Download G. Nervous system physiology a. Explain the basic

G. Nervous system physiology
a. Explain the basic electrophysiology of neural tissue.
Cell Membrane Potential
Resting potential is maintained by active transport of ions by Na+,K+ ATPase against
the passive diffusion of K+ out of the cell.
Conventionally negative (inside cell) -70 to -90mV
Ion gradients in nerve cell
ICF ECF
Na+
15
150 +60mV
K+
150
5.5 -90mV
Cl
9
125 -70mV
net resting potential -70mV
relationship between gradient and potential is described by the Nernst
equation:
RT Co 61.5
C
E=
ln
=
log o
FZ Ci
Z
Ci
the membrane potential as a whole is described by the Goldman field equation:
+
+
−
RT PK [K ]o + PNa [Na ]o + PCl [Cl ]i
V=
ln
+
+
−
F
PK [K ]i + PNa [Na ]i + PCl[Cl ]o
The membrane is much more permeable to K+ and Cl- than to Na+ or Ca2+. K+ causes
most of the potential, Cl- is passively distributed according to the membrane
potential.
Nerve cells
A myelinated nerve cell consists of a soma with dendrites, an axon hillock with axon
attached, sheathed in Schwann cells punctuated by Nodes of Ranvier, and ending in
terminal buttons.
When an electrical or other stimulus raises or lowers the resting potential of the
nerve cell slightly, the normal potential is restored over 0.5 to 1 ms by K+ and Cl- flux.
When the resting potential is raised above -63 mV, Na+ permeability through ion
channels increases, helping to sustain the electrotonic potential.
Above -55 mV, Na+ permeability increases suddenly, flux becoming greater than the
rate of transport out of the cell and an action potential results. The membrane
potential spikes to +35 mV. There is a rapid reduction in Na+ permeability and a
slower increase in K+ permeability and flux, repolarizing the cell. The Na+ channels
enter an inactivated state, causing the absolute refractory period, before returning to
the resting state.
Channels are concentrated at the Nodes of Ranvier. When an action potential occurs
at one node, it induces a depolarization at the adjacent node, starting another action
potential if the node is not refractory. This is saltatory conduction. Because of the
refractory period, saltatory conduction is unidirectional.
Extracellular Na+ concentration does not affect excitability much as the membrane
isn't very permeable. A rise in extracellular K+ stabilizes cells by decreasing the
membrane potential. A rise in extracellular Ca2+ stabilizes cells by increasing the
depolarization required to initiate an action potential.
Ca2+ may play a role in the spike due to influx through Na+ channels and also enters
the cell through separate channels during the late phase of hyperpolarization.
Nerve fibres
Classified by diameter (∝ conduction velocity)
Aα (Ι)
proprioceptive, somatic motor
Aβ (II)
light touch, pressure
Aγ
motor to muscle spindles
Aδ (III) pain, heat, touch
Nervous
1.G.1
James Mitchell (December 24, 2003)
B
preganglionic autonomic
C (IV)
pain, sympathetics
Larger fibres are more susceptible to pressure and hypoxia and less susceptible to
local anaesthetics.
When bundled into nerves, the electrical behaviour seen is different from individual
fibres due to a range of sensitivities and conduction velocities of the fibres in a nerve.
Nerves display compound action potentials and show a ceiling responce to maximal
stimuli.
Synapses
Junctions between nerve cells.
May be electrical (gap junction) or chemical:
consist of a synaptic knob containing vesicles of transmitter, a 20-30 nm
synaptic cleft and postsynaptic membrane.
Release of neurotransmitter is initiated by rising intracellular Ca2+ during
action potentials causing exocytosis.
Neurotransmitter binds to receptors on the postsynaptic membrane, opening
specialized Na+ channels which raise the membrane potential (Excitatory PostSynaptic Potential) or to Cl- channels which lower the membrane potential
(IPSP). Slow EPSPs and IPSPs are caused by transmitters which alter the
permeability to K+.
Each neurone releases only one neurotransmitter and so is either excitatory or
inhibitory. Inhibitory interneurones allow one neurone to act to generate both
EPSPs and IPSPs.
If enough EPSPs sum in time and place, an action potential can be generated.
There is also direct transmission of electrical potential within a single cell
without action potentials.
b. Describe sensory and motor pathways.
sensation
receptors
mechano
skin (multiple types), deep tissue, muscle (spindle), tendon
others: hearing, balance, baroreceptors
temperature
warm and cold, peripheral and hypothalamic
pain
mechano and polymodal
chemo
general: taste, smell
specific: carotid/aortic bodies (O2 and CO2), hypothalamic (osmolarity,
glucose, amino acids, fatty acids)
stimulation produces a change in discharge frequency which decays with
adaption. Vibration and light touch require rapid adaption, pain and
proprioception display minimal adaption.
afferent pathways
fibre types are specific to receptor types
Ia
17 µm annulospiral muscle spindle fibres
Ib
16 µm Golgi tendon organs
II
8 µm most skin receptors
III
3 µm crude touch and sharp pain
IV
unmyelinated 0.5 µm to 2 µm pain, itch, temperature, touch
transmission from the primary afferent is often transmitted by both a fast
transmitter, causing a brief depolarization and one or more slow transmitters
causing a prolonged EPSP which causes sensitization to further signals
Nervous
1.G.2
James Mitchell (December 24, 2003)
signals can also be prolonged by reverbatory circuits, or reverbatory curcuits
can produce a continuous rate of depolarization which is modified by
inihibitory or excitatory inputs
perception in the cord is sharpened by convergence and lateral inhibition
excitation in the cord is limited by descending inhibitory pathways and
synaptic fatigue
ascending pathways
dorsal column-medial lemniscal system
primary large myelinated afferents divide into two branches
medial runs directly to the brain in the dorsal columns
lateral synapses in the dorsal horn to provide
spinal reflexes
spinocerebellar tracts
spinocervical tract
input to contralateral spinothalamic tract
dorsal column fibres synapse in the cuneate and gracile nuclei,
cross and ascend to the thalamus and then the cortex
anterolateral pathway
transmits pain, heat, cold, itch, tickle and crude touch
primary afferents synape in the ipsilateral dorsal horn
secondary fibres cross to the opposite anterolateral tract and ascend as
the anterior and lateral spinothalamic tracts, the spinoreticular and
spinotectal tracts
synapse in the reticular nuclei of the brainstem and the thalamus
descending pathways
c. Describe the physiology of pain.
In Pain Pharmacology (2.B.3).
d. Describe the physiology of cerebrospinal fluid.
function
protection “floating” of brain and spinal cord
constant chemical environment
some nutrient content
some excretory function
transport of neurohormones within CNS
production
0.35 ml/min (500 ml/day) not affected by ICP unless CPP <70 mmHg
total volume 150 ml
choroid plexus produces 40-70%
fenestrated endothelium in capillaries
controlled secretion by epithelial cells
Na+/K+ ATPase-driven transport of ions, glucose and nutrients
ependyma adds 30-60% by oxidation of carbohydrates and ultrafiltration
composition
CSF
plasma
pH
7.31
7.41
+
Na
141
140
mmol/l
K+
2.9
4.6
mmol/l
Ca2+
1.3
2.5
mmol/l
Mg2+
1.2
0.8
mmol/l
Cl
124
101
mmol/l
glucose 3.5
4
mmol/l
protein 0.3
70
g/l
Nervous
1.G.3
James Mitchell (December 24, 2003)
reabsorption
90% in arachnoid villi
10% in spinal subarachnoid
determined by ICP
zero at 68mmCSF
equilibrium at 112mmCSF
drugs
diuretics ↓ production
acetazolamide reduces H+ availability for Na+/H+ exchange
frusemide inhibits NaCl transport
ethacrynic acid inhibits Na+/H+ exchange
spironolactone inhibits Na+ transport
steroids ↓ production
digoxin weak ↓ production from Na+,K+ ATPase inhibition
volatile agents
most ↓ absorption
some ↓ production (halothane, sevoflurane)
e. Describe the autonomic nervous system and explain its role in controlling body
function.
In Thoracic Anatomy (3.G.1).
f. Describe neurotransmitters and their physiological role.
released from presynaptic neuron
synthesis
only one type of fast transmitter in one neuron
ACh
choline + acetyl-CoA
amines
synthesized in cytoplasm
e.g. tyrosine → DOPA → dopamine → noradrenaline → adrenaline
glutamate → GABA
tryptophan → 5-OH trp → 5HT
histidine → histamine
amino acids are derived from uptake from blood and transamination
NO
synthesized from arginine by NO synthase
neuropeptides
synthesized in RER
very small quantities
transported to terminals by axonal transport
much more potent but act slowly and for a prolonged period
storage
vesicles near the synaptic junction for all transmitters except NO
release
in response to action potential
detail above and in Physiol H and Pharm B VII
metabolism
ACh
cholinesterase
amines
reuptake by pre- and post-synaptic membrane transport
MAO and COMT
GABA transaminated by GABA-T → succinic semialdehyde → succinate
Nervous
1.G.4
James Mitchell (December 24, 2003)
rapid
slow
Class I
acetylcholine
Class II (amines)
noradrenaline
adrenaline
dopamine
serotonin
histamine
Class III (amino acids)
γ-aminobutyric acid
glycine
glutamate
aspartate
Class IV
NO
lipids
arachadonic acid derivatives
neurosteroids
hypothalamic
TRH
LHRH
somatostatin
pituitary
ß-endorphin
MSH
prolactin
LH
TSH
GH
ADH
oxytocin
gut and brain
leu-enkephalin
met-enkephalin
substance P
CGRP
gastrin
cholecystokinin
VIP
neurotensin
insulin
glucagon
others
angiotensin II
bradykinin
carnosine
sleep peptides
calcitonin
receptor types (not dealt with elsewhere)
GABAA
pentameric transmembrane ligand-gated Cl- channel
multiple subunit types (α, ß, γ, ∂, ρ) → hundreds of receptor subtypes
several binding sites
Nervous
1.G.5
James Mitchell (December 24, 2003)
GABA → opens Cl- channel, IPSP
BDZ requires α, ß, γ subunits, binds α → ↑ GABA binding
several subtypes of BDZ binding site
ß-carboline binds at BDZ site → ↓ GABA binding (inverse agonist)
alcohol, barbiturates, progesterone also facilitate GABA transmission
GABAB
G-protein linked receptor
↑ K+ conductance, ↓ Ca2+ conductance
presynaptic inhibitory role in pain transmission and elsewhere
activated by baclofen, midazolam → analgesia
other GABA receptor roles
monocyte chemotaxis
ß cells in the pancreas
glutamate receptors
AMPA, kainate
ligand-gated Na+ channels
4 or 5 subunits, multiple subunit types, hundreds of channel subtypes
fast excitatory response
NMDA
complex receptor, Ca2+ channel when activated
normally inactive with Mg2+ in channel
inhibited by ketamine, phencyclidine binding in channel
binding of glycine facilitates activation
prolonged depolarization causes escape of Mg2+
activation causes ↑ Ca2+ conductance
prolonged activation causes NO production, c-fos expression
may play a role in neuronal death (↑ glutamate released from ischaemic
nerve cells)
glycine
pentameric Cl- channel → IPSP
α and ß subunits
antagonized by strychnine → convulsions
g. Explain the physiology of the control of intracranial and intraocular pressure.
ICP
uniform pressure within cranial vault
normal range 5-13 mmHg at rest
rises with intrathoracic pressure due to transmission of BP changes
determined by
brain volume
blood volume
CSF volume
changing one must alter the others (Monroe-Kellie Doctrine) as volume is
constant
measurement
qualitative
MRI, CT
quantitative
catheter in ventricle/cerebrum/subarachnoid/extradural space
transducer outside or at tip of catheter
cerebral circulation
Circle of Willis supplied by ICA and basilar arteries
grey matter 80 ml/100 g/min, white 20 ml/100 g/min, total 50 ml/100 g/min
slightly less in cord
Nervous
1.G.6
James Mitchell (December 24, 2003)
measurement
Kety-Schmidt technique
uses Fick principle
uptake of tracer = perfusion x extraction
Qb = F ∫ (Ca - Cv) dt
Qb = Cb • Massb
Cb = Cv • λ (at equilibrium)
Cv λ
F
=
Massb
∫ (Ca - Cv) dt
N2O at low concentration is the tracer used
Ca and Cv are measured continuously
at radial artery and IJV
until equilibrium
λ is assumed to be 1 for N2O
result is expressed in ml/100 g/min
radioactive tracers
133
Xe, 85Kr as gases
organic compounds including 11C, 15O, 13N or 18F
detected by scintigraphy, PET, autoradiography
flow probes
doppler, electromagnetic
MRA
O2 extraction monitoring
jugular bulb oximetry
near IR spectroscopy
flow is autoregulating
CPP 50-150 mmHg (CPP = MAP - ICP)
largely myogenic and gas pressure determined
PCO2 causes linear response in CBF over 20-70 mmHg
1-2 ml/100 g/min/mmHg
due to pH change, so attenuated with buffering over time
PO2 causes rise in CBF below 50 mmHg
no change at 60-300 mmHg
small fall >300 mmHg
vessels are innervated by sympathetic, parasympathetic, trigeminal and
intrinsic nerves which have little effect
if BBB is impaired: α agonists ↓ CBF, ß agonists ↑ CBF
requirements
22 ml/100 g/min
EEG changes
15 ml/100 g/min
isoelectric EEG
6 ml/100 g/min
cell death
directly related to O2 requirement (CMRO2)
normal 3-3.5 ml/100 g/min
5-10 s reserve before unconsciousness
reduced by
cerebral depressants (barbiturates etc) up to 60% reduction
hypothermia up to 90% reduction at 17˚
h. Describe the integration of central nervous system activity via the cerebellum,
hypothalamus and limbic system.
i. Describe the physiology of sleep.
j. Outline the basis of the electroencephalogram.
Nervous
1.G.7
James Mitchell (December 24, 2003)
In Monitoring (3.B.2).
Nervous
1.G.8
James Mitchell (December 24, 2003)