Neuro Flashcards
what are skeletal muscles innervated by?
large diameter Aa motor neurones which are fast conducting
what is a motor unit?
The number of muscle fibres controlled by one motor neurone. It may contain 10-150 fibres.
Smaller motor units exist in areas requiring fine control e.g facial, extraocular, intrinsinc laryngeal muscles
what is the main neurotransmitter in the motor end plate
Acetylcholine
Steps of acetylcholine production
- Acetyl CoA is produced from ATP which is formed in Krebs cycle
- Choline comes mainly from recycled breakdown products of ACh & diet. small quantities are synthesized in the liver.
- Choline Acetyltransferase increases the speed which they combine to form ACh
Acetyl-CoA + Choline = Acetylcholine
What are the types of smooth muscle?
1.Visceral- large sheets in blood vessels & lining of hollow viscera eg bladder, uteru, GIT
- Multiunit: important for fine control eg iris, also in large arteries, bronchi, erector pili muscles
How much CSF is produced per day
Around 500ml
How much CSF is there at any one time?
Around 125 ml
Normal ICP
5-15mmHg (some places quote 8-12)
Cerebral blood flow
50ml/100g brain tissue/ min when between a MAP of 60 and 150 mmHg
equates to around 750ml/min blood flow going to the brain.
Cerebral perfusion pressure calculation
CPP= MAP - ICP
MAP =(SBP + 2xDBP)/ 3
What is fluid flux across BBB mainly determined by?
Plasma osmolality (not oncotic pressure)
Sim for CPP 60-70 mmHg
How is ACh stored
1% Immediate Pool (VP2) adjacent to release sites on presynapatic membrane.
80% Reserve Pool (VP1)) tethered to filamentous network of actin, synapsin and synaptotagmin ready for use in case of repetitive nerve stimulation.
19% stationary store in pre-terminal part (not immediately available).
What happens when action potential arrives at neuromuscular junction ?
(triggered release)
- Voltage gated calcium channels open, allowing influx of calcium ions
- Calcium activates SNARE proteins on vesicular & pre-synaptic membranes
- Once activated ACh vesicles dock to presynaptic membrane allowing exocytosis of ACh into the cleft. There is also release of ACh from the reserve pool (VP1)
Note: botulinum toxin targets SNARE proteins preventing ACh release into the cleft & hence causes a flaccid paralysis.
How does ACh release cause a postsynaptic end-plate potential?
- ACh diffuses across synaptic cleft to bind with the nicotinic ACh receptors, allowing sodium influx and depolarisation of the end-plate.
- 100-300 vesicles are required to depolarise the post-synaptic membrane
Tell me about the nicotinic Acetylcholine Receptor
-The nicotinic ACh receptor is a ligand-gated ion channel comprised of 5 subunits.
-total molecular weight of 250kDa
-each subunit has 4 a-helices that span the membrane
Adults: 2a, B, D, E subunits
Foteus:2a, B D, Y subunits (think babY)
For it to function, 2ACh molecules must bind to the 2a-subunits allowing a lumen to open 0.65nm wide allowing Na+, Ca2+, K+ movement.
ACh is bound for 1-2ms before being release back into the synaptic cleft.
How is ACh deactivated
Acetylcholinesterase rapidly hyrolysis ACh once released from the receptor.
AChE is bound to collagen-Q on the bottom of the post-synaptic membrane and has 2 binding sites:
-Anionic site- negatively charged glutamate group forms reversible bond with the quartenary amide group on ACh
-Esteric site: contains serine amino acids which hyrdolyses ACh into choline and acetic acid.
Choline is reabsorbed via presynaptic transporters & recycled
What is syncytial function?
syncytial function
-only occurs in visceral smooth muscle cells
-is the ability for an action potential to propagate to the next muscle cells due to gap junctions
In contrast, multiunit smooth muscle dont have connecting gap junctions. Each cell or fibre has its own nerve ending (think fine control)
Mechanism of smooth muscle contraction
1.initiation
-involuntary
-energy derived from glycolysis
-visceral smooth muscle is spontaneous or controlled by ANS.
-initiated through a rise in intracellular calcium coming from extracellular fluid.
- Cross-bridge formation
-calcium binds to calmodulin which activates calmodulin dependent light chain kinase .
-this catalyses myosin head phosphorylation allowing ATPase activation.
-ATP is hydrolyses to provide energy for actin and myosin filaments to slide over each other - Speed of Contraction;
-takes longer to develop and lasts longer as it lacks T-tubules & SR- greater diffusion distance to fibred & reduced surface area. Mechanism is also slower in smooth muscle
Mechanism of smooth muscle relaxation
-requires dissociation of calcium-calmodulin complexes. Myosin is they dephosphorylated by myosin light chain phosphatase.
-actin-myosis-cross-bridges remain intact at this point & is known as the latch-bridge mechanism to produce sustained contraction with low energy expenditure.
Visceral smooth muscle spontaneous activity
Visceral smooth muscle has an unstable membrane potential, therefore does not really have a resting potential. It averages around -50mV, which gets lower as the tissue is active, and higher with inactivity.
When threshold potential is achieved, the action potential propagates through syncytial function.
Parasympathetic smooth muscle tone
ACh released from PNS binds to M3 mAChR which are G-protein coupled & activated phospholipase C & IP3-> increase calcium influx. Therefore PNS allows increased motility, secretion & relaxation of sphincters
Sympathetic smooth muscle tone
-Opposite effect to parasympathetic. -Through alpha receptors: IP & diacyglyerol-> activated phospholipase C
-Beta receptors: Gproteins->cAMP. for some reason result sin decrease in calcium.
humoral factors influencing smooth muscle control
epinephrine & mechanical stress
multiunit smooth muscle function
non-synctial
action potentials don’t tend to occur spont, therefore control is by PNS & SNS & humoral factors (epinephrine & histamine)
Each muscle cell has it’s own nerve endings to allow fine control due to well localised contractions.
Nitric oxide function with smooth muscle
relaxes smooth muscle.
1. stimuli such as mechanical stretch & ACh cause increase in intracellular calcium in the endothelial cell
2. Nitric oxide synthase is activated to produce nitric oxide
3. NO diffuses into smooth muscle to activate guanyly cyclase-> formation of cyclic guanosine monophosphate (cGMP_ from GTP.
4. Activation of protein kinases leads to fall in intracelluar calcium in vascular smooth muscle & muscle relaxation
1.where does smooth muscle source calcium from
2.Where does the calcium bind to?
3. Function of calcium binding?
1.extracellular fluid. Sarcoplasmic reticulum is poorly developed
2. Calmodulin
3. Calcium-calmodulin complex activated myosin light chain kinase
1.where does skeletal & cad muscle source calcium from?
2.Where does the calcium bind to?
3. Function of calcium binding?
- Sarcoplasmic reticulum (intracellular)
- Calcium in skeletal & cardiac muscle binds to Troponin C
- Calcium binding removes inhibition of Troponin I resulting in exposure of myosin-binding sites.
which ACh receptors are nicotinic
-all pre-ganglions ACh receptors in the ANS (Except sympathetic for sweating which are muscarinic)
-postganglionic sympathetic NS ACh receptors (all except post-ganglionic Parasympathetic NS ACh receptors, which are muscarinic)
ACh receptors at motor end-plate of NMJ are nicotinic
what are extra junctional receptors
present in small numbers at sites in muscle membrane distant to motor end-plate.
significant in denervation when they proliferate over the muscle membrane (occurs in severe burns & some muscle diseases)
is nerve cell resting membrane potential negative or positive and how is this maintained
negative inside cell (-70 mV in neurones)
-some constantly open na and K channels
but Na/K/ATPases move three sodium out, 2 potassium in therefore next movement of positive ions out of cell resulting in negative resting membrane potential
What is the Nernst equation.
What is the Goldmann equation
Nernst equation calculated the electrochemical gradient of the cell state. Goldman equation calculates the membrane resting potential by calculating the sum of all equilibrium potentials.
Steps of action potential
- above threshold stimulus occurs
- opens voltage-gated Na+ channels to move sodium inside cell
- Threshold of -55mV is reached and depolarisation is unstoppable (propagation occurs)
- Spike potential with the junction between rapid depolarisation to +35mV
- Rapid repolarisation
6 rate of repol slows after 70& of repol is complete - slight overshoot causes hyperpolarisation and a refractory period
Classification of neurones
- monopolar- 1 axon, found in ANS
- Bipolar- 2 axons, associated with special sense organs
- Multipolar- 3 dendrites, or >1 axon- form majority of CNS
What are Glial cells- give examples
Glial cells e.g schwann cells support and nurture neurones. There are 10-50x more glial cells than neurones.
-persistent pain states may be associated with glial activity.
3 types:
1. Microglia (savenger cells) derived from immunie system- activated and become phagocytic in response to infection or inflammation.
- Astrocytes (2types)
-fibrous- form white matter- support neurones, isolate synapses and absorb neurotransmitters that are released from synapses.
-protoplasmic astrocytes- maintain electrolyte balance, in particular K+ levels - Oligodendrocytes- provide myelination to axons in the CNS (while schwann cells myelinate axons in PNS)
What is the BBB made of
BBB is a highly selective semipermeable border of endotheial cells that regulates transfer of solutes and chemicals between circulatory system & CNS. Tight junctions of 2nm wide gaps.
-created by both forms of astrocytes (fibrous and protoplasmic)
- send processes around capillaries to prevent leakage of electrolytes & fluid.
-not present at birth but forms in early life as astrocytes grow & interact with capillaries.
This is why neonates are at risk of brain damage from neonatal jaundice
What conditions affect the BBB
Which structures are outside of the BBB
circumventricular organs
-posterior pituitary (secretes ADH & Oxy)
-choroid plexus (secretes CSF)
-pineal gland (secretes melatonin)
-Area postrema (senses toxins for emesis, vasopressin, angiotensin for autonomic regulation. (also area postrema chemoreceptor trigger zone- target for several anti-emetics)
-Organ vasculosum of the lamina terminalis (OVLT)- detects changes in sodium conc & serum osmolality & feeds this info to hypothalamus for osmoregulation
-subfornical organ
-median eminence of hypothalamus
https://derangedphysiology.com/main/cicm-primary-exam/nervous-system/Chapter-111/blood-brain-barrier
what drugs can pass the BBB
-small molecular mass, to facilitate diffusion, e.g ethanol
-highly lipid solubility e.g Propofol
-high conc gradient (low protein binding, small Vd, low potency- therefore large conc of drug)
-sufficient molecular similarity to another actively transported substrate e.g
-Lithium (pretends to be sodium),
-valproate (pretends to be lactate)
-Monoclonal AB, pretend to be real antibodies
which transporters are highly prevalent on BBB membranes
glucose transporters (GLUT 1 and GLUT 3)
What are the different areas of the brain responsible for?
-Frontal lobe- Upper motor neurones involved in motor control
-parietal- main sensory area
-Temporal lobe- visual and auditory information processing, comprehension of language and memory recall and formation
-Cerebellum- co-ordinating movement, balance, posture
-Limbic system- receives interconnecting fibres from temporal, frontal, hypothalamus and thalamus & is involved in learning, emotions, behaviour & endocrine responses via hypothalamus. The hypothal has neural centres for thirst, hunger, body temp & helps regulate fear, sleep, pain, wakefulness, pleasure, arousal anger, emotions.
What is the brains main energy substrate & what does it use in starvation
Glucose is the brains main energy substrate (90%). In starvation, the brain utilises ketones as well.
Cerebral blood flow anatomy
brain receives blood from two internal carotids and from basilar artery formed from 2 vertebral arteries.
cerebral blood flow autoregulation
occurs via 3 mechanisms:
1. MAP 60-150 mm/Hg
2. PaCO2
3. PaO2 response is at high levels of O2 at around 7-8kPa
- Myogenic theory- response to stretching of blood vessels
- Metabolic theory- blood flow maintained by extravascular concentration of metabolic vasoactive substances. The subsequent increased flow washes out the vasoactive substances allowing vessel diameter to return to normal.
Monro-Kellie Doctrine
75ml blood
75ml CSF
1400g brain
CPP=MAP -ICP (-CVP some quote but not always)
With space occupying legions, the increase in volume is accomodated through fluid shifts out of the cranium, but only to a certain point (critical volume) after which ICP rises sharply, resulting in reduction of CPP
CSF
1. where is it produced
2. Where does flow occur
3. composition of CSF
- Choroid plexus of lateral, 3rd & 4th ventricles. The rest around blood vessels & ventricular walls.
- In subarachnoid space surrounding and supporting cranial structures, then absorbed through arachnoid villi into cerebral venous sinuses into the venous system
- identical composition to brain ECF, but differs to blood by:
-pH of 7.3. (blood 7.4),
-Na 150 (145)
-K 2.9 (blood 4.8)
-HCO3 21 (26)
-Protein <0.4 (blood 70)
-Glucose 3.5 (blood 5)
-Osmolarity 285 (285)
Functions of CSF
- protection
- chemical bugger
- transport medium for nutrients, metabolites & neurotransmitters
Patient has vertical diplopia, ad difficulty reading/walking downstairs. on examination her left eye is elevated and adducted & she reports tilting head to the right improves vision.
What palsy is this?
Trochlear nerve palsy
trochlear nerves (CN IV) is responsible for superior oblique (SO4- down & out)
Sympathetic nervous system:
1. where do preganglionic fibres originate from & travel?
2. what type of fibres are the preganglionic SNS nerves
- Where do postganglionic fibres arise & what type of fibres are they.
- What is the adrenal medulla classed as in this context
- Preganglionic sympathetic fibres arise from thoracolumbar segments of cord (T1-L2) & travel in lateral parts of spinal cord.
- preganglionic SN are myelinated B fibres
- Postganglionic sympathetic fibres arise from ganglia located on the sympathetic chain & are unmyelinated C fibres.
- The adrenal medulla is a modified ganglion & outflow is from medullary catecholamines of adrenaline:norad 70:30
PARASympathetic nervous system:
1. where do preganglionic fibres originate from & travel?
2. what type of fibres are the preganglionic PSNs nerves
- Where do postganglionic fibres arise & what type of fibres are they.
PSNS maintains internal organ function whilst at rest.
1. PSNS outflow is craniosacral with CN 3, 7, 9, 10 & sacral outflow. Preganglionic fibres arise from brainstem & are myelinated B fibred
what type of receptor are acetylcholine nicotinic receptors
ligand binding ion channel receptors, with 4 subtypes- skeletal, CNS pain pathways, autonomic ganglia & CNS movement & cognition pathways
(muscarinic are G-protein receptors with 5 subtypes depending on the secondary messenger M1->M5)
SNS & PNS effect on pulmonary circulation
SNS causes mild pulmonary constriction allowing more even distribution of blood flow across the 3 zones of lung
PNS has no effect on pulmonary circulation
PNS effect on the heart rate
PNS has greater effect on resting HR than SNS, as if no ANS input- intrinsic HR SA node=100-120.
If SA node not functioning, AV node kicks in with resting HR of 40-60bpm
effect of a1 sympathetic stimulation on vasculature
vasoconstriction
1.Where are reflexes controlled?
2. What are the main components of reflexes
1.within grey matter of spinal cord
2.
-Sensory neurones (large diameter type 1a and 1b fibres. Cell body is in dorsal root ganglion, fibres enter spinal cord via dorsal horn)
-Interneurones (intermediary connection between sensory & motor neurones. Large number of these)
-Motor neurones- large diameter alpha fibres connecting directly to the min skeletal muscle body
NB- some sensory neurones connect directly with motor neurones (monosynaptic) e.g patella reflex
muscle fibre types
- extrafusal fibres (main group making up contractile unit) group of fibres innervated by a single alpha motor neurone (motor unit)
- Intrafusal fibres (part of muscle spindle & innervated by smaller gamma (Y) motor neurones)
what are muscle sensory units made from
1.muscle spindles: convey info from actual changes and changes in length and tension so muscle fibres to CNS. Muscle spindles stretch and stimulate contraction of extrafusal fibres to maintain the length of the muscle.
- Golgi tendon organs: sense change in muscle tension. each is innervated by a single afferent type 1b myelinated axon.
where are muscle spindles found?
mainly in muscle groups providing posture and fine movement (hand, foot, neck).
Each muscle spindle contains upto 1- intrafusal muscle fibres enclosed in a connective tissue capsule in parallel to extrafusal fibres and attach to them or tendons.
types of intrafusal muscle fibres
- nuclear bag fibre- dilated central part involved in dynamic & static response to stretch of muscle
- nuclear chain fibre- thinner, only involved in static response
Centre of intrafusal fibres are non-contractile whilst ends are contractile. Supplied by gamma (y) motor neurones which regulate how ensitive the psindle is to stretch by tightening or relaxing the fibres within the spindle.
tell me about muscle stretch reflex
-muscle stretch reflex is a monosynaptic reflex in response to muscle stretching providing automatic regulation of skeletal muscle length.
-Rapid over few milisecs as no interneurones/CNS influence
1. muscle lengthens stretching the muscle spindle
2. sensory afferents synapse with the a-motor neurone
2. extrafusal contraction
Reciprocal inhibitions occurs via inhibiotry intrneurones allowing relaxation of the antagonistic muscle.
what happens if efferent neurone in patellar reflex is severed?
hypotonia
What is the result if the efferent neurone in patellar reflex continues to fire without inhibition?
hypertonia (spasticity)
This occurs in CVA, as the central modulation is lost.
