Nerves and Muscle 1 - Week 4 Flashcards
(144 cards)
1
Q
What are neurons?
A
-Neurons are collectors and integrators of information that receive exciting and dampening impulses on their dendrites and the cell body, the perikaryon.
- They integrate the information provided by the impulses on their axon hillock, the portion of the cell
body from which the axon arises.
-If the integration is positive, they send out signals through the axon to other nerve cells or target cells such as a muscle fibre.
-Impulses travel along axons as action potentials.
2
Q
What are synapses/ glial cells?
A
-A single neurone can integrate the inputs of hundreds of synapses from many different neurons.
-Much of a neuron’s body and
its dendrites are covered by synapses.
-The spaces not covered by synapses are covered by glial cells.
-Neurons are fully
covered by glial cells or synapses, from the tips of their dendrites to the synapse(s) of their axons, advantageous for tight control of the ionic composition of the thin layer of liquid around them, which is essential for the precise control of action potential generation.
-There is no neuronal
surface exposed to extracellular matrix fluid.”
3
Q
What are myelin sheaths?
A
-Myelin sheaths are insulators.
-They are formed by tightly spiralled, very thin layers of Schwann cells, or oligodendrocytes in
the CNS, around the axon.
-Schwann cells are the principle glial (helper) cell of the peripheral nervous system.
-On electron micrographs, it isn’t possible to distinguish between axons and dendrites.
-The myelin sheath appears as dark electron dense band at low magnification and individual dark lines at high magnification.
-When look at myelin layers in high magnification, can see it has intraperiod lines which is equivalent to the extracellular space - likely it represents the glycocalyx on the outside of the cell membrane.
4
Q
What are Ranvier nodes?
A
- In myelinated nerves, depolarisation only happens at Ranvier nodes, the areas not covered by myelin.
- These areas are not completely naked, however, but covered by thin outgrowths of Schwann cells.
5
Q
What is common to all neurons?
A
-Neurons come in different shapes but what is common to all of them is a very large surface to volume ratio due to extensive branching.
6
Q
What are key forms of neurons in the PNS?
A
Pseudo-unipolar or sensory neurones, and motor neurones.
7
Q
What is the CNS?
A
-The central nervous system consists of the brain and spinal cord.
-It is encased by a minimally permeable, multi-layered
connective tissue sheet, the meninges which lies inside a casing of bone (skull and vertebral system).
-The fluid inside the meninges is called cerebrospinal fluid.
-It has a different composition to interstitial fluid in the rest of the body.
-The CNS contains the nerve cell bodies of the voluntary nervous system.
8
Q
What is the PNS?
A
- Peripheral nerves are covered by ganglia (Schwann cells and satellite cells), which are surrounded by specialised connective tissue cells.
- Less controlled environment.
- The PNS contains the axons and dendrites travelling through rest of the body.
9
Q
What is white and gray matter?
A
-When describing the structure of the CNS, the terms ‘white’ and ‘gray’ matter were used.
-Gray matter refers to areas that have clusters of neurones.
-White matters are areas with predominantly nerve connections, which are to a significant percentage
myelinised, which renders them very light due to the high fatty acid content of myelin.
10
Q
What is an anatomical nerve?
A
- A collection of axons (of motor neurons) and/ or dendrites (of sensory neurons), bundled and ensheathed into fascicles, which themselves are held together by connective tissue to a nerve trunk.
- Small nerves are just one fascicle, also called nerve fibre bundles.
- Large nerves have several fascicles, held together by a ring of dense collagenous connective tissue (epineurium).
11
Q
What is the epineurium?
A
- Collagenous connective tissue surrounding a peripheral nerve.
- Surrounds multiple nerve fasciciles.
12
Q
What is the perineurium?
A
- Sheath with flat cells of epithelial character (brownish, tight junctions) with collagen fibres between them.
- Bundles axons into fascicle and forms a seal.
- The perineurium forms a seal around the nerve fibre bundle.”
13
Q
What is the endoneurium?
A
- Appears as loose connective tissue (red) between axons/ dendrites within a fascicle.
- Its cells are specially adapted for helping maintain the fascicle.
14
Q
How do you differentiate between blood vessels and small nerves?
A
- Larger blood vessels have coagulated red blood cells in them and often a thick outline.
- Nerves have ‘wavy’ content with elongated nuclei when cut obliquely or longitudinally, and often reddish rings with whitish content when cross sectioned.
- They normally have a defined, thin outline (perineurium).
15
Q
What is the dorsal root ganglion?
A
A cluster of sensory neuron cell bodies in the dorsal root of a spinal nerve.
16
Q
How do satellite cells appear?
A
- As cross sectioned, flat nuclei covering the sensory nerve cell bodies.
- They are the support cells in the PNS ganglia.
17
Q
What is a summary of the PNS?
A
- The principle glial cell is the Schwann cell, which produces one myelin sheet per cell or encases unmyelinated nerve
extensions. - Anatomical nerves are bundles of nerve extensions held together by epineurium, perineurium and endoneurium.
- Nerve cell bodies situated in PNS ganglia are covered by satellite cells, the principle support cells of such ganglia.”
18
Q
What is the membrane potential?
A
-In the region very close to the outside of the cell, there is an excess of positive ions, and on inside of cell, there’s an excess
of negative ions.
-This balance between the two creates the membrane potential.
-This is just the effect right at the surface of the cell, within the cell it’s a very different environment.
-Charge distribution across a membrane represents a
microenvironment, but one that has a big influence on cellular activity and function.
19
Q
What is resting membrane potential in a red blood cell?
A
-30mV.
20
Q
What is resting membrane potential in smooth muscle?
A
-90mV.
21
Q
What is resting membrane potential in a neurone?
A
-70mV.
22
Q
How many Na+ and K+ ions do the pump move in and out?
A
Kicks out 3 sodium ions for every two potassium ions that enter.
23
Q
What happens once the threshold potential is reached?
A
-Once it gets to the threshold potential, rapid depolarisation of neuronal cell membrane occurs.
-Stronger the stimuli, the faster
the threshold is reached.
-Characteristics of action potential same for all stimulus.
24
Q
What is the all or none law?
A
-The principle that the strength by which a nerve or muscle fibre responds to a stimulus is not dependent on the strength of the stimulus.
- If the stimulus is any strength above threshold, the nerve or muscle fiber will either give a complete response or no
response at all.
25
What are the features of an action potential?
- There's a rising phase due to rapid depolarisation, where it goes above 0mV membrane potential such as there's a positive charge on the inside of the cell membrane.
- Then goes back down below the resting potential and then slowly increases back to resting membrane potential, hyperpolarisation.
- At the peak, there's an excess of positive charge - it's a localised effect on the membrane.
26
What is the ionic basis of action potential generation?
-At the rising phase there is rapid depolarisation that takes membrane potential above 0mV.
-This is due to the opening of
voltage dependent Na+ channels, which are normally closed at resting membrane potential, but once it gets to threshold potential, they open and lots of Na+ influxes.
- At the point where you're measuring membrane potential, have accumulation
of positive charge on inside of cell membrane.
-Then almost as quickly, have a repolarisation involving the efflux of K+ through voltage dependent potassium ion channels that are normally closed at resting potential.
-Sodium ion influx is reduced because membrane potential is changed.
-Enough K+ will leave from inside to outside of cell membrane such that enough negative charge is restored on the inside of the cell membrane.
27
What is the fast positive feedback?
-Once get triggering of events, membrane is depolarised and there is increased permeability of Na+, so an increased influx of
Na+.
-This leads to a positive feedback event in the action potential upstroke, taking it from negative to positive membrane voltage on inside of cell.
28
What is slow negative feedback?
- In the action potential downstroke, as membrane becomes depolarised, there is increased K+ permeability, so increased K+ outflow, leading to membrane hyperpolarisation.
- Inactivation of voltage gated Na+ channels to reduce Na+ influx is not enough for action potential repolarisation, need opening of voltage gated potassium ion channels.
- For action potential to occur, voltage gated sodium ion channels must activate more quickly than voltage gated potassium ion channels, so need a change in Na+ permeability that is more active and rapid than the change in K+ permeability.
29
What is the refractory period?
-The refractory period is a period of time during which a cell is incapable of repeating an action potential.
-In terms of action potentials, it refers to the amount of time it takes for an excitable membrane to be ready to respond to a second stimulus once it returns to a resting state.
-The depolarisation that produces Na+ channel opening also causes delayed activation of K+ channels and Na+ channel inactivation, leading to repolarisation of the membrane potential as the action potential sweeps along the length of an axon.
-In its wake, the action potential leaves the Na+ channels inactivated and K+
channels activated for a brief time.
-These transitory changes make it harder for the axon to produce subsequent action
potentials during this interval, which is called the refractory period.
-Thus, the refractory period limits the number of action
potentials that a given nerve cell can produce per unit time.
30
What is the relative refractory period?
- The relative refractory period is the interval of time during which a second action potential can be initiated, but initiation will require a greater stimulus than before.
- Corresponds to hyperpolarisation.
31
What is the absolute refractory period?
- The absolute refractory period is the interval of time during which a second action potential cannot be initiated, no matter how large a stimulus is repeatedly applied.
- Corresponds to depolarisation and repolarisation.
32
What is nerve conduction velocity affected by?
Axon diameter, myelination and temperature.
33
How does axon diameter effect nerve conduction velocity?
- Increasing diameter, increasing nerve conduction velocity.
- Less internal resistance as current travels further before being dissipated.
34
How does myelination effect nerve conduction velocity?
- Decreases current leakage across membrane over internodal surface.
- Current travels further before being dissipated.
- Voltage gated channels concentrated at nodes of Ranvier.
- Gating of channels only has to occur at nodes, not continuously as in unmyelinated tissue.
35
What is spatial summation?
Spatial summation occurs when multiple presynaptic neurones together release enough neurotransmitter (e.g. acetylcholine) to exceed the threshold of the postsynaptic neurone.
36
What is temporal summation?
- Temporal summation occurs when one presynaptic neurone releases neurotransmitter many times over a period of time.
- The total amount of neurotransmitter released may exceed the threshold value of the postsynaptic neurone.
- The higher the frequency of the action potential the more quickly the threshold may be exceeded.
37
What is the EPSP?
-An excitatory postsynaptic potentials is a temporary depolarisation of postsynaptic membrane caused by the flow of positively charged ions into the postsynaptic cell as a result of opening of ligand-sensitive channels.
-Increasing amounts of
neurotransmitter gives rise to a very short term depolarisation.
-Change in membrane potential is proportional to amount of
neurotransmitter released.
-These are small changes in membrane potential.
-If two nerves fire, and are close physically in terms of both distance and time, get a degree of summation.
38
How does the EPSP influence
| post-synaptic action potential?
-Stimulation from nerve leads to EPSP but it may not reach threshold potential.
-If stimulations are more frequent, that summation gets closer to threshold potential and if interval is shorter, summation ensures each reaches threshold, and then
in the nerve you'll detect the generation of the action potential which will move all the way down the axon.
39
What are key properties of fast excitatory synapses?
-They are ionotropic events, so ligand-gated cation selective ion channels.
-Mainly due to Na+ influx into post-synaptic cell which depolarises membrane potential of post-synaptic cell.
-Gated by neurotransmitter molecule, centrally by the amino acid glutamate, glutaminergic, and peripherally by acetylcholine, cholinergic. EPSP brings Vm nearer to threshold, increasing
chance of action potential firing and increasing excitability and summation to elicit action potential.
40
What is the IPSP?
-An inhibitory postsynaptic potentials (IPSP) is a temporary hyperpolarisation of postsynaptic membrane caused by the flow of negatively charged ions into the postsynaptic cell.
-So for example, have basal K+ channels and ligand gated anionic channel.
-Chloride ions in excess on outside of cell and in lower concentrations inside.
-Release from neurotransmitter of amino acid GABA, an inhibitory neurotransmitter. GABA interacts with specific receptor connected to an ion channel, leading to opening
of that ion channel and movement of chloride ions from outside to inside of cell.
-Membrane potential becomes more negative.
-Release of GABA causes hyperpolarisation.
41
What are some properties of fast inhibitory synapses?
-It's an ionotropic event as has ligand gated Cl- or K+ selective ion channels.
-Mainly influx of Cl-, hyperpolarising membrane
potential of post-synaptic cell. IPSP brings Vm further from threshold, decreasing chance of action potential firing, and
summation inhibits action potential firing and reduces excitability.
-Inhibitory neurotransmitters are amino acid molecules.
42
What is the structure and function of muscles?
-Striated (skeletal/voluntary) muscle attaches to the bones by tendons and appears stripy under a microscope.
-Skeletal muscles contract and relax to move bones at a joint.
-The cells in striated muscle are highly specialised muscle fibres.
-Each fibre contains many nuclei (multinucleate), mitochondria (provides ATP for contraction) and sarcoplasmic reticulum (contains
calcium ions).
-The cell membrane of a muscle fibre is the sarcolemma.
-Parts of the sarcolemma fold inwards across the fibres
and stick into the sarcoplasm (cytoplasm containing organelles such as mitochondria).
-These folds are fibules and help spread electrical impulses through the sarcoplasm.
-Muscle fibres are made of myofibrils, which are made of many short units called sarcomeres.
-The ends of sarcomeres have a Z line and the middle has an M line (attachment for myosin).
-They contain bundles of protein filaments (myofilaments) called actin and myosin which move past each other to make muscles contract.
-They produce alternating patterns of light and dark bands: Dark A bands contain the thick myosin filaments and some overlapping thin actin filaments.
-Light I bands contain thin actin filaments only.
-Around the M line is the H zone which contains myosin filaments only.
-When the muscle contracts, the dark band overlaps the intermediate band, shortening the length of the muscle and the sarcomere.
43
What is the sliding filament model?
-Sarcomeres contract when myosin interacts with actin to form a cross bridge - this happens in a sequence of steps: An action
potential travels into the muscle fibre via T tubules, which are in contact with the sarcoplasmic reticulum (muscle ER).
-As the action potential reaches the sarcoplasmic reticulum, Ca2+ ion channels open and Ca2+ diffuses into the sarcoplasm.
-The calcium ions released by the sarcoplasmic reticulum now bind to troponin.
-This causes the tropomyosin molecule to move, which exposes the myosin binding site on the actin filament.
-This allows myosin to attach to actin and form the
actin-myosin cross-bridge.
-Once attached to actin, the myosin heads change shape, pulling the actin filaments along which releases a molecule of ADP.
-Then, a molecule of ATP attaches to the myosin head, causing it to change shape and detach from the actin filament.
-After this, ATPases are activated by the Ca2+ ions released by the sarcoplasmic reticulum.
-These ATPases breakdown the ATP attached to the myosin heads - this allows the myosin heads to return to its original position.
-The myosin heads are now detached and can attach to another binding site further down the actin filament and the process repeats.
-This process results in the actin filaments in one sarcomere being pulled in opposite directions, towards each other.
-As filaments slide past one another it causes the sarcomere to shorten - this process is known as Sliding Filament Model.
44
What is a sarcomere?
-A sarcomere is the basic contractile unit of muscle fibre.
-Each sarcomere is composed of two main protein filaments—actin and myosin—which are the active structures responsible for muscular contraction.
-The thick filaments are myosin and the thin filaments are actin.
-Sarcomeres
are held in register by cross connections at the level of every Z disk and the middle of each sarcomere.
-This generates the striated appearance of skeletal muscles and the heart - that's why they're called striated muscles.
45
What is myosin?
-Myosin is the principle motor protein for movements by interacting with filaments.
-Once it binds tightly to actin filaments, it releases ADP and then it needs to take up ATP in order to come off the actin filament again and initiate a further contraction.
-In order to detach from the actin filament after going through a cross bridge cycle (myosin pulling itself along actin filaments), the myosin head needs to take up a new ATP.
-Once the intracellular ATP has vanished in the striated muscles, normally a
few hours after death, rigor mortis occurs, the stiffening of muscles after death.
-If ATP is used up, the lack of oxygen doesn't allow it to be replenished in mitochondria, and eventually most myosin heads get stuck as they can't detach, leading to stiff
muscles.
46
What are actin filaments created from?
Individual actin molecules.
47
What is the structure of a muscle fibre?
-Several hundred myofibrils are tightly packed in a muscle fibre.
-A muscle fibre is a synctyium, hundreds of precursor cells
have fused to form a fibre which can accommodate many and long myofibrils.
-Each muscle fibre is about 20-100micrometres
thick, and 1mm to 8cm in length.
48
What is the length-tension relationship?
-The amount of force developed by a sarcomere depends on the degree of overlap between thick and thin filaments.
-Thus the force a muscle can develop is dependent on its starting length.
-At full stretch, few of the myosin heads have access to actin in the thin filament and the force is weak, at optimal length, all of the myosin filaments have access to actin, the force is maximal,
at full contraction, then ends of the thin filament get in each others way and the force is reduced.
-Our muscles are adapted to
be in the maximal range of their length-tension relationship for our most frequent daily movement.
49
What is endomysium?
-Loose connective tissue with some delicate and some strong fibres, surrounding each muscle fibre.
-Connects to basement
membrane.
50
What is perimysium?
-Mixed connective tissue, some dense, some loose, separating groups of muscle fibres into fascicles.
-Main venue for nerves
and supporting blood vessels.
51
What is a fascicle?
Bundle of muscle fibres held together by perimysia.
52
What is epimysium?
Relatively loose connective tissue between fascia and muscle body.
53
What is fascia?
Dense layer of connective tissue covering the muscle.
54
How do striations arise?
The striations arise because the myofibrils are held in register by intermediate filaments (consisting primarily of desmin) that
link neighbouring Z discs laterally as well as longitudinally.
55
What does the non-myofibrillar
| cytoskeleton provide?
-At the level of each Z-disc, the non-myofibrillar cytoskeleton (desmin fibres) provides a strong link to the basement membrane
and into the surrounding connective tissue.
-Force is not just transmitted longitudinally, it is also dissipated laterally, into the
collagenous tissue network surrounding each fibre.
56
What is muscular tissue?
-Derived from mesoderm and composed of cells, or multinucleated syncytia, whose cytoplasm contains filaments made of contractile proteins, primarily actin and myosin.
-Skeletal muscle, due to the organisation of those proteins, takes on a striated appearance.
-The proteins are arranged in a way to allow for the maximum generation of force in that direction.
-Cardiac muscle is different from skeletal muscle as the striations are less obvious, but it's still striated.
-For smooth muscle, don't see
striations.
57
How is smooth muscle structurally organised?
- For skeletal, striations indicate very clear organisation of contractile proteins.
- By contrast, the way in which proteins are arranged in smooth muscle is more net like in terms of structure.
- This allows for a change in shape of the particular organ in which you've got smooth muscle, whether it's the GI tract or the bladder, for example.
- Smooth muscle is supported by and contains connective tissue.
- Unlike skeletal, smooth muscle doesn't act upon structures such as bones, there isn't a tendon that links the muscle to a fixed part of the body.
- If consider stomach, it's not fixed within abdomen in way skeletal muscle would be fixed to bones, but within stomach will see variety of different types of smooth muscle which perform different roles.
58
How is the smooth muscle organised as sheets?
-Within organs, way in which muscles orientate can be different.
-Can be structurally organised as single sheets or multiple sheets.
-In single sheets, e.g. arterioles and airways, the organisation of the muscle will be circularly orientated, effectively allowing to constrict or to expand or relax and allow either blood or air to move through.
-Under normal circumstances, the vessel diameter and pressure are tonically maintained, so usually a degree of active contraction which allows for that relaxation and further contraction depending upon circumstances.
-By varying the diameter, it controls the flow of fluid or air,
and control pressure within particular part of the system.
-In multiple sheets, e.g. ileum, two sheets are perpendicular to each other.
-Within GI tract, for example, will see some longitudinal and circular layers, fitting with the physiological function of the
GI tract, that it has to move digested food through different parts of the system.
-The varying diameter and length give rise to peristalsis, that movement of a large physical body.
59
How is smooth muscle innervated?
- Two major ways in which muscles are organised, that is they're all very closely linked together and the nerves there may have a few varicosities that interact in some of those muscle cells.
- So those muscle cells are closely related to each other but only a few of the muscle cells receive innervation from nerves - this is single unit arrangement for smooth muscle.
- Other type is multiunit.
- Smooth muscle cells not connected to each other, they're separate.
- Every smooth muscle cell receives an innervation from a nerve.
60
What is the arrangement of multi-unit smooth muscle?
-Multi-unit muscle, e.g. bronchioles, large arteries, ciliary body and iris.
-Muscle fibres are structurally independent, so not linked together, and it's the nerves that link them to coordinate activity.
-Each unit has to be stimulated separately.
-Similar to skeletal muscle to allow fine control and graded contraction.
-No neuromuscular junction but diffuse distribution of
neurotransmitter receptors.
-Each unit behaves individually like in skeletal muscle.
-Neurogenic - normally quiescent (in a state or inactivity).
-Contraction has to be neuronally stimulated.
-Excited by autonomic nervous system, not somatic nervous system.
-Individual neuronal
regulation of each muscle cell.
-Regulated and initiated by circulating hormones.
61
What is the arrangement of single unit (visceral) smooth muscle?
- e.g. arterioles, lymph, vessels, GI tract and urogenital tract.
- Electrically coupled to each other by gap junctions.
- Non-selective channels allow intracellular communication.
- Action potential propagates between cells.
- Fibres act in unison allowing for synchronised contraction and relaxation, e.g. uniform, coordinated contraction of uterus during labour.
- Units behave as one entity.
- Myogenic.
- Capable of spontaneous, synchronised contraction.
- Regulated and initiated by ANS, plexus (intrinsic neuronal cells) and circulating hormones.
- Can be initiated by stretching.
62
How do multi unit and single unit contraction compare in smooth muscle contraction?
-Single unit and nature of gap junctions allows for propagation of action potential from one cell through to another.
-Is only one varicosity associated with one of the cells, but there's a potential for the transmitter released from here to act on receptors on
all of these smooth muscle cells.
-For smooth muscle cells, there will be nutrients provided by the cardiovascular system, and
in addition to nutrients, may be hormones which can influence activity of smooth muscles.
-For the multi-unit, each cell has its own varicosity and is influenced separately by that varicosity and that may well coordinate activity.
-This is a multi-unit arrangement and will also be influenced by circulated hormones.
63
What is the stretch-relaxation response of a single unit smooth muscle?
-e.g. bladder.
-Tension initially rapidly develops on stretch and expansion to accommodate an increase in volume.
-It then relaxes back to original tone but now at a new longer length.
-Connective tissue prevents over stretching, unlike skeletal
muscle which is elastic.
-This is because smooth muscle allows hollow organs to fill with a maintained muscle tension (tone),preventing uncontrolled expulsion, e.g. bladder and uterus.
-This stretch-relax response is unique to smooth muscle.
64
What are the contractile properties of smooth muscle?
-Length-tension relationships.
-When skeletal contracts, it will reduce its length by about a third.
-It can stretch or relax in
response to conditions, and can increase by about 20%.
-So some movement associated with length of cell.
-Smooth muscle more varied in terms of length it can change.
-Can reduce length by up to 60% and depending upon circumstances, it can stretch but remain under same tone associated with that, so is more variable.
-Smooth muscle can increase length by up to 2.5 folds.
65
How is smooth muscle contraction different to that of skeletal muscle?
-The way in which smooth muscle will elevate calcium ion levels depends upon the number of calcium ion channels on surface of cells and generation and release of calcium from intracellular stores by IP3.
-That differs to skeletal muscle which is more
related to the number of fibres in terms of contraction.
66
What is excitation-contraction coupling?
-Common to all muscles, contraction requires increased calcium ion concentration. Ca2+ source differs to that of skeletal muscle, as there are no transverse tubules or T-system, and the nature of smooth muscle cells means small enough for Ca2+
to diffuse quickly about.
-Calcium ion influx across plasma membrane by opening of voltage gated Ca2+ channels and depolarising stimuli.
-Ca2+ mobilised from intracellular stores, either by metabotropic receptors, or G-protein stimulated.
-Graduation not by recruitment and summation - cannot increase number of fibres excited, especially for single unit smooth muscle.
-It is achieved by varying level of intracellular calcium ions."
67
What happens in smooth muscle when calcium elevated?"
-Way in which orientated in terms of smooth muscle cells, is has network structure, which gives versatility in terms of the way in which the shape of cells can change.
-Smooth muscle will contain contractile proteins actin and myosin light chain.
-A third protein is calmodulin.
-Calcium ions are a key mediator of contractile proteins.
-There's an enzyme which can occur in an active and inactive form, myosin light chain kinase.
-Kinase is an enzyme that when activated will give a phosphate group to another
protein.
-Myosin phosphatase is an enzyme that removes phosphate group.
-So when calcium ion concentration is elevated,
there will be contraction by the sliding filament theory.
-Interaction of actin with myosin to form X-bridges but Ca2+ binds to calmodulin, not troponin C like in skeletal muscle.
-Not a physical but a biochemical effect in smooth muscle.
-Ca2+-calmodulin complex activates myosin light chain kinase enzyme.
-MCLK phosphorylates myosin light chain.
-MLC must first be
phosphorylated for actin to bind.
68
What is the relaxation mechanism in smooth muscle?
-Reversal of the increased calcium ion concentration leads to dissociation of calmodulin from MLCK rendering the MLCK
catalytically inactive and incapable of phosphorylating MLC.
-So noradrenaline in terms of bronchiole smooth muscle activates a group of receptors called beta-adrenoreceptors, leading to reduction in Ca2+ concentration.
-If don't have as much calcium,
don't get calmodulin-calcium complex, so don't get activated form of MLCK, get inactive form, reversing contraction.
-Myosin phosphatase reverses process in smooth muscle - its activity is generally constant.
-For there to be a change in the contractile state of the muscle, it's driven by changes in intracellular calcium ions.
69
What are motor end plates?
- Specialised chemical synapses formed at the sites where the terminal branches of the axon of a motor neurone contact a target muscle cell.
- Each muscle fibre is innervated by this synapse.
70
How is skeletal muscle fibre controlled?
-Via motor nerves of the somatic nervous system.
-Muscle fibres are innervated by motor neurones located in the spinal cord.
-One synapse per fibre, normally in the middle between the two ends of the fibre.
-Muscle fibre action potentials can only be generated by the motor end plates, or electrical stimulation with considerable voltage - there are no gap junctions.
-Very quick immediate feedback via proprioception (neural feedback loops), which includes the signals from muscle spindles (innervated
by gamma motor neurones, provide information about the length changes of a muscle) and Golgi tendon organs (provide information about the strength of a muscle's contraction).
-This allows very precise control of movement.
71
What does a motor unit comprise?
A motor neurone and the fibres it innervates.
72
What is muscle spindle?
- Muscle fibres surrounded by perineurium-like sheath.
- Muscle spindles are stretch receptors within the body of a muscle that primarily detect changes in the length of the muscle.
- They convey length information to the central nervous system via afferent nerve fibres.
- This information can be processed by the brain as proprioception.
73
What happens to skeletal muscle upon a nerve impulse?
- A motor neurone normally innervates several muscle fibres.
- Each muscle fibre has one single nerve contact (neuromuscular junction).
- Upon a nerve impulse, the fibre membrane (sarcolemma) depolarises and action potentials run down on each side of the neuromuscular junction as part of the process of excitation-contraction coupling.
74
What are the different fibre types?
-Our muscles have different fibre types, some contract slower and some faster due to different isoforms of myosin they have in their thick filaments.
-In skeletal muscle, there are two principle fibre types, type I (slow) and type II (fast), based on their isoform of myosin (there are three myosin isoforms, I, IIa and IIx.
-Slow myosin, type I, are stuck longer to the actin filaments,
and therefore their contraction cycle is slower.
-Fast myosins, type II, are faster in their contraction cycle.
-Type I fibres have higher oxidative capacity, so more mitochondria and more capacity for aerobic respiration than type II.
-Type II fibres have higher glycolytic capacity than type I, so can produce more lactate.
-Each fibre in a given motor unit is of the same type, i.e.
has the same myosin isoform, oxidative and glycolytic capacities.
-Being commanded by the same nerve cell, they do the
same amount of work.
75
What is motor unit recruitment?
-In voluntary movement, type I motor units are recruited first, with type II being added depending on demand.
-Even during a fast movement, the small type I fibre motor units are recruited first.
-If more force is demanded, larger, type II, motor units are
recruited sequentially, with type IIX normally last, i.e. at maximum muscle force.
-This is the Size Principle, since type II motor units have more fibres, i.e. are larger than type I.
76
What can skeletal muscle cells be adaptable to?
- Exercise.
- Someone who is a runner will have larger and more type I fibres and more mitochondria and enhanced endurance.
- A weightlifter would have both type I and II enlarged and fewer mitochondria.
- Would have more strength and less endurance.
- Larger fibres as more myofibrils packed into fibre.
- So increased mitochondrial content upon endurance training, and muscle hypertrophy (added myofibrils within fibres) upon resistance training.
77
How is skeletal muscle developed?
- During embryonic development, mononucleated precursor cells migrate into the spaces where muscle form.
- They then multiply and eventually align and fuse into muscle fibre precursors before starting to synthesise proteins that make up the sarcomere.
- During development, most but not all of the myoblasts (muscle cell precursors) fuse into fibres.
- A few percent appose very closely to a muscle fibre, but don't fuse - these are called satellite cells.
- They represent a stem cell reserve in case a muscle fibre needs serious repair that includes replacing of nuclei or has to be fully torn down and replaced.
- The nuclei in muscle fibres are terminally differentiated, they cannot divide anymore.
78
Where are satellite cells found?
Small cell outside muscle fibre membrane but underneath basement membrane.
79
Why is the heart a dual circuit peristaltic pump?
-Dual circuit as plumbing on left and right side are contiguous, the pipes are effectively connected.
-Peristaltic as operates in a
squeezing action.
-Contraction is constant.
-Muscle activation is near synchronous in ventricles.
-Left side and right side have
same cardiac output, or will get backing up of fluid in system, so has to pass through right side at exact same flow rate as it does in rest of body.
-Can increase function of pump by two actions, inotrophy and chronotropy.
80
What is inotropy?
Increased force of contraction leading to increased stroke volume - the physical volume of blood ejected with each
contraction.
81
What is chronotropy?
Increasing frequency of contraction, which increases heart rate.
82
How is cardiac muscle adapted for constant activation/ max efficiency?
-Heart adapted in many ways to deal with ceaseless contraction and maintain cardiac output.
-Different from skeletal muscle,
which sits in a series of tubes, nesting side by side against each other.
-Cardiac muscle nestle next to each other but are also
branched and physically connected to each other by intercalated discs.
-This is designed to maximise propagation of electrical
activity through heart.
-Fibres in heart arranged to maximise efficiency of contraction, like wringing out a cloth.
-Fibres more vertical on inside and more transverse on outside.
-Therefore this helical action causes twisting of the heart.
-Heart moves around a lot more to maximise expulsion of blood with each contraction.
-As a result of constant activity, myosin isoforms are far more homologous than skeletal muscle.
83
How are cardiac muscle cells adapted for synchronous electrical activity?
-Cardiac cells are branched and connected by intercalated discs with desmosomes which allow strong adherence, holding system together.
-There are low resistance gap junctions which allow propagation of the myocardial action potential through
the heart, improving electrical activity.
84
-What happens when cardiac muscle is activated?
-When cardiac muscle is activated with each heart beat from the sino-atrial node, there's a wave of depolarisation that occurs across heart.
-There's a whole series of adaptations including purkinje fibres, atrioventricular node and other adaptations to maximise electrical conductivity, to activate contraction and make this as synchronous as possible.
-Necessary to activate left and right side of heart at same time, so there's a wave of depolarisation that occurs across heart, electrical activity that moves down and initiates contraction.
-Can pick up electrical activity of whole heart using electrocardiogram, ECG.
-It is quite a complex wave form.
-Tells us a bit about what's happening to muscle, but there's a whole series of different electrical events happening in heart which can measure on chest wall.
-We're looking at electrical activity at muscle membrane, the sarcolemma, and this is the ventricular action potential.
-Have series of action potentials resulting in contraction.
-If look at this in a single cardiac muscle fibre, get change in cell length as we're getting a contraction due to electrical activity.
-Electrical activity gets transformed into cardiac cell contraction.
-This is similar to single ventricular contraction, as duration is similar to cardiac contraction.
-Can describe change in cell length as a twitch contraction, as we're activating as a consequence of a single electrical event.
-The twitch contractions summate in heart at a single point in time.
-So series of twitch contractions
stacked up against each other.
-Each myocyte has its own action potential.
-The action potential has to get to position within the muscle, which it does by the transverse tubules.
-So have a sarcolemma,
the muscle membrane, which is excitable, and it allows propagation of cardiac action potential along it.
-Cardiac muscle cell, similar to what would see in skeletal muscle cell, has pores, invaginations of sarcolemma which go deep within muscle
fibre and wring myofibrils.
-So action potential therefore gains access to inside of myocyte and moves along T-tubules.
85
How are action potentials different in cardiac and skeletal muscle?
-The duration of the action potential in skeletal muscle, this shift in potential as a consequence of both sodium and calcium ions, happens over 3-4milliseconds and is gone by about 20milliseconds.
-Action potential in cardiac muscle is very long, so have depolarisation phase, it begins to repolarise and then has a pause for a long time, around 200ms, and then repolarises
in same manner as skeletal muscle.
-So about 400ms in total.
-Useful as avoiding activation methods skeletal muscle uses and relies upon in order to produce significant amounts of force.
-In skeletal muscle, have single electrical event which results in a twitch.
-Skeletal muscle is capable of regulating the amount of force it generates by increasing frequency of action potentials
arriving at T tubules.
-So principle is down to duration of twitch contraction and if you increase frequency, start summating twitches and get a partly fused tetanic contraction.
-When increase frequency further, tetanic contraction becomes smooth and
fused.
-This is how skeletal muscle can regulate its force.
-Doesn't happen in cardiac muscle, as plateau is making cardiac muscle refractory, meaning if were by accident further action potentials arriving at T-tubules, wouldn't result in further contraction.
-This is how cardiac muscle maintains twitch contractions and synchronises cardiac function.
86
What causes the cardiac plateau?
-Extracellular calcium crucial to maintain cardiac contraction.
-Doesn't happen in skeletal muscle - extracellular Ca2+ is not a factor.
-In cardiac muscle, the plateau in the action potential is as a result of influx of Ca2+ ions from extracellular space to
cytosol.
-This is due to opening of L-type Ca2+ channels at beginning of action potential.
-Channels open more slowly than the Na+ channels responsible for the first phase of the action potential.
-Opening of the L-type Ca2+ channels delay repolarisation
of the sarcolemma.
-Only a small amount of Ca2+ actually enters cell - raises cytosolic Ca2+ by approximately 0.02%.
-Remember this long action potential is moving down T-Tubules with each depolarisation wave.
87
Why is calcium handling crucial for regulating cardiac contraction?
-It is central to initiation of calcium-induced calcium release, CICR.
-Action potential moves along sarcolemma but can also
move down T-tubules.
-Have L-type channels both on surface of sarcolemma and within t-tubules themselves.
-Action potential causes opening of sarcolemma based L-type Ca2+ channels and allows some Ca2+ into cell.
-Also allows some Ca2+ to get
into cell deeper within myocyte.
-There's a little cloud of Ca2+ released via opening of this channel with depolarisation.
-These L-type channels within the t-tubules are associated with a structure called a diad, which consists of the L-type channel, ryanodine receptors and the terminal cisternae of the sarcoplasmic reticulum, which is the significant store of Ca2+ within the cell.
-The release of this cloud coming in via T-tubules results in release of Ca2+ from endings of network sarcoplasmic
reticulum and releases lots of Ca2+ which causes myosin actin interaction and causes contraction.
-Around 75-95% contractions generated by calcium induced calcium release.
-Also a set of L-type channels on sarcolemma which allow Ca2+ in as well - around 10-25% of Ca2+ available for contraction is accounted for by influx of Ca2+ here.
-Remember there was a transit, a brief increase in Ca2+ but then Ca2+ concentration in cell, in the cytosol, diminishes quite rapidly.
-This is because the sarcoplasmic reticulum has ATP dependent pumps which re-sequester a significant portion of the calcium as well as a
series of pumps and exchanges on the cell surface which expel calcium with each contraction.
-Change in concentration of
intracellular Ca2+ with each contraction will be 0.55-0.75micromolars at peak, considerably less than skeletal, where a single twitch results in increase of Ca2+ around 10-18micromolar.
88
How is cardiac muscle calcium handling different to skeletal muscle?
-The extent of the sarcoplasmic reticulum in skeletal muscle is greater than seen in cardiac muscle.
-In cardiac muscle, the
sarcoplasmic reticulum is much lacier than seen within skeletal.
-Also, instead of diads, which are these junctions between the
ryanodine receptors, the sarcoplasmic reticulum and the T-Tubules, in skeletal muscle they're a triad, and the T-tubule is central to this structure, and you have a set of ryanodine receptors either side associated with the sarcoplasmicm reticulum.
89
Why is the calcium transient key to many drug actions?
-Stretch is important in terms of how cardiac function is effected.
-Increasing diastolic length of cardiomyocytes causes an
increase in sensitivity of the myocyte to calcium ions. e.g. if went for a run, the increase in cardiac output has to go
somewhere, it supplies exercising muscles, but it then has to be returned to the heart.
-The venous return causes heart to swell, increase in size and stretch muscle and there's a feedback mechanism in which stretching of the muscle causes heart to contract harder.
-Many drugs work on modulating the calcium transient, and caffeine is an example, it's a positive inotrope,
causing increase in contraction as acting on calcium release channels of the sarcoplasmic reticulum.
-L-type Ca2+ blockers,
e.g. verapamil, is a negative inotrope, which can be beneficial in angina (chest pain) as reduced contraction reduces energy demand, reducing ischaemia, and therefore chest pain.
-Verapamil has multiple action, is also a blood pressure drug.
90
What is digitalis?
-Digitalis enhances Ca2+ release, increasing contractility.
-This improves heart function, and relieves symptoms of congestive heart failure.
-Toxic dose close to the therapeutic dose and can result in arrhythmia, hence administration is strictly
controlled.
91
How does the heart deal with ceaseless contraction?
- Has to have a highly adapted metabolic cellular physiogy to provide energy for cardiac contraction, as needs ATP to detach and re-energise the myosin head.
- ATP is essential to release myosin head from actin at point of binding and resets and re-energises head for next power stroke.
- At rest, only about 40% of cross bridges active.
92
How does cardiac muscle make lots of ATP?
- Heart needs fuel and will burn this fuel as long as plenty of oxygen available.
- Around 70% of ATP produced is from oxidation of fat, 20% of ATP is from oxidation of glucose and 10% from other sources like glycolysis, lactate and ketones.
- All of these processes occur within mitochondria.
- Over 5kg of ATP is synthesised and used per day.
- As ATP demand is high, will have loads of mitochondria.
- Cardiac muscle is packed full of mitochondria compared to skeletal muscle cells.
93
What is the structure of cardiac muscle mitochondria?
-They are a continuous reticulum and two distinct populations, interfibrillar and subsarcolemmal mitochondria, which have
different morphology.
-Mitochondria occupy huge volume in cardiac muscle.
94
How is force generation controlled in skeletal muscle?
- By two strategies, motor unit recruitment and tetanic contractions.
- Motor unit recruitment is activation of more muscle fibres.
- Alpha spinal motor neurones innervate in most cases a series of individual muscle fibres.
- Larger muscles have motor units with more muscle fibres per motor neurone.
- Second strategy is via maintaining tetanic contractions, increasing the number of action potentials arriving at the skeletal muscle neuromuscular junction of a single fibre.
95
What is motor unit recruitment?
- Smaller motor units are recruited at lower levels of muscle force and then other motor units and the firing of those alpha motor neurones are initiated as greater force is required.
- At higher levels of force, this is typically involving larger motor units meaning contractions which are at relatively lower level are easier to control and maintain within a set level than larger contractions.
- So can recruit or increase number of motor units to increase force as first strategy.
96
What is tetanic contraction?
-The second strategy within single muscle fibres is to increase number of action potentials being propagated along sarcolemma.
-Self propagating action potential, it's being propagated from the neuromuscular junction and this will result in
single twitch contraction, duration at which is around 200ms, from initiation to total relaxation.
-Skeletal muscle and membrane of it has ability to deal with trains of action potentials and these action potentials can be delivered in steadily increasing frequencies.
-But when we have a series of action potentials propagating along sarcolemma, will get summation of muscle force, because twitch contraction is of a set duration and by packing in action potentials will result in a steady increase in force because the first twitch doesn't have time to react completely to baseline and then therefore we get these responses
which can be a rough or partially fused tetanus.
-By increasing stimulation further, can get a steady fusing, an increased fusing of muscle force generation.
-By packing in a series of action potentials at a sarcolemma in a train of forces, fibre can maintain contraction.
-The duration is much increased by process of successive action potentials being propagated along
sarcolemma.
97
How does cardiac muscle avoid tetanic contraction?
-Cardiac muscle avoids tetanic contractions because a tetanic contraction within a ventricle is likely to result in death.
-So cardiac conduction system orchestrates the contraction of these ventricles, via sino-atrial node and the atrioventricular node causes wave of depolarisation to move through heart both across surface and within heart muscle itself.
-Can visualise this in terms of electrical activity via an ECG, but this isn't what is happening at the sarcolemma, and we're interested for the purpose of the regulation of cardiac muscle force in what is happening at sarcolemma within cardiac myocyte.
-Characterised by plateau, this very long duration, before repolarisation occurs.
-The action potential propagating along sarcolemma of cardiac myocyte results in contraction.
-Duration of contraction typically around 250ms to pack in ventricular contraction
within cardiac cycle.
-Have simultaneous contraction of thousands of individual myocytes, and cardiac conduction system designed to achieve this.
98
What are the differences between skeletal and cardiac to summarise?
- Skeletal muscle uses motor unit recruitment and tetanic contractions to produce force, which can be sustained.
- Both cardiac muscle and skeletal muscle require an increase in intracellular calcium to enable cross bridge formation.
- Cardiac muscle uses only calcium as the regulator of a highly orchestrated, synchronous contraction, to produce ventricular contraction.
- Only cardiac muscle uses calcium to prolong the cardiac action potential and prevent tetanus, and to regulate force via the actions of an extracellular calcium pool - calcium-induced calcium release.
99
What is a reflex?
An automatic unlearned reaction to a stimulus.
100
What is the basic structure of the spinal cord?
-The spinal cord is typically about 45cm, but will vary within different individuals of different heights.
-Originates at medulla
oblongata within base of brain. Spinal tissue in terms of gross anatomy has little difference between it and the medulla
oblongata.
-The spinal cord has two thickening areas within, the cervical enlargement, a narrowing in the thoracic region and the lumbar enlargement.
-Spinal cord exits from base of skull via foramen magnum and then the first enlargement, the cervical enlargement, is an increase in density of neuronal tissue associated with upper limbs.
-The lumbar enlargement is associated with the lower limbs neural tissue.
-The spinal cord terminates in the sacral region and then have conus medullaris and filum
terminale within sacral area.
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What can you see within a coronal cross section of the spinal cord?
-It's dominated by white matter and grey matter.
-White matter consists of nerve axons which are myelinated.
-Myelin is a fatty tissue which enhances the propagation of action potentials along the nerve axons, and the axons are arranged along the spinal cord.
-Grey matter sits within white matter and consists of cell bodies and synapses.
-This grey matter contains no
myelin, these nerve cell don't contain myelin around them.
-Within grey matter is a central canal filled with cerebrospinal fluid.
102
What does white matter contain?
-Has a series of columns called funiculi, arranged in dorsal, lateral and ventral areas.
-Dorsal in bipeds is the posterior of a biped.
-Ventral areas can be called the anterior region in bipeds.
-So white matter organised into these funiculi, which are
transmitting information up and down the spinal cord.
103
What is grey matter organised into?
Into different regions, the dorsal horn, an intermediolateral cell column which is only present between first thoracic, T1 and the second lumbar, L2, regions of spinal cord, and then a ventral horn.
104
How is the spinal cord of an adult different to that of a fetus?
-Adults also have a structure called a cauda equina at the base of the spinal cord which moves in position relative to the
vertebrae.
-So in a new born, the base of the spinal cord, the cauda equina, is situated in the third and fourth lumbar whereas
in adult, occupies first or second lumbar region, so has moved up spinal cord relative to vertebra.
-Ranges between T12 and L3 in adults in reality.
-Cauda equina is where the spinal cord becomes more diffused as nerve rootlets are splitting to pass through holes within pelvis and subsequently innervate lower limbs.
105
How many pairs of spinal nerves are in the vertebral column?
31 pairs all mixed - sensory and motor - in a dorsal ventral arrangement.
106
What is a lumbar puncture?
-Possible to obtain diagnostic information from spinal cord by a lumbar puncture.
-In order to do this need to locate L4 ileac crest and insert a large needle between L4 and L5 vertebra into subarachnoid space.
-Therefore possible to sample
cerebrospinal fluid and this is useful in a variety of disease situations.
107
Why is the epidural space useful clinically?
-Possible to administer drugs into this area.
-Administration of drugs into subarachnoid space is usually undesirable as cerebrospinal fluid within which spinal cord is sitting is also contiguous with the brain and therefore if you were to administer an anaesthetic for example in subarachnoid space, then have potential to anaesthetise areas of brain which is potentially
extremely dangerous.
-If can administer anaesthetic to epidural area, can use it for specific anaesthetic procedures.
-Useful in child birth.
-In labour, epidurals used in many situations to reduce pain from usual contraction.
108
What are the ascending funiculi in white matter?
- White matter contains funiculi, sending info up and down spinal cord.
- First going to deal with ascending funiculi and these are organised into specific regions related to function.
- So have dorsal columns, the gracile/ hindlimb column and cuneate/ forelimb columns, as well as spinocerebellar columns, dorsal and ventral.
- Finally, more ventrally have spinothalamic columns, lateral and anterior.
109
How does structure in terms of
| ascending funiculi vary in spinal cord?
-Structure of spinal cord in terms of ascending funiculi vary with level at which looking at spinal cord.
-So at cervical level, have
gracile/ hindlimb and cuneate/ forelimb funiculi.
-However, in lumbar region, only gracile/ hindlimb funiculi is present because cuneate/ forelimb innervation has split off to communicate with other limbs.
110
What are the descending funciculi in white matter?
- Descending funiculi organised into different compartments, seven in total.
- Have lateral corticospinal, rubrospinal, lateral reticulospinal, vestibulospinal, medial reticulospinal, tectospinal and anterior corticospinal.
- Both ascending and descending funiculi are replicated on both sides of spinal column.
111
What is some motor nerve terminology?
- Motor nerves are the ones leaving the ventral nerve roots.
- Spinal motor neuron is a lower motor neuron (motoneurone), and it's innervating a motor unit of skeletal muscle, a group of muscle fibres innervated by a single spinal alpha motor neurone.
- Muscle fibres organised into similar fibre types.
- Muscle receives variety of trains of action potentials to effect contraction and within muscle activated on a consistent/ chronic basis, this generally conditions muscle into slow muscle fibres.
- Muscles activated more intermittently activated by phasic nerve information, trains of pulses, tending to result in development of fast type II muscle fibres.
- There are also upper motor neurones and these originate in brain and innervate spinal motor neurones, allowing info from brain to be conveyed to motor neurones, so this is essential for voluntary muscle contraction.
112
What is spinal motor homunculus?
Spatial organisation of neural tissue relative to anatomy.
113
What is the difference between reflexes and volitional control?
-Reflexes are a stimulus response mechanism whereas volitional control is effected by internal desire.
-Reflexes are innate whereas volitional control is learned.
-Reflexes are hard wired and pre-programmed whereas volitional control is conditioned
and programmed - example of this is learning a skill, it's not down to reflexes, it won't be modified by a consequence of
learning that particular skill, but volitional control will.
114
What are the three classifications of reflexes?
Superficial, deep (myotactic) and visceral (autonomic).
115
What are examples of superficial reflexes?
Corneal (blink), nasal (sneeze) and plantar (toes curl).
116
What are examples of deep reflexes?
Patellar (knee jerk).
117
What are example of visceral reflexes?
Pupillary (dilation/ constriction) and micturition (voiding bladder).
118
What are two examples of myotactic reflexes?
-Firstly, postural control within soleus muscle.
-Soleus muscle important in postural sway as stretch of this muscle is being affected from the achilles tendon in a standing position.
-The soleus is constantly active during standing as one of the muscles very actively involved in postural sway.
-All of this postural sway activity is as a consequence of a monosynaptic reflex or a
myotactic reflex.
- Also, patellar/ knee jerk reflex. Both of these are spinal, stretch reflexes occurring due to stretching of muscle, resulting in activation of muscle spindles.
-Gamma spinal motor neurones being activated and then these fusing with synapses in spinal column to result in activation of muscle.
119
What is Babinski's reflex?
- Flexor response, toes curl down toward plantar surface, seen in normal healthy adults.
- Extensor response, toes curl up and fan out, is a sign of pathology or damage in adults.
- Extensor response is seen in babies or when adults are asleep.
- Abnormal Babinski reflex indicative of upper motor neurone damage or brain disease that impacts on the corticospinal tract.
120
How does a simple, monosynaptic reflex work?
-Within muscles there are gamma spinal motor neurones and they are stretch receptors which convey afferent
information via dorsal horn and these are synapsing within grey matter of spinal cord and they are synapsing towards efferent motor neurones, and there's a very simple monosynaptic reflex as a consequence.
-The stretch receptor results in signal which results in excitation of the efferent motor neurone and activation of the muscle as a consequence.
121
What is central modulation of spinal reflexes?
- Whilst there's a simple monosynaptic reflex, there's also central modulation of these spinal reflexes because there are often branches of these afferent nerve fibres and these synapse with ascending motor neurones to send information to the brain.
- Conversely can also get inhibition of these reflexes via descending motor neurones which are causing inhibition of synapse associated with efferent motor neurone fibres and therefore reflex can be inhibited.
- So can convey both sensory and inhibitory information via the central modulation of spinal reflexes.
122
What is reciprocal inhibition?
-An example of a complex reflex, preventing antagonist muscle activity.
-Important that when a particular muscle is activated
that the antagonist muscle is relaxed in order to make the agonist muscles action as effective as possible.
-And so an afferent fibre terminating in the grey matter of the spinal cord is synapsing to efferent fibre and therefore causing activation of the
extensor muscle, but there's also additional circuitry, there's an inhibitory interneurone synapsing with a branch from that afferent fibre which then causes inhibitory activity within flexor muscle.
-So have extensor which want to activate in this particular situation and a flexor which want to inhibit.
-Typical of reciprocal inhibition and this occurs in patellar or knee jerk reflex at third lumbar region. "
123
What is a crossed extensor reflex?
-Coordinates contralateral muscles, enabling you to walk up stairs because one muscle can remain stationary and operate as a base for the movement of another muscle, so for instance the muscles of the limb is an example.
-So this nociceptor, or
receptor which is detecting stretch in this particular situation via a cutaneous afferent is then synapsing with this three branched interneuron which performs three different functions.
-The first is to inhibit the extensor muscle, activate the
flexor, which is the muscle we want to activate and the third neuron is crossing the spinal cord and then innervating with an inhibitory and an excitatory neurone for the converse of what's happening on the contralateral side, so instead of the flexor muscle being activated, the extensor muscle is being activated on the other side and flexor muscle being inhibited.
124
What are the symptoms of myasthenia gravis?
Muscle weakness, ptosis (droopy upper eyelid), cannot prolong muscle contraction and progressive symtoms.
125
What is myasthenia gravis (MG)?
- Disorder of neuromuscular transmission.
- Women are affected about twice as often as men.
- Peak onset in women between second and third decades, and peak in men between fifth and sixth decades.
126
What is a synapse?
-Neurones communicate via synapses.
-Key properties of synapse is that it's unidirectional, there is an irreversible delay of
about 0.3-0.5ms and transmission of information is via chemical means.
-Synapses are junctional zones between neurones.
127
What is a neuromuscular junction?
Specialised synapses between alpha motor neurones and muscle cells/ myocytes.
128
What is the structure of an NMJ with regards to a single axon single muscle fibre, and what is another way motor units can present themselves?
-The neuromuscular junction is the point of contact between the alpha motor neurone which is exiting via the ventral horn of
the spinal cord and is in this case innervating a single muscle fibre.
-In this case have single alpha motor neurone supplying a
single muscle fibre.
-Example of a one to one ratio between motor neurone and muscle fibre, typically seen in eye muscle or where fine control is required.
-However, alpha motor neurone can have branches and innervate a series of muscle fibres, typical of large muscle, e.g. biceps.
-Single action potential will simultaneously activate all of these fibres.
-In these larger muscles, fine control is less important so larger number of muscle fibres are innervated by these branches.
-In each myocyte, there's one NMJ.
129
What is a connective tissue sheath?
- A tendon is connected to a connective sheath, which bounds a series of muscle fibres.
- Contraction of these muscle fibres results in transmission of tension to the tendon and therefore results in movement of joint to which tendon is attached.
130
How does packaging of muscle fibres differ to that of muscle fibrils?
-Packaging of muscle fibres, these muscle cells, is different to the packaging of muscle fibrils within individual muscle cells.
-So a muscle fibre cell can also be called a myocyte.
-Within each muscle fibre cell, myofibrils packaged into groups.
-Net of bunches of myofibrils in a single myocyte.
-Have single NMJs on myocytes being innervated by an alpha motor neurone which
may branch and may innervate a whole series of muscle fibre cells to form a motor unit.
131
What is the structure of a motor end plate?
- Presynaptic bouton contains a number of vesicles which are important for the process of neuromuscular transmission.
- This bouton is a very active region and has plenty of mitochondria.
- Have presynaptic membrane associated with vesicles.
- Have synaptic cleft, a gap of approximately 0.1-0.3pm.
- Have postsynaptic membrane which is invaginated.
- Folds associated with nACh receptors.
- There are plenty of sub-sarcolemmal mitochondria just at surface of myocyte.
- This folded membrane is continuous with sarcolemma, so has potential to communicate with it.
132
How does an action potential in the motor neurone lead to contraction of the muscle fibre?
-Action potential in motor neurone arrives at axon terminal, the presynaptic bouton.
-Terminal membrane depolarises and
voltage gated calcium channels open.
-Results in calcium mediated exocytosis of acetylcholine into extracellular space, in this
case the synaptic cleft.
-ACh then interacts with nicotinic acetylcholine receptors (nAChR) on invaginations of postsynaptic membrane.
-Results in influx of sodium ions and efflux of potassium ions from muscle cells via nAChRs, resulting in receptor generated potentials, RGPs.
-If RGPs are sufficient to pass threshold, an action potential is generated.
-Action potential propagates through muscle, which leads to release of calcium ions from sarcoplasmic reticulum leading to muscle contraction.
133
What happens in calcium mediated
| exocytosis of acetylcholine?
-Acetylcholine contained within vesicles.
-Within vesicles are a series of acetylcholine molecules.
-Calcium mediated exocytosis occurs when these vesicles fuse with presynaptic membrane and release acetylcholine into synaptic cleft.
-This is done as a result of action of voltage gated calcium channels.
-Occurs because there's a gradient of calcium ions from outside of presynaptic bouton, approximately 1mM, vs around 0.01mM within bouton itself.
-Arrival of action potential down axon to
presynaptic bouton causes opening of voltage gated calcium channels, allowing calcium to flow from extracellular space into
presynaptic bouton down calcium ion gradient.
134
What is quantal exocytosis?
-Results in release of secretory vesicles into synaptic cleft in packets as vesicles operate as packets or quanta.
-They're released randomly at rest as voltage gated calcium channels have limited efficiency.
-These quanta of ACh packaged within
vesicles continue to release small quantities of acetylcholine into synaptic cleft.
-Each release of ACh within one of these
quanta from a single synaptic vesicle will cause a small membrane depolarisation at post synaptic membrane, and this is what's called a miniature end plate potential, a mepp, approximately -0.4mV in amplitude.
135
What happens when ACh interacts with nAChR?
-ACh interacts with nicotinic acetylcholine receptors in a process called stimulus secretion coupling.
-Reality is a single action potential arriving at a presynaptic bouton results in release of about 60 ACh vesicles.
-Each vesicle contains about 10,000 ACh molecules, this is the reality of our quantal release of transmitting.
-nACh receptors have a much higher percentage in post synaptic membrane than number of ACh released with each action potential.
-There's around 10^7-8 nACh receptors
on post synaptic membrane, around 10-100 million, this is the concept known as receptor reserve.
-For the excess of nAChreceptors relative to number of acetylcholine molecules which are likely to be present due to arrival of action potential at presynaptic bouton, enhances capacity for detection of ACh release via this exocytotic process, it's enhancing the
sensitivity.
136
What is the structure of an nACh receptor?
- Consists of a five subunit structure.
- Binding of acetylcholine results in a conformational change of this structure and it opens the channel resulting in movement of sodium ions into cell and potassium ions out.
- This is an ionotropic receptor.
137
How does an action potential at the pre
| synaptic bouton result in an end plate potential?
-An action potential arriving at the presynaptic bouton opens voltage gated calcium ion channel, allowing calcium ions via this strong electrochemical gradient to move into presynaptic bouton and causes exocytosis of ACh which is packaged in
vesicles at presynaptic membrane of presynaptic bouton.
-ACh bind to nACh receptors on post synaptic membrane causing conformational change in receptor, resulting in sodium ion influx and potassium ion efflux from myocyte, causing local depolarisation.
-Process results in an end plate potential.
138
What are the time delays in a synapse?
-Calcium ion entry takes between 150-300microsecs, exocytotic process takes between 10-30microsecs, and conformational
change takes around 100-150microsecs.
-This results in a total time delay of approximately 370microsecs, delaying
neuromuscular transmission.
139
How does an end plate potential result in
| contraction?
-Still don't have an action potential being generated in the sarcolemma of the muscle, only an end plate potential at the post
synaptic membrane of the NMJ.
-Need to propagate an action potential to allow it to spread across the sarcolemma, across the muscle cell and then result in contraction.
140
How do we measure changes in membrane potential during a synapse?
-By electrophysiological recordings, performed in vivo or ex vivo.
-Recordings made from individual muscle fibres before, during and after stimulation of motor neurone.
-Resting potential of the post synaptic membrane, so the sarcolemma of the
muscle near a NMJ, is around -90mV.
-They have threshold of excitation that becomes important at around -70mV.
-Have miniature end plate potentials, resulting from quantal release of vesicles, random release of vesicles in exocytotic process
from the presynaptic bouton.
-Occurring as voltage gated calcium ion channels at presynaptic boutons are inefficient and therefore there's some random release and this causes some small changes in potential as a consequence.
-If have a large stimulus arriving at pre-synaptic bouton, potentially will get an end plate potential.
-Can see it's inefficient to get past threshold, -70mV. If were to produce a greater stimulus, and this is typically that resulting from the arrival of an action potential at presynaptic bouton, get a larger end plate potential.
-The point at which this passes through the threshold of activation of the post-synaptic membrane results in propagation of a muscle action potential which then spreads across the sarcolemma.
-Miniature end plate potentials and end plate potentials are both receptor generated potentials.
-Will be a rise in intracellular calcium within cytosol of muscle.
-Closely associated with contraction and cystolic calcium levels are said to drive
contraction as a consequence.
-The calcium transient, it rises and falls quite quickly.
141
What is a one to one synapse?
- Each muscle cells has one NMJ to reinforce this and therefore usually a one to one synapse.
- So one presynaptic action potential results in one post synaptic action potential and this will result in a twitch contraction.
142
In summary what happens when ACh is released into synaptic cleft?
- It binds to nACh receptors.
- If there are sufficient quanta of ACh released, the large number of receptors will result in an end plate potential.
- If this end plate potential is sufficient it will open voltage gated sodium ion channels with postsynaptic membrane, causing a larger influx of sodium ions into myocyte and this will propagate an action potential.
- That propagating action potential spreads across sarcolemma and then will move down into the T-Tubules, invaginations of the myocyte.
- This allows communication with the ryanodine receptors and these are closely associated with the sarcoplasmic reticulum, and these are arranged in triads within skeletal muscle, and this action potential arriving at the ryanodine receptors, opens more voltage gated calcium channels and releases calcium ions from sarcoplasmic reticulum which results in muscle contraction.
- This process occurs in skeletal muscle, not cardiac muscle as has no NMJs.
- Calcium released from sarcoplasmic reticulum retaken up by sarcoplasmic reticulum quickly, which is why there's a calcium transient, and there's a twitch contraction, because ATP dependent calcium pumps retake up calcium ions and retain within sarcoplasmic reticulum for next contraction.
143
How do we terminate ACh action?
- It's hydrolysed via an enzyme called acetylcholinesterase in synaptic cleft into acetate and choline.
- This is then taken up by presynaptic bouton, repackaged in vesicles which recycles the ACh through system.
- This is a swift process.
- It's an active enzyme and so nACh receptors on post-synaptic membranes are only activated for around 1ms with each action potential arriving at pre-synaptic bouton.
144
How do we treat MG?
- Increase ACh levels at the NMJ.
- Improve reuptake or reactivation of ACh and this is what is used to regulate and improves symptoms of MG.
- Acetylcholinesterase can be inhibited in a finely controlled manner via drugs, blocking enzymes action, and therefore prolongs amount of time ACh present within synaptic cleft, and increase chances of its binding to nACh receptor and improve generation of end plate potentials, action potentials and muscle contraction.
