diff --git a/basal-ganglia.md b/basal-ganglia.md index 4cfb977..4395f86 100644 --- a/basal-ganglia.md +++ b/basal-ganglia.md @@ -1,5 +1,6 @@ ## Modulation of movement by the basal ganglia +
@@ -13,18 +14,27 @@
+ +
+ +
+ Note: * 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): + - also with "non-motor" circuits (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 (wordnet, verb) +: vary the frequency, amplitude, phase, or other characteristic of (electromagnetic waves) +: adjust the pitch, tone, or volume of +: regulate -- @@ -51,20 +61,23 @@ Note: We will discuss… -* Basal Ganglia components -* Other disinhibition loops +* basal ganglia components +* inhibiting inhibition, "disinhibition" loops +* relevant neurotransmitter receptor signaling systems --- ## Corpus striatum -* Corpus striatum ('striped body') contains two nuclei– the caudate and putamen +* Corpus striatum ('striped body') contains two portions– the caudate and putamen * Function as the input zones for the basal ganglia * Most regions of the cortex project to the striatum. Prominent innervation from the associational cortical areas of the frontal and parietal lobes. Collectively called the corticostriatal pathway -* Neurons in striatum that receive corticostriatal input are called medium spiny neurons. Large dendritic trees, integrate information form a variety of structures +* Neurons in striatum that receive corticostriatal input are called **medium spiny neurons**. Large dendritic trees, integrate information from a variety of structures Note: +Caudate and putamen separated by white matter (internal capsule) in mid to caudal coronal view sections of the brain + -- @@ -76,6 +89,7 @@ Most cortical areas project to the striatum, except for primary auditory cortex Note: +Axonal input to the striatum originates from all over the cortex, but with little input from the primary sensory areas of visual and auditory cortex --- @@ -98,6 +112,12 @@ basal forebrain nuclei : roles in attention, wakefulness, REM sleep +fornix +: latin for "arch" +: output of hippocampus +: hippocampal commissure in mid region +: mammillary body at one end of this tract + --- ## Anatomy of the basal ganglia: caudate and putamen @@ -254,8 +274,9 @@ Note: Recall that the superior colliculus contains upper motor neurons concerned with eye movements -[http://www.youtube.com/watch?v=P6uTlnyNaTs](http://www.youtube.com/watch?v=P6uTlnyNaTs) +Record spikes with microelectrodes inserted into caudate and SNr and superior colliculus. +Count spikes surrounding eye movement period, y axis is count (histogram), x axis is time (100s of msec to sec) --- @@ -266,7 +287,7 @@ Recall that the superior colliculus contains upper motor neurons concerned with Note: -Overall excitatory by disinhibiting the upper motor neurons in the cortex (promotes movement, initiation of motor commands) +Overall effect of direct pathway on neocortex is excitatory by disinhibiting the upper motor neurons in the cortex (promotes movement, initiation of motor commands) --- @@ -290,7 +311,7 @@ Note: Note: -Overall inhibitory. Serves to modulate the disinihibitory actions of the direct pathway +Overall effect on upper motor neuron activity in neocortex is inhibitory. Serves to modulate the disinihibitory actions of the direct pathway --- @@ -576,7 +597,7 @@ Note: Function of huntingtin gene product unclear. [Null expression in mice lethal](https://doi.org/10.1016%2F0092-8674%2895%2990542-1) -upregulates brain derived neurotrophic factor (BDNF). evidence that [huntingtin interacts with 19 different proteins](https://doi.org/10.1016%2FS0968-0004%2803%2900168-3) +evidence that [huntingtin interacts with 19 different proteins](https://doi.org/10.1016%2FS0968-0004%2803%2900168-3) @@ -643,7 +664,7 @@ https://www.youtube.com/watch?v=OjM9Gl_MLyQ * Basal ganglia are also involved in loops that modulate non-motor behaviors * Work in a similar way to suppress outputs * The limbic loop regulates emotional behavior and motivation -* Tourette’s may be a problem with limbic loop (no longer have inhibitions about language?) +* Tourette’s may be a problem with limbic loop (no longer have inhibitions with language selection?) * Drugs of abuse affect dopamine release * Schizophrenia, may be due to aberrant activity in limbic and prefrontal loops resulting in hallucinations disordered cognition diff --git a/limbic.md b/limbic.md index 0446dfa..484357a 100644 --- a/limbic.md +++ b/limbic.md @@ -12,7 +12,7 @@ Note: emotion : a natural instinctive state of mind deriving from one's circumstances, mood, or relationships - : instinct +: instinct viscera : of or relating to viscera @@ -49,7 +49,7 @@ mild traumatic brain injuries and mental health. https://en.wikipedia.org/wiki/Medical_and_mental_health_of_Abraham_Lincoln -http://www.theatlantic.com/magazine/archive/2005/10/lincolns-great-depression/304247/ +https://www.theatlantic.com/magazine/archive/2005/10/lincolns-great-depression/304247/ --- @@ -62,8 +62,6 @@ http://www.theatlantic.com/magazine/archive/2005/10/lincolns-great-depression/30 Note: -Visceral -: relating to deep inward feelings rather than intellect -- @@ -157,7 +155,6 @@ Note: * Phillip Bard / Walter Hess, early 1900s. Conducted seminal studies that determined the hypothalamus is a critical center for coordination of both the autonomic and somatic components of emotional behavior -
Cat sham rage
Neuroscience 5e Fig. 29.1, LeDoux *Handbook of Physiology* 1987
@@ -171,6 +168,8 @@ Connection from ventral hypothalamus to midbrain needs to be present to elicit s Bard suggested that emotional behaviors are often directed towards self-preservation (point also made by Charles Darwin). + + --- ## Affective attack expression @@ -212,6 +211,7 @@ Note: Note: +excellent article about [emotional control](https://kids.frontiersin.org/article/10.3389/frym.2017.00069) --- @@ -475,6 +475,10 @@ Feelings may be a kind of emotional working memory. Containing both immediate co Note: + + + + -- ## Emotions are lateralized diff --git a/motor1.md b/motor1.md index 6aa1783..4266b0d 100644 --- a/motor1.md +++ b/motor1.md @@ -6,6 +6,10 @@ * Allows us to maintain balance and posture, move our body, limbs, eyes, tongue & communicate through speech +
+ +
+ Note: @@ -404,7 +408,6 @@ This table summarizes the somatosensory afferents types, and variety in their fu Tab. 1 after Rosenzweig 2005 --- --- ## The stretch reflex diff --git a/motor2.md b/motor2.md index 4ca3e38..dfa72b0 100644 --- a/motor2.md +++ b/motor2.md @@ -2,6 +2,9 @@
Neuroscience 5e Fig. 16.1
+
+ +
Note: @@ -140,11 +143,15 @@ Reticular formation neurons functions : cardiovascular (regulate output of nucleus ambiguous) and respiratory control (ventrolateral medulla) : sensory motor reflexes : coordination of eye movements -: regulation of sleep and wakefulness +: regulation of sleep and wakefulness : coordination of limb and trunk movments +: netlike, difficult to recognize distinct neuronal clusters +: does not have a uniform function as thought classically + * rostral portions (mesencephalic and pontine) of reticular formation modulate forebrain activity (Moruzzi and Magoun EEG Clin. Neurophys 1949) * cholinergic neurons (superior cerebellar peduncle) and noradrenergic neurons (locus coeruleus) and serotonergic neurons (raphe nuclei) + * "reticular activating system" * caudal portions involved in premotor coordination of lower somatic and visceral motor neuron pools feedforward postural control. stabilization during ongoing movements. @@ -163,6 +170,10 @@ feedforward postural control. stabilization during ongoing movements. Note: +* rostral portions (gold, mesencephalic and pontine) of reticular formation modulate forebrain activity (Moruzzi and Magoun EEG Clin. Neurophys 1949) + * cholinergic neurons (superior cerebellar peduncle) and noradrenergic neurons (locus coeruleus) and serotonergic neurons (raphe nuclei) + * "reticular activating system" +* caudal portions (red) involved in premotor coordination of lower somatic and visceral motor neuron pools --- @@ -275,8 +286,6 @@ Somatotopic representation across S1 and M1 Wilder Penfield 1940s -Link not working (shockwave director needed) -[http://www.pbs.org/wgbh/aso/tryit/brain/probe.html](http://www.pbs.org/wgbh/aso/tryit/brain/probe.html) --- @@ -325,6 +334,13 @@ most corticobulbar inputs (except lower face and tongue) terminate bilaterally. maps: muscle, movement sequences, intention? +H. Kuypers experiments +: rhesus monkey +: test function of direct vs indirect pathways from motor cortex +: transect spinal cord at medulla, leaving indirect path to spinal cord via brainstem reticular formation +: stand walk run climb intact with proximal and axial muscles, but precise distal limb usage with hands impaired (e.g. can't pick up food objects). Independent use of fingers doesn't return + + --- ## The corticospinal and corticobulbar tracts @@ -335,7 +351,7 @@ Note: Corticobulbar is yellow, corticospinal in red. Note that most corticospinal axons cross the midline in the caudal medulla. Corticobulbar is for facial muscles. -internal capsue to cerebral peduncle at base of midbrain to scatter among pontine fibers and basal pontine gray matter then coalesce at ventral surface medulla to form medullary pyramids +internal capsule to cerebral peduncle at base of midbrain to scatter among pontine fibers and basal pontine gray matter then coalesce at ventral surface medulla to form medullary pyramids *corticobulbar axons terminate primaryly on local circuit neurons rather than brainstem motor neurons* @@ -416,7 +432,7 @@ right shows the response of a thumb muscle by a fixed latency to the single spik Note: -*stimualtion that more roughly corresponds to volitional movemetns (hundreds of ms to sec), Graziano 2005.* With these stimus, movements are sequentiall distrubted across mutliple joints and purposeful. +*stimualtion that more roughly corresponds to volitional movements (hundreds of ms to sec), Graziano 2005.* With these stimus, movements are sequentiall distrubted across mutliple joints and purposeful. Coordinated movements of hand and mouth after stimulation near the middle of the precentral gyrus towards head (**like for eating**). @@ -428,7 +444,7 @@ Blue crosses are start positions, curved black lines are final positions are red ## Directional tuning of an upper motor neuron in the primary motor cortex -
Monkey trained to move joystick in response to light
Neuroscience 5e Fig. 17.8
+
Monkey trained to move joystick in response to light
Neuroscience 5e Fig. 17.8, adapted from Georgeopoulos et al, 1986
Note: @@ -439,13 +455,15 @@ Note:
Activity of a single neuron recorded in motor cortex -is dependent on the direction of the future movement -
Neuroscience 5e Fig. 17.8
+is dependent on the direction of the future movement. +Red line indicates movement onset, blac +
Neuroscience 5e Fig. 17.8, adapted from Georgeopoulos et al, 1986<
Note: -Notice that the neuron is broadly tuned, even with this colored shading. +raster plots, black dashes are individal spikes from one recorded neuron, 5 trials in each direction depicted +Notice that the neuron is broadly tuned to a wide range of angles --- diff --git a/neurophysiology1.md b/neurophysiology1.md index a764257..41de7e0 100644 --- a/neurophysiology1.md +++ b/neurophysiology1.md @@ -838,7 +838,10 @@ Hodgkin and Huxley, Nature 1939 squid giant axon Image adapted from Principles of Neurobiology, L. Luo Garland Fig 2-19 which in turn adapted from Nature 1939. -Capacitance (farads) is the ability of a body to store an electrical charge. Any object that can be electrically charged exhibits capacitance. Dielectric materials. Storage of electrical energy temporarily in an electric field. **Unlike a resistor, an ideal capacitor does not dissipate energy. Instead, a capacitor stores energy in the form of an electrostatic field between its plates.** +Capacitance (farads) +: is the ability of a body to store an electrical charge. Any object that can be electrically charged exhibits capacitance. Dielectric materials. Storage of electrical energy temporarily in an electric field. **Unlike a resistor, an ideal capacitor does not dissipate energy. Instead, a capacitor stores energy in the form of an electrostatic field between its plates.** +: 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 + --- diff --git a/neurophysiology2.md b/neurophysiology2.md index 83f12b9..fd1ac52 100644 --- a/neurophysiology2.md +++ b/neurophysiology2.md @@ -159,6 +159,10 @@ If you command that the cell membrane potential be hyperpolarized, you get very This is because the cell membrane essentially acts as a parallel RC circuit where a resistor and a capacitor are connected in parallel and to a constant current source. Ion channels are resistors, lipid bilayer with the extracellular and intracellular environments act as capacitor, storing charge in the form of ions accumulating near the surface of the membrane. When a switch is turned on in an RC circuit current flows from the battery to the capacitor until the capacitor is charged to a voltage that is same as the battery. +: 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 + + + However when Hodgkin and Huxley depolarized the membrane, a transient inward current occurs followed by a slow outward current. diff --git a/neurotransmitters1.md b/neurotransmitters1.md index e835df1..83fafb2 100644 --- a/neurotransmitters1.md +++ b/neurotransmitters1.md @@ -1,16 +1,24 @@ -## Neurotransmitter receptors +## Neurotransmitters and receptors
-* Neurotransmitter receptors are embedded in the plasma membrane of the post-synaptic cell and are always one of the following: - 1. ion channels (**ionotropic** or 'ligand-gated' ion channel) - 2. receptors that interface with separate ion channels (**metabotropic**, or G-protein coupled receptors) -* Neurotransmitter receptor activation following ligand (neurotransmitter) binding results in the opening of ion channels and ionic flux. This ion flux is the postsynaptic current (or 'end plate' current for a muscle cell) -* These postsynaptic currents result in depolarization or hyperpolarization of the membrane potential (postsynaptic potential or 'end plate' potential) depending on the **types of ions** flowing through the channel pores and the ions' respective **electro-chemical driving forces** +* Neurotransmitters, ligands for receptors; >100 molecules + * small molecule transmitters + - acetylcholine (ACh), amino acids, biogenic amines, purines + * neuropeptides + - various polypeptides, 3–36 amino acids in length +* Neurotransmitter receptors + 1. **ionotropic**, 'ligand-gated' ion channels + 2. **metabotropic**, G-protein coupled receptors that modulate separate ion channels
+ +
+ +
+ Note: Diving a bit deeper into the structure and function of neurotransmitter (NT) receptors now... @@ -54,7 +62,9 @@ The ionotropic receptors are the ones you’ve probably seen in our synaptic dia Note: -Metabotropic transmitter receptors are G-protein coupled receptors, also known as seven-transmembrane domain receptors in you cell biology courses. +retinal vision reference for metabotropic modulation of ion channel function + +Metabotropic transmitter receptors are G-protein coupled receptors, also known as seven-transmembrane domain receptors in your cell biology courses. * neurotransmitter binds * g protein binds and is activated @@ -71,7 +81,7 @@ Effector enzymes for activated G-proteins include: * All G-protein receptor activations lead to downstream second messsaging (cAMP, diacylglycerol, IP3) --> protein kinases, Ca2+ --> leading to phosphorylation state changes including... ion channels * Three amplification steps here! (receptor production of G proteins, adenylyl cyclase production of cAMP, protein kinase substrate phosphorylation). Source signal amplification. -* 3% of our genome is codes for protein phosphorlation state genes (500 protein kinases and 200 protein phosphatases) +* 3% of our genome is codes for protein phosphorylation state genes (500 protein kinases and 200 protein phosphatases) * cAMP dependent protein kinases (PKA) * Ca^2+^ - calmodulin depedent protein kinase type II (CaMKII predominant in neurons, most abundant protein component of the post synaptic density) * Protein kinase C (PKC)- activated by Ca^2+ (moves PKC from cytosol to membrane) and diacylglycerol (DAG) and then phosphorylates substrates @@ -105,6 +115,78 @@ nACh Receptors are ionotropic or ligand-gated receptors where the ligand is ACh stochastic : having a random probability distribution or pattern that may be analyzed statistically but may not be predicted precisely +--- + +## nAChR + +* Pentamer- 5 subunits to make a pore. Selective for cations + - Pore diameter 10x greater than voltage-gated Na⁺ channels (3 nm vs 0.3 nm) +* Nicotine mimics ACh to stimulate receptor, an agonist +* nicotinic ACh receptors (nAChR) produce excitatory postsynaptic potentials (EPSPs or EPPs) +* Many toxins specifically bind and block nAChR; these are antagonists + * alpha-bungarotoxin (snake venom)– binds to alpha subunit of nAChR very tightly and prevents ACh from activating it + +Note: + +As we’ve shown in our examples earlier the nAChR receptor is a non-selective cation channel. Or another way to think of it is that it is selective for cations. + +5 subunits + +*nAChR permeable to Na+, K+, and Ca2+* + +In physiological solution, calcium flux estimated to be 2% of total current through nAchR. For comparison calcium flux is estimated to be 7% of the current in the voltage gated L-type calcium ion channel. But with high density clustering of many nAchRs at muscle end plate synapses, total calcium flux through these channels could influence the local environment significantly https://doi.org/10.1523/JNEUROSCI.10-10-03413.1990 + +This Ca^2+^ permeability depends on subunit composition of the nAchR pentamer. mammalian α9α10 receptors receptors show higher calcium ion selectivity (important function in cochlear hair cells) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4245820/ + + + + +from [#Picciotto:2000]: +>some subtypes of nAChR in the brain (those containing the b2 subunit) are located diffusely throughout the membrane of the neuron, with no obvious concentration at the synaptic junction (Hill et al. 1993). + +a number of alpha and beta subunits have expression throughout brain (medulla, superior colliculus, cortex, beta2 subunit expression 'very high' in thalamus). Only alpha3 KO mice have high mortality [#Picciotto:2000]. + +[#Picciotto:2000]: Picciotto, M. R., Caldarone, B. J., King, S. L., and Zachariou, V. (2000). Nicotinic receptors in the brain. Links between molecular biology and behavior, Neuropsychopharmacology, 22(5), 451-65. PMID 10731620 + +Low (nM) concentrations of nicotine are found in the blood of moderate smokers (Henningfield et al. 1983). These are sufficient to enhance excitatory transmission in cultures of neurons from the medial habenula or the hippocampus (Gray et al. 1996; McGehee et al. 1995) [#Picciotto:2000] + +Many effects of nicotine probably through presynaptic or preterminal nAChRs instead of through postsynaptic AChRs (Léna et al. 1993; Marshall et al. 1997; McGe- hee et al. 1995; Summers and Giacobini 1995; Vidal and Changeux 1993; Wonnacott et al. 1990; Yang et al. 1996) [#Picciotto:2000] + + +Most effects of nicotine go through nAChR + + + +--- + +## Structure of the nACh receptor + +* 5 subunits come together to make a pore +* Each subunit has 3-4 membrane spanning domains +* In muscles the receptor has 2α, β, δ, γ, ε subunits. The α subunits bind ACh, both need to be bound for channel to open. α subunits also binds bungarotoxin and nicotine +* Multiple isoforms for each subunit, depending on which isoform is in channel get different properties +* In neurons its slightly different. 5 subunits 3α:2β. Bungarotoxin only inhibits muscle nACh receptors + +
Neuroscience 5e Fig. 6.3
+ +
Neuroscience 2e 2001
+ + +Note: + +The alpha subunits bind ACh. + +Muscle nAChR +* Pentamers of 2α1, β1, γ, δ in fetal mammals vs. 2α1, β1, δ, ε in adult mammal +* ACh, nicotine, curare, and bungarotoxin binding sites are on the α1 subunits + + +Changes in subunit composition during development. + +curare is a competitive antagonist. + --- @@ -466,11 +548,11 @@ Note:
* How does a neuron integrate all the information it is getting? -* 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 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 +* For many neurons the axon hillock is where the decision to initiate an action potential is made. Contains a high density of voltage dependent Na^+^ channels; membrane with the lowest threshold +* Local state of the cell is sensed at the axon hillock. The bioelectrical state of the cell is a function of time, the combination of all the EPSPs and IPSPs going on at any moment +* The combined sub- or supra-threshold synaptic potential waveforms spread passively to the soma and axon hillock +* Temporal summation-- consecutive signals within a period of time are added together +* Spatial structure of the dendrites determines the degree by which a synaptic potential current decreases as it spreads passively. Summation of inputs is easier on same dendritic branch than on different branches @@ -481,10 +563,10 @@ Note: * 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) +: 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 +: 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) @@ -503,17 +585,3 @@ console.log( 1 - Math.E ** -1)
Neuroscience 5e Animation 5.2
- - diff --git a/neurotransmitters2.md b/neurotransmitters2.md index 4f9d80b..c896e4c 100644 --- a/neurotransmitters2.md +++ b/neurotransmitters2.md @@ -1,19 +1,23 @@ ## Neurotransmitters * More than 100 different molecules -* Two main types– - * small molecule neurotransmitters +* Two main types + * small molecule neurotransmitters - acetylcholine, amino acids, monoamines, purines * peptide neurotransmitters - polypeptides, 3–36 amino acids in length and often derived from longer polypeptides +
+ +
+ Note: We already defined what a neurotransmitter is. It is a substance that must be present inside a presynaptic neuron, it’s release must be dependent on calcium flux from an AP, and it must have specific receptors on the postsynaptic neuron. Abnormalities of neurotransmitter function contributes to wide range of neurological diseases and psychiatric disorders -two types: very small molecule and big molecule neurotransmitters. +two types: small and big molecule neurotransmitters. --- @@ -31,8 +35,13 @@ Note: Not expected to know chemical formulas for any neurotransmitters -*Most of which share a hydroxylated benzene ring* -*Catechol, also known as pyrocatechol or 1,2-dihydroxybenzene, is an organic compound with the molecular formula C6H4(OH)2* +biogenic amines or monoamines + +catecholamines : share a hydroxylated benzene ring +Catechol +: also known as pyrocatechol or 1,2-dihydroxybenzene +: is an organic compound with the molecular formula C6H4(OH)2 + --- @@ -55,9 +64,9 @@ Note:
-* Synthesis can occur - * at the soma (neuropeptides) - * at synaptic terminals (small molecule transmitters) +* Synthesis occurs + * at the soma (for neuropeptides) + * at the synaptic terminals (for small molecule transmitters) * Vesicle packaging– requires specific transporters on vesicle membrane. There are small clear-core vesicles (ACh and amino acids) and large dense-core (neuropeptides). Biogenic amines can be in either vesicle type.
@@ -159,7 +168,7 @@ TODO: * spatial location of release -Release– small clear-core vesicles release fast, large dense-core vesicles take more effort. Location in synapses is different +Release– small clear-core vesicles release fast, large dense-core vesicles take more input energy, more stimulation. Location of vesicle types in synaptic terminal is different --- @@ -237,7 +246,8 @@ VAChT packs ACh into vesicles using the acidic vesicle's proton gradient. The gr
-* Sarin and Soman: toxic irreversible AChE inhibitors. Also known as “nerve gases” for use in chemical warfare + +* Sarin and Soman: toxic AChE inhibitors. Also known as “nerve gases” for use in chemical warfare * Designed to dispersed as a vapor cloud or spray, which allows their entry into the body through skin contact or inhalation. Drug quickly penetrates into bloodstream and is distributed to all organs, including the brain * Symptoms: profuse sweating and salivating, uncontrollable vomiting, gasping for breath, convulsing, and gruesome death. These are due to rapid accumulation of ACh and overstimulation of cholinergic synapses throughout the CNS and PNS. Death occurs through asphyxiation due to paralysis of the muscles of the diaphragm @@ -250,6 +260,16 @@ Note: parasympathetic (Ach) vs sympathetic (norep) + +organophosphate functional group +: phosphate esters +: O=P(OR)3 +: diverse range of natural biomolecular forms (dna, rna, atp) +: many synthetic agents. insecticides, herbicides, flame retardants, plasticizers. And nerve agents (like the insecticides) for chemical warfare + +Larsen, Ashley; Gaines, Steven (2017-08-29). "Agricultural pesticide use and adverse birth outcomes in the San Joaquin Valley of California". Nature Communications. 8 (1): 302. doi:10.1038/s41467-017-00349-2. ISSN 2041-1723. PMC 5575123. PMID 28851866. + + -- ## Acetylcholine synthesis video summary diff --git a/neurotransmitters3.md b/neurotransmitters3.md index 7ab179c..2308258 100644 --- a/neurotransmitters3.md +++ b/neurotransmitters3.md @@ -1,11 +1,31 @@ -## Cholinergic receptors -* Best studied– the nicotinic ACh receptor (nAChR) +## Neurotransmitter receptors + +
+
+ +* Neurotransmitter receptors + 1. **ionotropic**, a 'ligand-gated' ion channels + 2. **metabotropic**, a G-protein coupled receptors that modulate separate ion channels +* Neurotransmitter receptor activation following ligand (neurotransmitter) binding results in the opening of ion channels and ionic flux. This ion flux is the postsynaptic current (or 'end plate' current for a muscle cell) +* These postsynaptic currents result in depolarization or hyperpolarization of the membrane potential (postsynaptic potential or 'end plate' potential) depending on the **types of ions** flowing through the channel pores and the ions' respective **electro-chemical driving forces** + +
+ +
+ +
+ +--- + +## nAChR + * Pentamer- 5 subunits to make a pore. Selective for cations -* Nicotine can mimic ACh to stimulate receptor, this is called an agonist. Most effects of nicotine go through this receptor -* nACh receptors produce EPSPs -* Many toxins specifically bind to and block nicotinic receptors called antagonists -* alpha-bungarotoxin (snake venom)– binds to alpha subunit of nAChR very tightly and prevents ACh from activating it + - Pore diameter 10x greater than voltage-gated Na⁺ channels (3 nm vs 0.3 nm) +* Nicotine mimics ACh to stimulate receptor, an agonist +* nicotinic ACh receptors (nAChR) produce excitatory postsynaptic potentials (EPSPs or EPPs) +* Many toxins specifically bind and block nAChR; these are antagonists + * alpha-bungarotoxin (snake venom)– binds to alpha subunit of nAChR very tightly and prevents ACh from activating it Note: @@ -24,7 +44,7 @@ This Ca^2+^ permeability depends on subunit composition of the nAchR pentamer. m from [#Picciotto:2000]: >some subtypes of nAChR in the brain (those containing the b2 subunit) are located diffusely throughout the membrane of the neuron, with no obvious concentration at the synaptic junction (Hill et al. 1993). - +https://us02web.zoom.us/j/86077044985?pwd=USt1SGJ6Wm1VSitncWlmTjgzSmZrQT09 a number of alpha and beta subunits have expression throughout brain (medulla, superior colliculus, cortex, beta2 subunit expression 'very high' in thalamus). Only alpha3 KO mice have high mortality [#Picciotto:2000]. [#Picciotto:2000]: Picciotto, M. R., Caldarone, B. J., King, S. L., and Zachariou, V. (2000). Nicotinic receptors in the brain. Links between molecular biology and behavior, Neuropsychopharmacology, 22(5), 451-65. PMID 10731620 @@ -34,39 +54,37 @@ Low (nM) concentrations of nicotine are found in the blood of moderate smokers ( Many effects of nicotine probably through presynaptic or preterminal nAChRs instead of through postsynaptic AChRs (Léna et al. 1993; Marshall et al. 1997; McGe- hee et al. 1995; Summers and Giacobini 1995; Vidal and Changeux 1993; Wonnacott et al. 1990; Yang et al. 1996) [#Picciotto:2000] +Most effects of nicotine go through nAChR + ---- +-- ## Structure of the nACh receptor * 5 subunits come together to make a pore * Each subunit has 3-4 membrane spanning domains * In muscles the receptor has 2α, β, δ, γ, ε subunits. The α subunits bind ACh, both need to be bound for channel to open. α subunits also binds bungarotoxin and nicotine -* Multiple isoforms for each subunit, depending on which isoform is in channel get different properties -* In neurons its slightly different. 5 subunits 3α:2β. Bungarotoxin only inhibits muscle nACh receptors -
Neuroscience 5e Fig. 6.3
+
Neuroscience 5e Fig. 6.3
+ +
Neuroscience 2e 2001
+ Note: The alpha subunits bind ACh. ---- - -## Muscle nAChR - +Muscle nAChR * Pentamers of 2α1, β1, γ, δ in fetal mammals vs. 2α1, β1, δ, ε in adult mammal * 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) +* Multiple isoforms for each subunit, depending on which isoform is in channel get different properties -
Neuroscience 2e 2001
+In neurons its slightly different. 5 subunits 3α:2β. Bungarotoxin only inhibits muscle nACh receptors -Note: - Changes in subunit composition during development. curare is a competitive antagonist. diff --git a/pain.md b/pain.md index 1c85aa4..66e803a 100644 --- a/pain.md +++ b/pain.md @@ -3,11 +3,15 @@ * 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: +nociceptive +: of or related to pain arising from stimulation of nerve fibers + 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) @@ -53,8 +57,8 @@ 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 +* Capsaicin receptors are nonselective cation channels opened by heat, low pH, and capsaicin (the hot in hot peppers)[^Caterina1997] +* Mice without TRPV1 (VR1) have impaired sensitivity to pain. Can drink capsaicin as if it were water[^Caterina2000]
Neuroscience 5e Box10A
Neuroscience 5e Box10A
@@ -62,6 +66,10 @@ Note: Note: +[^Caterina1997]: Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature. 1997 Oct 23;389(6653):816-24. doi: 10.1038/39807. PMID: 9349813. + +[^Caterina2000]: Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Petersen-Zeitz KR, Koltzenburg M, Basbaum AI, Julius D. Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science. 2000 Apr 14;288(5464):306-13. doi: 10.1126/science.288.5464.306. PMID: 10764638. + 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). @@ -128,7 +136,7 @@ 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 +* Due to the release of substances from the damaged cells (e.g. prostaglandins, bradykinin, histamine, serotonin, ATP) that increase sensitivity by interacting with the nociceptor ion channels (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 @@ -148,7 +156,7 @@ central sensitization (pain memories)-- is a CNS disease, not a symptom of other 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. +More fMRI brain activation (amplitude and size of activation) 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) @@ -167,10 +175,10 @@ Most interact directly with the receptors or ion channels of the nociceptive fib **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. +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, serotonin, prostaglandins, neucleotides, NGF, cytokines (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 @@ -181,8 +189,9 @@ nociceptive * 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. +* 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 that cross the midline in the same segment and then go up to the brain. Note: @@ -313,13 +322,14 @@ 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 + - 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 +* Why? 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. +e.g. prostaglandins lower threshold by phosphorylation of TTX resistant sodium channels. TrPV1 receptor potentiations. @@ -424,15 +434,27 @@ endogenous opioids 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 +- 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. +- children are not placebo reactors less than 10 yr old. +- acupuncture works likely as a placebo (needle can be stuck anywhere). -- hypnosis (80% of people can be hypnotized) -- 35% of people are placebo reactors +Placebo (wn -over) +: an innocuous or inert medication; given as a pacifier or to the control group in experiments on the efficacy of a drug +Placebo +: not well defined, especially trying to test therapeutic effects of non-pharmacological treatments (acupuncture) +: part of *every* treatment. Human touch, interaction, care compared with isolation and pain + +Musial Front Neurosci 2019: https://doi.org/10.3389/fnins.2019.01110 +Vincent and Lewith J R Soc Med. 1995: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1295163/ + + + + + +
+ Note: Today we will focus on the somatic sensory system also called the somatosensory system. @@ -48,13 +47,56 @@ Somatic sensation. The sense of self. The where and also partially what of being ## Overview of somatic sensory system -* Specific receptor neurons located in skin or joints receive stimuli +* Specific receptor neurons located in skin, muscle, 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: +--- + + +## Dermatomal segments + +...from the embryonic somites + +
Human embryo at three to four weeks
24d, 2.6mm, 19somites; 26d, 3.6mm, 25somites; *Dev Anatomy* Arey 1954
+ +
Human embryo at four to six weeks
28d, 5mm; 35d, 8mm; 42d, 12mm; *Developmental Anatomy* Arey 1954
+ +Note: + +somites, metameres +: mesoderm separates into localized structures called somites +: origin of the dermatomal segments +: happens around neural tube closure, third week of gestation in human +: develop in rostral to caudal direction +: positioning regulated by the highly conserved hox genes +: formed every 90 minutes in chick embryo +: chicken 50 somites, mice 65 somites, snakes 500, human 39-44 +: somites become the dermatomes and myotomes that make up the vertebrae, tissue regions of skin and muscle + + +Developmental Anatomy 1924, 1954 Arey +p. 98 +> Fig. 74 Human embryos of twenty-fout and twenty-six days, viewed from left side. A, Atwell embryo of 26 mm, with ninetween somites (Streeter; x23); B, 3.6mm, embryo with twenty-five somites (x16) + +Developmental Anatomy 1924, 1954 Arey +p. 99 +> Fig. 75 Human embryos of four and five weeks, viewed from the left side. A At 5 mm. B, at 8 mm +> Fig. 76. Human embryo of six weeks (12 mm). viewed from the right side. + +-- + +## Dermatomal segments of the body + +
the human dermatome
Grant, *An atlas of anatomy* 1962 [Public Domain](https://en.wikipedia.org/wiki/Public_domain)
+ +Note: + +image is public domain. Grant, John Charles Boileau - An atlas of anatomy, / by regions 1962 --- @@ -71,7 +113,9 @@ In this inset you see both mechanosensory and pain sensitive fibers connected to --- -## Various types of somatic sensory receptors +## Somatic sensory receptors + +Can vary characteristically by * Functions– pain, temperature, touch, and proprioception * Morphologies– free nerve endings or encapsulated @@ -113,17 +157,6 @@ The slowest ones are… Tab. 1 after Rosenzweig 2005 --- - -## Slowly adapting and rapidly adapting mechanoreceptors respond differently to stimulation - -
Neuroscience 5e Fig. 9.4
- - -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. - --- @@ -263,6 +296,19 @@ Work : no displacment, no work : no work in direction orthongonal to displacement + +-- + +## Slowly adapting and rapidly adapting mechanoreceptors respond differently to stimulation + +
Neuroscience 5e Fig. 9.4
+ + +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. + + --- ## Cutaneous mechanoreceptors @@ -385,8 +431,8 @@ Note: * **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" + * Density– higher cell density, higher resolution + * Two-point discrimination test @@ -398,7 +444,8 @@ Note: Note: - +--> --- @@ -461,6 +508,7 @@ Note: Note: + --- ## Dorsal column-medial lemniscus system @@ -477,7 +525,7 @@ Note: ## Dorsal column-medial lemniscus system -
+
Neuroscience 3e
Note: @@ -678,16 +726,6 @@ 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 - -
- - -Note: - --- diff --git a/vision1.md b/vision1.md index c59e4e4..f475879 100644 --- a/vision1.md +++ b/vision1.md @@ -239,7 +239,7 @@ Note: --- -## What does light do? +## What does light energy 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 @@ -247,25 +247,9 @@ Note: Note: -*reason for this backwards arrangement of hyperpolarization to depolarization is not currently known* - ---- - -## cGMP gated cation channels are key - -In the dark channels open due to cGMP binding. Na^+^ and Ca^2+^ rushes in and cell is depolarized - -
Neuroscience 5e Fig. 11.8
- - -Note: - -cyclic nucleotide gated cation channel - -the nucleotide cyclic guanosine monophosphate - -*these cGMP gated channels are permeable to both Na+ and Ca2+ actually* +*reason why depolarization is the baseline state in the dark is not known* +Greater energy effiency during rest maybe (less Na+/K+ ATPase activity)? --- @@ -278,18 +262,39 @@ the nucleotide cyclic guanosine monophosphate Note: +--- + +## cGMP gated cation channels are key + +In the dark channels open due to cGMP binding. Na⁺ and Ca²⁺ rushes in and cell is depolarized + +
Neuroscience 5e Fig. 11.8
+ + +Note: + +cyclic nucleotide gated cation channels in the outer membrane segment of the photoreceptors + +the nucleotide cyclic guanosine monophosphate + +*these cGMP gated channels are permeable to both Na+ and Ca2+ actually* + +Balanced by K+ selective channels in the inner segment of the photoreceptor cell + +Light transduction results in a **decrease in cGMP levels** thus closing the cGMP cation channels. K+ efflux becomes dominant and hyperpolarization ensues. Then less Ca2+ dependent transmitter release at synapse with bipolar cells --- + ## 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 (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 +* The opsin then can activate the trimeric G-protein **transducin** +* Transducin in turn activates a cGMP phosphodiesterase. The phosphodiesterase then hydrolyzes cGMP to GMP. Channel opening probability decreases, cell gets hyperpolarized Note: ---- +-- ## Phototransduction in rod photoreceptors @@ -372,10 +377,10 @@ Tremendous amplification. Single photon hitting rhodopsin is estimated to activa --- -## Need to inactivate opsin signaling after a light flash +## After photon absorbtion, opsin signaling is inactivated and cis-retinal gets regenerated * 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 retinal gets shed, transported to pigment epithelium cells, changed to cis-retinol and then reincorporated into opsin +* All-trans retinal gets shed, transported to pigment epithelium cells, changed to cis-retinal and then reincorporated into opsin Note: @@ -448,7 +453,7 @@ Why the cone shape? Shape of cone preferentially accepts light directed straight Note: ---- +-- ## Range of luminance values over which the visual system operates @@ -464,7 +469,7 @@ Note: ---- +-- ## More factoids @@ -531,7 +536,7 @@ Cone response over in about 200 ms (with an overshoot of inward current), wherea Note: ---- +-- ## Distribution of rods and cones in the human retina @@ -730,6 +735,9 @@ Off response Note: +luminance increment in receptive field center vs luminance decrements in receptive field center + +Contrast. luminance change, increments or decrements, carried by separate channels to brain by increased spike rate + Note: @@ -164,7 +167,7 @@ Note: Projection of the Binocular Field of View Relates to Crossing of Fibers in Optic Chiasm ---- +-- ## Visual pathways summary video @@ -259,7 +262,7 @@ Incr representation sound familiar? think of hand and lip representation in huma Note: ---- +-- ## Thalamocortical projections to the visual cortex ('optic radiation')