From 1953842d86166638bcc451db895fa1eeb2f17219 Mon Sep 17 00:00:00 2001 From: ackman678 Date: Tue, 11 Dec 2018 14:30:32 -0800 Subject: [PATCH] f2018 lectures end --- basal-ganglia.md | 67 +++--- motor1.md | 24 ++- neurotransmitters1.md | 23 +- neurotransmitters2.md | 33 ++- neurotransmitters3.md | 2 +- olfaction-gustation.md | 131 ++++++------ pain.md | 451 ++++++++++++++++++++++++++++++++++++++++ somatosensory.md | 461 +---------------------------------------- vision1.md | 117 +++++------ vision2.md | 104 +++++----- 10 files changed, 732 insertions(+), 681 deletions(-) create mode 100644 pain.md diff --git a/basal-ganglia.md b/basal-ganglia.md index fbe5888..4cfb977 100644 --- a/basal-ganglia.md +++ b/basal-ganglia.md @@ -15,17 +15,17 @@ Note: -- also with the non-motor loops (limbic system class): -* Learning, reward mechanisms - * Response-outcome associations - * Stimulus-response associations +* Modulate the initiation, termination, amplitude, and selection of movement + +* But basal ganglia also has varied non-motor roles: + - also with the non-motor loops (limbic system class): + - involved in learning, reward mechanisms + * Response-outcome associations + * Stimulus-response associations + - and also non-motor prefrontal cortex loops to help in selection of conscious goals, decisions [http://www.youtube.com/watch?v=Td4QGHNJ8Q0](http://www.youtube.com/watch?v=Td4QGHNJ8Q0) -* Modulate the initiation, termination, amplitude, and selection of movement - -*and selection of movement* -*Used in dopamine circuits* -- @@ -43,7 +43,7 @@ Today we will begin our examination of the pathways in the nervous system that m * Anatomical connectivity * Function– modulation through disinhibition -* Neuromodulators– dopamine +* Neurotransmitters– dopamine, GABA, glutamate * Diseases of the basal ganglia @@ -86,6 +86,18 @@ Note: Note: +mammillary body +: part of diencephalon, at junction with hypothalamus +: part of limbic system +: location at anterior end of the fornix +: relay from amygdala and hippocamus to thalamus by mamillo-thalamic tract +: role in recall of episodic memories + +basal forebrain nuclei +: major source of acetylcholine input to cerebral cortex +: roles in attention, wakefulness, REM sleep + + --- ## Anatomy of the basal ganglia: caudate and putamen @@ -95,9 +107,9 @@ Note: Note: -Main inputs: Striatum– caudate and putamen +Main input structures of basal ganglia system: Striatum– caudate and putamen -Main outputs of basal ganglia system include: Globus pallidus interna (thalamus) and substantia nigra pars reticulata (superior colliculus, eye movements) +Main output structures of basal ganglia system: Globus pallidus interna (projects to thalamus) and substantia nigra pars reticulata (projects to superior colliculus; eye movements) Intermediate nuclei in the basal ganglia system: Globus pallidus externa, STN, and substantia nigra pars compacta @@ -120,9 +132,6 @@ Note: Kreitzer Ann Rev Neurosci 2009 -*Inputs from cortical, thalamic, and brainstem structures?* - - Medium spiny neuron in the corpus striatum TODO: new image @@ -134,10 +143,12 @@ TODO: new image * Caudate receives cortical projections primarily from multimodal association cortices and motor areas from frontal lobe that control eye movements * Putamen receives input from the primary and secondary somatic sensory cortex and extrastriate visual cortex in occipital and temporal lobes, premotor and motor cortex, and auditory association areas in temporal lobe * These inputs are excitatory, glutamatergic synapses -* Each spiny neuron can get synapses from lots of different cortical neurons. Each cortical neuron synapses onto a few MSNs +* Each medium spiny neuron can receive input from lots of different cortical neurons Note: +Each cortical neuron synapses onto more than one MSN + --- @@ -194,23 +205,25 @@ Note:
-* Substantia nigra pars reticulata (SNr) neurons project to upper motor neurons in the superior colliculus that command eye movements without going to the thalamus * **Globus pallidus and pars reticulata neurons are GABAergic**. Unlike MSNs they have high levels of spontaneous activity– they are tonically active * Thus the output from the basal ganglia is normally inhibitory-- tonic inhibition -* When MSNs fire (in anticipation of movement) this inhibits the inhibition (**disinhibition**) and allows upper motor neurons to send commands to local circuit and lower motor neurons that initiate movement +* When MSNs fire (in anticipation of movement) this inhibits the inhibition (**disinhibition**) and allows upper motor neurons (in cortex and superior colliculus) to send commands to local circuit and lower motor neurons that initiate movement * Called the direct pathway
Note: +* Substantia nigra pars reticulata (SNr) neurons project to upper motor neurons in the superior colliculus that command eye movements without going to the thalamus --- ## Direct pathway of outputs from the basal ganglia -
Neuroscience 5e Fig. 18.4
+
sign shows normal effect (excite or inhibit) at that synapse
Neuroscience 5e Fig. 18.4
+ +*Remember that caudate/putamen medium spiny neurons are usually not active* Note: @@ -281,18 +294,20 @@ Overall inhibitory. Serves to modulate the disinihibitory actions of the direct --- -## Center–surround functional organization of the direct and indirect pathways +## 'Center–surround' functional organization of the direct and indirect pathways
Neuroscience 5e Fig. 18.8
Note: -think center-surround receptive fields for luminance contrast in retinal ganglion cells mediated by synaptic interactions between photoreceptors, bipolar cells, and horizontal cells in the outer plexiform layer. +Importantly, there is more spatially discrete connectivity in the converging input from MSNs onto selective patches of microcircuits in the GPi for the direct pathway. For the indirect pathway, the input is much broader from MSNs onto patches of microcircuits in the GPi-->STN-->GPe. Results in greater upper motor neuron excitation in center of microcircuit (channel of information) due to the direct pathway overriding a diffuse broader inhibition for competing surround circuits (different motor programs for example) from the indirect pathway. + +think about center-surround receptive fields for luminance contrast in retinal ganglion cells mediated by synaptic interactions between photoreceptors, bipolar cells, and horizontal cells in the outer plexiform layer. -difference of Gaussians is a feature enhancement algorithm --mexican hat distribution (shaped like a sombrero) +-'mexican hat' distribution (shaped like a sombrero) (normal distribution with a postive central tendancy and negative side saddles) -multidimensional generalization of this wavelet is called the Laplacian of Gaussian function @@ -300,7 +315,7 @@ think center-surround receptive fields for luminance contrast in retinal ganglio [-automatic scale selection in computer vision applications; see Laplacian of Gaussian https://en.wikipedia.org/wiki/Mexican_hat_wavelet](https://en.wikipedia.org/wiki/Mexican_hat_wavelet) -Attentional field has a Mexican hat distribution +Attentional field has a 'Mexican hat' distribution: http://www.sciencedirect.com/science/article/pii/S0042698904005735 @@ -578,15 +593,13 @@ Note: 15-34 cytosine-adenine-guanine (CAG) DNA repeats normally, 42-66 in Huntingtin's disease resulting in an unstable triplet repeat in coding region of gene. Polyglutamine --- -## The huntingtin protein has expanded glutamine repeats in the diseased state + --- diff --git a/motor1.md b/motor1.md index 94a3efd..6aa1783 100644 --- a/motor1.md +++ b/motor1.md @@ -385,16 +385,26 @@ helps form negative feedback loop
-sensory function | receptor type | afferent axon type | axon diameter (µm) | conduction velocity (m/s) +sensory function | receptor type | afferent axon type (alt name) | 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 +proprioception | muscle spindle | Aα (Ia + Ib), **myelinated** | 13–20 | 80–120 +touch | Merkel, Meissner, Pacinian, and Ruffini cells | A𝛽 (II), **myelinated** | 6–12 | 35–75 +pain, temperature | free nerve endings | Aδ (III), **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. + +Tab. 1 after Rosenzweig 2005 + +-- --- ## The stretch reflex @@ -673,7 +683,3 @@ spinal locomotor and brainstem respiratory CPGs (Yuste et al, Nat Rev Neurosci 2 : have an 'excitatory core' of mutually excitatory interneurons : ea. hemisegment of the spinal cord has this a core : reciprocal inhibition between contralateral hemisegments results in alternating left–right motor output - - - ---- diff --git a/neurotransmitters1.md b/neurotransmitters1.md index 7dba1fa..4f9d80b 100644 --- a/neurotransmitters1.md +++ b/neurotransmitters1.md @@ -646,14 +646,13 @@ Note: * Found primarily in groups of neurons in the raphe region of the pons and upper brainstem * The raphe nucleus projects widespread in forebrain areas that are implicated in sleep and wakefulness and mood -*See Fig. 6.17 Neuroscience 6e* Note: * dorsal raphe and median raphe nuclei. In brain stem. raphe nuclei just ventral to the 4th ventricle stretching from medulla * vesiclular monoamine transporter **VMAT** loads this (as well as other monoamines) into synaptic vesicles. -turkey/tryptophan—> sleep? Yes— but not really ([http://www.snopes.com/food/ingredient/turkey.asp](http://www.snopes.com/food/ingredient/turkey.asp)), you’d have to eat a lot more (maybe 3x more) than at a particular meal. And furthermore, lots of protein sources include amounts of tryptophan similar to or greater than that of turkey per gram of food content (including eggs, fish, cheese, also nuts, seeds, legumes). +turkey/tryptophan—> sleep? Yes— but not really ([http://www.snopes.com/food/ingredient/turkey.asp](http://www.snopes.com/food/ingredient/turkey.asp)), you’d have to eat a lot more (maybe 3x more) than at a particular meal. And furthermore, lots of protein sources include amounts of tryptophan similar to or greater than that of turkey per gram of food content (including eggs, fish, cheese, and some nuts, seeds, legumes). Tryptophan is present in all proteins, but is also And besides well timed carbohydrate ingestion with/after tryptophan consumption is important for increasing tryptophan transport from blood vessels and into brain tissue: @@ -661,9 +660,15 @@ And besides well timed carbohydrate ingestion with/after tryptophan consumption >The small, all-carbohydrate snack is tryptophan's ticket across the blood-brain barrier, where it can boost serotonin levels. +Tryptophan competes with other large aromatic neutrally charged amino acids for passage into brain from blood vessels. But tryptophan is the only amino acid known to bind non-covalently with serum albumin (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1133271/?page=1) (Curzon, 1973; Smith and Pogson, 1980). This is thought to protect it from insulin induced cellular metabolism (insulin rising after eating carbohydrates of course) by bringing tryptophan to high enough concentrations in blood to favor entry into brain. Indicates that the timing of carbohydrate ingestion may be helpful. + +Study looking at food/protein composition type and quantitative mesaures of cerebral serotonin levels after consumption (5-HT levels can change 8-fold in rat): https://doi.org/10.1016/j.physbeh.2009.05.004 + + --- + ## Histamine * Made from histidine, a metabolite of monoamine oxidase @@ -671,7 +676,6 @@ And besides well timed carbohydrate ingestion with/after tryptophan consumption * Mediates arousal and attention * Histamine receptors are in the immune system and in the CNS. Sedative effects of diphenhydramine (Benadryl) act through the CNS -*See Fig. 6.17 Neuroscience 6e* Note: @@ -689,8 +693,21 @@ diphenhydramine : also has some serotonin reuptake inhibitor capability : also has some anticholinergic (muscarinic) capability +--- + +## Projections from serotonergic and histaminergic neurons + +These projections are sparse (low synapse density) but widespread (most brain regions). + +
+
histaminergic axons from tuberomamillary nucleus of hypothalamus, +serotonergic axons from dorsal raphe nucleus of brain stem +
+
Neuroscience 6e Fig. 6.17, 5e Fig. 6.13
+ -- + ## Synthesis of histamine and serotonin
Neuroscience 5e Fig. 6.14
diff --git a/neurotransmitters2.md b/neurotransmitters2.md index 4b3d445..e835df1 100644 --- a/neurotransmitters2.md +++ b/neurotransmitters2.md @@ -450,13 +450,12 @@ IPSP * In general EPSPs in neurons are small 0.2–0.4 mV * Most neurons are somewhere between 10–20 mV below threshold. If everything was linear that it would take the sum of 50 or so inputs to trigger AP -* Not so simple. Some inputs are bigger than others, the inputs can be summed differently– spatially or temporally -* A single neuron can have as many as 10,000 different synapses. Some excitatory some inhibitory, some strong some weak. Some at the tips of dendrites, some near the cell body -* Integration of all the postsynaptic potentials determines whether the neuron fires an action potential +* Not so simple-- synaptic inputs can be summed in space and time within a neuron +* Recall a single neuron may have as many as 10,000 different synapses. Some are excitatory some inhibitory, some strong some weak. Some at the tips of dendrites, some near the cell body +* Integration of all these little postsynaptic bioelectric waves determines whether the neuron fires an action potential Note: -Of course we are greatly simplifying everything here, a single neuron may have as many as 10K synaptic inputs. --- @@ -467,17 +466,33 @@ Of course we are greatly simplifying everything here, a single neuron may have a
* How does a neuron integrate all the information it is getting? -* In most motor neurons and interneurons the decision to initiate an action potential is at the axon hillock. Contains a high density of voltage dependent Na⁺ channels. Contains membrane with lowest threshold +* In many neurons the decision to initiate an action potential is at the axon hillock. Contains a high density of voltage dependent Na^+^ channels and is contains membrane with lowest threshold * Axon hillock is senses the local state of the cell, which is the combination of all the EPSPs and IPSPs going on at one time -* This is mostly due potentials that spread passively -* Temporal summation, process by which consecutive synaptic potentials at the same site are added together. Different synapses will have different time constants -* Length constant of the cell determines the degree to which a depolarization current decreases as it spreads passively. Easier to sum inputs on the same dendritic branch than on different branches -* Some dendrites even have voltage gated Na⁺ channels, these can amplify inputs +* This is due graded potentials that spread passively +* Temporal summation, process by which consecutive synaptic potentials at the same site are added together. +* Spatial structure of the determines the degree to which a depolarization current decreases as it spreads passively. Easier to sum inputs on the same dendritic branch than on different branches Note: +* Different synapses will have different time constants +* Some dendrites have voltage gated Na^+^ channels (albeit lower density than axons), these can amplify inputs +* Length constant of the cell determines the degree to which a depolarization current decreases as it spreads passively. Easier to sum inputs on the same dendritic branch than on different branches + +Time constant +: time needed for for resistive current (I~r~, current due to ions flowing through channels) and membrane potential (V~m~) to reach **63%** of their *asymptotic values* is proportional to the combination of resistance and capacitance of the circuit in question (across the cell membrane) +: membrane current (I~m~) is sum of I~r~ and the capacitive current (I~c~) +: I~m~ = I~r~ + I~c~ +: capacitance of membrane: during change in applied voltage or current across membrane, positively charged ions pile on surface of one side of membrane and **electrostatically** interact with cations on the other side of membrane surface (membrane acts as thin impermeable surfaces in parallel, like a capacitor), repeling them and inducing immediate, fast capacitive current along membrane +: capacitive current falls with an exponential time course. And the membrane potential rises with **same exponential** time course +: Relation of membrane potential at time *t* during charging of capacitance is given by V~t~ = V~inf~(1 - *e*^-t/RC^), where V~inf~ is the membrane potential at an infinite asymptotic value of the exponential curve. When t = RC, then we have V~t~ = V~inf~ ( 1 - *e*^-1^) ==> V~inf~ (0.63) + +```javascript +console.log( 1 - Math.E ** -1) +``` + + diff --git a/neurotransmitters3.md b/neurotransmitters3.md index 31be264..7ab179c 100644 --- a/neurotransmitters3.md +++ b/neurotransmitters3.md @@ -402,7 +402,7 @@ most receptors are metabotropic ## Catecholamine receptors -* Act exclusively by activating G-protein coupled receptors. Contribute to complex behaviors +* Act exclusively by activating G-protein coupled receptors. Contribute to complex behaviors * Norepinephrine and epinephrine each act on α and β adrenergic receptors * Mostly used to control smooth muscles, especially cardiovascular * B-blockers are used to treat hypertension, anxiety, and panic diff --git a/olfaction-gustation.md b/olfaction-gustation.md index f0897ea..1948b09 100644 --- a/olfaction-gustation.md +++ b/olfaction-gustation.md @@ -6,9 +6,9 @@ Note: -phylogenetically oldest sense. +Phylogenetically oldest sense. -not considered very important in humans compared to other senses, but think about the fantastically strong emotional memories tied to smells— the olfactory system when robustly stimulated can have much influence over the formation of olfactory tied memories through its direct connectivity to the limbic and memory systems of the brain. We’ll learn a bit about this connectivity later. +While it is not considered very important in humans compared to other senses, the olfactory and gustatory systems play a powerful role in influencing the behavior of animals including ourselves. Think about the fantastically strong emotional memories tied to smells— the olfactory system when robustly stimulated can have much influence over the formation of olfactory tied memories through its direct connectivity to the limbic and memory systems of the brain. We’ll learn a bit about this connectivity later. Mucus membranes of eyes face mouth @@ -48,20 +48,18 @@ Note: ## Human olfactory bulb - - -
Neuroscience 5e Fig. 15.2
+
Neuroscience 5e Fig. 15.2; Human brain ~20cm length; rat brain ~3cm length
-species | olf bulb surface area (cm2) ---- | --- -human | 10 -rat | 15 -cat | 20 -dog | >150 +species | olf bulb surface area (cm2) | number of olfactory receptor neurons +--- | --- | --- +human | 10 | 1.2x107 +rat | 15 | 1.5x107 +cat | 20 | +dog | >150 | 1.0x109
@@ -71,6 +69,22 @@ humans 12 million ORNS rats 15 million ORNS dogs 1 billion ORNS +human brain: 20cm long +rat brain: 3cm long + +--- + + +## Dogs smell better than humans + +
Neuroscience 5e Fig. 15.2
+ +
Neuroscience 5e Fig. 15.3
+ +Note: + +
Neuroscience 5e Animation 15.1
+ --- ## Organization of the human olfactory system @@ -92,8 +106,7 @@ The flow of olfactory information ## Olfactory perception * Is not as acute in humans as in a number of other animals -* Less acute in humans because of a smaller variety of functional olfactory receptor proteins, less receptor neuron density, and also a lesser amount of relative cortex used to process information -* Mice have ~1000 olfactory receptor genes, humans several hundred +* Less acute in humans because of less receptor neuron density and also a lesser amount of relative cortex used to process information Note: @@ -138,6 +151,12 @@ butyl mercaptan: similar to major constituent of defensive spray in skunk tert-butyl mercaptan: natural gas additive +D-limolene (citrus): humans can smell at 15 molecules per billion + +ozone: 10 molecules per billion + +small molecular changes can matter to odorants: D-carvone smells like spearming, L-carvone smells like caraway seeds in rye bread + --- ## Combinatorial coding @@ -205,7 +224,7 @@ Record from a neuron in the AOB, pink area is when mouse is sniffing at face. Y
* Female rodents (mice) grouped together synchronize their estrous cycle upon exposure to pheromones in male mouse urine (‘Whitten effect’). This depends on pheromone receptors and VNO—>AOB connectivity. -* VNO is vestigial in humans: VRs and TRPC2 are pseudogenes +* VNO is vestigial in humans * Myth: women who live in close proximity synchronize their menstrual cycle (the ‘McClintock effect’, after McClintock, Nature 1971). The current scientific evidence for this effect in human is not strong. * However there’s some evidence for odorants working as pheromone-like molecules to influence behaviors (attraction, fear) mediated by the main olfactory system @@ -217,6 +236,8 @@ Human pheromones?? vestigial. VNO anatomy is non-functional in human. +TRPC2 are pseudogenes in human. + myth of mcclintock effect. statistical issues with these studies, no one has reported human estrous cycle synchrony over more than 6-9 months as indeed the original study was on college women at wellsey over the period of one academic calendar year. Windshield wiper, coupled oscillator analogy. Just out of phase. But other animals… @@ -311,16 +332,10 @@ Linda Buck and Richard Axel "for their discoveries of odorant receptors and the ## Olfactory receptors -
Neuroscience 5e Fig. 15.9
- - -Note: - ---- - -## Olfactory receptors - -
Neuroscience 5e Fig. 15.9
+
+
Neuroscience 5e Fig. 15.9
+
Neuroscience 5e Fig. 15.9
+
Note: @@ -340,6 +355,17 @@ pseudogene Note: +--- + +## Olfactory receptor signal transduction + +* Binding of odorant to receptor activates a Gα (Called G-olf) that in turn activates adenylyl cyclase +* cAMP gates a Na+/Ca2+ cation channel. Calcium rushes in and activates a Cl- channel. Chloride normally high in-low out in olfactory neurons and thus Cl- leaving also depolarizes cell + +Note: + + + --- ## ORN receptor potentials generated in cilia @@ -363,17 +389,6 @@ blue is all cell nuclei green for OMP at right ---- - -## Olfactory receptor signal transduction - -* Binding of odorant to receptor activates a Gα (Called G-olf) that in turn activates adenylyl cyclase -* cAMP gates a Na+/Ca2+ cation channel. Calcium rushes in and activates a Cl- channel. Chloride normally high in-low out in olfactory neurons and thus Cl- leaving also depolarizes cell - -Note: - - - --- ## Olfactory receptor signal transduction @@ -422,18 +437,6 @@ Eucalyptol is cineole Camphor is the smell of turpintine. Aromatic ---- - -## Dogs smell better than humans - -
Neuroscience 5e Fig. 15.2
- -
Neuroscience 5e Fig. 15.3
- -Note: - -
Neuroscience 5e Animation 15.1
- --- @@ -503,7 +506,7 @@ Subtle changes in a molecules structure can be detected by different receptors Note: -* fig origin unknown. No find through image search +* todo --- @@ -705,17 +708,6 @@ Composite fMRI image showing different locations of activation in insular cortex Note: - ---- - -## Transduction mechanisms in a generic taste cell - -
Neuroscience 5e Fig. 15.20
- - -Note: - - --- ## Taste receptors @@ -729,6 +721,27 @@ Note: Note: +--- + +## Transduction mechanisms in a generic taste cell + +
Neuroscience 5e Fig. 15.20
+ + +Note: + + +amiloride sensstive ant channenels for salt + + h+ sens trip channel for sour + + T1R2-T1R3 g protein recept for sweet + + T1R1T1R3 g proteain recep for umami with trpM5 IP3 Ca2+ channels + + T2R gprotein for bitter with TRPM5 ca2+ channel + + --- ## Taste receptors diff --git a/pain.md b/pain.md new file mode 100644 index 0000000..1c85aa4 --- /dev/null +++ b/pain.md @@ -0,0 +1,451 @@ +## 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 + + + + +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 perception involves activation of specialized neurons (not just mechanoreceptors) + +* 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: + +Scheme for transcutaneous nerve recording + + +--- + +## 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 + +
+
+ +* 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 + +
+ +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: + + + +--- + +## Nociceptive component in the ventral posterior 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
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. Soldiers wounded in battle feel less pain than if one gets the same injury at home +* Pain can be subjective. Depends on context. +* There is a descending pain pathway that can impinge on the dorsal horn to quiet neurons + +Note: + +e.g. prostaglandins lower threshold for phosphorylation of TTX resistant sodium channels. + +TrPV1 receptor potentiations. + +cox2 inhibit prostaglandin syn + + +--- + +## 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 + +
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. CB1 on presynaptic terminals of dorsal horn nociceptive terminals can be activated by endocannabinoid release in a retrograde fashion and decrease the release of neurotransmitters such as GABA and glutamate. *Interestingly, the analgesic effecs of PAG stimulation is blocked if CB1 antagonists are administered* highlighting the importance of endocannabinoids in descending control of pain transmission. + +-- + +## 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 opioids + +- 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 + + + diff --git a/somatosensory.md b/somatosensory.md index d500609..dd8361f 100644 --- a/somatosensory.md +++ b/somatosensory.md @@ -40,6 +40,8 @@ Sensory systems: * Functional systems on one side of the body generally respond/control the other side of the body +Somatic sensation. The sense of self. The where and also partially what of being a self within a spatiotemporal domain of reference. The sense of being one. Being one. One. An animal entity's core. + --- @@ -187,7 +189,7 @@ 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) +: piezoelectric ceramics (Lead zirconate titanate or PZT Pb[Zr~x~ Ti~1~-x ]O~3~ ) and single crystal materials (gallium phosphate, quartz, tourmaline) - piezo for mechanical stress @@ -345,16 +347,21 @@ pacinian corpuscle ## Activity patterns in different mechanosensory afferents while Braille is read -
Neuroscience 5e Fig. 9.6
+
Neuroscience 6e/5e Fig. 9.6; from Phillips 1990
Note: -Each dot represents an action potential recorded in a single mechanosensory afferent fiber. +Each of the four raster plots show extracellular recordings from single mechanosensory afferent fibers. Each dot represents the time (x axis) in which an action potential occured as a pattern of braille dots was moved across the finger. The pattern was then displaced a small distance (relative to tip of finger) and the recording was made again, being repeated numerous times to give the y axis for each plot. 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 + +Actually original work done in macaque monkey (Johnson1981, J Physiol). Rotating drum braille pattern stimulator. + + + --- ## Differences in mechanosensory discrimination across the body surface @@ -697,451 +704,3 @@ Note:
Neuroscience 5e Fig. 9.12
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 - - - - -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 perception involves activation of specialized neurons (not just mechanoreceptors) - -* 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: - -Scheme for transcutaneous nerve recording - - ---- - -## 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 - -
-
- -* 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 - -
- -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: - - - ---- - -## Nociceptive component in the ventral posterior 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
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. Soldiers wounded in battle feel less pain than if one gets the same injury at home -* Pain can be subjective. Depends on context. -* 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 - -
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. CB1 on presynaptic terminals of dorsal horn nociceptive terminals can be activated by endocannabinoid release in a retrograde fashion and decrease the release of neurotransmitters such as GABA and glutamate. *Interestingly, the analgesic effecs of PAG stimulation is blocked if CB1 antagonists are administered* highlighting the importance of endocannabinoids in descending control of pain transmission. - --- - -## 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 opioids - -- 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 - - - diff --git a/vision1.md b/vision1.md index acbd78f..c59e4e4 100644 --- a/vision1.md +++ b/vision1.md @@ -10,7 +10,7 @@ Note: ## Today’s learning goals -* Be able to identify the different parts of the eye and their functions +* Identify the major parts of eye and retinal anatomy 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 @@ -25,8 +25,7 @@ Note: Note: - ---- +-- ## Anatomy of the human eye video @@ -82,6 +81,10 @@ Contraction of ciliary muscle as a ring around the lens causes zonule fibers to Pupil has circular muscles that contract when pupil closes, and radial bands of muscles that contract when pupil dilates. +* Efferent pathway controlling the iris and ciliary muscle are via the Edinger-Westphal nucleus --> ciliary ganglion (parasympathetic, cranial nerve III, oculomotor nerve) --> ciliary muscle + * more on this in vision2 + + --- ## Myopia & Hyperopia @@ -138,10 +141,10 @@ genetic disorder, diabetes, surgery, long term steroid use, UV light ## 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 +* The retina is part of the central nervous system! +* Contains neural circuitry that converts photon 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 +* Surrounded on one side by pigmented epithelium which contains melanin that helps reduce backscattering of light. Also plays a key 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 @@ -153,7 +156,9 @@ neural tube—> CNS (and retina)
Public domain [commons.wikimedia](https://en.wikipedia.org/wiki/Neural_crest#/media/File:Neural_crest.svg)
-spiral ganglion neurons in cochlea are also from neural tube/CNS +* olfactory bulb mitral neurons (primary afferent neurons of olfactory system) are from neural tube (telencephalon) +* retinal ganglion neurons in retina (first order afferent neurons of visual system) are from neural tube (diencephalon) +* spiral ganglion neurons in cochlea (first order afferent neurons of auditory system) are also from neural tube --- @@ -162,28 +167,14 @@ spiral ganglion neurons in cochlea are also from neural tube/CNS Light travels through the retina to hit the photoreceptors in the photoreceptor layer
Neuroscience 5e Fig. 11.5
-
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. @@ -195,6 +186,17 @@ number of rods and cones vary across the retina. In the center where vision is b 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 @@ -202,6 +204,8 @@ high degree of convergence, together with more direct path in and near fovea (on * 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) +
Neuroscience 5e Fig. 11.5
+
[H. Kolb Webvision, med.utah.edu](http://webvision.med.utah.edu/book/part-i-foundations/gross-anatomy-of-the-ey/)
Neuroscience 5e Ch. 11
@@ -217,7 +221,7 @@ Note: * 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 +* Light absorption leads to **hyperpolarization** of the photoreceptor. This leads to less release of neurotransmitter to the post-synaptic cell Note: @@ -247,9 +251,9 @@ Note: --- -## cGMP gated Na⁺ channels are key +## cGMP gated cation channels are key -In the dark channels open due to cGMP binding. Na⁺ rushes in and cell is depolarized +In the dark channels open due to cGMP binding. Na^+^ and Ca^2+^ rushes in and cell is depolarized
Neuroscience 5e Fig. 11.8
@@ -267,7 +271,7 @@ the nucleotide cyclic guanosine monophosphate ## 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 mV or so +* cGMP gated cation channels in outer segment are open allowing ions to flow inside the cell. This leads to a resting potential of -40 mV 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 @@ -279,7 +283,7 @@ 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 +* 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 (photon absorbtion breaks a carbon double bond and switching from cis to trans configuration) 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 @@ -295,18 +299,21 @@ Note: Note: -Vertebrates typically have four cone opsins (LWS, SWS1, SWS2, and Rh2) +Four types of cone opsins in vertebrates (LWS, SWS1, SWS2, and Rh2) [from: https://en.wikipedia.org/wiki/Opsin](https://en.wikipedia.org/wiki/Opsin) +name | abbr | type | bandwidth | color | human gene +--- | --- | --- | --- | --- | --- long-wave sensitive | LWS | cone | 500–570 nm | green, yellow, red | OPN1LW "red" / OPN1MW “green" -short-wave sensitive 1 | SWS1 | cone | 355–445 nm | ultraviolet, violet OPN1SW "blue" -short-wave sensitive 2 | SWS2 | cone | 400–470 nm | violet, blue (extinct in therian mammals) -rhodopsin-like 2 | Rh2 | cone | 480–530 nm | green (extinct in mammals) -rhodopsin-like 1 (vertebrate rhodopsin) | Rh1 | rod | ~500 nm | blue-green OPN2 = Rho = human rhodopsin +short-wave sensitive 1 | SWS1 | cone | 355–445 nm | ultraviolet, violet | OPN1SW "blue" +short-wave sensitive 2 | SWS2 | cone | 400–470 nm | violet, blue (extinct in therian mammals) | +rhodopsin-like 2 | Rh2 | cone | 480–530 nm | green (extinct in mammals) | +rhodopsin-like 1 (vertebrate rhodopsin) | Rh1 | rod | ~500 nm | blue-green | OPN2 = Rho = human rhodopsin Melanopsin OPN4 -: circadian rhythms, pupillary reflex, and color correction in high-brightness situations +: circadian rhythms, pupillary reflex, and color correction in high-brightness situations +: expressed in a small fraction of retinal ganglion neurons distributed across retina therian mammals : giving birth to live young @@ -368,7 +375,7 @@ Tremendous amplification. Single photon hitting rhodopsin is estimated to activa ## Need to inactivate opsin signaling after a light flash * Rhodopsin kinase/arrestin– activated rhodopsin is phosphorylated by rhodopsin kinase, permitting the protein arrestin to bind to rhodopsin. **Prevents further activation of transducin**, thus ending the phototransduction cascade -* All-trans retinol gets shed, transported to pigment epithelium cells, changed to cis-retinol and reincorporated into opsin +* All-trans retinal gets shed, transported to pigment epithelium cells, changed to cis-retinol and then reincorporated into opsin Note: @@ -492,20 +499,16 @@ Cone response over in about 200 ms (with an overshoot of inward current), wherea *15-30 rod to bipolar cell convergence, reduces spatial resolution of rod system but increases light detection* + --- @@ -788,13 +791,13 @@ Note: --- -## ON and OFF RGCs +## ON and OFF bipolar cells
-* 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 +* RGC dendrites terminate in separate strata of the inner plexiform layer, forming selective synapses with different types of bipolar cells +* Bipolar cells do not use action potentials, but use graded (passive/electrotonic) potentials to release neurotransmitter * 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
@@ -804,6 +807,8 @@ Note: off center bipolars: AMPA receptors (sign conserving) on center bipolars: mGluR6 (sign inverting) +RGC dendrites: ON in sublamina A and OFF in sublamina B + +
Neuroscience 5e Fig. 11.18; y-axis is voltage
Note: -Explain distinction of graded potential vs. action potentials +graded potential vs. action potentials + +yaxis in plots is membrane potential middle panels are membrane potential/graded potential. Bottom is spikes/APs. @@ -887,26 +894,6 @@ Note: plus sign: sign conserving synapse minus sign: sign inverting synapse - - - --- ## Summary diff --git a/vision2.md b/vision2.md index 68fa45f..690c016 100644 --- a/vision2.md +++ b/vision2.md @@ -119,7 +119,7 @@ Other visual functional organization that is present at birth includes maps of o
-* There is an overlap in visual fields, such that most objects are seen by both eyes +* There is an overlap in visual fields, such that objects in the central visual field 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) @@ -194,6 +194,14 @@ Note: ## Laminar organization of the LGN +
+
+ +* 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 + +
+
Human LGN
[Brain Biodiversity Bank MSU, NSF](https://msu.edu/~brains/brains/human/coronal/montage.html)
@@ -208,19 +216,11 @@ Neurons in different layers receive 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: +parvocellular retinal ganglion cells : small dendritic trees, small receptive fields, used for high acuity form vision, color vision -what is parvo and magnocellular? Different subtypes of RGCs that we’ll cover more in just a minute… +magnocellular retinal ganglion cells : large dendritic trees, larger receptive fields, used for motion vision --- @@ -509,9 +509,7 @@ Torsten N. Wiesel Note: - ---- - + --- @@ -563,40 +554,6 @@ Note: Note: ---- - -## Subdivisions of the extrastriate cortex in the macaque monkey - -
Neuroscience 5e Fig. 12.16, Maunsell & Newsome 1987
- -
Neuroscience 5e Fig. 12.16, Felleman & Van Essen 1991
- - -Note: - -* extrastriate areas V2, V3, V4, MT -* - -V2 -: orientation, spatial frequency, and color like V1 -: secondary visual cortex -: feedforward connections from V1 (direct and via the pulvinar) -: feedback to V1 -: sends connections to V3, V4, and V5 -: binocular disparity -: illusion contours -: some attentional modulation - -V3 -: global motion - -MT -: middle temporal area -: neurons responding selectively to direction of moving edge, but don't care about color - -V4 -: neurons that selectively respond to color, but don't care about direction of its movement - --- ## Organization of the dorsal and ventral visual pathways @@ -617,6 +574,39 @@ V4 Note: +-- + +## Subdivisions of the extrastriate cortex in the macaque monkey + +
Neuroscience 5e Fig. 12.16, Maunsell & Newsome 1987
+ +
Neuroscience 5e Fig. 12.16, Felleman & Van Essen 1991
+ + +Note: + +* extrastriate areas V2, V3, V4, MT + +V2 +: orientation, spatial frequency, and color like V1 +: secondary visual cortex +: feedforward connections from V1 (direct and via the pulvinar) +: feedback to V1 +: sends connections to V3, V4, and V5 +: binocular disparity +: illusion contours +: some attentional modulation + +V3 +: global motion + +MT +: middle temporal area +: neurons responding selectively to direction of moving edge, but don't care about color + +V4 +: neurons that selectively respond to color, but don't care about direction of its movement + --- @@ -661,7 +651,7 @@ prosopagnosia: face blindness. Our patient Dr. P from earlier? --- -## Weird visual defects +## Defects due visual cortex damage * Cerebral achromatopsia * Do not see in color- only black and white. Lesions in extrastriate cortex areas such as V4/ventral stream