptors (C fibers) respond to temperature, pressure, or chemicals, are unmyelinated and conduct at speeds of 1 m/s +* Aδ and C fibers have cold temperature gated ion channels. When they fire they are perceived as pain +* Pain receptor receptive fields are generally pretty large, presumably because the detection of pain is more important than its exact location
-
Neuroscience 5e Fig. 7.14
+Note: + + + +--- + +## Two categories of pain perception + +* first pain (sharp), Aδ fibers +* second pain (dull, longer lasting) C-fibers + +
selective block of either Aδ or C fibers
Neuroscience 5e Fig. 10.2
+ + +Note: + + +--- + +## Hyperalgesia + +* Enhanced sensitivity and response to stimulation of the area around the damaged tissue. Stimuli that would not ordinarily be perceived as pain now is. For example after a sunburn a normal shower now feels painful +* Due to the release of stuff from the damaged cells, such as prostaglandins, bradykinin, histamine, serotonin, ATP, can increase the sensitivity of nociceptors by interacting with the channel (directly or indirectly) and making it open easier, or by interacting with other receptors on nociceptive fibers to potentiate activity of TRP channels +* Aspirin and ibuprofen inhibit cyclooxygenases (COX-2 inhibitors), necessary for prostaglandin synthesis +* Shows that pain and injury are inter-related + +Note: + + +- allodynia (hyper sensitization), clinically relevant pain from normally unpainful stimuli. Contrast with nociceptive pain (actual response to real tissue injury associated with inflammation like aches, sprains, arthritis, cancer pain, headache). Clinical issue is shifting noxious stimuli in pain sensation-stimulus intensity activation curve to the left into innocuous stimuli +- injury to a nerve is called neuropathic pain (phantom limb pain falls into this category), nerves in limbs, spinal cord, or brain can all call neuropathic pain. Also shingles, MS, spinal cord injury, cancer pain. Often severe burning sensation pain and chronic. +- phantom limb pain, often severe grip sensation (nails digging into hand) + + +Nice talk on pain from [Allan Basbaum UCSF](https://www.youtube.com/watch?v=gQS0tdIbJ0w). Argues against the existence of a 'pain' pathway. Can't just cut nerve to abolish pain-- maybe for acute pain but not chronic pain. peripheral sensitization. + +tissue injury --> arachidonic acid, cyclooxgenase--> prostaglandins --> C fiber threshold lowered --> allodynia + +central sensitization (pain memories)-- is a CNS disease, not a symptom of other diseases it is argued (A. Basbaum) + +Sensory discriminative (SI and SII) and affective motivational (limbic system activated, including cortical areas anterior cingulate gyrus, insular cortex (between parietal and temporal lobes ventral to S1)) dimensions of the pain experience. (MC Bushnell, Basbaum lecture). **Anterior cingulate gyrus positively correlates with unpleasant experience** + +More fMRI brain activation (amplitude and size of actiation) in parts of brain with same painful stimulus for females vs males. Pain threshold almost the same (45degs hot) between the sexes but is a little bit lower for women. But pain tolerance is much higher in women. (Casey et al, Basbaum lecture). Who can tolerate delivering a baby. + +Expectancy can alter pain (sawamoto 2000 interesting fMRI study, after Basbaum lecture 51:07). Imaging the brain of an empathetic spouse (female) reveals activity patterns characteristic of a spouse that is in pain (no citation someone from germany, Basbaum lecture 52:27) + +--- + +## Inflammatory response to tissue damage + +
Neuroscience 5e Fig. 10.7
+ + +Note: + +Another type of peripheral sensitization can occur due to substances released within damaged tissues can modulate the response of nociceptive fibers. A host of molecules that can augment the activity of free nerve endings like… + +Most interact directly with the receptors or ion channels of the nociceptive fibers. e.g. TRPV1 capacin receptor can be potentiated form the channels direct interactions with extracellular protons that are released by immune cells or through indirect interaction with other enzyme receptors like TrkA for NGF or bradykinin receptors. + +**Prostaglandins reduce the threshold depolarization needed for AP generation by phosphorylation of special TTX resistant Na+ channels expressed in nociceptor afferents and also incr levels of cAMP.** + +Cells that contribute to this inflammatory soup include mast cells, patelets, basophils, macrophages, neutrophils, endothelial cells, keratinocytes, and fibroblasts. Cells are responsible for releasing protons (lowering the pH), arachidonic acid, bradykinini, histamine, serotonini, prostaglandins, neucleotides, NGF, cytkines (interleukin 1beta, and TNF-alpha). COX2 inhibitors, NSAIDs -- or nonsteroidal anti-inflammatory drugs block Cox-1 and Cox-2 enzymes so that prostaglandins can't be made. + + +>a peptide that causes blood vessels to dilate (enlarge), and therefore causes blood pressure to fall + +nociceptive +: of or related to pain arising from stimulation of nerve fibers + +--- + +## Pain pathways + +* Spinothalamic tract +* Cell bodies found in the most lateral parts of the dorsal root ganglia, but not discretely localized. +* Innervate neurons in the dorsal horn of the spinal cord. Some of these neurons project within the spinal cord. These are important for reflex behaviors. +* Others project axons cross the midline in the same segment and then go up to the brain. + +Note: + + + +--- + +## Major pathways for pain (and temperature) sensation of the body + +
Neuroscience 5e Fig. 10.6
+ + +Note: + +nociceptive projections into dorsal horn branch into ascending and descending collaterals forming the dorsolateral tract of Lissauer (named after 19th c. German neurologist). + +C fibers (slow pain) terminate in layer 1 (Rexed’s laminae, named after anatomist who first described spinal gray matter layers in 1950s) of dorsal horn. + +Adelta (fast pain) terminate in layer 5 of dorsal horn where Abeta mechanosensory terminals innervate. + +--- + +## Pathways for pain (and temperature) sensation of the face + +
Neuroscience 5e Fig. 10.6
Note: @@ -549,17 +898,237 @@ Note: --- -## Summary +## Nociceptive component in the ventral posterior nuclei in the thalamus -* Signaling exists in all neurons to help them adjust to their environment -* Lots of ways to do this. There are various: -* Signals -* Receptors -* G-proteins -* 2nd messengers -* Downstream targets +* Pain and temp go to VPM and VPL nuclei just like the mechanosensory axons +* VPM from the face, VPL from the body +* Presumably responsible for our ability to locate a pain with respect to body position + +
upper body medial, lower body lateral
Berne and Levy, Physiology 6e Elsevier
Note: +--- + +## Cerebral cortex + +* VPM and VPL neurons project to primary somatosensory cortex. These thalamic neurons have small receptive fields and are likely used to locate where the pain is, but are not responsible for dull aches that are associated with chronic pain as ablation does not reduce pain +* There are also direct projections to the reticular formation (in medulla), and the midline thalamic nuclei. These neurons project to areas of the limbic system and are responsible for the emotional aspects of pain + +Note: + + + +--- + +## Anterolateral system sends information to different parts of the brainstem/forebrain + +
Neuroscience 5e Fig. 10.5
+ + +Note: + +sensory discrimative: location, intensity, and quality of noxious stimulation + +affective-motivational: unpleasant feeling, fear, anxiety, autonomic activation for fight-flight + +--- + +## Spinothalamic tract + +
+
+ +* Also called anterolateral column part of the ventral column +* Note where axons cross over the midline +* Touch and pain are on opposite sides below medulla +* Touch and pain are on the same side above medulla + +
+ +
Neuroscience 2e 2001
+ +Note: + + + +--- + +## The anterolateral and dorsal column-medial leminiscal systems cross the midline at different sites + +
Neuroscience 5e Fig. 10.4
+ +Note: + +nociceptive and mechanosensory pathways + +-- + +## Pain vs touch + +* 2nd order mechanosensory axons cross at the level of the medulla but 2nd order pain axons cross at about the segment their cell bodies are in +* If there is a damage on one side of the spinal cord, below the injury site, there would be no sense of touch on the same side and no sense of pain on the contralateral side + +--- + +## Referred pain + +
+
+ +* Few if any neurons in dorsal horn are specialized solely for the transmission of visceral pain +* It is conveyed to brain via dorsal horn neurons that also get inputs from skin +* Therefore a person may feel pain at a site completely different than its source + +
+ +
referred pain
+ +Note: + +anginal pain which is pain arising from heart muscle that is not being adequately perfused with blood. Referred to the upper chest wall, with radiation into the left arm and hand. + +Innervation of same neuron in the dorsal horn of the spinal cord. + +--- + +## Pain perception is subjective + +* Rubbing the site of injury can make pain less severe +* Pain is somewhat subjective. Depends on context. Soldiers wounded in battle feel less pain than if one gets the same injury at home +* There is a descending pain pathway that can impinge on the dorsal horn to quiet neurons + +Note: + + +--- + +## Brain modulation of ascending pain signals + +* Stimulation of periaqueductal grey (in midbrain) or rostral medulla reduces pain, producing analgesia +* Stimulation only reduces pain sensation, animal/person still responds to touch, temp etc, just feels less pain +* Cerebral cortex and hypothalamus project to periaqueductal gray which then projects to nuclei in the medulla (Raphe nuclei, reticular formation), which project to the dorsal horn and inhibit ascending pain fibers, forming a descending pathway that modulates pain + +Note: + + +-- + +## Modulation of ascending pain signal transmission + +1. Axons from neurons with mechanoreceptors can synapse onto inhibitory interneurons in spine to dampen pain response +2. Descending pathways from the brainstem can dampen pain response + +
Neuroscience 5e Fig. 10.8
+ + +Note: + +enkephalins, endorphins, dynorphins— present in the periacq. gray matter, ventral medulla, and in spinal cord regions in dorsal horn. + +Also CB1 and endocannabinoids work similiarly here in the dorsal horn. + +-- + +## Modulation of ascending pain signal transmission + +* Axons from neurons with mechanoreceptors can synapse onto inhibitory interneurons in spine to dampen pain response +* Descending pathways from the brainstem can dampen pain response + +
Neuroscience 5e Fig. 10.8
+
Neuroscience 5e Fig. 10.8
+ + +Note: + +enkephalins, endorphins, dynorphins— present in the periacquaductal gray matter, ventral medulla, and in spinal cord regions in dorsal horn. + +Also CB1 and endocannabinoids work similiarly here in the dorsal horn. + + +-- + +## Descending systems modulate the transmission of ascending pain signals + +
Descending pathways from cortex and hypothalamus
Neuroscience 2e 2001
+ + +Note: + + +-- + +## Descending systems modulate the transmission of ascending pain signals + +
Descending output from periaqueductal gray–rostral medulla reduces activity in spinothalamic tract
Neuroscience 2e 2001
+ + +Note: + +-- + +## Endogenous opioids dampen pain signal transmission + +* Opioid receptors (metabotropic) are expressed in the areas of descending pain pathway (also expressed in other areas, such as muscles of the bowel and anal sphincter) +* Ligands– enkephalins, endorphins, and dynorphin. Found in all descending pain areas +* Opioids decrease the chance that a nociceptor afferent will fire by causing inhibition +* Opiate antagonist naloxone (competitive opioid receptor antagonist) blocks stimulation produced analgesia as well as morphine-induced analgesia. Suggests that they are the same thing + +Note: + +endogenous opioids +: all are 5–30 a.a. long peptides +: enkephalins, endorphins, dynorphins + +* leucine-enkephalin +* methionine-enkephalin +* alpha-endorphin +* alpha-neoendorphin +* beta-endorphin +* gamma-endorphin +* dynorphin A +* dynorphin B + +- oxycontin, percoset + +--- + +## Placebo effect + +* Sugar pills can reduce perception of pain +* Effect can be blocked by naloxone, a competitive antagonist of opioid receptors +* Therefore placebo effect is based on a biochemical change in the brain, as are all perceptions + +Note: + +- mind separate from body. No– this highlights something that neuroscientists already widely accept, that you cannot separate the mind from the body, the mind is body and vice versa +- what is or is not reality philosophers +- highlights descending control and higher order processing of pain +- endogenous opioid + +- children are not placebo reactors less than 10 yr old. acupuncture works likely as a placebo (needle can be stuck anywhere). Hypnosis can alter perception (reduce activity in anterior cingulate) without sensory discrimination (Rainville Science 1997). But not sensitive to naloxone, so not through opiate system. + +- hypnosis (80% of people can be hypnotized) +- 35% of people are placebo reactors + + +--- + +## Phantom limbs and phantom pain + +
Neuroscience 5e Box 10D
+ +Note: + +Phantom limbs can be another fascinating clue to higher order processing of somatic sensation. This stems from the fact that for amputees, almost have an illusion that the missing limb is present. + +It’s been proposed that there is an internal mismatch between the brain’s representation of the body and the pattern of peripheral tactile input that results in the illusory sensation. + +R. Melzack 1989 Can Psychol Phantom limbs + +TINS 1990 + +[http://www.youtube.com/watch?v=Esgl1q73wP8](http://www.youtube.com/watch?v=Esgl1q73wP8) + --- diff --git a/2016-10-16-lecture10.md b/2016-10-16-lecture10.md deleted file mode 100644 index 88b89b2..0000000 --- a/2016-10-16-lecture10.md +++ /dev/null @@ -1,1309 +0,0 @@ -## Sensory systems - -* The CNS consists of discrete systems for each of the modalities of sensation (touch, vision, hearing, taste, smell) -* Each functional system involves several CNS regions that carry out different types of information processing -* Identifiable pathways link the components of a functional system -* Each part of the brain projects in an orderly fashion onto the next, thereby creating topographic maps. Neural maps not only reflect the position of receptors on a sensory surface, but also their density -* Functional systems on one side of the body generally control the other side of the body - -Note: - - - ---- - -## Parallel processing of sensory information - -
- -Note: - -Totally fascinating to think out how all this works. Talk about which ones we will go over, common principles, all can get linked together. - ---- - -## Somatic sensory system - -* Touch, vibration, pressure, position of limbs (sense of self), pain, temperature. -* Monitors the external and internal forces acting on the body at any moment. -* Leads to the ability to identify shapes and textures of objects. -* Detects potentially harmful circumstances. - -Note: - -Today we will focus on the somatic sensory system also called the somatosensory system. - - - -Responsible for a bunch of fairly important things including touch or tactile discrimination, vibration, pressure, limb positioning or proprioception, pain, temperature. - - - -Monitors external and internal forces acting on the body— e.g. touch is external, proprioception/self positioning is internal. - - - -Gives rise to our ability to identify objects, also called stereognosis. - - - -And of course helps us become alarmed to potentially dangerous environments. - - - - - - - -soma - -: the parts of an organism other than the reproductive cells - -: the body as distinct from the soul, mind, psyche - - - ---- - -## Overview of somatic sensory system - -* Specific receptor neurons located in skin or joints receive stimuli. -* Information is carried to brain via the spinal cord, brainstem, thalamus, to the post central gyrus of the parietal lobe, which in turn project to higher order cortical areas. -* Projections are topographic with respect to body region, and the amount of cortical space allocated to various body parts is proportional to the density of sensory receptors in that area. - -Note: - - - ---- - -## Somatosensory pathway– from somatic sensory neuron to cortex - -Touch and pain have different - -routes to the brain. - -
- -Note: - -We’ve already become aware that the dorsal root ganglia contain sensory neurons that act as sensory receptors for the body with the cell body located in the ganglion and processes extending to the sensory periphery— e.g. this mechanosensory afferent fiber connected to your index finger, or a proprioceptive neuron sensing internal muscle stretch connected to your knee joint for the myotactic reflex that we’ve discussed previously. - - - -In this inset you see both mechanosensory and pain sensitive fibers connected to the finger— notice that these are coming from two different neurons (red and blue) and the ascending process from the DRG neurons course through the spinal cord to higher brain regions through different routes. More on this later. - - - -anterolateral tract vs dorsal column - - - ---- - -## Somatosensory receptors - -
- -Note: - -The sensation of touch, pain, or temperature all starts with specialized receptors and nerve endings in the skin. In all cases ion channels open on the receptor neuron ending that can depolarize and initiate an AP with a sufficiently strong stimulus. - - - - - -[from: http://www.ncbi.nlm.nih.gov/gene/63895](http://www.ncbi.nlm.nih.gov/gene/63895) - --piezo type mechanosensitive ion channel component 2 - --protein encoded by this gene contains more than thirty transmembrane domains and likely functions as part of mechanically-activated (MA) cation channels - --channels serve to connect mechanical forces to biological signals - --piezo greek for push. - ->Piezoelectric Effect is the ability of certain materials to generate an electric charge in response to applied mechanical stress - --reversible: mechanical stress <–> electricity - --gass stoves, cigarette lighters, - - - - - ---- - -## There are many types of somatic sensory receptors - -* Have different functions– pain, temperature, touch, and proprioception. -* Different morphologies– free nerve endings or encapsulated. -* Different conduction velocities– fast vs. slow -* Differ locations– skin, muscle, tendon, hair -* Different rates of adaptation– slow vs. fast - -Note: - -Variety of somatosensory receptors. - ---- - -## Types of somatosensory afferents - -
- -Note: - -This table summarizes the somatosensory afferents types, and variety in their functions, morphologies, and AP conduction velocities. - - - -The fastest ones are… - - - -The slowest ones are… - - - - - ---- - -## Slowly adapting and rapidly adapting mechanoreceptors respond differently to stimulation - -
- -Note: - -Another type of somatosensory afferent variability I mentioned was rate of adaptation– this figure highlights this difference where if we were performing extracellular electrode recordings close to somatic sensory we find that some types adapt slowly, with sustained spiking as a stimulus stays on, whereas others adapt rapidly with their spiking activity strong at the beginning of the stimulus but quiet as the stimulus is maintained. - ---- - -## General properties of sensory receptors - -* Stimuli applied to skin, deforms or changes the nerve endings, produces a receptor potential that triggers an action potential -* Quality of stimulus (what it represents and where it is) is determined by the relevant receptor and the afferent neuron’s targets in the brain. -* Quantity or strength of stimulus is determined by the rate of action potential discharge. - -Note: - - - ---- - -## Skin harbors morphologically distinct mechanoreceptors - -Neuroscience 5e Fig. 9.5 - -
- -Note: - -So here are 5 types of morphologically different somatic sensory receptors— - - - - - ---- - -## Low threshold (or high sensitivity) mechanoreceptors - -* Provide information about touch, pressure, vibration, and cutaneous tension. -* Four major types of encapsulated mechanoreceptors: -* Meissner’s corpuscle, -* Pacinian corpuscles, -* Merkel’s disks -* Ruffini’s corpuscles. -* Called low-threshold mechanoreceptors because even weak stimulation causes them to fire action potentials. Innervated by large myelinated axons (type Aβ fast). - -Note: - - - ---- - -## Meissner corpuscle - -* Located in the superficial layers of the skin, between the dermal papillae just beneath the epidermis. -* Generate rapidly adapting action potentials after minimal stimulation. Adapt fast. -* Have small receptive fields -* Account for 40% of the sensory innervation of the human hand. Particularly good in transuding info about low-frequency vibrations. -* Detects movement of textures across the skin - -Note: - - - ---- - -## Merkel’s disks - -* Located in epidermis, precisely aligned with the ridges (finger print part of fingers). -* 25% of the mechanoreceptors in the hand. -* Are particularly dense in finger tips, lips, and genitalia. -* Slow adapting, selective stimulation leads to the feeling of light pressure. -* Have small receptive fields. - -Note: - - - - - - - -[from: http://www.ncbi.nlm.nih.gov/gene/63895](http://www.ncbi.nlm.nih.gov/gene/63895) - --piezo type mechanosensitive ion channel component 2 - --protein encoded by this gene contains more than thirty transmembrane domains and likely functions as part of mechanically-activated (MA) cation channels - --channels serve to connect mechanical forces to biological signals - -[-http://www.nature.com/nature/journal/v509/n7502/full/nature13251.html 2014](http://www.nature.com/nature/journal/v509/n7502/full/nature13251.html) - -[-http://www.ncbi.nlm.nih.gov/pubmed/25471886 2014](http://www.ncbi.nlm.nih.gov/pubmed/25471886) - - - - - - - ---- - -## Ruffini’s corpuscles - -* - -* Lie parallel to the skin -* Large receptive fields -* Detect cutaneous stretching produced by digit or limb movements -* 20% of receptors in hand -* Slow adapting - -Note: - - - ---- - -## Pacinian corpuscles - -* Have large encapsulated endings located in subcutaneous tissue. -* The onion-like capsule acts like a filter allowing in only high frequency stimulation. -* Adapts more rapidly than Meissner’s and has a lower response threshold. -* Has large receptive fields. -* Stimulation induces a sense of vibration or tickle. -* Involved in the discrimination of fine surface textures. -* 10-15% of cutaneous receptors in the hand - -Note: - - - ---- - -## Properties of afferent systems - -
- -Note: - - - ---- - -## Cutaneous mechanoreceptors - -
- -Note: - - - ---- - -## Simulated activity patterns in different mechanosensory afferents as Braille is read - -Neuroscience 5e Fig. 9.6 - -
- -Note: - - - - - -Each dot represents an action potential recorded in a single mechanosensory afferent fiber. - - - -Horizontal line of dots in the raster plot represents the pattern of activity in the afferent when moving the pattern across the finger. The pattern position is then displaced slightly by a small distance and then the pattern is moved again and the spike pattern is displayed on the next row. - - - -Individual Braille dots can be distinguished in the pattern of Merkel afferent neural activity - - - ---- - -## Differences in mechanosensory discrimination across the body surface - -* The accuracy of our sense of touch is not the same all over the body. -* Can use two-point discrimination tests to show this. -* Fingers can distinguish things 2 mm apart, forearms 40 mm apart. -* Mechanosensory receptors are more numerous in finger tips and have smaller receptive fields. -* Doesn‘t explain everything about ability to discriminate two points. The CNS is also involved with discrimination. Two point thresholds vary with practice, and depend on the stimulus. - -Note: - - - ---- - -## Sensitivity of tactile discrimination varies with location on the body surface - -Neuroscience 5e Fig. 9.3 - -
- -
- -Note: - - - ---- - -## Receptive field - -* Receptive field (RF)– the area in the periphery within which sensory stimulus can modulate the firing of the sensory neuron. -* Spatial resolution of the RF: -* Size– smaller RF, higher resolution -* Density– higher density, higher resolution -* “Two-point discrimination test” - -
- -Note: - - - ---- - -## Discrimination can also be at the level of - -## the primary or secondary sensory neuron - -
- -
- -Note: - - - ---- - -## Title Text - -
- -Note: - -[from: http://physiologyonline.physiology.org/content/28/3/142](http://physiologyonline.physiology.org/content/28/3/142) - - - ---- - -## Title Text - -
- -Note: - -[from D. Ginty, Science: http://science.sciencemag.org/content/346/6212/950](http://science.sciencemag.org/content/346/6212/950) - - - ---- - -## Title Text - -
- -Note: - -[from: http://www.nature.com/nrn/journal/v12/n3/fig_tab/nrn2993_F1.html#close](http://www.nature.com/nrn/journal/v12/n3/fig_tab/nrn2993_F1.html#close) - - - ---- - -## Discrimination can also be at the level of - -## the secondary sensory neuron - -
- -Note: - - - ---- - -## Receptive fields can be direction selective - -* Crickets sense of touch comes from air currents moving sensory hairs. -* Left: Specific hairs only fire if blown a certain direction. -* Right: summation of recordings from a single neuron whose hair has been blown from every direction. It only fires an AP when it is moved in a certain direction. - -
- -
- -Note: - - - ---- - -## Lateral inhibition to make discreet borders - -
- -Note: - - - ---- - -## Mechanoreceptors specialized in proprioception - -* Some sensory receptor’s job is to relay information of self. Where are my limbs and other body parts? -* Muscle spindles: Are located in most muscles. Contain specialized muscle fibers encapsulated by connective tissue. -* Axons from sensory neurons wrap around this connective tissue and fire depending on muscle length. -* Feeds back to γ motor neurons that change spindle length to compensate as needed. -* Golgi tendon organs do a similar thing but with tendons. - -Note: - -Proprioception are stimuli that are produced and perceived within an organism, such as the positioning and movement of the body - - - ---- - -## Proprioceptors provide information about the position of body parts - -Neuroscience 5e Fig. 9.7 - -
- -Note: - - - ---- - -## Pathways for sensory information - -* The cell somas of mechanosensory axons are located in the dorsal root ganglion (DRG). One on each side of the spinal cord, one for each segmental spinal nerve. -* DRG neurons called first-order because they initiate the sensory process. -* All sensory axons cross the midline one time. -* All map to primary somatic sensory cortex, located in the postcentral gyrus. -* Mechanoreceptors and proprioception receptors use the Dorsal-column-medial lemniscus pathway to get to brain. -* Pain and temperature use spinothalamic (anterolateral pathway). - -Note: - - - ---- - -## Dorsal column-medial lemniscus system - -* DRG neurons– first order, initiate process -* Contains info from mechanoreceptors concerned with tactile discrimination and proprioception. -* Upon entering spinal cord, axons bifurcate into ascending and descending branches, which in turn send out collateral branches to several spinal segments. -* Some branches go to ventral horn of the cord and synapse on neurons that are part of the reflex system - -Note: - - - ---- - -## Dorsal column-medial lemniscus system - -
- -Note: - - - ---- - -## 2nd order neurons - -* The major branches of DRG neurons are ascending and go up the dorsal columns of the spinal cord ipsilaterally. -* They terminate in the gracile and cuneate nuclei (dorsal column nuclei) in the caudal (posterior) medulla. -* Axons are organized such that lower limbs are mapped medially (gracile nucleus) and the upper limbs, trunk, and neck in the cuneate nucleus. -* Axons from both nuclei cross the midline in the medulla and send projections to the somatic sensory portion of the thalamus, the ventral posterior lateral nucleus, VPL. Cuneate axons medial, gracile projections lateral. - -Note: - - - ---- - -## Mechanosensory pathways - -cross in the medulla - -upper and lower body - -use slightly different pathways. - -Neuroscience 5e Fig. 9.8 - -
- -Note: - - - ---- - -## Trigeminal tract - -* Information about the face takes a different route to the thalamus. -* Trigeminal nerve (cranial nerve 5, three subdivisions, ophthalmic, maxillary, and mandibular). -* Enters the brainstem at the level of the pons and terminates in the trigeminal brainstem complex. This complex has two main components, the principal nucleus (mechanosensory stimuli) and the spinal nucleus (pain and temp). -* Crosses midline in the pons and ascends to thalamus. - -Note: - - - ---- - -## Trigeminal pathway - -Info from head and face - -mid-pons - -midbrain - -
- -Note: - - - ---- - -## The somatic sensory components of the thalamus - -* Ventral posterior complex (VPC)– -* Ventral posterior lateral nucleus (VPL) receives projections from the medial lemniscus carrying all somatic sensory information from the body and posterior head. -* Ventral posterior medial nucleus (VPM) receives axons from the trigeminal info from the face. -* VPC contains a complete representation of the body. - -Note: - - - ---- - -## VPL and VPM location in human thalamus - -
- -Note: - - - ---- - -## Somatic sensory cortex - -* All axons from ventral posterior complex project primarily to layer IV of the somatic sensory cortex. -* Located in parietal lobe, post-central gyrus -* Divided into regions, Broadmann’s areas 3a, 3b, 1 and 2– primary somatic sensory area, SI. - -Note: - - - ---- - -## Brodmann’s cytoarchitectural map - -
- -Note: - - - ---- - -## Somatic sensory portions of the thalamus and cortical targets - -
- -Note: - -Cross section view shows that there are really 4 subdivisions of primary somatosensory cortex - - - -In VP complex, Upper body medial, Lower body lateral - ---- - -## Receptive fields of somatosensory cortical neurons - -* Area 3b and 1– cutaneous stimuli -* 3a– proprioceptive stimuli -* 2– tactile and proprioceptive stimuli -* SI is organized in columns, by receptive field, and modality. Stick an electrode vertically, all neurons share same region of body. - -Note: - - - ---- - -## Somatotopic order in the human primary somatosensory cortex - -
- -Note: - - - ---- - -## Somatotopic order in the human primary somatosensory cortex - -somatotopy - -areas of high receptor density - -get more cortical space - -
- -
- -Note: - - - ---- - -## More cortical space for body areas with higher somatic receptor density - -
- -
- -Note: - - - ---- - -## More cortical space for body areas with higher somatic receptor density - -
- -
- -Note: - - - ---- - -## Whisker ‘barrels’ in rodent cortex - -
- -Note: - - - ---- - -## The ‘homunculus’ reflects sensory receptor density - -
- -Note: - - - ---- - -## Magnified cortical representations of sensory apparatus - -
- -
- -Note: - - - - - - - -[from: http://www.pnas.org/content/109/Supplement_1/10647/F3.expansion.html](http://www.pnas.org/content/109/Supplement_1/10647/F3.expansion.html) - - - ---- - -## Higher order processing - -* SI sends out projections to other areas of cortex. -* SII, adjacent to SI. Receives info from all 4 SI areas and sends it to amygdala and hippocampus. Plays roles in fear conditioning and tactile learning and memory. - -Note: - - - ---- - -## Higher order processing - -
- -Note: - - - ---- - -## Pain - -* Submodality of the sense of touch, warns of injury and things that should be avoided. -* More subjective than the other senses. The same stimulus can produce different responses in different individuals, or in the same individual in different circumstances. - -[http://www.youtube.com/watch?v=s28fCIQKJTA](http://www.youtube.com/watch?v=s28fCIQKJTA) - -Congenital insensitivity to pain: - -Note: - - - -Congenital insensitivity to pain - -[from: http://ghr.nlm.nih.gov/condition/congenital-insensitivity-to-pain](http://ghr.nlm.nih.gov/condition/congenital-insensitivity-to-pain) - ->20 cases have been reported in the scientific literature - ->Mutations in the SCN9A gene cause congenital insensitivity to pain. The SCN9A gene provides instructions for making one part (the alpha subunit) of a sodium channel called NaV1.7. - ->NaV1.7 sodium channels are found in nerve cells called nociceptors that transmit pain signals to the spinal cord and brain. The NaV1.7 channel is also found in olfactory sensory neurons, which are nerve cells in the nasal cavity that transmit smell-related signals to the brain. - ->The SCN9A gene mutations that cause congenital insensitivity to pain result in the production of nonfunctional alpha subunits that cannot be incorporated into NaV1.7 channels. As a result, the channels cannot be formed. - ->autosomal recessive pattern - - - - - ---- - -## Pain involves specialized neurons not just extrastimulation of touch receptors. - -* Scheme for transcutaneous nerve recording. -* Nociceptor doesn’t fire until pain is felt. Other thermoreceptors fire at all temps and at about the same frequency - -
- -Note: - - - ---- - -## How do we detect pain? - -* A family of ion channel receptors have been found that open in response to heat as well as capsaicin called TRP (transient receptor potential) channels. -* Structurally resemble voltage-gated K⁺ channels, having 6 transmembrane domains that make a pore. -* When open allows Ca²⁺ and Na⁺ across membrane to generate a receptor potential. - -Note: - - - ---- - -## Heat gated ion channels - -* Capsaicin receptors are nonselective cation channels opened by heat, low pH, and capsaicin (the hot in hot peppers). -* Mice without TRPV1 (VR1) have impaired sensitivity to pain. Can drink capsaicin as if it were water. - -
- -
- -Note: - - - - - -transient receptor potential cation channel subfamily V member 1 (TrpV1), also known as the capsaicin receptor or the vanilloid receptor 1 (VR1) - - - -function of TRPV1 is detection and regulation of body temperature. In addition, TRPV1 provides a sensation of scalding heat and pain (nociception). - - - - - -43ºC threshold (110ºF) - - - ---- - -## Heat gated ion channels - -* Capsaicin receptors are nonselective cation channels opened by heat, low pH, and capsaicin (the hot in hot peppers). -* Mice without VR1 have impaired sensitivity to pain. Can drink capsaicin as if it were water. - -
- -Note: - - - ---- - -## Nociceptors - -* This figure compares the activation of VR1 channels by pure capsaicin and extracts of various peppers. - -Nature 1997 Oct 23;389(6653):816-24 - -
- -Note: - - - ---- - -## Nociceptors - -* Transfer information about pain. -* Three major classes of nociceptors: Aδ mechanosensitive nociceptors, Aδ thermal nociceptors, and polymodal nociceptors. -* Aδ mechanosensitive nociceptors-activated by intense pressure, are lightly myelinated and have speeds of 5-30 m/s. -* Aδ thermal nociceptors are activated by very hot or very cold temperatures. Are lightly myelinated. -* Polymodal nociceptors (C fibers) respond to temperature, pressure, or chemicals, are unmyelinated and conduct at speeds of 1m/s. -* Aδ and C fibers have cold temperature gated ion channels. When they fire they are perceived as pain. -* Pain receptor receptive fields are generally pretty large, presumably because the detection of pain is more important than its exact location. - -Note: - - - ---- - -## Two categories of pain perception - -* first pain (sharp), Aδ fibers -* second pain (dull, longer lasting) C-fibers - -selective block of either Aδ or C fibers - - - - - -
- -Note: - - - ---- - -## Hyperalgesia - -* Enhanced sensitivity and response to stimulation of the area around the damaged tissue. Stimuli that would not ordinarily be perceived as pain now is. For example after a sunburn a normal shower now feels painful. -* Due to the release of stuff from the damaged cells, such as prostaglandins, bradykinin, histamine, serotonin, ATP, can increase the sensitivity of nociceptors by interacting with the channel (directly or indirectly) and making it open easier, or by interacting with other receptors on nociceptive fibers to potentiate activity of TRP channels. -* Aspirin and ibuprofen inhibit cyclooxygenases (COX-2 inhibitors), necessary for prostaglandin synthesis. -* Shows that pain and injury are inter-related - -Note: - - - ---- - -## Hyperalgesia - -Correlation between the perception of pain in a human subject and impulse - -firing in a monkey C multimodal heat receptor under normal conditions and during hyperalgesia. - -
- -Note: - - - ---- - -## Inflammatory response to tissue damage - -
- -Note: - -Another type of peripheral sensitization can occur due to substances released within damaged tissues can modulate the response of nociceptive fibers. A host of molecules that can augment the activity of free nerve endings like… - - - -Most interact directly with the receptors or ion channels of the nociceptive fibers. e.g. TRPV1 capacin receptor can be potentiated form the channels direct interactions with extracellular protons that are released by immune cells or through indirect interaction with other enzyme receptors like TrkA for NGF or bradykinin receptors. - - - ->a peptide that causes blood vessels to dilate (enlarge), and therefore causes blood pressure to fall - - - - - - - - - -nociceptive - -: of or related to pain arising from stimulation of nerve fibers - ---- - -## Pain pathways - -* Spinothalamic tract -* Cell bodies found in the most lateral parts of the dorsal root ganglia, but not discretely localized. -* Innervate neurons in the dorsal horn of the spinal cord. Some of these neurons project within the spinal cord. These are important for reflex behaviors. -* Others project axons cross the midline in the same segment and then go up to the brain. - -Note: - - - ---- - -## Major pathways for pain (and temperature) sensation - -
- -Note: - - - - - -nociceptive projections into dorsal horn branch into ascending and descending collaterals forming the dorsolateral tract of Lissauer (named after 19th c. German neurologist). - -C fibers (slow pain) terminate in layer 1 (Rexed’s laminae, named after anatomist who first described spinal gray matter layers in 1950s) of dorsal horn. - -Adelta (fast pain) terminate in layer 5 of dorsal horn where Abeta mechanosensory terminals innervate. - ---- - -## Pathways for pain (and temperature) sensation of the face - -
- -Note: - - - ---- - -## Nociceptive component in the VP nuclei in the thalamus - -* Pain and temp go to VPM and VPL nuclei just like the mechanosensory axons. -* VPM from the face, VPL from the body -* Presumably responsible for our ability to locate a pain with respect to body position. - -Upper body medial - -Lower body lateral - -
- -Note: - - - ---- - -## Cortex - -* VPM and VPL neurons project to primary somatosensory cortex. These thalamic neurons have small receptive fields and are likely used to locate where the pain is, but are not responsible for dull aches that are associated with chronic pain as ablation does not reduce pain. -* There are also direct projections to the reticular formation (in medulla), and the midline thalamic nuclei. These neurons project to areas of the limbic system and are responsible for the emotional aspects of pain. - -Note: - - - ---- - -## The anterolateral system sends information to different parts of the brainstem/forebrain - -
- -Note: - - - ---- - -## Pain vs touch - -* 2nd order mechanosensory axons cross at the level of the medulla but 2nd order pain axons cross at about the segment their cell bodies are in. -* If there is a damage on one side of the spinal cord, below the injury site, there would be no sense of touch on the same side and no sense of pain on the contralateral side. - -Note: - - - ---- - -## Spinothalamic tract - -* Also called anterolateral column part of the ventral column -* Note where axons cross over the midline. -* Touch and pain are on opposite sides below medulla -* Touch and pain are on the same side above medulla - -
- -Note: - - - ---- - -## The anterolateral and dorsal column-medial leminiscal systems cross the midline at different sites - -
- -Note: - -nociceptive and mechanosensory pathways - ---- - -## Referred pain - -* Few if any neurons in dorsal horn are specialized solely for the transmission of visceral pain. -* It is conveyed to brain via dorsal horn neurons that also get inputs from skin. -* Therefore a person may feel pain at a site completely different than its source. - -
- -Note: - - - -anginal pain which is pain arising from heart muscle that is not being adequately perfused with blood. Referred to the upper chest wall, with radiation into the left arm and hand. - - - -Innervation of same neuron in the dorsal horn of the spinal cord. - ---- - -## Pain perception is subjective - -* Rubbing the site of injury can make pain less severe. -* Pain is somewhat subjective. Depends on context. Soldiers wounded in battle feel less pain than if one gets the same injury at home. -* There is a descending pain pathway that can impinge on the dorsal horn to quiet neurons. - -Note: - - - ---- - -## Direct electrical stimulation of the brain produces analgesia - -* The observation is that stimulation of periaqueductal grey (in midbrain) or rostral medulla reduces pain. -* Stimulation only reduces pain sensation, animal/person still responds to touch, temp etc, just feels less pain. -* These areas are part of a descending pathway that modulates pain. Cortex and hypothalamus project to periaqueductal gray which then projects to nuclei in the medulla (Raphe nuclei, reticular formation), projects to dorsal horn, where they can inhibit ascending pain fibers. - -Note: - - - ---- - -## Modulation of ascending pain signal transmission - -* Axons from neurons with mechanoreceptors can synapse onto inhibitory interneurons in spine to dampen pain response. -* Descending pathways from the brainstem can dampen pain response. - -
- -Note: - - - - - -enkephalins, endorphins, dynorphins— present in the periacq. gray matter, ventral medulla, and in spinal cord regions in dorsal horn. - - - -Also CB1 and endocannabinoids work similiarly here in the dorsal horn. - - - - - - - ---- - -## Descending systems modulate the transmission of ascending pain signals - -* Descending pathways from cortex and hypothalamus - -
- -Note: - - - ---- - -## Descending systems modulate the transmission of ascending pain signals - -* Through periaqueductal gray rostral medulla reduce activity in spinothalamic tract. -* Reduction of activity in the spinothalamic tract. - -
- -Note: - - - ---- - -## Opioids - -* Opioid receptors (metabotropic) are expressed in the areas of descending pain pathway (also expressed in other areas, such as muscles of the bowel and anal sphincter). -* Ligands– enkephalins, endorphins, and dynorphin. Found in all descending pain areas. -* Opioids decrease the chance that a nociceptor will fire, cause inhibition. -* Opiate antagonist naloxone blocks stimulation produced analgesia as well as morphine-induced analgesia. Suggests that they are the same thing. - -Note: - - - ---- - -## Endogenous opioids - -
- -Note: - - - ---- - -## Endogenous opioids dampen pain signal transmission - -
- -Note: - - - ---- - -## Placebo effect - -* Sugar pills can reduce perception of pain. -* The effect can be blocked by naloxone, a competitive antagonist of opioid receptors. -* The placebo effect is based on a biochemical change in the brain, as are all perceptions. - -Note: - - - - - --mind separate from body. No– this highlights something that neuroscientists already widely accept, that you cannot separate the mind from the body, the mind is body and vice versa. - --what is or is not reality philosophers - - - --highlights descending control and higher order processing of pain. - - - -endogenous opioid - - - ---- - -## Phantom limbs and phantom pain - -
- -Note: - -Phantom limbs can be another fascinating clue to higher order processing of somatic sensation. This stems from the fact that for amputees, almost have an illusion that the missing limb is present. - - - -It’s been proposed that there is an internal mismatch between the brain’s representation of the body and the pattern of peripheral tactile input that results in the illusory sensation. - - - - - -R. Melzack 1989 Can Psychol Phantom limbs - -TINS 1990 - - - - - -[http://www.youtube.com/watch?v=Esgl1q73wP8](http://www.youtube.com/watch?v=Esgl1q73wP8) - ---- - ---- - diff --git a/2016-10-16-signal-transduction.md b/2016-10-16-signal-transduction.md new file mode 100644 index 0000000..8cae6ff --- /dev/null +++ b/2016-10-16-signal-transduction.md @@ -0,0 +1,565 @@ +## Signal transduction + +* Neurons can change their state (e.g. which receptors, channels, neurotransmitters are opened, modulated, or expressed) depending on what is going on in their local environment +* They receive signals from other neurons (neurotransmitters) and other cells (hormones, growth factors, and trophic factors) +* They have specialized machinery that can transduce these signals to changes in their physiological state. + +Note: + +Today we take a broad overview of signal transduction pathways that work to change the physiological state of neurons. Many of the pathways and second messengers should be familiar to you from basic cell biology. + +* hormones, estradiol, testosterone & (LH, FSH, progesterone) + +--- + +## Different types of cell-cell communication + +* Synaptic signaling +* Paracrine signaling– acts over a short range +* Endocrine signaling– secretion of hormones into the blood stream +* Membrane protein signaling– two cells next to each other signal through closely associated membrane proteins + +Note: + +What types of cell-cell communication underly signaling? The answer is familiar ones like… + +--- + +## Synaptic, paracrine, and endocrine signaling + +
Neuroscience 5e Fig. 7.1
+ +Note: + + +--- + +## Components of signaling + +* Signal (the message) +* Receptor (signal detection) +* Effector/target molecules (mediate the cellular response) +* Intracellular signal transduction refers to the events between the receptor and the effector targets +* Signal amplification often occurs during signal transduction + +Note: + + +--- + +## Signal amplification + +* results in a tremendous increase in the potency of the initial signal +* permits precise control of cell behavior + +
Neuroscience 5e Fig. 7.2
+ +Note: + + +--- + +## Types of receptors + +
+
+ +* Ligand gated ion channels (channel linked receptors/ionotropic receptors)– e.g. nAChR, AMPA receptors +* Enzyme linked receptors– typically have extracellular binding site for signals. Has intracellular domain with catalytic activity regulated by signal. Most are protein kinases that phosphorylate intracellular proteins. e.g. tyrosine kinase +* G-protein coupled receptors– 7-transmembrane spanning receptors that signal through trimeric G-proteins intracellularly. The proteins can alter the function of many downstream proteins. e.g. muscarinic AChR, metabotropic glutamate receptors +* Intracellular receptors– activated by cell permeant or lipophilic signaling molecules like steroid hormones. Signal binds directly to an intracellular protein which then activates transcription + +
+ +Note: + + + +--- + +## Categories of cellular receptors + +
Neuroscience 5e Fig. 7.4
+ + +Note: + +We already know how ion channels work. + +For enzyme linked receptors the signal binds extracellularly, which activates the intracellular enzymatic domain of the same protein catalyzing the production of a product from a substrate. + +--- + +## Categories of cellular receptors + +
Neuroscience 5e Fig. 7.4
+ + +Note: + +For g protein coupled receptors, the signal binds to the receptor, then the g-protein binds and becomes activated. + +For intracellular receptors, the signaling molecule passes through lipid membrane, binds to the intracellular receptor and activates the receptors which can then enter the nucleus to regulate transcription. + + +--- + +## Downstream of activated receptors: G-proteins + +* G-proteins– GTP binding proteins +* G-proteins generally couple the active receptor to downstream targets. Called G-proteins because they hydrolyze GTP +* Two types of G-proteins: + * Heterotrimeric G- proteins, composed of an α,β, γ subunits. Multiple members of each class. α subunit binds and hydrolyses GTP + * Small G-proteins– monomeric GTPases (e.g. ras) +* Active when bound to GTP, inactive when bound to GDP + +Note: + +G proteins couple receptor activation to downstream effects for G-protein coupled receptors. + +They hydrolyze guanine triphosphate to guanine diphosphate so that downstream proteins can become phosphorylated and activated. + +There are two types… + +heterotrimeric composed of three distinct subunits. It is the alpha subunit that binds to the guanine nucleotides GDP and GTP. + +binding of GDP allows the alpha subunit to bind to the beta and gamma subunits to form an inactive trimer. Binding of the extracellular signal to the receptor allows the g-protein to bind the receptor and GDP to be replaced with GTP. Then the alpha subunit with GTP is free to dissociate from the trimer and bind downstream effector molecules to mediate a host of responses inside the cell. + +The monomeric GTPases also relay signals from membrane receptors to intracellular targes like the cytoskeleton. Ras is the first small G protein discovered (rat sarcoma tumors). Helps regulated cell differentiation and proliferation, relaying signals from receptor kinases. + +Rate of GTP hydrolysis is important property of G-protein mediated signaling and can be regulated by proteins like GAPs (or GTPase activating proteins) that replace GTP with GDP to return G proteins to their inactive form. + +* - Guanosine-5'-triphosphate (GTP) is a purine nucleoside triphosphate. +* - Effector enzymes for activated G-proteins include adenylyl cyclase, guanylyl cyclase, phospholipase C, and others. +* - In some cases G-proteins can directly modulate ion channels. mAChR that slow heart rate from vagus nerve stimulation are thought to be due to beta/gamma G protein subunits binding to and modulating K channels. Alpha subunits of g proteins can lead to rapid closing of voltage-gated Ca and Na channels. + +--- + +## Types of GTP-binding proteins + +
Neuroscience 5e Fig. 7.5
+ + +Note: + + +--- + +## Trimeric G-protein signaling + +* Ligand binds receptor +* α subunit binds activated receptor +* GTP exchanged for GDP +* Dissociates complex and activates +* α and βγ subunits + +
Molecular Biology of the Cell 4e Fig. 15.28
+ + +Note: + + + +--- + +## Downstream targets of G-proteins + +* Ion channels– can be directly-activated by both the βγ subunits (can gate some types of K⁺ channels) or by α subunits (can cause closing of voltage sensitive Na⁺ and Ca²⁺ channels) +* Enzymes that produce 2nd messengers– e.g. adenylyl cyclase, guanylyl cyclase, and phosopholipases +* Each 2nd messenger does different things +* Wide diversity of physiological responses + +Note: + +In some cases G-proteins can directly modulate ion channels. mAChR that slow heart rate from vagus nerve stimulation are thought to be due to beta/gamma G protein subunits binding to and modulating K channels. Alpha subunits of g proteins can lead to rapid closing of voltage-gated Ca and Na channels. + +Effector enzymes for activated G-proteins include adenylyl cyclase, guanylyl cyclase, phospholipase C, and others. + + +--- + +## Effector pathways associated with G-protein coupled receptors + +
Neuroscience 5e Fig. 7.6
+ + +Note: + +There are many types of alpha, beta, and gamma g-protein subunits allowing a specific and diverse range of downstream responses. + +This shows three examples of different heterotrimeric g proteins bound to 3 types of receptors with 3 different cellular responses. + + +--- + +## Second messengers: calcium + +* Maintained at low concentrations inside cytosol +* Binds to many proteins and regulates their activity +* Calmodulin– binds Ca²⁺ and then can activate calmodulin dependent protein kinases +* IP3 receptors– channel that lets calcium out of ER + +Note: + + +Maybe the most common intracellular messenger in neurons. + +One target of calcium is calmodulin, a calcium binding protein abundant in the cytosol of all cells. Calcium binding to this protein initiates downstream effects by binding to targets like protein kinases. + + +--- + +## Proteins involved in delivering and removing calcium to the cytoplasm + +
Neuroscience 5e Fig. 7.7
+ + +Note: + +ATPase called the calcium pump (Ca-proton pump). Works on cell membrane and also pumps calcium into intracellular organelles like ER and mitochondria. + +Na/Ca exchanger that replaces intracellular Ca with extracellular sodium ions. + +VGCCs + +calcium binding effector proteins like calmodulin mediate downstream effectors of calcium. + +calcium binding buffer proteins serve as calcium buffers (calbindin, common in strongly expressed in some neuron subtypes). Can blunt the magnitude and kinetics of calcium signals. + +Channels that allow Ca to be released from the the interior of the ER like the inositol trisphosphate receptors (IP3). These are regulated by IP3, a second messenger. + +Another one intracellular releasing channel is the ryanodine receptor. These are activated by cytoplasmic Ca and for at least muscle cells, membrane depolarization. + + +--- + +## Calcium activates calmodulin + +
Molecular Biology of the Cell 4e Fig. 15.40
+ +Note: + + +--- + +## Calcium second messaging video summary + +
Neuroscience 5e Animation 7.2
+ +Note: + + +--- + +## Second messengers: cyclic nucleotides + +* cAMP and cGMP– derivatives of ATP and GTP. Made by adenylyl cyclase and guanylyl cyclase +* Bind to many targets– cAMP to protein kinase A, cGMP to protein kinase G +* Phosphodiesterases cleave cAMP and cGMP to inactivate them + +Note: + + +--- + +## cAMP formation and destruction + +
Molecular Biology of the Cell 4e Fig. 15.31
+ + +Note: + + + +--- + +## Second messengers: diacylglycerol and IP3 + +* Formed from the cleavage of lipids (phosphatidylinositols) by phospholipase C +* Diacylglycerol (DAG) activates protein kinase C +* IP3 opens calcium channels + +Note: + + + +--- + +## Diacylglycerol and IP3 + +
Molecular Biology of the Cell 4e Fig. 15.35
+ + +Note: + +Phosphatidylinositol 4,5-bisphosphate: PIP2 + + +--- + +## Neuronal second messengers + +
Neuroscience 5e Fig. 7.7
+ + +Note: + +This table summarizes neuronal second messengers, their sources, targets, and inactivation mechanisms. + + +--- + +## Second messenger life cycles + +
cyclic nucleotides
Neuroscience 5e Fig. 7.7
+ +
lipid signals
Neuroscience 5e Fig. 7.7
+ + +Note: + +And this depicts the mechanisms involved in production and degradation or removal of cyclic nucleotides and DAG and IP3. + + +--- + +## 2nd messengers target protein kinases and phosphatases + +* Phosphorylation can rapidly alter a protein’s activity +* Phosphorylation is carried out by protein kinases and usually occurs on Ser/thr and tyr residues +* Dephosphorylation is carried out by protein phosphatases +* 2nd messengers typically activate Ser/Thr kinases +* Extracellular signals (e.g. growth factors) activate Tyr kinases + +Note: + +Second messengers regulate neuronal functions by modulating the phosphorylation of intracellular proteins. This addition and removal of phosphate groups rapidly and reversibly modulates protein function. + +Phosphorylation is carried out by protein kinases. + +Phosphate groups are removed by phosphatases. + +Protein substrates of kinases and phosphataes include enzymes, neurotransmitter receptors, ion channels, structural proteins. + + +--- + +## Regulation of cellular proteins by phosphorylation + +
Neuroscience 5e Fig. 7.8
+ + +Note: + + + +--- + +## Ser/thr kinases + +* PKA– cAMP dependent protein kinase. Ser/thr kinase. Tetramer of 2 regulatory and 2 catalytic subunits. cAMP binds the regulatory subunits causing the release of catalytic subunits +* CaMKII– Ca²⁺/calmodulin-dependent protein kinase. Ser/thr kinase, very abundant in brain. 12 or so subunits. Downstream targets: many ion channels, other signal transduction proteins, tyrosine hydroxylase. Thought to be involved in learning/memory +* PKC– Ser/thr kinase activated by DAG and Ca²⁺. DAG causes PKC to move from the cytosol to the membrane where it binds Ca²⁺ and gets activated + +Note: + + + +--- + +## Mechanism of activation of protein kinases + +
binding of cAMP to regulatory subunits free up the catalytic subunits
Neuroscience 5e Fig. 7.9
+
binding of calmodulin opens up protein to activate catalytic domain
Neuroscience 5e Fig. 7.9
+
DAG causes PKC to change its localization which leads it to be active
Neuroscience 5e Fig. 7.9
+ + +Note: + + + +--- + +## Protein kinase A activation + +
Molecular Biology of the Cell 4e Fig. 15.32
+ + +Note: + + +--- + +## Other kinases + +* Protein tyrosine kinases– Two types receptor tyrosine kinases (Eph receptors, growth factor receptors) and cytoplasmic kinases (many oncogenes). Cytoplasmic tyrosine kinases are particularly important for cell growth and differentiation +* MAP kinases– mitogen activated kinases. Are often intermediate kinases, become activated by kinases and kinase other proteins. Often found downstream of receptor tyrosine kinases + +Note: + +Mitogen activated protein kinases (MAP kinases) + +* first identified as having a role in cell growth +* also called extracellular signal regulated kinases (ERKs). +* normally inactive in neurons, but activated when phosphorylated by other kinases +* part of kinase cascades. +* activation can be triggered by extracellular growth factors that bind receptor tyrosine kinases that activate monomeric G proteins like ras. +* can phosphorylate transcription factors + +--- + +## MAP kinase cascade + +
Molecular Biology of the Cell 4e Fig. 15-56
+ +Note: + + +--- + +## Nuclear signaling + +* Sometimes 2nd messengers (e.g. cAMP) can go into the nucleus where they can change the transcription of genes +* Transcription factors are proteins that interface with RNA polymerase to select promoter regions of genes +* These transcription factors can be regulated by phosphorylation + +Note: + +CREB is an important nuclear signal + +* [from https://en.wikipedia.org/wiki/Estrogen_receptor:](https://en.wikipedia.org/wiki/Estrogen_receptor) +* >estrogen receptors are largely located in the cytosol. Hormone binding to the receptor triggers a number of events starting with migration of the receptor from the cytosol into the nucleus, dimerization of the receptor, and subsequent binding of the receptor dimer to specific sequences of DNA known as hormone response elements. + + +--- + +## Steps involved in transcription of DNA to RNA + +
Neuroscience 5e Fig. 7.10
+ +Note: + +uas: upstream activator sequence + +[from https://en.wikipedia.org/wiki/Upstream_activating_sequence:](https://en.wikipedia.org/wiki/Upstream_activating_sequence) + +>upstream activating sequence or upstream activation sequence (UAS) is a cis-acting regulatory sequence. It is distinct from the promoter and increases the expression of a neighbouring gene. + +-upstream from minimal promoter TATA box, binding site for transactivators +-a cis acting regulatory sequence (like IRES) + +--- + +## CREB + +* CREB (cAMP response element binding protein). An important transcription factor +* Normally bound to DNA but not active. Phosphorylation activates it and it activates transcription. CREB is important for transcription of tyrosine hydroxylase, neuropeptides, neurotrophins and channel proteins +* Important for learning and memory, mothering instincts, synaptic plasticity + +Note: + +--- + +## Transcriptional regulation by CREB + +
Neuroscience 5e Fig. 7.11
+ + +Note: + + +--- + +## Chemical signaling mechanisms video summary + +
Neuroscience 5e Animation 5.2
+ +Note: + + +--- + +## Mechanism of action of NGF + +
Neuroscience 5e Fig. 7.12
+ + +Note: + + +nerve growth factor, binds to tyrosine kinase receptor (TrkA) leading to… + +--- + +## Signaling at cerebellar parallel fiber synapses + +
+
+ +* Glutamate released from presynaptic cell binds ionotropic and metabotropic glutamate receptors +* AMPA receptor opens and excites cell +* mGluR receptor activates a signal transduction pathway that feeds back and decreases AMPA receptor activity +* Called long term depression because now the same stimulus will lead to less depolarization than before (weakened synapse) + +
+ +
Neuroscience 5e Fig. 7.13
+ + +Note: + +Can result from strong synaptic stimulation at cerebellar purkinje neurons or from weak synaptic stimulation in the hippocampus. + +* Both parallel fibers and climbing fibers must be simultaneously activated for LTD to occur. With respect to calcium release however, it is best if the parallel fibers are activated a few hundred milliseconds before the climbing fibres. + +LTD is thought to result mainly from a decrease in postsynaptic receptor density, + +likely from phosphorylation of AMPA receptors by PKC and their elimination from the synapse and involves mapk cascade + +* Hippocampal/cortical LTD can be dependent on NMDA receptors, metabotropic glutamate receptors (mGluR), or endocannabinoids.[4] +* LTP involves + + +--- + +## Regulation of tyrosine hydroxylase by protein phosphorylation + +
+
+ +* AP invades axon terminal +* Voltage-gated Ca²⁺ channels open +* Intracellular Ca²⁺ does two things: +* Short term causes vesicle fusion +* Long term activates protein kinases +* Activation of protein kinases +* Phosphorylation of tyrosine hydroxylase +* Increased catecholamine synthesis +* Increase in transmitter release +* Increase in post-synaptic response + +
+ +
Neuroscience 5e Fig. 7.14
+ + +Note: + + + +--- + +## Summary + +* Signaling exists in all neurons to help them adjust to their environment +* Lots of ways to do this. There are various: +* Signals +* Receptors +* G-proteins +* 2nd messengers +* Downstream targets + +Note: + + +--- diff --git a/2016-10-31-lecture11.md b/2016-10-31-lecture11.md new file mode 100644 index 0000000..4deeaa3 --- /dev/null +++ b/2016-10-31-lecture11.md @@ -0,0 +1,1046 @@ +## Vision + +* A glance at an object lets us know where it is, its size, shape, color, texture, direction and speed of movement. +* We can do this at many different intensities of light from faint light to bright sunlight. +* Two main components of the CNS are responsible for this: the retina in the eye and the visual centers of the brain. + +Note: + +--- + +## Today’s learning goals + +* Be able to identify the different parts of the eye and their functions. +* Understand the main proteins involved in the signal transduction pathway that leads to changes in neurotransmitter release by photoreceptors in response to light. +* Learn the neural pathway that takes information from photoreceptors to the brain. +* Understand the concept of the receptive field. + +Note: + + + +--- + +## The human eye + +
+ +Note: + + + +--- + +## Anatomy of the Human Eye + +
+ +Note: + + + +--- + +## Title Text + +[http://courses.pbsci.ucsc.edu/mcdb/bio125/Animation11-01AnatomyoftheHumanEye.mov](http://courses.pbsci.ucsc.edu/mcdb/bio125/Animation11-01AnatomyoftheHumanEye.mov) + +
+ +Note: + + + +--- + +## Parts of the eye + +* Outside: +* Sclera– outer layer composed of white fibrous tissue. +* Cornea– front part of eye, transparent, provides 80% focusing power of the eye +* Middle: +* Iris– colored portion of the eye, contains muscles that adjust the pupil size under neural control. Open during dim light, closed during bright light. +* Ciliary body– ring of tissue that encircles the lens and includes both a muscle component and a vascular component. +* Choroid– composed of a rich capillary bed that serves as the main blood supply for the photoreceptors and contains melanin containing cells. +* Inside: +* Retina– neural part of the eye, detects light, processes information, and sends it to the brain. +* Lens– transparent structure that and change shape to allow fine focus. +* Aqueous humor– in anterior chamber, supplies nutrients to anterior eye. +* Vitreous humor– gelatinous substance in posterior chamber, provides shape, contains macrophages that removes debris. + +Note: + + + +--- + +## Anterior of the human eye in the unaccommodated and accommodated state + +Accommodation to focusing on near objects involves the contraction + +of the ciliary muscle, which reduces tension of the Zonule fibers + +and the lens is allowed to increase its curvature + +
+ +
+ +Note: + + + +Increased curvature in an optical lens increases the refraction of light, allowing closer focal distance. + + + +Contraction of ciliary muscle + + + + + +--- + +## Myopia & Hyperopia + +* Myopia: eyeball too long or cornea too curved while lens is as flat as can be. Image focuses in front. Near sightedness +* Hyperopia: eyeball too short or refracting system too weak. Image focuses behind eye. Far sightedness + +Getting old sucks…need reading glasses + +
+ +Note: + + + +Getting old lens loses elasticity with age. + + + + + + + + + +diopter (us), is a unit of measurement of the optical power of a lens or curved mirror, which is equal to the reciprocal of the focal length measured in metres (that is, 1/metres) + +--- + +## Diseases of the anterior eye + +* Cataracts– clouding of the lens +* Floaters– happens when the vitreous slowly shrinks, it becomes stringy and the strands cast a shadow on the retina. +* Refractive errors, near and far sightedness. + +
+ +
+ +Note: + + + + + +Lens proteins denature and degrade over time, and this process is accelerated by diseases. + +genetic disorder, diabetes, surgery, long term steroid use, UV light + + + +[from: https://en.wikipedia.org/wiki/Lens_(anatomy)](https://en.wikipedia.org/wiki/Lens_(anatomy)) + +>Crystallins are water-soluble proteins that compose over 90% of the protein within the lens + +>The three main crystallin types found in the human eye are α-, β-, and γ-crystallins. + +>The refractive index of human lens varies from approximately 1.406 in the central layers down to 1.386 in less dense layers of the lens.[10] This index gradient enhances the optical power of the lens + +>Crystallins tend to form soluble, high-molecular weight aggregates that pack tightly in lens fibers + +>lens capsule is a smooth, transparent basement membrane that completely surrounds the lens. The capsule is elastic and is composed of collagen. It is synthesized by the lens epithelium and its main components are Type IV collagen and sulfated glycosaminoglycans (GAGs) + +>cells of the lens epithelium also serve as the progenitors for new lens fibers. It constantly lays down fibers in the embryo, fetus, infant, and adult, and continues to lay down fibers for lifelong growth + +>lens fibers form the bulk of the lens. They are long, thin, transparent cells, firmly packed, with diameters typically 4–7 micrometres and lengths of up to 12 mm long + +>In many aquatic vertebrates, the lens is considerably thicker, almost spherical, to increase the refraction + +>among terrestrial animals, however, the lens of primates such as humans is unusually flat + +--- + +## The retina + +* The retina, despite its peripheral location, is part of the CNS. +* Contains neural circuitry that converts light energy into action potentials that travel out of the eye within the optic nerve into the brain. +* Is a layered structure, relatively simple for a CNS structure. +* Surrounded on one side by pigmented epithelium which contains melanin that helps reduce backscattering of light. Also plays a role in maintenance of photoreceptors. +* 5 types of neurons in the retina: photoreceptors, bipolar cells, retinal ganglion cells, horizontal cells, and amacrine cells. +* A direct 3 neuron chain is the basic unit of transmission. Photoreceptor to bipolar cell to ganglion cell. + +Note: + + + + + +neural crest—> PNS + +neural tube—> CNS (and retina) + + + +--- + +## Anatomy of the retina + +* Light travels through the retina to hit the photoreceptors in the photoreceptor layer + +Neuroscience 5e Fig. 11.5 + +
+ +
+ +Note: + + + + + +[from: http://www.huffingtonpost.com/2015/03/18/human-retina-backwards_n_6885858.html](http://www.huffingtonpost.com/2015/03/18/human-retina-backwards_n_6885858.html) + +>researchers at Technion–Israel Institute of Technology in Haifa built a computer model of a human retina and then compared how light behaves in the model with the way it behaves in the retinas of guinea pigs. + +>The comparison showed that when light travels through cell layers before reaching the rods and cones (photoreceptors), it's actually being sorted into red, green, and blue light + +>What's doing the sorting? Tiny structures known as Muller glia cells, according to the researchers. + +However >"We should also remember that several animal classes do not have a 'backward-pointing' eye, and also have Muller cells," + +>study was presented at a meeting of the American Physical Society on March 5, 2015 in San Antonio, Texas. + + + +[from: http://hubel.med.harvard.edu/book/b8.htm](http://hubel.med.harvard.edu/book/b8.htm) + +>Because the rods and cones are at the back of the retina, the incoming light has to go through the other two layers in order to stimulate them. We do not fully understand why the retina develops in this curious backward fashion. + +>One possible reason is the location behind the receptors of a row of cells containing a black pigment, melanin (also found in skin) + +number of rods and cones vary across the retina. In the center where vision is best (fovea) there are only cones. This area is about 0.5mm in diameter. + +125 million rods and cones in each eye. But only 1 million ganglion cells. How is visual information then preserved. Think of two paths: the direct path and an indirect path involving lateral interactions mediated by horizontal cells between receptors and bipolars and amacrine cells between bipolars and ganglion cells. + + >The total area occupied by the receptors in the back layer that feed one ganglion cell in the front layer, directly and indirectly, is only about one millimeter + +high degree of convergence, together with more direct path in and near fovea (one cone—>one bipolar—>one ganglion cell) can explain the 125:1 ratio of receptors to optic nerve fibers without having really bad vision. + + + + + + + + + + + + + +--- + +## Layers of the retina + +* Three main cell body layers (photoreceptor cell bodies, inner nuclear layer, and ganglion cell layer) +* Two main synaptic transmission layers (outer plexiform and inner plexiform) + +
+ +
+ +Note: + + + +--- + +## Phototransduction + +* Unlike most sensory system neurons, photoreceptors do not exhibit action potentials– light causes a graded change in membrane potential that changes the rate at which neurotransmitter is released. +* Within the retina projections are rather short– do not need action potentials. +* Light absorption leads to hyperpolarization of the photoreceptor. This leads to less release of neurotransmitter to the post-synaptic cell. + +Note: + + + +--- + +## Cones and rods hyperpolarize in response to light + +
+ +Note: + + + +--- + +## What does light do? + +* In the dark, the resting potential of the photoreceptor is -40 mV. +* Light shining onto outer segment leads to the hyperpolarization of the photoreceptor and reduction of neurotransmitter released. +* In the dark the number of Na⁺ channels open at the synaptic terminal is relatively high, and therefore the rate of neurotransmitter release is high. In the light the number of open Na⁺ channels is reduced and rate of neurotransmitter release is reduced. +* Of course, this seems kind of backwards compared to what you’ve have learned thus far. + +Note: + + + +--- + +## cGMP gated Na⁺ channels are key + +in dark channel open due + +to cGMP binding. + + + +Na⁺ rushes in + +cell depolarized + +
+ +Note: + + + +--- + +## In the dark + +* cGMP gated Na⁺ channels in outer segment are open allowing ions to flow inside the cell. This leads to a resting potential of -40 or so. +* The probability of these channels being open is regulated by the levels of cGMP. +* In the dark, high levels of cGMP keep the channels open. + +Note: + + + +--- + +## In the light + +* A photon of light is absorbed by photopigment (retinal or retinaldehyde, an aldehyde of Vitamin A) that is coupled to a protein in the outer segment called opsin. Absorption causes a change in conformation of retinal that in turn changes the conformation of opsin. +* This leads to the disassociation of trimeric G-proteins (special α subunit called transducin) from the receptor. +* Transducin activates a cGMP phosphodiesterase which degrades cGMP to GMP. Channel opening probability decreases, cell gets hyperpolarized. + +Note: + + + +--- + +## Phototransduction + +
+ +
+ +Note: + + + + + + + +Vertebrates typically have four cone opsins (LWS, SWS1, SWS2, and Rh2) + + + +[from: https://en.wikipedia.org/wiki/Opsin](https://en.wikipedia.org/wiki/Opsin) + +long-wave sensitiveLWScone500–570 nmgreen, yellow, redOPN1LW "red" / OPN1MW “green" + +short-wave sensitive 1SWS1cone355–445 nmultraviolet, violetOPN1SW "blue" + +short-wave sensitive 2SWS2cone400–470 nmviolet, blue(extinct in therian mammals) + +rhodopsin-like 2Rh2cone480–530 nmgreen(extinct in mammals) + +rhodopsin-like 1 (vertebrate rhodopsin) Rh1rod~500 nmblue-greenOPN2 = Rho = human rhodopsin + + + +>Like type II opsins, type I opsins have a seven transmembrane domain structure similar to that found in eukaryotic G-protein coupled receptors. + +* but these can be proton pumps (bacteriorhodopsin), chloride pumps (halorhodopsin), channelrhodopsin (ChR), archaerhodopsin (Arch) +* >are used by various bacterial groups to harvest energy from light to carry out metabolic processes using a non-chlorophyll-based pathway +* serve them as light-gated ion channels, amongst others also for phototactic purposes + +>Type II opsins (or animal opsins) are seven-transmembrane proteins (35–55 kDa) belonging to the G protein-coupled receptor (GPCR) superfamily + + + +--- + +## Phototransduction in rod photoreceptors + +
+ +Note: + + + + + +cGMP, cyclic nucleotide gated channel + + + + + +[more info: http://webvision.med.utah.edu/book/part-ii-anatomy-and-physiology-of-the-retina/photoreceptors/](http://webvision.med.utah.edu/book/part-ii-anatomy-and-physiology-of-the-retina/photoreceptors/) + + + + + +--- + +## Title Text + +[http://courses.pbsci.ucsc.edu/mcdb/bio125/Animation11-02Phototransduction.mov](http://courses.pbsci.ucsc.edu/mcdb/bio125/Animation11-02Phototransduction.mov) + +
+ +Note: + + + +--- + +## Signal amplification + +* One photon of light can activate 800 transducin molecules. This leads to about 800 phosphodiesterases activated. Each phosphodiesterase cleaves 300 or so cGMPs/second. This can result in the closing of about 200 ion channels (2% of total). 106–107 Na⁺ ions per second are prevented from entering the cell for a period of ~1 second. +* Changes membrane potential about 1 mV. + +Note: + + + + + +~30 mV working (dynamic) range for photoreceptors. But adaptation scales this to work for different background light levels. + +--- + +## Need to inactivate opsin signaling after a light flash + +* Rhodopsin kinase/arrestin– activated rhodopsin can be phosphorylated by a specific kinase and intracellular Ser/Thr residues. This creates binding sites for arrestin which binds and prevents the activation of transducin. +* All-trans retinol gets shed, transported to pigment epithelium cells, changed to cis-retinol and reincorporated into opsin. + +Note: + + + +--- + +## Light adaptation– or how do we adjust to different light intensities? + +* There is a million times more photons in a bright sunny day than at starlight and yet we can detect difference in light intensity under both conditions. +* Because at low levels of light more channels close per photon than at higher levels of light. Therefore, as light levels increase it takes more photons to close the same number of channels. +* This is due to the changes in the intracellular Ca²⁺ levels. Ca²⁺ can come in through Na⁺ channels. When they close (in the light), Ca²⁺ levels decrease. This does a number of things to make it harder to close more channels with each new photon. 1. Ca²⁺ normally inhibits guanylyl cyclase, lower Ca²⁺ in light leads to more cGMP. Therefore more PDE activation is needed to reduce cGMP levels and close more channels. 2. Ca²⁺ also inhibits rhodopsin kinase. Lower Ca²⁺ levels activates more kinase. With more kinase the activated opsin becomes inactivated. Leads to less PDE activation per photon, less channels closed per photon. +* This prevents us from saturating our photoreceptors and thus allows us to see changes in illumination over a wider range of light intensities. + +Note: + + + +--- + +## The retinoid cycle and photoadaptation + +
+ +Note: + + + +--- + +## Cell types of the retina: photoreceptors + +* Rods and cones– have an outer segment comprised of membranous disks that contain photopigment and an inner segment that contains the cell nucleus and synaptic terminals. +* The absorption of light by photopigment in outer segment initiates a signal transduction cascade that changes the membrane potential of the cell, and therefore the amount of neurotransmitter released plus or minus light energy. +* Photoreceptors synapse with bipolar cells and horizontal cells in the outer plexiform layer. + +Note: + + + +--- + +## Rods and cones + +
+ +Note: + + + +--- + +## Structural Differences Between Rods and Cones + +
+ +Note: + + + + + + + +Why the cone shape? Shape of cone preferentially accepts light directed straight into the eye through the pupil instead of off axis. Known as the Stiles–Crawford effect. + + + + + + + +--- + +## EM section through a kangaroo rat rod cell + +stalk + + + +Outer segment + +Inner segment + +
+ +Note: + + + +--- + +## Rods and cones are distinguished by: + +* shape +* type of photopigment they contain +* distribution across the retina +* pattern of synaptic connections +* specialized for different aspects of vision +* + +* Rod system– low spatial resolution but extremely sensitive to light +* Cone system– high spatial resolution but is relatively insensitive to light. + +Note: + + + +--- + +## Range of luminance values over which the visual system operates + +* Rods– used mostly for dim light to almost indoor lighting +* When only rods are used called scotopic vision. Not very good. +* Cones dominant in visible light. Called photopic. +* Twilight uses both called mesopic vision. + +
+ +Note: + + + +--- + +## More factoids + +* Rods produce a reliable response to a single photon of light, it takes over a 100 photons to produce a comparable response in a cone. +* Cones adapt better than do rods– about 200 ms for a cone, 800 ms for a rod. +* + +* Rods synapse onto specific bipolar cells (rod bipolars) that synapse onto amacrine cells which contact both cone bipolars and ganglion cells. Cones go bipolar to RGC directly. +* Rods exhibit convergence– many rods synapse onto a single bipolar cell, many bipolars onto a single amacrine cell. +* Cones can be 1 cone - 1 bipolar - 1 ganglion cell + +Note: + + + +--- + +## Differential responses of human rods and cones + +
+ +
+ +Note: + + + +cone response over in about 200 ms, whereas the rod response can continue for more than 600 ms. + + + + + +[from https://en.wikipedia.org/wiki/Adaptation_(eye):](https://en.wikipedia.org/wiki/Adaptation_(eye):) + +>The human eye can function from very dark to very bright levels of light; its sensing capabilities reach across nine orders of magnitude. This means that the brightest and the darkest light signal that the eye can sense are a factor of roughly 1,000,000,000 apart. + +> in any given moment of time, the eye can only sense a contrast ratio of one thousand. + +>the eye adapts its definition of what is black. + +> takes approximately 20–30 minutes to fully adapt from bright sunlight to complete darkness and become ten thousand to one million times more sensitive than at full daylight + +>takes approximately five minutes for the eye to adapt to bright sunlight from darkness + +>Dark adaptation is far quicker and deeper in young people than the elderly + + + +--- + +## Rods and cones are not distributed equally in the retina + +* Human retina– 91 million rods, 4.5 million cones. +* In most places the density of rods exceeds that of cones. +* Changes dramatically in the fovea, central retina (1.2 mm in diameter). +* Cones increase in density 200 fold, become highly packed. Center of the fovea, called foveola is totally rod free. +* Gives high visual acuity, which decreases rapidly away from the fovea. +* Reason why we are constantly moving our heads to center our eyes toward what we want to look at. +* Reason why it it best to see a dim object by looking away from it. + +Note: + + + +--- + +## Distribution of rods and cones in the human retina + +
+ +Note: + + + +--- + +## Retinal disease + +Loss of peripheral retina, Rods + +Loss of photoreceptors in the macula, cones + +
+ +
+ +
+ +Note: + + + +--- + +## Distribution of rods and cones in the human retina + +* Other cell layers are displaced in the fovea. Allows light to hit cones with less interference. + +
+ +Note: + + + +--- + +## Cones and color vision + +* 3 types of cones, each having different absorption spectra- called blue (S-cones), green (M-cones), and red (L-cones) opsin. +* Most people can match any color by changing the intensities of these three colors (RGB). +* 5-6% of males are color blind- due to mutations in the red or green opsins. They are X-linked and near each other. + +Note: + + + +--- + +## Cone absorption spectra and distribution in the retina + +
+ +Note: + + + +--- + +## Many deficiencies of color vision are the result of genetic alterations in the red or green cone pigments + +
+ +Note: + + + +--- + +## Many deficiencies of color vision are the result of genetic alterations in the red or green cone pigments + +
+ +Note: + + + +--- + +## Color blindness + +[http://www.prokerala.com/health/eye-care/eye-test/color-blindness-test.php](http://www.prokerala.com/health/eye-care/eye-test/color-blindness-test.php) + +
+ +Note: + + + +--- + +## Rods and cones + +Rods + +* 90 – 120 million +* Peripheral vision +* Located everywhere except fovea +* Very sensitive to light +* Used in low light situations +* One type +* Highly convergent +* Black and White + + + +Cones + +* 4-6 million +* Central vision +* High density in the macula and fovea +* Less sensitive to light +* Most normal lighting conditions +* Three types +* Nonconvergent +* Color vision + +Note: + + + +--- + +## Other cell types of the retina + +* Bipolar cells– cell bodies in the inner nuclear layer. Gets info from photoreceptors in outer plexiform layer and transmits it to ganglion cells and amacrine cells in inner plexiform layer. Rods and cones use specific types of bipolars. +* Ganglion cells– cell bodies in ganglion cell layer. Output neurons of the retina. Receives info from bipolar and amacrine cells and sends it out through the optic nerve. +* Horizontal cells– cell bodies in inner nuclear layer. Makes multiple contacts with photoreceptors and bipolar cells. Largely responsible for luminance contrast. +* Amacrine cells– cell bodies in inner nuclear layer. Makes contact in the inner plexiform layer with bipolar cells and ganglion cells. Several distinct subclasses. Coordinate ganglion cell activity. e.g. motion + +Note: + +luminance contrast = luminance difference/average luminance + +: same as antagonistic center-surround RFs + + + + + +--- + +## Retinal ganglion cells (RGC) + +* RGCs are the cell that sends action potentials to the brain. +* Much of the information in vision has to do with changes in light intensity. Example black and white movies. +* In order to understand how the brain makes sense of the differences in light intensity that the eye sees, it is important to know what makes RGCs fire. +* Record from an RGC and shine light onto different photoreceptors. Find: +* Even in the dark RGCs are spontaneously active. +* Receptive fields of RGCs are circular. Smaller in the center of the retina and bigger in the periphery. +* Find two classes of RGCs. Those that have receptive field profiles that are ON center and those that are OFF center. +* The receptive fields of RGCs overlap so that multiple RGCs see each point of space. + +Note: + + + +--- + +## Stephen Kuffler 1950s + +* Measured the action potentials from specific RGCs after shining light on the retina. +* Determined that RGCs have receptive fields. Found that a receptive field can be divided into center and a surround. +* Ganglion cells come in two types- ON-center/OFF surround and OFF-center/ON surround, in roughly equal proportions. +* ON center RGCs fire more when light that hits the center is brighter than that of the surround and fire less when it is darker in the center than in the surround. OFF center fire less when it is brighter in center and more when it is darker in the center. +* Acts like having separate luminance channels. Changes in intensity whether increases or decreases, are always conveyed by action potentials. RGCs are not photodetectors but are detecting the contrast between areas. + +Note: + + + +--- + +## On and Off center RGCs + +When light goes on-depolarizes + +When light goes on- hyperpolarizes + +Off response + + + +
+ +Note: + + + +--- + +## On- and off-center retinal ganglion cell responses to stimulation of different regions of their receptive fields + +
+ +Note: + + + +--- + +## On- and off-center retinal ganglion cell responses to stimulation + +
+ +Note: + + + +--- + +## Responses of On-center ganglion cells whose receptive fields are distributed across a small spot + +
+ +Note: + + + +--- + +## Responses of On-center ganglion cells whose receptive fields are distributed across a light-dark edge + +
+ +Note: + + + +--- + +## Run that by me again + +* For an ON- center/OFF-surround RGC, a point of light that fills the entire center but not in the surround will give maximal stimulation (increased action potentials). i.e. brighter in center than in surround. +* A point of light in surround but not in the center will hyperpolarize the RGC (reduce baseline spike rate). +* Light that crosses into both will be in the middle depending on the relative amounts. +* Both center and surround illuminated is basically the same as being in the dark (background levels). +* RGCs fire depending on contrast, not by absolute light intensity. +* + +Note: + + + +--- + +## Responses of On-center ganglion cells based on changes in center intensity + +
+ +
+ +Note: + + + +--- + +## Title Text + +[http://courses.pbsci.ucsc.edu/mcdb/bio125/Animation11-03InformationProcessingintheRetina.mov](http://courses.pbsci.ucsc.edu/mcdb/bio125/Animation11-03InformationProcessingintheRetina.mov) + +
+ +Note: + + + +--- + +## ON and OFF RGCs + +* Have dendrites that arborize in separate strata of the inner plexiform layer, forming selective synapses with different types of bipolar cells. ON in sublamina A and OFF in sublamina B. +* Synapse with bipolar cells. Bipolar cells do not use action potentials, but use graded potentials to release transmitter. +* There are two types of bipolar cells– ON center and OFF center. OFF center uses AMPA receptors (ionotropic) that cause the cell to depolarize in response to glutamate released by photoreceptors. ON center use metabotropic glutamate receptors that lead to the closing of Na⁺ channels and hyperpolarize the cell. + +Note: + + + +--- + +## On and Off center RGCs + +
+ +Note: + + + +--- + +## Circuitry responsible for generating receptive field center responses + +* Light hits cone causes hyperpolarization of cone, leads to less release of glutamate. +* Two bipolar cells synapse with cone, an on-center and off center bipolar cell. +* On center bipolars are normally inhibited by glutamate, less glutamate, less inhibition, more release of neurotransmitter onto RGCs which increases of on-center RGC firing. +* Off center bipolars are normally activated by glutamate, become hyperpolarized, decrease transmitter release, which leads to a decrease in firing rate of Off-center RGCs + +Note: + + + +--- + +## Light in center causes ON ganglion cells to increase firing rate and OFF ganglion cells to decrease their firing rate + +
+ +Note: + +Explain the graphs better. Make the distinction of graded potential vs. action potentials + +--- + +## Horizontal cells create circuitry that is responsible for generating the antagonistic surrounds of RGCs + +* Light hitting surround cones hyperpolarizes causing less glutamate to be released onto horizontal cell dendrites. +* Horizontal cells hyperpolarize because of less glutamate (have AMPA receptors) and decrease their rate of transmitter release (GABA) onto the synaptic terminals of the nearby photoreceptors. +* Horizontal cells normally inhibit cones (use GABA), thus now cones are less inhibited (depolarized), and release more glutamate than without surround. +* This leads to a depolarization of off-center RGCs, causing them to increase their firing rate. +* And hyperpolarizes on-center RGCs, causing them to decrease their firing rate. + +Note: + + + +--- + +## Circuitry that generates the antagonistic surrounds of retinal ganglion cell receptive fields + +
+ +Note: + + + +A bunch of photoreceptors, but all the 1-1-1 circuits are overlapping giving series of slight shifted center-surround receptive fields. + +--- + +## Circuitry that generates the antagonistic surrounds of retinal ganglion cell receptive fields + +* Light hits cone in surround +* Less glutamate released on horizontal cell +* Horizontal cell is hyperpolarized, releases less GABA onto cone in center. This depolarizes center cone relative to before light. +* More glutamate released by center cone to ON and OFF bipolars. +* Off-center depolarized, on-center hyperpolarized. +* Off-center ganglion cell fires more +* On-center fires less. + +
+ +Note: + + + +--- + +## Circuitry that generates the antagonistic surrounds of retinal ganglion cell receptive fields + +
+ +Note: + + + +--- + +## The Hermann grid illusion + +
+ +Note: + + + +--- + +## Explanation of the Hermann grid + +
+ +Note: + + + +--- + +## Summary + +* Light falls on photopigment, that is transformed to action potentials that ganglion cells convey to the brain. +* Phototransduction occurs in rods and cones that have different properties that meet the conflicting demands of sensitivity and acuity. +* RGCs have a center-surround arrangement of receptive fields that makes them good at contrast detection and relatively insensitive to background illumination. + +Note: + + + +--- + +--- + diff --git a/2016-10-31-lecture12.md b/2016-10-31-lecture12.md new file mode 100644 index 0000000..36903d3 --- /dev/null +++ b/2016-10-31-lecture12.md @@ -0,0 +1,1036 @@ +## Brain damage and visual perception + +
+ +
+ +Note: + +Let’s begin by going discussing one of the fantastic true stories told by the famous NYC neurologist, Oliver Sacks, who passed away just a few months ago and who weaved engaging clinical accounts and wrote a number of best selling books regarding cases of patients having extraordinary behaviors that resulted from strange or unknown neurological disorders including this one called The Man Who Mistook his Wife for a Hat. —>Indeed one of these accounts was about a man who actually mistook his wife’s face for a hat. This man, who was an accomplished musician and teacher at a school of music had developed trouble seeing faces and recognizing many types of objects in general as a result of degeneration in the visual system, likely from a stroke or something. + + + +…these types of stories summarize a large bit of what neuroscience is about— understanding fundamental circuits that comprise brain function and animal behavior as well as the dually fascinating and devastating consequences that occur when the formation of those fundamental circuits goes awry. + + + + + +--- + +## Brain damage and visual perception + +* The patient (‘Dr. P’): +* good visual acuity & color vision +* good recognition of abstract geometric objects (cubes, spheres, etc) +* Trouble recognizing friends, family, pupils +* Trouble recognizing complex objects +* + +* Describing a rose: “About six inches in length. A convoluted red form with a linear green attachment” +* Describing a glove: “A continuous surface, infolded on itself. It appears to have five outpouchings” + +👵🏻 + +🎩 + +2016-02-16 12:29:41 + +Note: + +Let’s begin by going discussing one of the fantastic true stories told by the famous NYC neurologist, Oliver Sacks, who passed away just last summer and who weaved engaging clinical accounts and wrote a number of best selling books regarding cases of patients having extraordinary behaviors that resulted from strange or unknown neurological disorders including this one called The Man Who Mistook his Wife for a Hat. —>Indeed one of these accounts was about a man who actually mistook his wife’s face for a hat. This man, who was a well regarded and accomplished musician and teacher at a NY school of music had developed trouble seeing faces and recognizing many types of objects in general as a result of degeneration in the visual system, likely from a stroke. + + + +This patient (let’s call him Dr. P)… was cognitively sharp, had good vis… + +Hard time + + + +visual agnosia, prospognosia, lesion somewhere in temporal lobe of the cerebral cortex for reasons we will hopefully discover partially by the end of today’s class. + + + +For him the visual world was a series of lifeless abstractions, seeing and describing the world almost the way a machine would see it without grasping the big picture. + + + +…these types of stories summarize a large bit of what neuroscience is about— understanding fundamental circuits that comprise brain function and animal behavior as well as the dually fascinating and devastating consequences that occur when the formation of those fundamental circuits goes awry. + + + + + +--- + +## Central visual pathways: retinal targets + +* The retina projects to multiple areas in the brain. Each area is specialized for different functions. +* Dorsal lateral geniculate nucleus (dLGN)- located in the thalamus- receives visual info from retina and sends it to the visual cortex. Most important visual projection with respect to visual perception. +* Pretectum-located at midbrain-thalamus boundary. Responsible for pupillary light reflex. +* Superior colliculus-in midbrain, coordinates head and eye movements. +* Suprachiasmatic nucleus- in hypothalamus-involved in day night cycles. + +Note: + +Last time + +--- + +## Title Text + +* + +The human visual system + + + +* Hubel, 1988 + +
+ +Note: + +The output neurons of the eye-- the retinal ganglion cells-- form synaptic connections in two visual centers the lateral geniculate nucleus and the superior colliculus. + + + +And the geniculate neurons have in turn formed synaptic connections with the visual cortex, thus forming the basic visual pathway from the eye to the cerebral cortex. + + + + + +--- + +## Title Text + +[http://courses.pbsci.ucsc.edu/mcdb/bio125/Animation12-01VisualPathways.mov](http://courses.pbsci.ucsc.edu/mcdb/bio125/Animation12-01VisualPathways.mov) + +
+ +Note: + + + +--- + +## Some important visual system terms: + +* + +* Optic disc, optic nerve- All the retinal ganglion cell (RGC) axons exit the eye at the optic disk (results in a blind spot) and form a big myelinated nerve called optic nerve (cranial nerve II). +* Optic chiasm- where the optic nerve enters the brain, at the base of the hypothalamus. +* Optic radiation- portion of the internal capsule (connection between thalamus and cortex) containing the axons from dLGN that project to the visual cortex +* Primary visual cortex (V1), area 17, striate cortex + +Note: + +finger test + +--- + +## Title Text + +The human visual system + +
+ +Note: + + + +--- + +## Title Text + +The human visual system + +
+ +Note: + + + +--- + +## The pupillary light reflex + +* Light hits retina, sends out axons to both sides of brain that go to the pretectum. +* Pretectal neurons project to contra- and ipsi-lateral Edinger-Westphal nuclei (in midbrain). +* Edinger-Westphal nucleus projects to the ciliary ganglion (PNS). +* Ciliary ganglion projects to the constrictor muscle in the iris. Shining light in one eye leads to constriction of both eye’s muscles. + +[- atropa belladona](https://en.wikipedia.org/wiki/Atropa_belladonna) + +- ‘deadly nightshade’ + +* : atropine +* : mydriasis +* : dilation of the pupil + + + +
+ +Note: + + + +--- + +## Circuitry responsible for the pupillary light reflex + +Typical test question: Where is the site of injury if shining a light into the left eye + +causes both eyes to constrict but shining light into the right eye does not + +cause either eye to constrict? + +[http://library.med.utah.edu/kw/animations/hyperbrain/parasymp_reflex/reflex.html](http://library.med.utah.edu/kw/animations/hyperbrain/parasymp_reflex/reflex.html) + +Neuroscience 5e Fig. 12.2 + +
+ +Note: + + + + + +answer: right optic nerve + +--- + +## Title Text + +Intrinsically photosensitive RGCs (containing melanopsin) are required for day/night activity cycles + +
+ +
+ +Note: + + + +--- + +## The spatial relationships among the RGCs are maintained in their targets. + +* Referred to as visual maps or topographic maps. +* Images are inverted and left-right reversed as they are projected onto the retina through the lens. +* The left half of the visual world is represented in the right half of the brain and vice versa (compare to somatosensory system). +* Because humans are binocular, some inputs from each eye project ipsilaterally and some contra-laterally. + +Note: + + + +--- + +## Title Text +* Hubel, 1988 + +The visual pathway– retinotopy + + + + + +retina + + + + + + + +superior + +colliculus, + +dLGN, + +visual cortex + + + +
+ +
+ +Note: + +Neighboring retinal ganglion cells in the eye detect changes in contrast from similar portions of the visual field, thus forming a 2D map of visual space in the retina. This spatial representation of objects in the retina is then projected onto -->multiple down stream visual areas, so that maps of retinal topography, or retinotopy, are maintained at multiple levels in the visual system. + + + +Other visual functional organization that is present at birth includes maps of ocular dominance, where the responses of neuronal groups is dominated by that of one eye or the other and orientation selectivity where the responses of neighboring neurons is dominated by high contrast edges of particular orientation. + + + + + +--- + +## Title Text + +The visual scene is inverted on the retina + +
+ +
+ +Note: + +or vicious little cujo + +--- + +## Binocular vision + +* There is an overlap in visual fields, such that most objects are seen by both eyes. +* Objects in the left visual field are seen by the nasal retina of the left eye and the temporal retina of the right eye. +* Objects on extreme periphery are seen only by the nasal retina on that side. +* Nasal retinal derived axons cross the midline at the optic chiasm (contra lateral) and temporal retinal axons do not cross at the chiasm (ipsilateral). +* Images in the left visual field project onto the nasal retina of the left eye and the temporal retina of the right eye. These go to the same side of the brain. Therefore the left visual field is mapped onto the right side of the brain. +* The visual map is maintained all the way to V1. The two halves of the visual fields only merge after getting connections from the other half through the corpus callosum. + +Note: + +humans have binocular vision, such that there is overlap… + +this is crucial for stereopsis, or depth perception (finger disparity) + +--- + +## Projection of the visual field onto the retina + +Neuroscience 5e Fig. 12.3 + +
+ +
+ +Note: + +So now lets go over the projection of the visual field on to the retina in a little more detail that our cujo example a minute ago. + + + + + +--- + +## Title Text + +Binocular visual field + + + +Neuroscience 5e Fig. 12.4 + +
+ +Note: + +Projection of the Binocular Field of View Relates to Crossing of Fibers in Optic Chiasm + +--- + +## Title Text + +Binocular visual field + +[http://courses.pbsci.ucsc.edu/mcdb/bio125/Animation12-01VisualPathways.mov](http://courses.pbsci.ucsc.edu/mcdb/bio125/Animation12-01VisualPathways.mov) + +
+ +Note: + + + +--- + +## Title Text + +* At the optic chiasm, visual information from the two sides of the head cross. +* In animals with eyes on the sides of the head, the entire visual field for each side is sent to the opposite side of the brain (to the tectum). +* In forward-looking animals, the visual image is split +* An object on the right side of the visual field is seen by both left hemi-retinae (but not by the right hemi-retinae). The optic nerves leave the retinae, and at the optic chiasm, the two left hemi-retinae projections go left, while the two right hemi-retinae go right. + +Fig 16-2 Neurobiology, + +by Gary G. Matthews, Blackwell Science + +Binocular visual field: species differences + +
+ +Note: + +dev book + +--- + +## The human visual system + + + +LGN + +
+ +Note: + + + +--- + +## Lateral geniculate nucleus (LGN) + +* 90% of the retinal axons go to the dLGN in the thalamus +* dLGN projects to visual cortex (striate cortex). +* Contains 6 layers, that are specific with respect to eye (ipsi vs contra) and with respect to type of ganglion cell— magnocellular (detects gross shape and movement) and parvocellular (form and color). +* Layers align in order to align visual fields. +* Each dLGN receives input from 1 or 2 RGCs therefore like RGCs there also have center-surround responses that are either on or off. + +Note: + + + +--- + +## Laminar organization of the LGN + +* Neurons along the projection line see the same point in space +* But neurons in different layers are receiving info from different types of RGCs. + + + +
+ +Note: + + + +--- + +## Laminar organization of the LGN: segregation of optic tract inputs + +* Each LGN layer is eye-specific +* The projections from the retinal ganglion cells maintain the field of view as it was seen - this is called a retinotopic map. The LGN contains 6 layers of cell bodies; each layer receives input from only one eye. The two most ventral layers receive M (magno) ganglion cell inputs, while the other 4 receive P (parvo) inputs. + +
+ +Note: + + + + + + + +what is parvo and magnocellular? Different subtypes of RGCs that we’ll cover more in just a minute… + +--- + +## Visual cortex + +* The first point in the central visual pathway where the receptive fields of cells are significantly different from those of the retina. +* located in occipital lobe near the parieto-occipital sulcus. +* There is topographic organization of each visual hemifield. +* Upper visual field is represented below the calcarine sulcus, the lower field above the calcarine sulcus. +* Superior and inferior visual fields take different routes to the visual cortex. Meyer’s loop, where superior axons diverge and go into temporal lobe before going to occipital lobe + +Note: + + + +--- + +## Title Text + +
+ +Note: + + + +--- + +## Projection to cortex + +* The visual field is projected in a retinotopic fashion. +* The right visual field is projected onto the left cortex, while the left visual field is represented on the right.. +* The region of the fovea, because of its high sensitivity and density of cones, is represented by a huge amount of the cortex. + +
+ +Note: + +Incr representation sound familiar? think of hand and lip representation in human somatosensory cortex we discussed a couple classes ago… + + + + + +--- + +## Visuotopic organization in the right occipital lobe + +* PN12060.JPG + +Neuroscience 5e Fig. 12.5 + +
+ +Note: + + + +--- + +## Optic radiation paths to the visual cortex + +Lower visual field (dorsal retina) + +Upper visual field- ventral retina + +(c) 2001 Sinauer Associates, Inc. + +
+ +Note: + + + +--- + +## Visual field defects + +* The spatial relationships in the retina are maintained in the brain… +* Careful analysis of the visual field defects of a patient can often indicate where brain damage is located. +* Anopsias— relatively large deficits +* Scotomas— smaller deficits. + +Note: + + + +--- + +## Visual field deficits resulting from damage along the primary visual pathway + +Black means blind + +Blue means see + +Neuroscience 5e Fig. 12.6 + +Blindness in R eye + +Bitemporal hemianopsia + +L homonymous hemianopsia + +Upper quadrant hemianopsia + +Homonymous hemianopsia with macular sparing + +
+ +Note: + + + +--- + +## The columnar organization of visual cortex + +* The visual cortex is layered. Each layer has stereotypical inputs and outputs. LGN projects to layer 4. Output layer is layer 5. +* Each column of neurons in the vertical plane typically respond to the same part of the visual field and the same orientation. +* Neurons in the horizontal plane respond to neighboring areas of the visual field and change orientation preferences that repeats each milimeter or so. +* Neurons in layer 4 respond to just one eye or the other (monocular cells) but other layers have neurons that can respond from either eye. This sets up ocular dominance columns in the cortex. + +Note: + +Now let’s go over the structural and functional organization of visual neocortex + +--- + +## Anatomical organization of visual cortex + +Neuroscience 5e Fig. 12.10 + +
+ +Note: + + + +--- + +## Neurons in the primary visual cortex respond selectively to oriented edges + +* David Hubel and Torsten Wiesel— measured responses of neurons in visual cortex. Found not center-surround like RGCs and LGN neurons but found that they respond to bars or lines but only of a particular orientation. +* Two types of cells: Simple, respond to stimulus only if matches orientation. Spots of light don’t do much, bars or lines make them fire. They also have surround inhibition. Receptive fields can be generated by having 3-4 LGN neurons innervate one simple cell. +* Complex cells- bigger receptive fields, not strongly orientation selective, no clear on or off zones, detect movement. + +Note: + + + +--- + +## Neurons in the primary visual cortex respond selectively to oriented edges + +Neuroscience 5e Fig. 12.8 + +
+ +Note: + + + +--- + +## Neurons in the primary visual cortex respond selectively to oriented edges + +Neuroscience 5e Fig. 12.8 + +
+ +
+ +Note: + + + +--- + +## Neurons in the primary visual cortex respond selectively to oriented edges + +Neuroscience 5e Fig. 12.9 + +
+ +Note: + +Natural scenes consist of a spectrum of high contrast, oriented edges. + +--- + +## Information from multiple LGN inputs are used to make cortical neuron receptive fields + +* Filtering of info from multiple LGN cells is used to make simple and complex cells in visual cortex + +red dots inhibitory synapses + +[LGN on cell: http://www.youtube.com/watch?v=jIevCFZixIg](http://www.youtube.com/watch?v=jIevCFZixIg) + +[V1 simple cell: http://www.youtube.com/watch?v=Cw5PKV9Rj3o](http://www.youtube.com/watch?v=Cw5PKV9Rj3o) + +[Hubel: https://www.youtube.com/watch?v=y_l4kQ5wjiw](https://www.youtube.com/watch?v=y_l4kQ5wjiw) + +
+ +Note: + +other hubel vid I saw and marked times… + + + +* david hubel 1:24-2:18: +* 125 million rods and cones in each eye. +* misha pavel, sobel filter +* try to build a robot to see and interpret images and it's hard. + +: 4:45 nice example of movement and perception of cat face + + + + + +--- + +## Types of simple cell receptive fields + +
+ +Note: + + + +--- + +## Some cells are selective for the direction of movement + +We use multiple types of visual information for perception: + +[https://www.youtube.com/watch?v=y_l4kQ5wjiw](https://www.youtube.com/watch?v=y_l4kQ5wjiw) + +
+ +Note: + +others selective for movement, disparity + + + +* david hubel 1:24-2:18: +* 125 million rods and cones in each eye. +* misha pavel, sobel filter +* try to build a robot to see and interpret images and it's hard. + +: 4:45 nice example of movement and perception of cat face + + + + + +--- + +## Figure 12.11 The basis of functional maps in primary visual cortex + +The basis of functional maps in visual cortex + +Neuroscience 5e Fig. 12.11 + +
+ +Note: + + + +--- + +## Mapping receptive fields in the living brain + +* Illuminator adds red light to help measure oxy-deoxy hemoglobin levels (a sign of increased neural activity). +* Show monkey monitor that contains a given orientation of a line. Tell computer to color-code areas that respond to a certain orientation. +* Repeat for all such orientations, get a pinwheel affect. + +
+ +Note: + +data display, surface of brain + +--- + +## Repeating units of orientation columns in visual cortex + +
+ +Note: + + + +--- + +## Mixing of pathways from the two eyes first occurs in the visual cortex + +Fig. Neuroscience (c) 2001 Sinauer Associates, Inc. + +
+ +Note: + + + +--- + +## Ocular dominance bands in layer 4 of primary visual cortex (V1, area 17) + +Hubel, Wiesel, and Levay 1976 + +
+ +Note: + + + +If we were to peer at layer 4 only and perform a histological procedure that labels thalamocortical inputs from only one eye we would see a pattern like this in primate cortex, resembling ocular dominance bands or stripes. + + + +--- + +## Columnar organization of ocular dominance + +
+ +
+ +Note: + + + +--- + +## The Nobel Prize in Physiology or Medicine (1981) + +“for their discoveries concerning information processing in the visual system” + +David H. Hubel + +Torsten N. Wiesel + + + +
+ +
+ +
+ +Note: + + + +--- + +## Maps in the visual system- ocular dominance columns and orientation selectivity in visual cortex + + + + + + + +Ocular + +dominance + +Orientation + +selectivity + +
+ +
+ +Note: + +The organization of connections from each eye is shown here where if we were to look at a chunk of primary visual cortex from ferrets, cats, or monkeys we would find ocular dominance columns where the response properties of neighboring cells is dominated by that of one eye or the other and which can be demonstrated by electrophysiological recordings or by histological staining for cytochrome oxidase. + + + +Overlaid on this map of alternating ocular dominance columns is a map of orientation pinwheels in visual cortex shown by the isocontour lines on the surface *here* and by the colored orientation map *here* -->where the colored map represents the preferred response of neighboring neurons to high contrast edges presented at different orientations in the visual field. + +--- + +## Parallel processing in the visual system + +* Separate pathways for color and movement. +* In human retina there are three main types of retinal ganglion cells, called M, P , and K types. M and P types best characterized. +* M cells are bigger, have larger receptive fields, faster conduction velocities, and respond transiently to visual stimulation. P cells smaller, respond in a sustained fashion. +* P cells respond to color. This is because their center and surround are from different cones. +* M cells do not respond well to color because center and surround are from the same type of cones. +* M, P, and K RGCs go to different layers in the LGN which in turn project to different layers in V1. + +Note: + + + +--- + +## P type RGCs are sensitive to color contrast + +
+ +Note: + + + +--- + +## Magno-, parvo-, and konio-cellular streams of information in the visual system + +
+ +Note: + + + +--- + +## Extrastriate visual areas + +* There are many other areas of the brain that process visual information, each gets info derived from primary visual cortex (V1). +* Specialized for different functions. +* MT middle temporal area, responds to direction of a moving edge without regard to its color. +* V4, responds to color of a stimulus without regard to form. +* 10 different visual areas, each with a topographic map. +* Damage in these areas can really give weird experiences. + +Note: + + + +--- + +## Subdivisions of the extrastriate cortex in the macaque monkey + +Neuroscience 5e Fig. 12.16 + +
+ +
+ +Note: + + + +--- + +## Localization of multiple visual areas in the human brain using fMRI + +Neuroscience 5e Fig. 12.17 + +
+ +Note: + + + +--- + +## Organization of the dorsal and ventral visual pathways + +Dorsal stream: object location (Where?) + +* Knowing location of objects in space. Linking visual data with movement/action + +Ventral stream: object recognition. (What?) + +* Color: V4 (temporal-parietal junction). +* Face recognition: fusiform gyrus + +Neuroscience 5e Fig. 12.18 + +
+ +Note: + + + +--- + +## Hierarchical visual processing + +
+ +Note: + +“the brain is a complex of widely and reciprocally interconnected systems and that the dynamic interplay of neural activity within and between systems is the very essence of brain function”. And indeed if you look at this—> anatomical wiring diagram for different visual areas represented by different colors you will notice that we use an organized constellation of brain regions to process and route different types of visual information + +--- + +## Subdivisions of the extrastriate cortex in the macaque monkey + +Van Essen 1992 + +
+ +
+ +Note: + +but he also emphasized that “the brain is a complex of widely and reciprocally interconnected systems and that the dynamic interplay of neural activity within and between systems is the very essence of brain function”. And indeed if you look at this—> anatomical wiring diagram for different visual areas represented by different colors you will notice that we use an organized constellation of brain regions to process and route different types of visual information and each one of these brain regions consists of many thousands of these basic cortical column building blocks described on the previous slide. + +--- + +## Face recognition cells in the fusiform gyrus + +
+ +Note: + +responses of a monkey’s neuron in their homologous area to fusiform gyrus to various facelike or non facelike stimuli. + + + +color synesthesia: association of colors with certain numbers, letters, or objects + +prosopagnosia: face blindness. Our patient Dr. P from earlier? + +--- + +## Grandmother neurons in the human brain? + +[http://www.youtube.com/watch?v=Y7BZlDfVR6k](http://www.youtube.com/watch?v=Y7BZlDfVR6k) + +Quiroga et al., Nature 2005 + +
+ +Note: + +Invariant visual representation by single neurons in the human brain. Quiroga et al., Nature 2005 + + + +Recordings were made in medial temporal lobe of the cerebral cortex including entorhinal cortex and hippocampus course of clinical procedures to treat epilepsy. + + + +Interestingly this cell did not respond to pictures of Jennifer Aniston with Brad Pitt, maybe this cell had ‘moved on’ just like Miss Aniston. But other cells in this work did respond to selectively to Aniston with her friend’s costar Lisa Kudrow. + + + +One object per neuron? + + + +however these results may be best understood in a non-visual context. Some of the example cells responded not only to pictures but also to the printed name of a particular person or object. So this type of invariance must be based off learned associations. + + + +--- + +## Grandmother neurons: a sparse neural code + +C. Connor, Nature 2005 + +
+ +Note: + +invariant visual representation by single neurons in the human brain. Quiroga et al., Nature 2005 + + + +Connor Nature 2005, N&V on Quiroga et al: + +>a more technical term for the grandmother issue is ‘sparseness’. + +>At earlier stages in the object recognition pathway the neural code for an object is a broad activity pattern distributed across a population of neurons, each responsive to a discrete visual feature. At later, higher order processing stages, neurons become increasingly responsive for combinations of features and the code becomes increasingly sparse. + + + +sparse and non-variant + +--- + +## Weird visual defects + +* Cerebral achromatopsia +* Do not see in color-only black and white. Legions in extrastriate cortex regions like V4 or in ventral stream. +* Lesions in MT regions cause people to have defects in detecting motion (Hard to pour drinks accurately, see moving cars, etc). +* Blind sight +* Disruptions in V1 cause blindness. +* However some people can “guess” what an object is. Implies that there are other projections from eye to brain (superior colliculus) that can somehow compensate for loss of V1. + +Note: + + + +--- + +--- +