Neural Circuits (CPG, Respiration, Sleep) Flashcards
central pattern generators
neuronal circuits that when activated can produce rhythmic motor patterns such as walking, breathing, flying, and swimming in the absence of sensory or descending inputs that carry specific timing information
why are motor circuits easy to study and measure?
motor behaviours are easy to define and measure unlike cognitive
invertebrate examples for CPG models
lecture 11 first page
lobster/crab - stomach chewing crayfish - escape clione - swimming tritonia - escape (bend + jump) leech - muscle activation locust - complex, flight/kick
advantage of invertebrate models of CPG
disadvantages
simple NS (few Ns and small no.types), can record during motor behaviour
may be complex with electrical signals in places where might not see, may not be possible to record close to postsynaptic and integrative sites, techniques not developed for many species, signalling differs for vertebrates so generalisation issue
advantages of vertebrate models of CPG
disadvantages
applicable to humans, use molecular genetic techniques, better Abs and pharmacological agents
complexity (tadpole/lamprey better), great redundancy (lots each type), harder to record in situ, anaesthesia in vivo changes activity
vertebrates examples for CPG model
cats - locomotion, plot limb movement
lamprey - swim, primitive NS
tadpoles - swim, simple in early development
rat/mice - use gene knockouts
how to study motor pattern generation
1) define behaviour - measure
2) neural machinery - record muscles/nerves
see if movement related to neural activity
Leech swimming motor pattern
waves of bending and how fast travel along length
measure tension and nerve recordings
left segments activity before right so head to tail bending (delay)
Cat locomotion (phases)
swing phase - from PEP to AEP (posterior extreme position to anterior)
stance phase - foot on ground so hip move and other foot move
measure angles and see change in neural activity
Humans walk/run
record angles and activation of muscle groups
Reflex Hypothesis
rhythmic movements generated through sequence of reflexes (dependent on feedback)
Central Hypothesis
central circuits generate without sensory feedback so reflexes not important
which hypothesis is correct? (reflex or central)
removing all sensory feedback shows all rhythmic motor behaviour like laughing is controlled by central networks -> CPGs
but movement feedback coordinates behaviour because removing sensory feedback alters motor pattern (but is still generated) so it entrains motor pattern that is centrally generates
e.g. human disease w/o feedback means can still walk but differs
Lamprey (categories, entrain, CC)
swim, wiggle spinal cord left right (oscillations in membrane potential match motor nerve recordings)
categories of neurones - 2 motor, CC interneurones, edge cells, dorsal cells, giant interneurones, lateral interneurones, excitatory interneurones
imposing slower movement slows CPG because stretch receptors in spinal cord
killing opposite side of spinal cord disturbs rhythm of other side - CC role
modern view on CPGs (conclusion)
central circuit has everything for motor activity
turned on/off by higher command centres (decision)
coordinate sensory input (if in at wrong time)
stretch receptors in muscles fine tune and entrain patterns
Xenopus embryo (tadpole) (HRP, classes, origins of drive)
lower vertebrate model of swimming used HRP (horse radish peroxidase) to see if it would cross the spinal cord from one side to other categorise types of neurones (lecture 12 first page)
2 classes of C motor neurones - d descending interneurone and c commissural interneurones on opposite sides of spinal cord and form neural circuit for swimming
reciprocal inhibitory interneurones - commissural with crossed axon, important in circuit because glycinergic inhibition (it uses glycine NT) will change speed of swimming/block
immunocytochemistry to identify neurones
stain with glycine Ab so show neurones that use glycine as NT
criteria to determine if neurone contributes to CPG
lecture 12 bottom first page and top second page
is it active during motor behaviour? (some copy rhythm not generate) - necessary but not sufficient
is it used to reset rhythm? - sufficient but not necessary
if inactivate/destroy/block activity does the generation stop?
need to demonstrate all 3
tonic and phasic
slow and fast
V2a in Zebrafish
excitatory interneurones, removing cells affects ability to produce swimming and NMDA which usually excites neurones and swimming has a weaker effect
activation of these cells sufficient for swimming (blue light experiment - have light sensitive ion channels
the wiring diagram
lecture 12 page 3
post-inhibitory rebound
inject -ve current so hyperpolarises, then fires AP when recovers (rebound) so circuit carries on
pacemaker neurones in Clione
carry on generating rhythm without input (endogenously)
carries on if drag cell out ganglion so endogenous pacemaker
mid-cycle inhibition
between APs
lamprey spinal neurones pacemaker properties
some cells still oscilate w/o AP (NMDA and TTX to stop AP)
injecting current changes speed/freq of oscillations
computational and mathematical models of neural circuits
uses?
want simple model to understand complex
combine models of body and movement to neurones
understand roles of cells and components
make predictions on function
extract general principles of circuit behaviour
breathing disorders
Joubert syndrome (rapid breath) Rett syndrome (difficult while awake) Ondine's curse (while asleep) Sleep apnoea (obstructive) Sudden Infant Death Syndrome (don't know cause)
phases of respiratory pattern
inspiratory (phrenic nerve innervates diaphragm)
expiratory (post-inspiratory)
then active expiration (induced by exercise, cough, sneeze, force air out)
The pre-Bötzinger complex (preBötC)
a central pattern generator in brain stem in medulla oblongata that is important for the generation of respiratory rhythm
with long columns of cells going from cVRG (caudal ventral respiratory group) to rVRG (rostral)
and a few nuclei in pons
NTS
sensory control of breathing
damage to medulla
severely compromise breathing
experiment in rodent neonates showing breathing CPG
record from nerves equivalent to phrenic, shows rhythmic bursts of respiration
without pons the brainstem can generate rhythm but speeds a bit
weak evidence that preBotC involved in breathing
good evidence (Jack Feldman)
neurones fire before breathing
axonal projections restricted to medulla
activation GABA receptors cause apnoea (maybe leaked and affected others)
isolate medulla and chop bits off and record
hardly any rhythm w/o region 8 and none w/o region 9 so critical area with preBotC
experiment showing NK1 receptor
substance P on preBotC speeds and enhances respiratory rhythm so have receptor for P (NK1)
toxin with P ligand internalised and kills neurones
saporin toxin (from flower)
ribosome inhibitor - so protein production
SP-saporin, SP-SAP (substance p with saporin) injected to brainstem and NK1R neurones killed
and severe breathing perturbations
why is the genetic approach better?
better than killing neurones because genetic is reversible
genetic approach to preBotC
insect allatostatin receptor in preBotC expressed in mammal brain, nothing happens till inject allatostatin ligand which is inhibitory and rapid inactivation of neurones (reversible)
breathing weaker and apnea
chemosensory control of breathing
PO2 falls, PCO2 increases –> breathing increases
where is O2 sensed?
in periphery, chemosensory cells in carotid bodies in bifurcation (branches) of carotid artery
external branch to head, internal branch to brain (supplies blood to brain)
what are the effect of changing O2?
phrenic nerve more powerful and breathing stronger in hypoxia
type 1 glomus cells release ATP which activates P2X 2/3 receptors on sinus nerve which acts as NT so firing of sinus nerve
what happens when cut carotid sinus nerve?
this goes from the carotid body to the NS, there is no response but weaker phrenic nerve so important in detection
plasticity of hypoxia
periodic hypoxia caused short term enhancements of breathing but then long term facilitation minutes after last hypoxia
Congenital Central Hypoventilation Syndrome
Ondine’s curse - breathing stops when asleep
lack chemosensitive reflexes
need ventilation when young, fine when adult (only in sleep)
where is PCO2 detected?
ventral surface of medulla oblongata
rostral and caudal area
detected as CO2 or pH (bigger response if pH too)
Cx26
connexin 26 gap junction protein
receptor opens when CO2 binds
CO2 binds lysine residue (amine of lysin) which salt bridge to arginine of neighbour subunits
conformational change traps channel in open state so allow ATP to leave cell and excite respiratory neurones so breathe stronger
knockout Cx26 from glial cells causes no change in CO2 dependent respiratory rate (carotid body affect it) but tidal volume reduced by 1/2
so 1/2 reponse mediated by CO2 sensing
Keratitis Ichthyosis Deafness (KID) syndrome
mis-sense mutation Cx26
skin abnormalities, visual impairement, deafness
central apnea
patterns of sleep
slow wave sleep (non-REM)
REM sleep
occur in organised fashion with diff characteristics
slow wave sleep (non-REM)
deepest
slow Delta waves in EEG
brain relatively inactive - energy expenditure low
muscles relaxed but capable at moving - adjust every 20 mins
some dreaming but less vivid
REM sleep
rapid eye movement
paradoxical
short periods throughout night get longer till wake
might wake during night
brain as active as consciousness (energy expenditure high)
vivid dreams
body paralysed so don’t act out dreams
underwater mammals
dolphins have to come to surface to breathe
sleep with 1/2 brain at a time or microsleep (short) add up to enough throughout day
evolution of sleep
can’t record EEG and have no SW/REM of fish/amphibia so look at behavioural sleep
birds/mammals/placentals (humans) have behavioural and REM/SW
invertebrates have behavioural sleep
behavioural sleep
sleeping posture, sleeping site, quiescent, elevated arousal threshold (hard to wake)
purpose of sleep
out of trouble (maybe) rest/repair brain coding development learning/memory resistance to illness brain flushing
illness and sleep experiment
given rhinovirus
< 7 hours sleep meant 3x more likely to get cold than >8 hrs
brain temperature and sleep
rats - sleep in light so less metabolic activity and brain cooler
dolphins - temp drops in 1/2 sleeping
humans - raised temp increases SW
development and sleep
10 weeks premature - 80% REM 2-4 weeks premature - 60-65% REM born - 50% REM age 2 - 30-35% REM adult - 25% REM
brain flushing of waste in sleep
experiments
CSF tracer diffuses further in brain during sleep
inject TMA ion - less current in sleep, extracellular space bigger so more parts for TMA to escape and assists removal of waste
toxic AB peptide - beta amyloid link to Alzheimer’s, come out quicker during sleep
memory and sleep
unrelated words not remembered if 12 hrs awake,
unrelated when 12 hrs sleep remembered as well as related words when awake
performance increases as sleep increases (if both components of sleep)
benefits with motor skills, visual, word association
rats replayed brain activity during maze during sleep but quicker
areas of brain controlling sleep
VLPO (ventral lateral preoptic area) controls SW (slow wave)
basal forebrain
TMN (tuberomammillary nucleus) in wakefulness
LDT + PPT REM on nuclei
Raphe + LC REM off nuclei
lateral hypothalamus
many more
basal forebrain
Stimulating the basal forebrain gives rise to acetylcholine release, which induces wakefulness and REM sleep, whereas inhibition of acetylcholine release in the basal forebrain by adenosine causes slow wave sleep
preoptic areas, cholinergic neurones, projections to cortex so awake and inhibition sends to sleep
neurones active during SW not REM/awake
some state dependent activity so active in SW or awake/REM or don’t care
lesion in basal forebrain causes insomnia
areas controlling REM
LDT/PPT cholinergic switch REM on
LC/DRN switch REM off (noradrenaline&5-HT)
ascending arousal system - nuclei using 5-HT or histamine or noradrenaline project up to cortex and tweak circuit so awake
TMN uses histamine for wakefulness
neurones fire before REM, others during REM to turn off
REM/SW coordinated by…?
VLPO area
part in REM, other in SW
orexin (hypocretin)
mRNA, peptides, narcolepsy, neurones in LH
mRNA in hypothalamus
peptide stimulate orphan G-coupled R and increase foot uptake
2 peptides and 2 receptors - orexin A activates both Rs, orexin B only Ox2R
narcolepsy - suddenly fall asleep, lack orexin neurones in hypothalamus
orexinergic neurones in lateral hypothalamus (LH) project to other nuclei that control sleep , prevent rapid switching from sleep to wakefulness if lose neurones
orphan G-coupled receptor
without ligand
learning and plasticity changes….
microstructure of brain
brain stops developing around age..?
but can…
20
still change in adults like taxi drivers learn roads
spatial knowledge in..?
so taxi drivers have..?
hippocampus
bigger posterior hippocampus because more neurones activated and anterior slightly smaller
simple model of learning
aplysia lives in the sea
gill withdrawal reflex inhibits plasticity when prod - learn that it’s meaningless so withdraw less each time but if shock tail gill withdrawal increases then decrease again
types of synaptic plasticity
homosynaptic
heterosynaaptic
homosynaptic plasticity
activity-dependent
only require pre and post synaptic cell
enhancement(facilitation) or depression depends on activity in pre
heterosynaptic
modulatory input-dependent
3rd player - modulator neurones change strength of synapse
changes in synaptic transmission (aplysia e.g.)
increase NT with more vesicles per AP or increase receptor sensitivity with more of them
Aplysia - more vesicles, AP broadens with 5-HT because inhibits K in repolarisation so takes longer so more Ca
(5-HT act on GPCR activates cAMP activates PKA phosphorylates S type K channel so prevent opening)
long term changes - some PKA to nucleus activate CREB activates genes, alter expression, new synapses
human hippocampus pathway
input to Dentate gyrus synapse to CA3 to CA1 AP cause EPSP in CA1 (glutamate release from pre) activate AMPA receptor (glutamate R) synapse highly plastic (homosynaptic)
Morris water maze
hidden platform, mouse tries to find it
can’t remember where with hippocampal lesion
LTP (definition, experiment, requirement)
long term potentiation
persistent strengthening of synapses based on recent patterns of activity - so learning and memory
activate Schaffer colateral axons CA3 to 1 and measure amplitude - tetanus increases synaptic strength and repeated tetanus means increase lasts a few hours
requirements for LTP - post synaptic cell (CA1) depolarisation and calcium influx and activation of NMDARs
NMDA receptor features
1) EPSP slower lasts longer so window for coincidence detection (if another neurone is stimulated) and summations of EPSP during tetanus
2) voltage dependent Mg blockage of NMDA channel, detect coincidence, depolarise to draw Mg out
3) Ca permeability, so influx into post critical to triggering consequence of coincidence and results in synapse strengthening
coicidence
neurone encodes info by detecting temporally close but spatially distributed input signals
LTP process
high f firing of presynaptic causes EPSP by AMPA
AMPA potentials summate and depolarisation causes NMDA unblock so Ca influx
Ca activates calmodulin which activates calmodulin kinase 2 (CaMKII) and phosphorylates AMPA and vesicles with AMPA fuse so more receptors in membrane and enhanced synapse
Hebbian plasticity
if activation of synapse results in postsynaptic firing AP then synapse strengthens
(depolarise enough to unlock NMDA)
aplysia vs hippocampal LTP
heterosynaptic and homosynaptic while hippocampal is homo
change down to presynaptic NT increase while hippoc. down to change in receptor number and kinetics
5HT triggers cAMP as 2nd messenger while hippoc. Ca influx through NMDA activates CaMKII
