Block 4: autonomic nervous system Flashcards
Describe the topology of the spinal nerves.
There are two spinal cord enlargements – the cervical (C4-T1) and lumbosacral (T11-S1) enlargements. The cervical enlargement contributes to the brachial plexus; the lumbosacral enlargement contributes to the lumbosacral plexus. These correspond to the upper and lower limbs. The vertebral column grows faster than the spinal cord. In between the vertebrae are intervertebral foramina – 31 spinal nerves emerge from these specific gaps in the vertebral column. Each of these pairs of spinal nerves relates to a spinal segments. C1 does not emerge from intervertebral foramina, but from between the occipital bone and the skull (called the atlas). Also, spinal nerves are named after the vertebrae below them from C1-C7 – after this, they are named for the one above – this is why C8 exists when there are only 7 cervical vertebrae. However, the vertebrae and spinal nerves are not completely equivalent (there are 7 cervical vertebrae, but 8 cervical segments; also there are 4 coccygeal vertebrae, but only 1 coccygeal segment). There are 8 cervical, 12 thoracic, 5 lumbar, 5 sacral, and 1 coccygeal segments.
Dorsal and ventral rootlets converge to become roots, and these dorsal and ventral roots converge to form spinal nerves (mixed sensory and motor fibres). These spinal nerves then diverge into dorsal and ventral rami.
Ventral (posterior) rami are distributed two ways:
1) Thoracic ventral rami form the intercostal nerves (extend the inferior margin of the rib and innervate intercostal muscles and skin over the thorax)
2) All other ventral rami form five major plexi- nerves arise from plexi after branching, usually containing axons from >1 spinal nerve. As the dorsal ramus travels posteriorly, it supplies the erector spinae muscles. The ventral ramus supplies body wall and limb plexi.
Nerves arising from each region of the spinal cord correspond to a specific area of the body where they innervate – this is known as a dermatome. Myotome is anatomically and functionally related to skeletal muscle, whereas dermatomes refer to the skin. C1 does not have a dermatome.
Describe the intrinsic beating of the heart, and how the ANS mediates this.
Cardiac impulses originate in pacemaker cells of the sinoatrial (SA) node of the heart. Hyperpolarisation-activated cyclic nucleotide gated (HCN) channels are expressed on these cells and open upon hyperpolarisation following repolarisation after action potentials (APs) which correspond to each heartbeat. When opened, HCN channels facilitate a hyperpolarisation-activated nonselective cation current (If) into the pacemaker cells, causing a steady-state, spontaneous depolarisation. When this reaches the threshold potential of T-type, and subsequently, L-type Ca2+ channels, it results in the generation of an AP which is conducted throughout the SA tissue via gap junctions. This characteristic of pacemaker cells gives rise to their automaticity and thus to the spontaneous, rhythmic beating of the heart. However, the rate of SA depolarisation can be mediated by the cardiac autonomic nervous system (ANS) by modulating the rate of If through HCN channels and counter-balancing this depolarisation with efflux channels.
Intrinsic heart rate (HR) sits at around 100BPM, though this varies with age and health status. Balanced function between the two divisions of the ANS, sympathetic and parasympathetic, is crucial for maintaining cardiovascular homeostasis. The two operate in a complementary manner, with the sympathetic acting to increase HR and the parasympathetic to reduce HR. Resting HR is largely mediated by the parasympathetic system, whereas increased HR (i.e. during physical activity or anxiety) can be due to both reduced parasympathetic activity and increased sympathetic activity.
The parasympathetic division of the cardiac ANS originates mainly in the nucleus ambiguus and dorsal motor nucleus within the medulla oblongata. Preganglionic parasympathetic axons constitute a visceral portion of the vagus nerve (CNX), and synapse to effector neurons at intracardiac ganglia. Acetylcholine is released by postganglionic neurons and acts upon muscarinic (M2) post-junctional receptors expressed on pacemaker cells. Gβγ subunits of M2 receptors promote potassium efflux by activating G-protein-coupled inward rectifying potassium channels, hyperpolarising the membrane to counteract If through HCN channels. Additionally, Gαi/o subunits inhibit adenylyl cyclase to prevent the production of cyclic adenosine monophosphate (cAMP), a molecule responsible for the upregulation of HCN channel activity and activation of protein kinase A (PKA) which subsequently upregulates activity of voltage-gated calcium channels. M2-mediated downregulation of these processes therefore slows If and reduces conductance of calcium channels, resulting in a longer time being required for threshold to be reached, increasing the time between heart beats, and increasing HR.
The sympathetic branch which innervates the SA node originates with preganglionic neurons which project from the intermediolateral nucleus of spinal cord levels T1-4 to the cervicothoracic sympathetic nerve chain, where they synapse to postganglionic, adrenergic neurons. Noradrenaline release from these postganglionic effector neurons acts on β1-adrenoceptors expressed on pacemaker cells. Gαs subunits increase synthesis of cAMP from ATP via increased activity of adenylyl cyclase, and cAMP acts on the cyclic nucleotide binding domain of HCN channels to upregulate their activity. cAMP also activates PKA to upregulate calcium channel sensitivity as previously discussed, and together these effects increase the rate of If. This results in L-type Ca2+ channel threshold and corresponding AP generation being reached sooner, thereby decreasing time between heart beats and increasing HR.
What is EC coupling and what is its importance in regulating blood pressure?
Excitation-contraction (EC) coupling is the mechanism that links activation to contraction of a muscle cell. This usually involves membrane depolarisation by activation of ligand-gated ion channels or a second messenger system, and results in contraction principally controlled by influx of clacium ions. Vascular smooth muscle is continuously active (has a tone), but can be contracted more and can be relaxed. Flow of fluid through a cylindrical tube can be calculated with the equation:
Q=(πΔPr^4)/8ηl
Where Q = flow rate; ΔP = change in pressure across tube; r = radius; η = viscosity; and l = length of tube.
By increasing pressure change or radius of the tube, flow rate is increased; by increasing liquid viscosity (thickness) or length will decrease flow. There are many influences which can act on blood vessels, these can be long-range or local factors- for instance, nerves can influence smooth muscle tone with neurotransmitters (long-range); and vascular adipose can do this via paracrine signalling (local). Blood flowing down vessels exerts shear stress on the blood vessel walls, and this can be detected by the vascular endothelium (also flow rate and type of flow- laminar or turbulent). Endothelium can release factors to affect smooth muscle tone in response to these physical factors.
Define reactive hyperaemia, active hyperaemia, myogenic tone, and flow-dependent vasodilation.
Reactive hyperaemia (or post-occlusive reactive hyperaemia, PORH) results from a blood supply being cut off for a while, causing metabolites to build up- the response is dilation when blood supply is restored as a reaction to flush them out.
Active hyperaemia is when vasodilation is used to flush out toxic metabolites without any occlusion.
Myogenic tone is a form of autoregulation where increased blood pressure results in smooth muscle stretch, and it contracts in response to this stretch to prevent too much blood flow- this is crucial for maintaining blood flow in principle areas such as the coronary circulation to the brain.
Flow-dependent vasodilation is the opposite to myogenic tone. Here, increased blood pressure causes smooth muscle to stretch and relax in stead of contrict (endothelium release NO which relaxes via cGMP pathway- this is constitutively active).
Define special tasks, structural adaptations, and functional adaptations of vasculature, and relate these to the cerebral circulation.
Specialised tasks are designed to bring sufficient blood flow at required time and remove waste at the required time (task that the organ requires at a particular time from the vascular bed). Structural adaptations include capillary bed density and activity, cross-connections and collaterals. Functional adaptations include autoregulation and basal tone.
The role of the cerebral circulation is to maintain constant blood flow to the brain (55ml/min/100g). The arterioles in the brain are very short, so vascular resistance is actually mostly provided by arteries. The special task of the cerebral circulation is to allow for high rate of oxidative metabolism to the brain while supplying it with steady blood flow. Additionally, local brain areas have specific metabolic and flow requirements. A key strucutral adaptation in the cerebral circulation is the circle of Willis (see workshop notes). Other strucutral adaptations include the high capillary density and the BBB. A functional adaptation is a high basal blood flow to the grey matter and self preservation- other organs will always be sacrificed to maintain cerebral perfusion (ie if you were bleeding out and losing blood, flow would be “taken” from other organs to continue supplying the brain). There is also considerable autoregulation in the cerebral vessels, meaning that regardless of arterial pressure, the cerebral blood flow will not be affected (within certain parameters). However, we can see that hypercapnia (high CO2 concentrations) is extremely detrimental to this process. Another functional adaptation is regional hyperaemia – this can clearly be seen with modern imaging techniques. This means that when certain areas of the brain are active, they get increased blood flow. The mechanism by which this works is in part to do with the metabolites which are released during activity which act on the vascular smooth muscle to cause vasodilation. This can be referred to as neurovascular coupling.
Describe the structure, function, and expression of acetylcholine receptors.
There are two families of acetylcholine receptors- nicotinic (ionotropic) and muscarinic (metabotropic).
Both sympathetic and parasympathetic nervous systems use nicotinic acetylcholine receptors at their respective ganglia. Nicotinic receptors are comprised of 5 subunits around a central pore- each subunit has 4 transmembrane domains, with an extracellular N and C-terminus . They can be broadly divided into two subtypes regarding where they are expressed in the body – muscle-type and neuronal-type.
Muscle-type receptors are present in the neuromuscular junction – they interface the nervous system with skeletal muscle. They are primarily excitatory in that they increase cation permeability (sodium and potassium). Can be activated by acetylcholine, as well as a couple of other endogenous molecules. These receptors can be slightly different in the embryonic and adult form. In the embryonic form, they are composed of 2x alpha-1, beta-1, gamma, and delta subunits (always have at least two alpha subunits). In the adult, its 2x alpha-1, beta-1, delta, and epsilon.
Neuronal-type receptors can be ganglion-type or CNS-type. Ganglion-type neuronal nicotinic receptors have 2x alpha-4 and 3x beta-4 subunits. CNS-type neuronal nicotinic receptors can have 2x alpha-4 and 3x beta-2 subunits, or 5x alpha-7 subunits (homomeric).
Where acetylcholine binds depends on the receptor subtype- for muscle-type receptors, the binding sites are at the interface of alpha-delta and alpha-epsilon (2 acetylcholines are required to activate the receptor). In the neuronal-type receptors, the binding sites are at the interface of alpha-beta. It is always between an alpha subunit and another, which is why there is always 2x alpha.
Describe the structure, functions, and expression of adrenoceptors.
There are recognised to be 9 adrenoceptor subtypes (α1A, α1B, α1D, α2A, α2B, α2C, β1, β2, and β3). All adrenergic receptors are metabotropic.
α1 adrenoceptors are expressed on smooth muscle and liver tissues. They act to constrict blood vessles, bronchi, GI sphincters, uterus, bladder sphincter, seminal tract, and the iris (radial muscle). They relax GI tract muscle, and stimulate glycogenolysis in the liver. They achieve this through phospholipase C activation.
α2 adrenoceptors can constrict or dilate vascular smooth muscle and relax (presynaptically) GI smooth muscle. They also decrease insulin secretion in pancreatic islets. They do this through reduced activity of the cAMP pathway.
β1 adrenoceptors are expressed on the heart SA tissue and cardiac muscle and salivary glands. They increase HR and contractile force and stimulate amylase secretion by upregulation of the cAMP pathway.
β2 adrenoceptors are widely expressed. They dilate blood vessels and bronchi, but relax GI, uterus, bladder detrusor, seminal tract, and ciliary smooth muscles. They increase HR and contractile force (though their effect is negligible apart from in the case of heart failure), can mediate tremor, increased muscle mass and speed of contraction, and glycogenolysis in skeletal muscle, and can increase glycogenolysis in the liver. They also inhibit histamine release from mast cells, and do all this through upregulation of the cAMP pathway.
β3 adrenoceptors mediate thermogenesis in skeletal muscle, and lipolysis and thermogenesis in fat tissue by upregulation of the cAMP pathway.
Describe how VNS can be used to treat heart failure, and some of the side effects associated with this.
Baroreflex sensitivity is a measure of the progression of heart failure. The R-R interval (time between heart beats) can be used to measure HR. When blood pressure increases, the RR interval should increase (reducing HR) – this is good baroreflex sensitivity. In patients with heart failure, baroreflex sensitivity is low, so increases in blood pressure are not combated by decreases in HR. Since the parasympathetic system is involved in determining RR interval (as well as sympathetic), this could suggest that there is an issue in parasympathetic activity in heart failure patients. This was found to affect both cardiovascular mortality as well as all-cause mortality. It was also found that atropine (muscarinic blocker) created huge increases in HR in non-heart failure patients but had smaller effects on patients with heart disease (shows that heart failure patients have underactive parasympathetic activity on the heart). They also found that baroreflex sensitivity in healthy individuals was highly reliant in parasympathetic activity. The underactive cardiac parasympathetic system in heart failure patients may therefore be a contributing factor to symptoms and mortality.
VNS was then used first by Li et al. (2004) in rat models of heart failure. A vagus nerve stimulator and telemetry device (for HR and BP) were implanted into surviving rats a week following coronary artery ligation. After another week, VNS treatment began for 6 weeks. It was found that rats treated with VNS underwent less hypertrophy (less compensated heart failure), that sympathetic activation was inhibited, and that brain natriuretic peptide (biomarker for heart failure) levels in the blood were reduced. Survival rate was also increased by 30-40% over the course of the 6 weeks.
Potential side effects of VNS can be quite mild or can be quite severe. Mild side effects include pain and coarse voice (due to vagal innervation of the voice box). More severe side effects include asystole (heart stops beating temporarily). The auricular branch of the vagus nerve carries sensory information from the tragus, concha, and the cymba concha (external ear) to the superior vagal ganglion, and then project to brainstem nuclei (some evidence that they project to the NTS). Therefore it may be possible to stimulate the auricular branch of the vagus nerve to elicit effects without invasive procedure.
Summarise how breathing is controlled by the PNS and CNS.
Breathing occurs spontaneously, but can be subject to volitional control (e.g. holding breath deliberately), vocalisation, emotional events, reflexes, and physiological challenges. Chemoreceptors provide feedback on blood PO2, PCO2, and pH. Mechanoreceptors provide feedback on mechanical status of the lungs, chest wall, and airways. The brain integrates this information, and sends signals back to respiratory muscles to mediate contraction.
Peripheral chemoreceptors are small, highly vascularised bodies in the aortic arch and carotid sinuses. Aortic chemoreceptors sit beside baroreceptors in the aortic arch, and project to the NTS via the vagus nerve. Carotid chemoreceptors and baroreceptors reside in the carotid arteries, where they bifurcate into internal and external carotids. These project to the NTS via the glossopharyngeal nerve. Peripheral chemoreceptors typically respond to hypoxia (reduction in arterial PO2), which will result in an increase in ventilation to restore blood oxygen levels. Progressive reductions in inspired oxygen have little effect until about 60mmHg (at rest, arterial PO2 = ~100mmHg). Below 60mmHg, hypoxic response elicits progressive hyperventilation.
Central chemoreceptors are clusters of neurons in the brainstem which respond to hypercapnia (or increased pH). These neurons are integrated by other clusters of neurons. If hypercapnia is detected, ventilation in increased to restore blood gas levels. Unlike peripheral chemoreceptors, central chemoreceptors respond to very small changes in PCO2 – very large and almost immediate increase in ventilation (major role in moment to moment control).
Sensory receptors that detect changes in pressure, movement, and touch (detect movement of lung and chest wall). These are located throughout the respiratory tree, and are activated by inflation of lungs. These receptors project to the NTS via the vagus nerve. These are responsible for integrating respiratory patterns with other movements such as posture and locomotion. There are several type of mechanoreceptor throughout the respiratory tree, characterised by their location, stimulus, and reflex. For example, airway smooth muscle mechanoreceptors respond to inflation/distension of airways, and when activated will terminate inspiration (i.e. when fully inhaled, will stop inhaling). Airway epithelium mechanoreceptors respond to rapid lung inflation/deflation or oedema, and will activate a shortened expiration.
The nucleus tractus solitarius (NTS), a bilateral nucleus of the dorsal medulla, receives information from mechanoreceptors and peripheral chemoreceptors. Clusters of respiratory neurons (in the ventral medulla) in the brainstem are responsible for processing these NTS afferents. These respiratory neurons are involved in producing the rhythmic output of breathing. There are many kinds of respiratory neuron, including pattern generating and rhythm generating neurons. Pattern generating neurons are activated during a specific point in the respiratory cycle (i.e. some are inspiratory, some are expiratory, and some are phase-spanning). The amplitude and frequency of depolarisation of these pattern generating neurons can be modulated. Rhythm generating neurons produce a rhythmic output which underlies intrinsic respiratory output – they have spontaneous automaticity, similar to pacemaker SA node cells. These rhythm generating neurons reside in the preBotzinger complex of the medulla – this can be fully isolated, and will continue to produce a rhythmic output for about a day with no input.
Rhythmic neural signals are sent to the spinal cord from the brainstem and innervate the diaphragm and intercostal muscles via the phrenic nerve and intercostal nerves, respectively. The phrenic nerve exits the spinal cord at C3-5, and the intercostal nerves exit at levels T1-11.
Volitional control of breathing (voluntary) is controlled by the primary motor cortex. One particular part of the M1 homunculus induce diaphragmatic hiccups when stimulated (near the dorsal aspect of M1). These signals travel through the corticospinal tract, decussate, and exit the spinal cord as part of the phrenic nerve to innervate the diaphragm.
