Unit I, Week 1 Flashcards
1
Q
Gray matter or white matter?
Nucleus - ?
Lemniscus - ?
Ganglion - ?
Peduncle - ?
A
Nucleus - gray matter
Lemniscus - white matter
Ganglion - gray matter
Peduncle - white matter
2
Q
Gray matter or white matter?
Cortex - ? Funiculus - ? Body - ? Fasciculus - ? Tract - ?
A
Cortex - gray matter Funiculus - white matter Body - gray matter Fasciculus - white matter Tract - white matter
3
Q
Astrocyte
A
large glial cell with long processes that insinuate between neural elements
4
Q
Astrocyte functions (5)
A
1) Maintain ionic equilibrium by taking up K+ and neurotransmitters (e.g. glutamate)
2) Role in transport of nutrients from blood vessels to nearby neurons
3) Role in local regulation of blood flow
4) Central role in response to injury - prevent axonal regrowth
5) Maintain blood-brain-barrier
5
Q
Astrocyte and uptake of glutamate
A
Astrocytes take up glutamate and convert it to glutamine → glutamine back to local neurons → neurons convert glutamine back to glutamate
Glutamate uptake also regulates local blood flow
6
Q
Microglia
A
major phagocytic cells in CNS, undergo rapid proliferation to clear debris from brain in response to tissue damage
Arise embryologically outside neural tube, from hematopoietic tissues
Major role in brain plasticity via synapse editing - glial cell dysfunction can cause neurological/psychological disorders
7
Q
Oligodendrocyte
A
form myelin in CNS, may myelinate several nearby axons
Prevents regeneration of axons in CNS
8
Q
Schwann cell
A
glial cell in PNS, form myelin in PNS, myelinates only one axon
Determine if axon can regrow, creates path new axon can grow on
9
Q
Dendrite
A
Passive conductors of electrical energy (signal decreases with distance)
10
Q
Axon
A
Contains voltage-sensitive ion channels capable of propagating AP
11
Q
Nissl substance
A
distinctive rough endoplasmic reticulum in neuronal cell bodies
Neurons have lots of protein production in cell body that can then be transported down axon to peripheral terminals
12
Q
Autoregulation of cerebral blood flow:
increased BP –> ?
A
increased BP → mechanical stretch of arteriole wall → activation of second messenger cascade → inhibition of calcium-activated-K+ channel → prevent K+ out = depolarization → Ca2+ influx → activation of arteriole muscle wall
13
Q
Functional Hyperemia
A
Local increase in neuronal activity → increase in local blood flow (basis for fMRI and PET scans)
14
Q
Two mechanisms causing functional hyperemia
A
1) NO released by neurons diffuses to reach local vessels to cause dilation
2) Astrocytes
15
Q
Why substances in circulatory system do not freely enter brain parenchyma
A
Capillaries in brain are NOT fenestrated, connected by tight junctions → requires diffusion or transport through endothelial cell
BBB maintained by astrocytes - tell endothelial cells to maintain tight junctions
16
Q
How astrocytes regulate local blood flow in proportion to neuronal activity:
increased neuronal activity –> ??
A
Astrocyte “foot processes” extend towards local blood vessels, contact vessel walls → carry nutrients and oxygen to from vessels to neurons and regulates vessel function
Increased neuronal activity →
1) increased astrocytes uptake of glutamate (most prevalent NT)
2) → causes release of arachidonic acid in astrocytes
3) → arachidonic acid converted by P450 enzyme to form epoxyeicosatrienoic acid (EET)
4) → astrocyte EET released and acts to hyperpolarize arteriole membrane
5) → decrease vascular tone → larger lumen → increased blood flow
17
Q
Nerve regeneration in the PNS
A
Minor damage → distal portion of nerve ending degenerates, but regeneration begins from end still attached to cell body
Long term effects: alterations in sensory perception in affected area (hypersensitivity, hyperalgesia, allodynia)
18
Q
What type of cells are responsible for nerve regeneration in the PNS
A
Schwann cells
Regeneration of axons along course of original nerve, facilitated by Schwann cells
Schwann cells clear myelin debris, then line endoneurium to form substrate for outgrowth of axons from cut stump of nerve
19
Q
Nerve regeneration in the CNS
what cells are responsible for this process?
A
Damage →
Oligodendrocytes do not clear myelin debris - proliferate and upregulate expression of molecules (chondrotin, sulfate proteoglycans) that inhibit axonal outgrowth
-Axons do not regrow!
Microglia activate local astrocytes to form glial scar → chemical and physical barrier to neuronal regeneration
Capacity for CNS regrowth remains, but is limited
20
Q
Anterior circulation is supplied by what artery and brings blood to what part of the brain?
A
from internal carotid artery → entire cerebral hemisphere except medial occipital lobe and inferior part of temporal lobe
21
Q
Internal carotid artery branches into ________ and ________
A
anterior and middle cerebral arteries
22
Q
Anterior cerebral artery supplies blood to where?
A
Anterior cerebral → longitudinal fissure to supply anterior ⅔ of medial face of cerebral hemisphere and orbital cortex
23
Q
Middle cerebral artery supplies blood to where?
A
Middle cerebral artery → lateral fissure to supply lateral face of cerebrum (frontal, parietal, and temporal lobes)
Gives off penetrating branches to supply deep white and gray matter of cerebral cortex
24
Q
Posterior circulation of the brain gets blood from what artery and supplies blood to what region of the brain?
A
from vertebral arteries → brainstem, cerebellum, some cortex (medial occipital, inferior temporal lobe)
25
At the level of the _____, vertebral arteries fuse to form the ________ → splits at base of midbrain to form paired ________ → which 2 regions of the brain?
At level of pons, vertebral arteries fuse to form basilar artery → splits at base of midbrain to form paired posterior cerebral arteries → medial face of occipital lobe and inferior surface of temporal lobe
26
Along course of vertebral/basilar system, circumferential branches wrap around brainstem
What are the 3 named circumferential branches?
All circumferential branches supply blood to dorsal brainstem and overlaying cerebellum
1) Posterior Inferior Cerebellar Artery (PICA)
2) Anterior Inferior Cerebellar Artery (AICA)
3) Superior Cerebellar Artery (SCA)
27
Posterior Inferior Cerebellar Artery (PICA):
branch off of ______ artery, wraps ______ and supplies ________
branch off vertebral artery, wraps medulla and supplies most caudal cerebellum
28
Anterior Inferior Cerebellar Artery (AICA)
branch off ______ and wraps _______ and supplies ______
branch off basilar artery, wraps caudal pons, supplies anterior/inferior cerebellum
29
Superior Cerebellar Artery (SCA)
branch off ______ and wraps _______ and supplies ______
branch off basilar artery, wraps around rostral pons, supplies superior face of cerebellum
30
Vertebral arteries split into _______ and _______ to supply blood to the _________
Vertebral arteries → Anterior and posterior spinal arteries → rostral spinal cord
31
Posterior and Anterior circulation systems are INTERCONNECTED via what two mechanisms?
1) End-to-End Anastomosis between terminal vessels of two systems where they abut across cerebral cortex
2) Circle of Willis
32
Entire blood flow to CNS can be supplied via any of 3 major vessels: _______, _______ or ________
L Carotid, R Carotid, or Basilar artery
A slow occlusion will not cause problems, because blood supply can compensate via a different pathway
33
Review venous drainage images
DO IT
34
Review circle of Willis diagram
MEMORIZE THAT SHIT
35
Lateral Ventricles
Paired ventricle
include former 1st and 2nd ventricles
36
Interventricular foramen connects ______ with _______
connects lateral ventricles with 3rd ventricle (one for each lateral ventricle)
37
Cerebral aqueduct connects ______ with _______
connects 3rd and 4th ventricles
38
what connects the 4th ventricle with the subarachnoid space?
Three apertures (two lateral, one caudal) connect 4th ventricle with subarachnoid space
CSF gets reabsorbed through subarachnoid space
39
Ependyma
single cell layer lining ventricles
Leaky → CSF in ventricles exchanges freely with ECF in interstitial space in brain
40
Choroid Plexus
specialized ependymal cells that produce CSF
Brain capillaries lose their tight junctions in choroid plexus and ependymal cells acquire tight junctions → solutes diffuse out of capillaries, and actively transported across ependymal cells to get into CSF
41
CSF
buoys up brain, dampens shock of blows to head
500 ml of CSF produced daily by choroid plexus
Ionic composition very close to plasma, but highly regulated and stabilized because it is ECF for neurons
42
Resorption of CSF
by arachnoid granulations that line principal dural sinuses in subarachnoid space
43
Blockage in CSF flow or failure in resorption → ??
increase intracranial fluid pressure → hydrocephalus (CSF non-compressible, but brain tissue is compressible → ventricles expand at expense of brain tissue)
44
Non-Communicating Hydrocephalus
flow of CSF interrupted (e.g. by block of interventricular foramen of cerebral aqueduct)
45
Communicating Hydrocephalus
CSF gets into subarachnoid space, but isn’t resorbed properly into the bloodstream
46
Meninges: inside to outside = ______, ______ then ______
(inside) pia, arachnoid, then dura (outside)
47
Pia
single cell layer covering outside of CNS, not separable from brain surface
48
Arachnoid
loose spongy layer between pia and dura
Subarachnoid space filled with CSF
49
Dura
leathery layer closely applied to cranium, but loose on spinal column
50
EPSP/IPSP (inhibitory/excitatory post synaptic potential) vs. action potential
EPSP/IPSP:
- longer duration
- fluctuations in potential causing electrical current, but may or may not cause an AP
Action Potential:
- brief duration
- propagated along axon
51
Pyramidal cells
where summation of electrical potential changes in cerebral cortex occurs
Vertically oriented neurons
Cell body in deep layer, dendrites extend through all layers of cortex → guide flow of currents generated by postsynaptic potentials through entire thickness of cortex
52
Electroencephalography (EEG)
measures electrical potential fluctuations at scalp surface
Fluctuations produced by temporal and spatial summation of electrical currents caused by slow postsynaptic potentials (EPSPs, IPSPs)
- APs are very short and contribute very little
- Captures “field potentials”, which represent synchronized activity across many neuronal elements and include subthreshold synaptic potentials
- Measure populations of partially synchronized neurons, and not individual neuronal activity
53
Event Related Potentials (ERP)
EEG recording obtained during specific task
54
Magnetoencephalography (MEG)
measures small magnetic fields induced by electrical current flux
Measure populations of partially synchronized neurons, and not individual neuronal activity
55
Techniques for evaluating brain activity using ELECTROMAGNETIC properties (3)
1) EEG
2) ERP
3) MEG
56
Techniques for evaluating brain activity using HEMODYNAMIC properties (2)
1) PET
| 2) fMRI
57
Positron Emission Tomography (PET)
Inject positron-emitting radionuclide labeled tracer → radionuclide in radiotracer decays, releasing positrons that contact and annihilate electrons → each annihilation produces 2 photons traveling in opposite directions that then encounter detectors arranged circumferentially around subject
58
Types of radionuclide labeled tracers that can be used for PET scan and what they show
H2(15)O → ?
18-Fluorodeoxyglucose (18-FDG) → ?
18-Fluorodopa (18-FD) → ?
H2(15)O → rough measure of cerebral blood flow
18-Fluorodeoxyglucose (18-FDG) → map of glucose metabolism
18-Fluorodopa (18-FD) → loci in brain where L-dopa converted to dopamine
59
Functional MRI (fMRI)
Signal changes due to regional changes in deoxyhemoglobin concentration associated with synaptic activity
BOLD = Blood Oxygen Level Dependent Signal
60
fMRI - oxy vs. deoxy hemoglobin?
```
Oxyhemoglobin = diamagnetic, does NOT distort magnetic field
Deoxyhemoglobin = paramagnetic, distorts magnetic field
```
61
Diffusion Tensor Imaging (DTI)
Allows direct examination, in vivo, of some aspects of tissue micro-structure
Quantitative measure of integrity of white-matter fiber tracts
62
Connectomics
comprehensive description of structural relationships within nervous system, represented graphically
Graphs altered in a number of diseases, can be useful biomarkers for disease
63
Driving force
difference between reversal potential and actual potential
| Nernst Equation used to calculate the reversal potential
64
Electrical Synaptic Transmission
couple and synchronize cells that need to fire together via gap junctions between cells
Cytoplasmic continuity between cells
Rare in nervous system of mammals
65
Advantages of Electrical Synaptic Transmission (5)
1) Very fast transmission, delay is virtually absent
2) Simple
3) Bidirectional
4) Easy to trigger synchronous activity
5) No delay
66
Examples of electrical synaptic transmission (6)
1) Escape reflexes in animal kingdom
2) Cardiac muscle contraction
3) CNS: dear learning, emotional memory in hippocampus
4) Contribution to establishment of theta rhythms
5) Other synchronously firing networks
6) Development of retina and inner ear
67
Limitations of electrical synaptic transmission (4)
1) In order to provide enough current to depolarize postsynaptic cell to threshold, presynaptic terminal has to be comparable in size to postsynaptic cell
2) Electrical transmission is ALWAYS excitatory - no complex integration of excitatory and inhibitory signals
3) Signal cannot be amplified
4) Cannot modulate signal
68
Steps of synaptic transmission
from AP arriving in presynaptic terminal → until NT diffuses into cleft
→ terminal depolarizes → depolarization causes voltage gated Ca2+ channels to open
→ Ca2+ flows into cell
→ Ca2+ encounters docked and primed synaptic vesicles → Ca2+ binds synaptotagmin and triggers fusion of lipids of vesicle with surface membrane = fusion pore opening
→ NT diffuses out of vesicle into synaptic cleft via exocytosis
69
Steps of synaptic transmission after NT released into synaptic cleft
→ diffusion across synaptic cleft
→ NT binds postsynaptic membrane at receptor
→ receptors open and allow positive ions to enter cell (in case of NMJ)
→ Depolarization (EPSP)
→ if threshold reached causes AP
70
Postsynaptic receptor determines...
Postsynaptic receptor determines if signal is: excitatory or inhibitory, fast or slow, membrane potential change brief or persistent
71
SNARE complex
SNARE complex holds vesicle to presynaptic terminal to ensure that vesicle fuses with the membrane, and fuses only when you want it to
72
Synaptobrevin
protein on vesicle that interacts with corresponding molecules in presynaptic membrane
73
Synaptotagmin
protein on vesicle that senses calcium
74
SNAP25 and Syntaxin
SNAP25 and Syntaxin (binds synaptobrevin): in presynaptic membrane
75
How is Ca2+ pumped out of the cell after AP (2)
1) ATP driven Ca2+ pump (primary active transport)
| 2) Na-Ca exchanger (secondary active transport)
76
How can NT be removed from the synaptic cleft? (3)
1) Diffusion out of cleft into ECF
2) Recycled
3) Destroyed
77
NT recycling
- Pumped back into presynaptic terminal and back into synaptic vesicles (and neighboring glial cells)
- Least important at NMJ, most important in CNS
EX) Drugs like amphetamine, cocaine, and Prozac block reuptake of monoamine transmitters like dopamine and serotonin
78
NT destruction in synaptic cleft
NT destroyed by tethered extracellular degradative enzyme (Acetylcholine esterase destroys ACh at NMJ)
*Does not occur in CNS
79
After releasing their contents into the synaptic cleft, how are vesicle membranes re-internalized?
Vesicle membrane re-internalized (endocytosis) and refilled with NT
Clathrin shapes vesicle, while dynein pinches off new vesicle
Synaptic vesicle recycling can take several seconds in well rested synapse or up to a minute in a hard working one
80
How can NTs be produced?
Synthesized locally by enzymes in nerve terminal cytoplasm, then pumped back into vesicle via sodium-coupled transporter proteins in vesicle membrane
81
NMJ vs. CNS synapses:
```
Speed
Effect
Strength
Transmitter
Transmitter termination
"Intelligence"
```
NMJ
- Speed = fast
- Effect = excitatory
- Strength = strong
- Transmitter = ACh
- Transmitter termination = diffusion, degradation, minimal to no reuptake
- "Intelligence" = stupid
CNS
-Speed = fast or slow
-Effect = excitatory or inhibitory
-Strength = weak (many inputs required to have AP, no safety factor)
-Transmitter = many different kinds
-Transmitter termination = reuptake, diffusion, minimal to no degredation
"Intelligence" = smart
82
Motor unit
Single motor neuron branches to innervate many individual muscle fibers
axon + muscle fibers = Motor Unit
(smallest unit of force in skeletal muscle)
83
ACh receptor
ligand gated ion channel only located at synapse on muscle fiber
Permeable to ALL cations (non-selective cation channel, NSC) (Na+ and K+)
Synaptic reversal potential = -10 mV (between Ek/ENa)
84
Structure of ACh receptor
pentameric, 5 subunits arranged around central pore
2 ACh molecules must bind simultaneously, one to each of 2 alpha subunits
85
If threshold for AP (-50mV) in a muscle fiber is reached then...
→ voltage gated sodium channels open and AP propagates
Single muscle fiber twitch if threshold is reached regardless of how much threshold is exceeded
86
Acetylcholinesterase
located inside synaptic cleft, breaks down ACh
Breaks down half of ACh before it gets to postsynaptic side
87
Job description for motor nerve terminal
every time an AP arrives from CNS, you must secrete enough ACh to depolarize the muscle fiber you innervate to threshold for an AP (requires SAFETY FACTOR)
Depolarize muscle by 30 mV (-80 to -50 mV)
88
Amplification of Neuromuscular Signal - why do we need it, and how do we do it?
Nerve terminal is much smaller than muscle fiber it innervates → wouldn’t provide enough current needed to depolarize muscle by necessary 30 mV
**CHEMISTRY provides the amplifier
-Electrical signal converted to chemical signal with ACh release from up to 100 synaptic vesicles (each vesicle = 1 mV depolarization)
89
_______ and _______ are two opposing processes that occur together during repetitive stimulation
Synaptic facilitation and depression
90
Synaptic facilitation
During high frequency stimulation Ca2+ concentration inside nerve terminal increases because it can’t get pumped out fast enough → more Ca2+ to bind vesicles → number of quanta secreted INCREASES during repetitive stimulation
**Effect recovers within milliseconds
91
Myasthenic syndrome
antibodies to presynaptic Ca2+ channels - patients are weak and become stronger with exercise
facilitation allows stronger signals with repetitive stimulation
92
Synaptic Depression of Transmitter Release
- reduction of number of available vesicles during periods of high frequency activity
- Nerve terminal cannot replenish synaptic vesicles from reserve pool fast enough to keep up with demand
**Effect recovers in seconds up to about 1 minute
93
Myasthenia gravis
antibodies to postsynaptic acetylcholine receptors - patients are weak and become weaker with exercise
94
Direct (fast) Synapses
| aka ionotropic
neurotransmitter directly binds gate, instantly changing membrane permeability
Underlies our immediate conscious behavior and ability to respond quickly to sensory stimulation
95
Indirect (slow) Synapses
aka metabatropic
neurotransmitter receptor protein is NOT an ion channel, but a transmembrane protein that undergoes structural rearrangement when transmitter binds → G protein (second messenger) molecules diffuse and bind to nearby ion channels
- Slower to turn on, and turn off - 2nd messengers stay in cytoplasm longer than NT in synaptic cleft
- 2nd messengers can also cause changes in gene expression in nucleus
96
________ and _______ are examples of NTs that act via metabotropic receptors
Catecholamines (epi, norepi, and doapine)
Serotonin
97
_________ is a NT that can cause both fast (direct) and slow (indirect) activation in the same cell
Acetylcholine
Fast excitation via NSC channel = Nicotinic ACh receptor
Slow excitation via G protein channel = Muscarinic ACh receptor
98
Inhibitory synapses
membrane potential is below threshold - can be hyperpolarizing, depolarizing, or shunting (nothing happens)
EX) K+ selective channel
Some inhibitory nerve terminals synapse on other (excitatory) presynaptic terminals INHIBITING presynaptic transmitter release
EX) Cl- channels opened by GABA on presynaptic neuron, causing fewer Ca2+ channels to open in response to AP and thus less excitatory transmitter release
99
________ and ______ are the major inhibitory transmitters and open what kind of channels?
GABA and Glycine = major inhibitory transmitters
Opens Cl- channel
100
Inhibition is more powerful than one might predict from the size of an IPSP because…
Typically located closer to axon hillock
Reversal potential of inhibitory synapses near resting potential such that inhibitory postsynaptic potentials are small, BUT inhibition is powerful
101
Excitatory synapses
major NT is ______ and opens ______ channel
membrane potential more positive (closer to threshold)
EX) Na+ selective channel
Glutamate = major excitatory transmitter
-Opens NSC (nonselective) channel
102
Factors influencing neural integration (5)
1) Reversal potential (excitatory or inhibitory)
2) Size of each synapse
3) Distance of each synapse from soma/axon hillock
4) Number of excitatory vs. inhibitory synapses active
5) Leakiness of neuron
103
Spatial summation
individual synaptic inputs converge to summate, driving postsynaptic membrane potential towards threshold for AP, two or more different inputs contribute
104
Temporal summation
same individual input/synapse stimulated in succession (both facilitation and summation cause larger depolarization) → cell depolarizes more and more until threshold is reached
105
Smart synapses
- excitatory or inhibitory?
- what is NT?
- what types of receptors?
Involved in synaptic plasticity
- excitatory
- Glutamate is transmitter
- Contains two types of glutamate receptors:
NMDA receptor
AMPA receptor
106
AMPA receptor
NSC channel, gated open by glutamate transmitter
107
NMDA receptor
3 important properties
coincidence detector (requires two events to happen simultaneously before conducting ions)
1) Binds glutamate
2) Have pore plugged by magnesium ion
3) High permeability to Ca2+
108
What two events are required to open NMDA receptor
Requires presynaptic activation via glutamate binding to ligand gate, AND postsynaptic AP electrically “popping out” Mg2+ from pore → clears way for Ca2+ to enter cell
109
After NMDA receptor is opened and once Ca2+ is in postsynaptic cell, it STRENGTHENS the synapse by...(2)
1) 1) Insertion of additional AMPA receptors into postsynaptic membrane
2) Presynaptic strengthening by NMDA receptor activation
110
How are additional AMPA receptors put into postsynaptic membrane?
Ca2+ influx triggers exocytosis of vesicles containing AMPA receptors → increased size of glutamate induced synaptic potentials
111
How does presynaptic strengthening by NMDA receptor activation happen?
Requires RETROGRADE signal from postsynaptic cell to presynaptic terminal = postsynaptic NO synthesis → diffuses back across synapse to potentiate transmitter release
→ more transmitter quanta released in response to presynaptic AP
112
Silent synapses
no AMPA receptors, only NMDA receptors → only active with both pre and postsynaptic activation
Can become un-silent with insertion of AMPA receptors
Important in developing brain
113
Tetanus Toxin Mechanism of Action
Tetanospasmin binds peripheral nerve terminal
→ transported via axons and across synaptic junction to CNS → becomes fixed to gangliosides at presynaptic inhibitory motor nerve endings and taken up by endocytosis
→ blocks release of inhibitory neurotransmitter with zinc dependent endopeptidases that selectively cleave synaptobrevin protein on synaptic vesicles → spasms
114
Botulinum Toxin Mechanism of Action
Toxin is specific for PERIPHERAL nerve endings, prevents release of acetylcholine across synaptic cleft by selectively cleaving synaptobrevin protein via zinc dependent endopeptidase
115
Safety factor at NMJ
many more vesicles are released than are necessary to cause 30 mV depolarization to reach threshold
116
Is there a safety factor in CNS?
NO
- CNS synapse is weak, each presynaptic terminal (bouton) contains a single active zone, and a few dozen releasable vesicles
- A single AP in a CNS bouton often fails to produce exocytosis of any vesicles at all
- Each postsynaptic cell weight combined input from many separate individuals before deciding whether to fire an AP
117
Long Term Potentiation (LTP)
increase in synaptic current produced by a synapse after a pairing event
Associative plasticity that results when a presynaptic signal is combined with a unique signal from the postsynaptic cell
Relies on NMDA receptor (coincidence detector)
118
Long Term Depression (LTD)
decrease in synaptic current produced by synapse after pairing event
Low frequency stimulation causes synaptic responses to become smaller and stay smaller
119
What is the difference between synaptic facilitation and LTP?
Both increase amplitude of synaptic response
Facilitation is increased synaptic response amplitude due to higher Ca2+ concentration in presynaptic terminal, short term
LTP is increased synaptic response amplitude due to more postsynaptic receptors, longer term
120
How can you discriminate between facilitation and summation?
Facilitation is second synaptic event being larger due to Ca2+ in terminal
Summation is slow increase in membrane potential due to frequent stimulation - may or may not result in AP
121
Curare
competitively and reversibly inhibits nicotinic acetylcholine receptor at NMJ (competitive antagonist of N-M receptor)
-used to be used as a paralytic
122
Do curare or rocuronium stop the release of minis (basically NT incontinence)?
NO - curare and rocuronium work on post-synaptic membrane and minis come from presynaptic terminal
123
How does GABA-A and GABA-B signaling work differently?
```
GABA-A = iontropic, direct
GABA-B = metabotropic, indirect
```
124
Synthesis of Acetylcholine
Acetyl-CoA + Choline → ACh + CoA via Choline Acetyl Transferase (CAT)
Choline uptake is rate limiting step
125
Acetylcholine receptor types
Muscarinic Receptors
Nicotinic Receptors:
N-N (open receptor gated cation channel)
N-M
126
Muscarinic receptor subtypes and their general mechanism of action
M1-M3 (Gq → stimulate PLC activity)
M2-M4 (Gi/o → inhibit AC activity)
127
_______ is the rate limiting step in the synthesis of catecholamines (NE and dopamine)
Tyosine hydroxylase catalysis of tyrosine --> L-Dopa
128
Dopamine receptors general mechanism
D1 -->
D2 -->
D1 (Gs → stimulate AC activity)
| D2 (Gi/o → inhibit AC activity)
129
Norepinephrine receptors general mechanism
a1 adrenergic
a2 adrenergic
B1 adrenergic
B2 adrenergic
a1 adrenergic (Gq → stimulate phospholipase C)
a2 adrenergic (Gi/o → inhibit AC activity, K+ channel opening)
B1 adrenergic (Gs → stimulate AC activity)
B2 adrenergic (Gs → stimulate AC activity)
130
Rate limiting step in the synthesis of serotonin
Tryptophan hydroxylase catalysis of conversion of tryptophan --> 5-OH-tryptophan
131
Receptors for serotonin general mechanism
5HT-1A, 1B, 1D --> ?
5HT-2A, 2B, 2C --> ?
5HT3 --> ?
5HT4 --> ?
5HT-1A, 1B, 1D (Gi/o → inhibit AC activity, open K+ channel)
5HT-2A, 2B, 2C (Gq → stimulate PLC activity, close Ca2+ channel)
5HT3 (Ligand-gated cation channel, excitatory)
5HT4 (Gs → stimulate AC activity)
132
Monoamines (serotonin, NE, dopamine) are taken up and stored in vesicles by ________ and is degraded by _______
VMAT - vesicular monoamine transporter
Monoamine oxidase (MAO)
once serotonin is taken back up into cytosol, inactivated by MAO or transported into vesicles by VMAT
133
inhibition of VMAT results in...
block vesicular uptake of monoamines = increased degradation by MAO → decreased monoamine release/action
134
inhibition of MAO results in...
decrease degradation by MAO = more vesicular storage → increased monoamine release/action
135
GABA synthesis
Precursor = Glutamate
Glutamate → GABA via GAD (glutamic acid decarboxylase)
136
GABA-A vs. GABA-B receptors
GABA-A: opens ligand-gated Cl-channel → decrease neuronal excitability (IPSP)
-Postsynaptic only
GABA-B: Gi/o → inhibit AC, decrease Ca2+ conductance, open K+ channel
-Pre and postsynaptic
137
Benzodiazepines mechanism of action
AMPLIFY GABA EFFECT
bind GABA-A receptor, increase GABA inhibitory action
Treat seizures caused by depressed GABA activity and anxiety caused by excessive amygdala activity/depressed GABA activity)
138
Tiagabine mechanism of action
inhibit reuptake of GABA
139
Vigabatrin mechanism of action
inhibit degradation by GABA-transaminase (GABA-T)
140
Glutamate synthesis
Glutamine → glutamate via Glutaminase in nerve endings, stored in synaptic vesicles
Dependent on interaction between nerve terminals and glial cells
141
Ionotropic glutamate receptors (3)
NMDA (Ca2+ influx)
AMPA (Na+ and Ca2+ influx)
Kainate (Na+ influx)
142
Metabatropic glutamate receptors
R1-R5 --> ?
R2-R3 --> ?
R4-R6-R7-R8 --> ?
R1-R5 (Gq → increase PLC activity)
R2-R3 (Gi/o → decreased AC activity, inhibit VSCC, activate K+ channels)
R4-R6-R7-R8 (Gi/o → decreased AC activity, inhibit VSCC)
143
Hierarchical Systems
Clearly delineated pathways directly involved in motor control and sensory perception
Large myelinated neurons with rapid conduction velocity
Sensory info processed sequentially and integrated successively at relay nuclei on the way to cortex - lesion disrupts pathway
Relay and local circuit neurons present at each nuclei
144
Relay neurons
in pathways that transmit signals over long distances, feed forward
Excitatory → NT = glutamate
145
Local circuit interneurons
synapse on relay neuron cell body or on axon in spinal cord
Inhibitory → NT = GABA
146
Diffuse Systems
Modulate the function of hierarchical systems
**Neurotransmitters: ACh, monoamines
Produced in neurons whose cell bodies lie in small discrete nuclei (usually in brainstem)
Axons very divergent, single neuron can innervate functionally distinct parts of CNS
CANNOT convey topographically specific information
Affect vast CNS areas simultaneously, subserving global functions - e.g. attention, sleep-wake cycle, appetite, emotions
147
Primary vesicles
Prosencephalon (forebrain)
Mesencephalon (midbrain)
Rhombencephalon (hindbrain)
- Segmentation of hollow neural tube along rostrocaudal axis
- Gives rise to 5 secondary cerebral vesicles
148
5 secondary cerebral vesicles
```
Telencephalon
Diencephalon
Mesencephalon
Metencephalon
Myelencephalon
```
149
Prosencephalon --> ________ and ________
telencephalon and diencephalon
150
Paired telencephalon --> what adult brain structures?
cerebral hemispheres each with lateral ventricle
151
Diencephalon --> what adult brain structures?
thalamus, hypothalamus, subthalamus, epithalamus, and third ventricle
152
Mesencephalon --> what adult brain structures?
mesencephalon and cerebral aqueduct
153
Cephalic flexure
Bending of neural tube occurs between diencephalon (prosencephalon) and mesencephalon, prosencephalon bends 80 degrees forward
154
Rhombencephalon --> _______ and _______ as well as the ______ ventricle
metencephalon (cranial) and myelencephalon (caudal)
fourth ventricle
155
Metencephalon → what adult brain structures
pons, cerebellum
156
Myelencephalon → what adult brain structures
medulla
157
The spinal cord and central canal come from what embryologic structure
neural tube
158
Review of embryogenesis:
Inner cell mass --> _________ --> ___________
two layered germ disc (epiblast + hypoblast)
three layered germ disc (ectoderm, mesoderm, endoderm)
159
Primitive streak
formed when caudal half of epiblast (part of two layered germ disc) thickens and elongates via addition of cells
Cranial end → Primitive Node (aka Primitive Knot, Hensen’s node)
160
Primitive groove
formed in middle of primitive streak
161
Notochord is formed what what layer of the germ disc?
mesoderm
162
Notochord secretes ______ and influences the _____ layer to divide rapidly and form _________
sonic hedgehog
ECTODERM
thickened NEURAL PLATE
163
How is neural tube formed?
ECTODERM (of germ disc)→ NEURAL PLATE
Neural groove forms in center of neural plate → neural folds → folds fuse → NEURAL TUBE
164
What does the neural tube from?
the nervous system!
Cerebral hemispheres, segments of brainstem, spinal cord, and their respective fluid-filled cavities (ventricles)
Undergoes rostrocaudal patterning
165
Dorsoventral Patterning in Spinal cord
Neural progenitors develop into different cell populations based on distinct position along dorsal-ventral axis
Divide populations into alar plate and basal plate on each side of tube, separated by sulcus limitans
166
Basal Plate
Ventral aspect of neural tube
→ motor neurons (efferent)
167
Alar plate
Dorsal aspect of neural tube → afferent neurons receiving sensory input from cells of dorsal root ganglion carrying sensory information
168
Sulcus limitans
separates alar plate and basal plate on neural tube
169
Notochord secretes sonic hedgehog with higher concentration _______, contributing to what forebrain developmental dorsoventral pattern
Notochord secretes SHH, with higher concentration VENTRALLY than it is dorsally → dorsally get telencephalic vesicles forming
Without SHH, vesicles don’t form properly
170
3 discrete proliferative zones of forebrain that undergo dorsoventral patterning
1) Cortex (dorsal)
2) Lateral and medial ganglionic eminences
3) Basal forebrain
171
The ganglionic eminences form what adult brain structures?
Ganglionic eminence → subcortical gray matter (caudate, putamen, globus pallidus)
172
Rostrocaudal Patterning of Neural Tube
-Initial definition of RC patterning occurs with implantation (leading edge is caudal end of embryo)
RC patterning results in enlargements of rostral end of tube → primary cerebral vesicles (see above)
173
Rhombomeres
8 morphologically distinct elements of rhombencephalon
Cells in each rhombomere differ in morphology, axonal trajectory, NT synthesis, NT selectivity, firing properties, and synapse specificity
Specific combination of Hox genes expressed in particular rhombomere varies with position along AP (rostral-caudal) axis
174
Hox genes
transcription factors, activate expression of downstream genes → activate specific/distinct programs of differentiation
Trigger different programs of differentiation along rostrocaudal axis
175
Morphogens
secreted by anterior and posterior structures of neural tube, establishing a concentration gradient along AP axis
176
Morphogens are secreted from where and results in what type of development?
1) Primitive node --> Wnts, FGFs, Retinoic Acid → Caudal structure development
2) Anterior Visceral Endoderm (underlying prechordal plate) = Cerebrus, dickkopf → Forebrain development
177
Neuroepithelial cell layer
pseudostratified ectoderm of neural tube
Neuroepithelial cell layer will form all cellular elements of CNS (except microglia)
Period of rapid cell replication of daughter cells in this layer → cell migration
178
Radial migration
migration away from inner multiplication zone to outer edges of growing wall of neural tube
179
Telencephalon "inside out" development
Telencephalon develops in “inside-out” fashion to form cortex
Cortex = 6 cell layers, each with distinct pattern of organization and connections
Deepest layer formed first, each successive migration ascends farther, forming more superficial layers
Cells follow radial glial guides → important preceding cells “get off” the ladder before others can follow
180
Motor or sensory?
Precentral gyrus
Postcentral gyrus
Precentral gyrus = primary motor cortex
Postcentral gyrus = somatosensory cortex
181
Internal Capsule
pathway of axons that separate caudate nucleus and thalamus from putamen and globus pallidus
182
Pathway of axons from cerebral cortex:
_______ ---> _______ --> ______ ---> ________ --> _____
Corona radiata (above caudate and putamen)
→ internal capsule (separating caudate and putamen)
→ Crus cerebri
→ through pons
→ pyramid of brainstem (ventral surface of medulla) - where axons cross midline
183
Lateral corticospinal tract (aka pyramidal tract)
axons that travel from precentral gyrus (primary motor cortex) and descend into spinal cord
184
Describe the pathway of the lateral corticospinal tract (4)
1) Cells in precentral gyrus (primary motor cortex) stimulated (output cells in bottom layer of 6 layered cortex)
2) → cells project through white matter, continue down into brainstem where they cross midline at the decussation of the pyramid
3) → lateral corticospinal tract descends spinal cord and synapse on alpha-motor neuron (output cells on VENTRAL gray matter)
4) → joins spinal nerve and innervates contralateral muscle
185
alpha motor neuron
output cells on VENTRAL gray matter, large fiber diameter and fast conduction velocity
186
what determines where the lateral corticospinal tract terminates in spinal cord?
lateral corticospinal tract descends spinal cord and terminates in spinal cord depending on where in the cerebral cortex they originated
187
Anterior corticospinal tract
-how is this different from lateral corticospinal tract?
- Do not cross, remain ipsilateral
- Innervate alpha-motor neurons in more MEDIAL gray matter of spinal cord that are responsible for core muscle groups that maintain posture
- Innervate IPSILATERAL alpha motor neurons and cross at ANTERIOR WHITE COMMISSURE to other side
188
Anterior white commissure
where anterior corticospinal tract crosses midline in the spinal cord
189
What happens to your anterior and lateral corticospinal tract if you have a stroke on the R hemisphere?
1) lose lateral corticospinal input to L side
2) lose anterior corticospinal tract in R side
3) BUT anterior corticospinal tract on L side still intact and can maintain core muscle groups on R side by doing double duty via anterior white commissure
190
How do you determine what level in the spinal cord you are?
Cervical: large ventral gray matter to innervate arm
Thoracic: has narrow ventral gray matter (minimal muscles) and has sympathetic nervous system preganglionic sympathetic neurons from C8-L2 → has little notch of white matter
Lumbar: large ventral gray matter to innervate lower extremities
191
Upper motor neuron syndrome
(brain to spinal cord neuron damaged)
hyporeflexia or areflexia → emergence of hyperreflexia a few days later
Will produce weakness of all muscle groups innervated by UMNs
Immediate muscle weakness and hypotonia, hyporeflexia or areflexia
Followed by spasticity and HYPERreflexia in days to weeks (including extensor plantar response: Babinski)
SPASTIC PARESIS
192
Lower motor neuron syndrome
(spinal cord to muscle signal damaged)
permanent flaccidity (loss of motor tone) and long term loss of reflexes those motor neurons participate in
Will produce weakness in muscles innervated by those neurons
Long-term loss of reflexes that those LMNs participate in, and long term loss of muscle tone (FLACCIDITY) in those muscle groups
FLACCID PARESIS
Can also produce fasciculations
193
What happens if you damaged your cord at C5-C6? (in terms of upper and lower motor neuron syndrome)
everything above and below will be in tact
Weakness to all muscle groups innervated from C5 and below
Everything below will have UMN injury characteristics (hyporeflexia → hyperreflexia/spasticity)
For c5 and c6 segments will have LMN characteristics
194
Brown-Sequard Syndrome
Only destroy ½ of spinal cord → destroy pain and temperature info from contralateral side and dorsal column information from ipsilateral side
Crossed sensory deficit
195
Posterior/dorsal column medial lemniscal system transmits what kind of sensation?
Sensation of touch, vibration sense, and joint position sense
196
Posterior/dorsal column medial lemniscal pathway:
1) Big toe receptors in skin for different modalities → different axons depending on modality go to L5 _______
2) → L5 _______ (between ___ and __ vertebral body)
3) → spinal canal between two vertebrae → L5 _______ (near ____ vertebrae)
4) → enter ______ of spinal cord
5) → continue up in column of white matter called _________
6) → bottom of brainstem → synapse with second neuron in ________
7) → _______ neuron discharges and crosses midline, ascends _________ pathway
8) → synapses in ______
9) → 3rd neuron in pathway from sends signal to ______________
1) Big toe receptors in skin for different modalities → different axons depending on modality go to L5 dermatome (dermatome for toe)
2) → L5 dorsal root ganglion (between L5 and S1 vertebral body)
3) → spinal canal between two vertebrae → L5 segment of spinal cord (near T12 vertebrae)
4) → enter dorsal horn of spinal cord
5) → continue up in column of white matter (Fasiculus gracilis)
6) → bottom of brainstem → synapse with second neuron in nucleus gracilis
7) → N. gracilis neuron discharges and crosses midline, ascends medial lemniscus pathway
8) → synapses in thalamus (VPL, ventral posterior lateral)
9) → 3rd neuron from VPL sends signal to somatosensory cortex
197
What happens to the posterior/dorsal column medial lemniscal system above the T6 dermatome?
white matter dorsal column in spinal cord is FASICULUS CUNEATUS
-(just LATERAL to fasiculus gracilis in dorsal column)
→ NUCLEUS CUNEATUS in brainstem just lateral to nucleus gracilis
→ medial lemniscus
→ VPL sensory thalamus
→ somatosensory cortex
198
Pathway for sensation of pain and temperature
1) Heat/pain in foot → _____________ → enter L5 segment
2) → In dorsal horn, travel up or down in thin bundle of white matter = ____________
3) → synapse in _____________ contains second neuron cell body
4) → sends axons across midline via ___________
5) → signal then ascends via white matter in anterior/lateral spinal cord via ________ or aka _________
6) → up to _______ → cortex
same system for upper and lower extremities
1) Heat/pain in foot → small c-fibers (unmyelinated) with cell body in L5 dermatome → enter L5 segment
2) → In dorsal horn, travel up or down in thin bundle of white matter = Lissauer’s fasiculus
3) → synapse in Substantia gelatinosa gray matter contains second neuron cell body
4) → sends axons across midline via anterior white commissure
5) → signal then ascends via white matter in anterior/lateral spinal cord via spinothalamic tract or Anterior Lateral System (ALS)
6) → up to thalamus → cortex
199
Nuclear Movement
as cells divide, they undergo nuclear movement
As nuclei move, portion of progenitor cell with nucleus encounters different environments - determines if cell will become post-mitotic
200
S phase, M phase, G1, and G2 phase location of nucleus in nuclear movement
S Phase: DNA being synthesized, nuclei situated most superficially (nearest to pia)
M phase: mitosis, when cell division occurs, nuclei situated most deep (nearest to ventricle)
G1 and G2 gap phases: nuclei occupy intermediate position
201
What determines when a cell stops dividing and begins differentiating? (4)
1) Nuclear Movement - different environments based on nucleus location
2) Process detachment (from ventricular and external surface)
3) Plane of cleavage
4) Asymmetric inheritance of cytoplasmic proteins, mRNA, and other factors
202
Process detachment in neuronal cell proliferation and differentiation
Each dividing cell has processes attaching them to medially to ventricular surface, and laterally to external surface
During division, one process has detached from external surface, and remains attached to ventricular surface
After M phase, daughter cells can re-attach to external surface and continue dividing OR can detach other process from ventricular surface and cease dividing
203
Plane of cleavage in neuronal cell proliferation and differentiation
perpendicular vs. parallel to ventricular surface
-Perpendicular cleavage to ventricular surface → both daughter cells remain attached to ventricular surface and continue dividing in cell cycle
- Parallel cleavage to ventricular surface → only one daughter cell still attached to ventricular surface → exit cell cycle and begin differentiation
- -> ASYMMETRIC DIVISION
204
Asymmetric inheritance of cytoplasmic proteins, mRNAs and other factors
Asymmetric division → asymmetric inheritance of cell components → different cell fates
Helps determine if a cell exits cell cycle in M phase and begins differentiating
205
Neuron’s birthdate
the time a cell undergoes its last round of DNA synthesis (S phase)
After a cell’s “birthdate” it divides and exits the cell cycle from M phase
Cell then begins neuronal differentiation
Neurons that are born at the same time tend to end up together in the same layer, and follow similar programs of differentiation
206
Brain Regions of Secondary Neurogenesis (3)
1) External Granule Layer (Cerebellum)
2) Subventricular zone (olfactory neurons)
3) Dentate Gyrus (hippocampal neurons)
207
External Granule Layer
area of secondary neurogenesis until age 2
Granule layer initially located near rim of 4th ventricle, but cells migrate very high on top (near pia) before they are postmitotic to form a new neurogenic “secondary” region = External Granule Layer
External granule cell progenitors proliferate and once they exit the cell cycle, migrate to cerebellum (further down toward ventricle)
208
Subventricular Zone
area of secondary neurogenesis
cells initially located in ventricular zone of lateral ventricles → migrate very small distance before exiting mitotic cycle to subventricular zone
Cells in subventricular zone give rise to olfactory bulb neurons
Cells exit cell cycle and migrate rostrally to location of olfactory bulb
209
Dentate Gyrus
Cells migrate from ventricular zone to dentate gyrus secondary zone of neurogenesis --> hippocampal neurons
210
All 3 cell types of secondary zones of neurogenesis share 3 characteristics:
1) Arise in ventricular zone
2) migrate before exiting mitotic cycle to a new non-ventricular location
3) Proliferate postnatally in non-ventricular zone locations
211
Neurogenesis in the adult brain
= Secondary Zones of Neurogenesis
Majority of neurogenesis occurs prior to birth
212
Neurogenesis
the process of generating neural cells
We have 10^12 neurons in the adult brain, we only start with 10^5 → need to proliferate exponentially before differentiating
Begins after neuroectoderm rounds up and forms neural tube
Proliferating cells are located in ventricular zones (layer nearest to neural tube lumen/ventricle or central canal)
213
Radial Glia
cells that extend from deep ventricular zone to surface
Guide neurons during radial migration after preplate has formed
Reason why cortical cells that serve similar functions are arranged in columns → single progenitor found in clusters
Facilitate “inside-out” development of cortex (earlier born cells in inside layers, and later born ones in outside layers)
214
Tangential migration
EX?
causes single progenitor found dispersed throughout cortex tissue
EX) inhibitory GABA-containing cells in cerebral cortex
215
Chain Migration
neurons migrate from subventricular zone near lateral ventricle to olfactory bulb - does not involve radial glial cells, migrate in ROSTRAL MIGRATORY STREAM
Strands of cells moving on top of each other over large distances
216
Preplate
First postmitotic cells migrate from ventricular zone to form preplate at 8-9 weeks of embryogenesis
Post-mitotic cells accumulate in preplate → preplate divides into zones
217
Zones after preplate division (5)
1) Marginal Zone
2) Cortical Plate
3) Intermediate Zone
4) Subplate
5) Deep Ventricular Zone
218
Marginal zone
superficial zone adjacent to pial surface
219
Cortical plate
internal layer, forms 6 layers of cortex
Successive waves of neurogenesis produce new neurons in CP organized in specific layers
220
Intermediate zone
contains neuronal and radial glia processes, becomes white matter
221
Subplate
between ventricular zone and cortical plate
Earliest born cells, act as “pioneering” cells in circuit formation
Cells die once pioneering role is played out
Transient neuronal population
222
Deep ventricular zone
contains proliferating cells
223
For both the cerebral cortex and retina, describe where the first‐born cells are found with respect to the ventricular zone
Cerebral Cortex = Inside-Out - earliest born cells in deepest layer
Retina = Outside-In - earliest born cells on outside layer
-Ganglion cells born first, and photoreceptors last
224
Neural crest
forms between neuroectoderm and epidermis
Neural crest cells give rise to PNS and many other cell types (pigment cells, cartilage and are found in very diverse locations (gut, skin, dorsal root sensory ganglia)
225
Neural crest cell migration
Does not use radial glia cellular guides - migration fate influenced by neural crest cell’s position along rostral-caudal axis
Neural crest cells recognize proteins in the environment over which they migrate
ventral stream vs. dorsal stream
226
Dorsal Stream (neural crest cell migration)
flows dorsolaterally underneath ectoderm, but lateral to myotomes that give rise to pigment cells
227
Ventral Stream (neural crest cell migration)
flows ventro medially, dives under dorsal dermamyotomes (DM) → gives rise to sensory, autonomic, and enteric ganglia
228
What are some examples of proteins that neural crest cells recognize in the environment over which they migrate?
LAMININ and FIBRONECTIN found in ECF → INTEGRINS found on neural crest cells → act as permissive factors
Inhibitory “non-permissive” surfaces keep neural crest cells on track
CADHERINS expressed in final destination, act as adhesion molecules
229
Neural crest migration vs. Radial migration
Neural crest migration uses expression and recognition of proteins in the environment while radial migration uses radial glial cells as a guide scaffold by which neurons travel
230
Somatic Nervous System
voluntary skeletal muscle
| - Single neuron connects CNS with peripheral tissues
231
Autonomic nervous system
Sympathetic (SANS) and Parasympathetic (PANS)
232
Function of autonomic nervous system
involuntary, unconscious, automatic portion of nervous system
Regulate involuntary visceral smooth muscles, cardiac muscle, and glandular secretions (CO, blood flow to organs, digestion, etc.)
233
Double neuron connection: Autonomic nervous system
Pre/Post-ganglionic nerves connect at a ganglion
234
CNS origin: Parasympathetic
cranial nerve nuclei (tectal region of brainstem) and sacral segments (S2-S4)
235
Location of ganglia: parasympathetic
innervated organs
236
Length of pre/postganglionic neurons: parasympathetic
preganglionic LONG, postganglionic SHORT
237
Ratio of pre to postganglionic neurons: parasympathetic
1:1, discrete function
238
Neurotransmitter/receptors: parasympathetic
Preganglionic neurons release ACh → nicotinic cholinergic (N-N) receptors in ganglia
Postganglionic neurons release ACh → muscarinic cholinergic (M1-5) receptors in end organs
239
CNS origin: Sympathetic
Thoracic (T1-T12) and Lumbar (L1-L2) segments
240
Location of ganglia: Sympathetic
two paravertebral chains along spinal cord or in prevertebral ganglia in abdomen
241
Length of pre/postganglionic neurons: sympathetic
preganglionic SHORT, postganglionic LONG
242
Ratio of pre to postganglionic neurons: sympathetic
1:20-50, diffuse/widespread function
243
Neurotransmitter/receptors: Sympathetic
- Preganglionic neurons release ACh → nicotinic cholinergic (N-N) receptors in ganglia and adrenal medulla
- Postganglionic neurons release:
NE → a1-adrenergic receptors (blood vessels, eye, GI tract), B1-adrenergic (heart, low affinity), B2-adrenergic (smooth muscle)
ACh → muscarinic cholinergic (M) receptors in sweat glands
Dopamine → Dopamine D1 receptors in kidney vascular smooth muscle
- Adrenal medulla releases epinephrine and NE into general circulation → adrenergic synapses with a1, B1, and B2 receptors
244
Nicotinic receptor: ionotropic or metabotropic?
Ionotropic
245
3 types of nicotinic receptors
1. Ganglionic (Nn)
2. Skeletal muscle (Nm)
3. Neuronal CNS (Nn)
246
Muscarinic- ionotropic or metabotropic?
metabotropic
247
Where are muscarinic receptors located?
Postganglionic effector organs
248
Where are M1 receptors located?
CNS, enteric nervous system
249
Where are M2 receptors located?
Atria, SA, AV node
NOT VENTRICLES
250
Where are M3 receptors located? (5)
Glands, smooth muscle, bronchial muscle, GI/Gu tract, eye
251
G protein class coupled to M1
Gq
252
G protein class coupled to M2
Gi
253
G protein class coupled to M3
Gq
254
Muscarinic effect on the cardiovascular system
Decrease HR and AV conduction rate, and atrial contractility
Vasodilation (ONLY via production of NO → cGMP, NOT via innervation with PNS) = decrease BP (Note: this is an M3 effect)
255
Muscarinic effect on the respiratory system
bronchial muscle contraction, stimulate glands
256
Muscarinic effect on the GI tract
increased secretory and motor activity
257
Muscarinic effect on the GU tract
relax sphincters, contract detrusor muscle (promote voiding)
258
Muscarinic effect on the eyes
miosis (pupil constriction), accommodation (focus near vision), outflow of aqueous humor → decreased IOP
259
What are the receptors on:
1. dilator muscle of the eye
2. constrictor muscle and accommodation for near vision
3. thing on the eye that make aqueous humor
1. a1
2. M3
3. B2
260
Nicotinic neuronal (N-N) receptors are located where?
1. In autonomic ganglia
| 2. In CNS
261
N-N receptors effect in autonomic ganglia (2)
1. Cardiovascular: sympathetic effects (vasoconstriction, tachycardia, elevated BP)
2. GI/GU tract: parasympathetic effects (nausea, vomiting, diarrhea, urination)
262
N-N receptors effect in CNS
1. Mild alerting effect, tremor, emesis, respiratory stimulation
2. Activate “reward” pathway in limbic system (addicting potential)
3. Convulsions can occur at toxic doses
263
Peripheral adrenergic receptors in the vasculature (3)
1. a1 → vasoconstriction, increase in total peripheral resistance and BP (reflex bradycardia)
- Cutaneous, mucous membranes, splanchnic vasculature
- Renal vasculature constriction
2. B2 → vasodilation, decrease TPR and BP (reflex tachycardia)
3. D1 → renal vasculature relaxation
264
Peripheral adrenergic receptors in the heart (2)
1. B1 → increase SA node chronotropy, increase AV node conduction velocity, increase atrial/ventricular contraction (positive inotropy)
2. a2 → decrease in SNS outflow via CNS, decreases BP
265
Fight or flight
Sympathetic
i. Continuously active with level of activity constantly changing
ii. Widespread physiologic responses
266
Effects of fight or flight (5)
1) Increase HR, raise BP
2) Shift blood flow fro skin and splanchnic regions to skeletal muscle
3) Rise in blood glucose
4) Dilate bronchioles and pupils
5) Decrease GI/GU system activity
267
Rest and digest
Parasympathetic
i. Conservation and restoration of energy
ii. Single organ system, discrete, localized discharges
268
Effects of rest and digest
1) Slow HR, lower BP
2) Stimulate GI motility, secretions and nutrient absorption
3) Empty bladder and rectum
4) Protect retina from light (pupil constriction), focus for near vision
269
Tone
intrinsic level of activity determined by dominant branch
| also Billy's body, he's a toned motherfucka
270
Predominant tone in the body... any exceptions?
Predominant control almost always parasympathetic (exception = sympathetic control of blood vessels - do not have any parasympathetic innervation)
271
What are the questions you ask in at screen for PTSD?
1) Have had nightmares about it or thought about it when you did not want to?
2) Tried hard not to think about it or went out of your way to avoid situation that reminded you of it?
3) Were constantly on guard, watchful, or easily startled?
4) Felt numb or detached from others, activities, or your surroundings?
272
In the Diagnostic Criteria for PTSD, what is trauma defined as?
Exposure to actual or threatened death, serious injury, or sexual violence - direct exposure, witnessing, or learning of it.
Patient must view it as a trauma.
273
What are the main diagnostic categories of PSTD? (5)
- Trauma
- Intrusion
- Avoidance
- Negative alterations of cognition and mood.
- Arousal and reactivity
274
With regards to PSTD, what Sx are associated with Intrusion?
can’t get trauma out of their head, problems sleeping, nightmares, dissociative reactions, flashbacks
275
With regards to PSTD, what Sx are associated with Avoidance?
avoid distressing memories, thoughts, or feelings associated with traumatic event - can lead to isolation
276
With regards to PSTD, what Sx are associated with Negative alterations of cognition and mood?
- Inability to remember important aspect of the event
- Dissociative amnesia. Not other factors like head injury or drugs/alcohol)
- Persistence and exaggerated negative beliefs/emotional state (fear, horror, anger, built, shame)
277
With regards to PSTD, what Sx are associated with alternations in Arousal and reactivity?
- Irritable and angry outburst
- Reckless/self-destructive
- Hypervigilance
- Exaggerated startle response
- Problems w/ concentration
- Sleep disturbances; falling/staying/restless sleep
278
With regards to PTSD, disturbance lasts for a minimum of ___ days, maximum of ___ month, and occurs within ___ weeks of traumatic event
3 days
1 month
4 weeks
279
What are the main diagnostic categories of PSTD? (5)
-Trauma-Intrusion-Avoidance-Negative alterations of cognition and mood.-Arousal and reactivity
280
With regards to PSTD, what Sx are associated with Negative alterations of cognition and mood?
- Inability to remember important aspect of the event- Dissociative amnesia. Not other factors like head injury or drugs/alcohol)- Persistence and exaggerated negative beliefs/emotional state (fear, horror, anger, built, shame)
281
With regards to PSTD, what Sx are associated with alternations in Arousal and reactivity?
- Irritable and angry outburst- Reckless/self-destructive- Hypervigilance- Exaggerated startle response- Problems w/ concentration- Sleep disturbances; falling/staying/restless sleep
282
What are the mechanism by which ANS drugs act? (3)
Direct Agonist- Antagonist - Indirect Agonist/Antagonist
283
ANS drugs that act to mimic NT action at receptor level are ?
Direct Agonist
284
ANS drugs that act to block NT action at receptor level are ?
Antagonist
285
What is the MOA of Indirect Agonist/Antagonist ANS drugs?
Change normal action of NT.
286
Indirect Agonist/Antagonist ANS drugs change normal action of NT, in what ways do they/can they do this?
- Synthesis of NT.
- Storage and release of NT.
- Inactivation of NT following release. (*Less clinically useful because they affect all synapses for that particular NT regardless of which specific postsynaptic receptor subtype is present.)
287
Most clinically useful are drugs that act at the ____ (post or pre?)--synaptically at specific receptor subtypes as agonists or antagonists
POST!
288
Between a direct agonist and a direct antagonist ANS drug, which one is more clinical useful?
antagonist! More clinically useful, act post-synaptically at specific receptor subtype
289
Botulinum toxin*: ____1____ ACh release
Black Widow Spider toxin*: ____2____ ACh release.
1. blocks
| 2. increases
290
What are the two subtypes of Cholinergic Receptors?
Nicotinic ReceptorsMuscarinic Receptors
291
ligand gated, alter ionic permeability are the actions of what type of Cholinergic Receptors?
Nicotinic Receptors:
292
G-protein coupled receptors, alters enzyme activity are the actions of what type of Cholinergic Receptors?
Muscarinic Receptors:
293
Nicotinic Receptors: ?
ligand gated, alter ionic permeability
294
Muscarinic Receptors: ?
G-protein coupled receptors, alters enzyme activity
295
Gq → ____1___ PLCGi → ___2____ AC
1. increase
| 2. decrease
296
What [M] subtype is associated with Gq and what type of cell/organs are they on?
M1 = neuronal, GI glands
M3 = exocrine glands, smooth muscle
297
What [M] subtype is associated with Gi and what type of cell/organs are they on?
M2, M4 = heart, CNS
298
What are the direct acting Muscarinic Cholinergic Receptor Agonists?
Choline Esters:
- Acetylcholine*: not used, rapid hydrolysis by AChE
- Bethanechol*: synthetic analog of ACh, resistant to AChE.
Parasympathetic Alkaloids:- Pilocarpine*
299
What are the Nicotinic Neuronal (ganglionic) Receptor Agonists
- Nicotine* → increase BP, HR, vasoconstriction, increase GI motility, arousal, euphoria, increased attention Prolonged or toxic dose can cause antagonism due to persistent depolarization → renders membrane unresponsive
- Acetylcholine*
300
What is the MOA of Muscarinic Cholinergic Receptor Antagonists?
antagonize ACh, reversible (competitive) inhibitors (aka anticholinergic and antimuscarinic)
301
What are the Muscarinic Cholinergic Receptor Antagonists?
Alkaloids:
- Atropine*
- Scopolamine*Semi-Synthetic Agents: higher selectivity of antagonism particularly parasympathetic function (bladder especially).
- Oxybutynin*, Ipratropium*
302
What is the overall MOA of Acetylcholinesterase Inhibitors?
Indirect agonist?
303
List the Acetylcholinesterase Inhibitors. (4)
- Physostigmine
- Neostigmine, Pyridostigmine
- Edrophonium
- Organophosphates (nerve gas, insecticides) act indirectly to inhibit acetylcholine esterase → too much acetylcholine
304
nerve gas, insecticides are what type of Acetylcholinesterase Inhibitors?
Organophosphates
305
List the adrenergic agonist drugs:
- Epinephrine
- Pseudoephedrine
- Norepinephrine
- Phenylephrine
- Clonidine
- Isoproterenol
- Albuterol
- Dobutamine
- Dopamine
306
List the adrenergic antagonist drugs:
- Doxazosin
- Propranolol, Timolol = Non-selective B1 and B2
- Metoprolol, Atenolol = B1 cardioselective (only at lower doses)
- Labetalol, Carvedilol
307
What adrenergic antagonist drug is non-selective for beta1 and beta 2?
Propranolol, Timolol
308
What adrenergic antagonist drug is beta1 cardio-selective? (only at lower doses)
Metoprolol, Atenolol
