Brain Physiology

Basics

• The brain contains 10¹¹ neurons and perhaps 10-50 times as many glial cells. About 40% of human genes are involved in some part with its development and structure. The excitability of neurons is key to how they work. The structure of individual neurons also varies depending on the individual role they play. A neuron is composed of a cell body (soma) + multiple dendrites + a single axon
• A typical neuron has a large cell body. Input is via multiple dendrites and output is via an axon which can be a metre in length. There are multiple types of neuron all specialised for their particular role.
• Different Neurons have lots of sub-specialisation in terms of structure and function. The neurons are the fundamental building block of the CNS though only form 10% of the cells within the CNS. Their electrical excitable properties and ability to conduct nerve impulse mean that the neurones can transmit or even process information rather like a computer. Several neurons with different inputs can have this information pass on to one neurone which can either depolarise, hyperpolarise or have no effect at all depending on the state before the stimulus and the stimulus. The neurone is composed of a cell body or "soma" which contains mitochondria, Golgi apparatus and peroxisomes. Endoplasmic reticulum stains and is known as Nissl substance.
• Body: Contains Nissl substance - which is a collection of polyribosome and rough endoplasmic reticulum as well as neurofilaments and microtubules which for part of the cytoskeleton which continues into the Dendron and axonal processes.
• Dendrites: Typically long and thinly covered by dendritic spines. Multiple input points usually of high resistance preventing unwanted stimulation from background electrical activity. Attached to the cell body.
• Axon: Usually single and starts at the area called the axon hillock close to the cell body with a high concentration of sodium channels which forms a sort of trigger zone allowing the initiation of an action potential to travel along the axon.

Introduction

• The Resting membrane potential of a neuron is at -70 mV. The cell begins to depolarize at -55mV and when depolarized this rises to +40 mV. At times the cell is hyperpolarized when the membrane potential is less than -70mV. The intracellular concentration of potassium is high. It is the equilibrium potential of potassium (-90mV)? the point at which there is the equilibrium of potassium concentration across the cell membrane that resembles closest the actual value. The conductance through potassium channels at rest is much greater than through sodium channels. There is obviously movement of potassium out of the cell along its concentration gradient but this leaves a net negative electrical gradient within the cell. The effect of Na⁺, Cl- and Ca++ ions have relatively little effect. With an action potential, there is a transient increase in Na permeability and this leads to Na movement into the cell and the inside of the cell becomes more positive which acts to cause even greater Na permeability with a positive feedback loop that rapidly increases the membrane potential. There follows a transient rise in potassium permeability such that it flows out of the cell making the inside more negative even more so than at rest. The ions pass through voltage-gated ion channels. During an action potential, the charge inside the cell can become even more negative and this is called hyperpolarisation often due to further movement out of potassium ions which can render the cells refractory for a short period. The Nernst equation can be used to calculate resting membrane potentials. Interestingly different cells in the body have similar but not always identical resting membrane potentials e.g. neurons -70 mV, glial cells -90mV skeletal muscle cells? 80mV and smooth muscle cells -70 mV. Membrane potential State + 40 mV Depolarised -70 mV Resting -90 mV Hyperpolarised E K = - 90 mV E Na = + 60 mV Resting MP = - 70 mV

Summation

Imagine a neuron cell body with its dendrites abutted by the synaptic boutons of the distal end of other axons. The generation of an action potential is dependent on the input to the neuron in question. The axons may provide excitatory inputs raising the local membrane potential of the neuron or inhibitory reducing the cell membrane potential. The following may occur " Partial depolarization due to one or more depolarising or hyperpolarizing inputs which do not raise the membrane potential to a level at which depolarization occurs " Temporal excitatory summation - a series of impulses from one excitatory fibre over a period of time produces a membrane potential high enough to result in depolarisation " Spatial excitatory summation occurs when impulses in at least two excitatory fibres cause two synaptic depolarisations which trigger an action potential " Spatial excitatory summation with inhibition - impulses from at least two excitatory neurons fail to depolarize the cell due to inhibition from an inhibitory neuron " Spatial excitatory summation with inhibition - impulses from at least two excitatory neurons depolarize the cell despite inhibition from an inhibitory neuron When several stimuli arrive quickly one after another from the same fibre is called temporal summation. Spatial summation occurs when two or more stimuli arrive at a neuron but at different locations usually separated by micrometres. If the sum of the potentials reaches a certain point then an action potential is generated by the sudden opening of fast Na⁺ voltage-gated channels. Voltage-gated means that they open in response to changing membrane potential. The channels usually open when the membrane potential reaches - 55mV. An understanding of this is required in the understanding of neurological physiological and pathological processes from epilepsy to migraine. An increase in Na⁺ conductance and so influx making the inner cell more positive is excitatory whereas an increase in K⁺ conductance and so outflow is inhibitory as is increase Cl- conductance which flows in.

Neuronal transmission

Myelin is produced in the CNS by the oligodendrocytes which are derived from glioblasts. In the peripheral nervous system, myelination is by Schwann cells and these can only myelinate one axon whereas in the CNS oligodendrocytes can form myelin sheaths around multiple axons. There are gaps between adjacent myelinated areas called nodes of Ranvier where the action potential depolarization happens. Here in the CNS an astrocyte foot process also abuts.

A cell depolarizing will lead to adjacent cells depolarizing. The nodes of Ranvier are close enough to the next node so that a wave of depolarisation can pass quickly along the axon, to a quicker extent than were the cell to be unmyelinated. This is called "salutatory" conduction as the transmission jumps from node to node.

There are many diseases in the CNS and the PNS which are associated with demyelination possibly as myelin is composed of proteins that are strongly antigenic, With chronic stroke disease, there is often "white matter disease" due to ischaemia due to disease of the small penetrating arteries.

Synapses

A synapse is a point of contact between two neurons. They can be either electrical or chemical. Electrical ones are uncommon and are really there to allow a simultaneously continuous passage of an action potential. There is cytoplasmic continuity through 1.5 nm channels. Modulation is not possible as all cells are depolarized together. Seen in the respiratory centre of the brain such that they produce a sustained continuous discharge during inspiration or involved in the movement of the eyes - saccades. Chemical synapses lead to the release of a transmitter which may depolarise or hyperpolarise the postsynaptic membrane. Depolarisation is excitatory and hyperpolarisation is an inhibitory effect.

Chemical Synapse

The synaptic terminal allows the conversion of an action potential into a chemical response. At the distal end of the axon lies the presynaptic terminal separated from the postsynaptic membrane of usually a dendrite by a synaptic cleft which is about 20 nm across. The presynaptic terminal contains numerous vesicles of neurotransmitters that have been brought there by axonal transport. There is a degree of variability and the pos synaptic membrane may be to a dendrite, the body of a neuron or even another axon. A spreading wave of depolarization reaches and depolarizes the presynaptic terminal and causes the influx of calcium ions through voltage-gated calcium channels. These enter the cell and trigger secondary effects such as neurotransmitter release such as Acetylcholine, glutamate, GABA and others. This then crosses the synaptic cleft and may lead to changes in postsynaptic cells with the formation of an EPSP or IPSPs.

Neurotransmitters such as GABA allow Cl- ions to enter cells which make the internal more negative "hyperpolarises" them so making them less likely to depolarize and is so inhibitory. Other such as glutamate is excitatory and causes depolarization. These can generate an Excitatory postsynaptic potential (EPSP). Only at a certain strength with the EPSP generate a postsynaptic action potential. This depends on the number of activated ligand-gated channels.

Brain Metabolism

About 90% of normal brain metabolism required to maintain ion gradients and transmit electrical impulses comes from the oxidative breakdown of glucose. Other molecules such as ketone bodies may be metabolized in severe starvation. Other molecules such as lactate can also be metabolized. Neuronal cells have a very high metabolic rate and glycogen storage is poor. Anaerobic metabolism is not possible to any real extent. Glucose and oxygen supply must be continuous to match the high metabolic rate. Unlike other tissues glucose entry to cells is not dependent on Insulin. In patients with no Insulin, glucose can still enter neurons. However systemic hypoglycaemia will cause neuroglycopenia with marked symptoms and neuronal cell dysfunction. Prolonged hypoglycaemia will cause neuronal damage. Glutamate is taken up by ?? glial cells neurons which take up ammonia and is released as glutamine. This helps keep the brain free of ammonia which is very toxic to neuronal function. The cerebral cortex, basal ganglia and thalamus and inferior colliculus all have a high oxygen demand. Hypoxia for instance can lead to symptoms of Parkinsonism.

Internal Structure

• The axon is surrounded by an axolemmal membrane. The cytoskeleton composed of microfilaments and microtubules allows transport. Axonal transport within the cell can be from the cell body to the synapse (anterograde) or from the synapse to the cell body (retrograde). Microtubules can provide fast axonal transplant whereby molecules are actively transported by specific motor molecules. The proteins kinesin is involved in anterograde transport and cytoplasmic dynein is involved in retrograde transport.
• The outside of the axon is myelinated with a 1 um gap (node of Ranvier) every 1 mm. This helps increase the speed of salutatory conduction of action potential along the axon. Damage to myelin occurs in MS, ADEM and PML. Each axon has a few small branches terminated with a synaptic ending or bouton. Direction of information flow dendrites (many) Cell body Axon (single)

Axonal transport

• A typical neuron is composed of up to 7 dendrites which are branching structures that extend out from the neuronal cell body and largely receive input. Some dendrites particularly in the cortex have small projections called dendritic spines. The cell body also has a thickened area called an axon hillock and then a long extension forming an axon. The terminal end of the axon forms synaptic knobs often storing neurotransmitters in vesicular structures. The axons are often enveloped in myelin a protein-lipid complex which within the CNS is produced by an oligodendrocyte.
• Information appears to travel from dendrites to axons. Axons are low in ribosomes and most synthetic function occurs in the cell body and is transported along the axon by the axoplasmic flow. Flow into axons or dendrites is both anterograde which is mediated by kinesin. The speed of anterograde transport can be up to 40 cm/day. This is for transporting vesicles and neurotransmitter precursors and receptor proteins. There is also slow anterograde transport for structural elements at 1 cm/day.
• Retrograde transport is mediated by cytoplasmic dynein can also be quite fast at 12-20 cm/day. Failure of dynein is possibly linked to motor neurone disease. Both occur actively along microtubules. ATP is used for transport and neurons are rich in mitochondria. Microtubule binding proteins include ATPases. Viruses such as rabies and tetanus toxin can be carried centrally by the retrograde axoplasmic flow.

Cortical structure

• The cerebral cortex is made up of a 5mm layer of grey cells above a dense thick inner layer of white matter. The overall surface area is increased by the folds of sulci and gyri. The cortex can be seen to be composed of six layers of cells that vary in size and structure.
• Back in 1909 Brodmann produced a map of the cerebral cortex based on the microarchitecture of the cells and staining for Nissl substance which separates neurons from glial cells. This was before we had an understanding of many of the functions of these areas and the system has stood the test of time. Other improvements have been developed by others. It is quite clear that anatomy is related to function.
• Cells in the cortex are arranged in a columnar structure and can this can be seen with microelectrode stimulation. Areas with similar function lie close together. For example Broca's area lies within the inferior region of the precentral motor cortex near to those areas that control voluntary movement of the lips, tongue, larynx and pharynx. Broca's produces the content of speech content and damage here leads to expressive dysphasia.
• A lesion in the inferior area of the precentral motor cortex leads to dysarthria and facial weakness. Indeed Broca's discovery of dysphasia in a patient whose subsequent post mortem revealed a lesion due to syphilis in the area that became known as Broca's area was one of the key findings to suggest localization of function within the brain.

Astrocytes

• Astrocytes are the largest and commonest of glial cells. They are star-like shaped with multiple long processes that can make them resemble neurons. The cytoplasm is abundant with intermediate filaments which give the cells some rigidity helping to support the brain structure. Glycogen granules acting as a glucose store are found.
• Astrocytes stain for glial fibrillary acidic protein which is cell-specific. Unlike neurons, they are able to multiply and can form scar tissue when there is localised injury(gliosis). Astrocytes have foot processes that abut onto capillaries or pia mater forming a glial membrane. They have multiple functions indicated in the table on the right

Glial (from the greek for glue) cells

• It has been estimated to outnumber neurons by a factor of over 10 to 1. They are not involved with information processing (as far as we can tell) but perform general housekeeping and other functions in the CNS as will be discussed later.
• They also hold the structures of the CNS together. Neurons are packed within the CNS at about 80,000 per mm2 of cortex and this is uniform across most of the cortex. The exception is the high density of 200,000 per mm2 in the primary visual cortex. Astrocytes can resemble neurons in having long processes which resemble dendrites.
• However astrocytes do not contain Nissl bodies (densely packed rough endoplasmic reticulum seen in neuron cell bodies). Astrocytes do however stain for glial fibrillary acidic protein which is cell specific. Microglia are derived from the bone marrow and are cells of the immune system. They have several functions including acting as macrophages phagocytosing debris.

Basal Ganglia

• The basal ganglia is a collection of interconnected nuclei (neuronal cell bodies) lying deep below the cortex. It is composed of the following structures. The putamen (laterally) and globus pallidus (medially) form the lenticular or lentiform nucleus (lens-shaped).
• The caudate and putamen are also called the neostriatum. Grey matter strands cross the internal capsule to connect these structures and so gives the area the name of the corpus striatum. The putamen is the larger ovoid mass that lies laterally with its lateral side separated vary slightly from the insular cortex and the external capsule and claustrum.
• Medially attached to the Globus Pallidus. The Globus Pallidus is a smaller triangular-shaped structure and lies medially with its medial relation being the internal capsule. The globus pallidus is a major source of output from the basal ganglia. It is divided by a lamina into Globus pallidus externa and interna.
• The caudate nucleus is a large mass of grey cells making up a head, body and tail. Anteriorly seen on scans at the lateral border of the anterior horn of the lateral ventricle. It lies then on the lateral wall of the ventricle and there is a tail that passes to form the roof of the inferior temporal horn of the ventricle. The internal capsule separates it from the putamen. The caudate is notable as being diminished in size in Huntington's chorea.
• The caudate and putamen receive stimulatory input from the cerebral cortex mediated (Glutamate) and from the substantia nigra (Dopamine). The caudate/putamen gives an inhibitory output (GABA) to the Globus pallidus and substantia nigra. The Globus pallidus and Substantia nigra also send inhibitory signals to the ventral thalamic nucleus of the thalamus (GABA) which in turn feeds to the cortex (glutamate).
• The Basal ganglia are concerned with movements of the contralateral limbs and it would seem that it stimulates and inhibits various regions thus modulating motor output. All of these structures are prone to lacunar infarcts and deep haemorrhage

Brain Stem Anatomy/ Cranial nerves

The Brainstem contains all the cranial nerves other than Olfactory and optic nerves

Midbrain

• Oculomotor (IIIrd) nucleus: SEE ABOVE
• Edinger-Westphal nucleus: Lies in the posterior midbrain. It supplies parasympathetic fibres that terminate in the ciliary ganglion via cranial nerve III. It is mainly involved in pupillary constriction and the light accommodation reflex.
• Substantia Nigra (SN): The primary efferent neurotransmitter from the substantia nigra is dopamine. Parkinson disease damages the substantia nigra. Pathologically, the neurons lose their melanin and the nucleus becomes depigmented. Many neurons also contain inclusion bodies called Lewy bodies.
• Red nucleus (RN): mass located in the ventral portion of the tegmentum of the midbrain. It is a relay centre for many of the efferent cerebellar tracts. The crossed fibres of the superior cerebellar peduncle (SCP) pass through and around its edges.
• Edinger-Westphal nucleus: lies in the posterior midbrain, supplies parasympathetic fibres that terminate in the ciliary ganglion via cranial nerve III. It is mainly involved in pupillary constriction and the light accommodation reflex.

Pons

• Vestibulocochlear nerve (VIII): 2 distinct sensory divisions:
• Vestibular nerve : responds to position and movement of the head, serving functions often identified as equilibrium.
• Cochlear (or auditory) nerve : cochlear nerve mediates auditory functions.

Medulla

• Nucleus ambiguus: nucleus that lies in the depths of the medulla. It innervates the volitional muscles of the pharynx by way of both cranial nerves IX and X and the larynx (for phonation) via cranial nerve X. The larynx and pharynx have bilateral cortical input.
• Nucleus solitarius: nucleus in the medulla that receives afferent information from the larynx (via cranial nerve X) and posterior pharynx and mediates the gag and cough reflexes (cranial nerves IX and X). Pain sensation from these areas enters the brain stem through cranial nerves IX and X but terminates in the descending spinal tract of the trigeminal nerve.
• Salivatory nucleus: Superior salivatory nucleus sends efferent autonomic fibers (general visceral efferent) through cranial nerve VII to innervate the lacrimal, submandibular, and sublingual glands as well as the mucous membranes of the nose and hard and soft palate. The inferior salivatory nucleus sends efferent autonomic fibers via cranial nerve IX to innervate the parotid gland.
• Gustatory nucleus : nucleus in the medulla that receives afferent sensory information for the sensation of taste. Taste from the anterior two-thirds of the tongue is innervated by the chorda tympani (cranial nerve VII), the posterior one-third of the tongue is innervated by cranial nerve IX, and the epiglottis is innervated by cranial nerve X.