Fundamentals of neurobiology

To understand psychiatric disorders, it is important to have a working understanding of the normal structure and function of the nervous system.

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Fundamentals of neurobiology

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Fundamentals of neurobiology

Index
  1. Fundamentals of neurobiology
  2. Introduction to neurobiology
  3. Organisation of the nervous system
  4. Neurones
  5. Anatomical regions of the brain
  6. Cerebrum
  7. Lobes of the brain
  8. Neurosynaptic transmission
  9. Neurotransmission
  10. The synapse
  11. Process of chemical neurotransmission
  12. Neurotransmitters
  13. Neurotransmitters and receptors
  14. Glutamate
  15. GABA – gamma-aminobutyric acid
  16. Serotonin
  17. Noradrenaline
  18. Dopamine
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Fundamentals of neurobiology
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Introduction to neurobiology
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Organisation of the nervous system
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To understand psychiatric disorders, it is important to have a working understanding of the normal structure and function of the nervous system. The central nervous system (CNS; brain, spinal cord) and peripheral nervous system (PNS) are made up of neurones and glial cells (sometimes called neuroglia) as explained on the slide.[Tortora & Derrickson, 2009; Martin, 2003]

Martin JH. Neuroanatomy Text and Atlas. 3rd edition. McGraw-Hill, 2003.

Tortora GJ, Derrickson B. Principles of Anatomy and Physiology. 12th edition. John Wiley & Sons, 2009.

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Neurones
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The neurone constitutes the functional unit of the nervous system; there are over 100 billion neurones in the brain.[Purves et al., 2008; Martin, 2003; Kandel et al., 2000] Each neurone has the ability to interact with and influence many other cells, which creates a system of intricate complexity.[Purves et al., 2008] There are several different classes of neurones – a simplified neurone is shown on the slide, along with explanations of its various component parts.[Martin, 2003]

Although there are different types of nerve cells, the complexities of human behaviour stem not from the specialism of different types of neurones, but rather from the association of a great many neurones into coherent, and precise, anatomical circuits.[Kandel et al., 2000] In this way, nerve cells with similar properties can effect a variety of different functions, depending on how they are interconnected.[Kandel et al., 2000]

Neurotransmitters – chemicals in the nervous system that transmit nerve impulses between neurones.
Action potential – in neurophysiology, an electrical charge that moves through an axon.

Kandel ER, Schwartz JH, Jessell TM (eds). Principles of Neural Science. 4th edition. McGraw-Hill, 2000.

Martin JH. Neuroanatomy Text and Atlas. 3rd edition. McGraw-Hill, 2003.

Purves D, Augustine GJ, Fitzpatrick D, et al. (eds). Neuroscience. 4th edition. Sinauer Associates, 2008.

 

Other references used on slide

Oxford Concise Medical Dictionary. 2nd edition. © Oxford University Press, 1998.

Tortora GJ, Derrickson B. Principles of Anatomy and Physiology. 12th edition. John Wiley & Sons, 2009.

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Anatomical regions of the brain
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The brain is divided into four anatomical regions: the diencephalon, brainstem, cerebrum, and cerebellum, as described on the slide.[Kandel et al., 2000; Tortora & Derrickson, 2009]

Kandel ER, Schwartz JH, Jessell TM (eds). Principles of Neural Science. 4th edition. McGraw-Hill, 2000.

Tortora GJ, Derrickson B. Principles of Anatomy and Physiology. 12th edition. John Wiley & Sons, 2009.

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Cerebrum
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The cerebral cortex is the main functional unit of the cerebrum.[Tortora & Derrickson, 2009] The three main functional areas of the cerebral cortex are:[Tortora & Derrickson, 2009; Prise & Wilson, 2003]

  • motor areas that control voluntary movement (primary, secondary, and association motor areas)
  • sensory areas that allow for visual, auditory, gustatory, olfactory, and sensory perception (primary, secondary, and association sensory areas)
  • areas associated with higher mental functions.

The surface of the brain is highly convoluted, with folds and grooves.[Martin, 2003] These convolutions are an evolutionary adaptation that allows a greater surface area to fit within the confined, and limited, space of the skull.[Martin, 2003] The elevated convolutions are called ‘gyri’, and the grooves are called ‘sulci’, as shown on the slide.[Martin, 2003]

Gustatory – relating to the sense of taste.
Olfactory – relating to the sense of smell.
Nuclei – in neuroanatomy, localised masses of grey matter in the CNS.

 

Martin JH. Neuroanatomy Text and Atlas. 3rd edition. McGraw-Hill, 2003.

Price SA, Wilson LM. Pathophysiology: Clinical Concepts of Disease Processes. 6th edition. Mosby, 2003.

Tortora GJ, Derrickson B. Principles of Anatomy and Physiology. 12th edition. John Wiley & Sons, 2009.

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Lobes of the brain
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The brain can be thought of as comprising five ‘lobes’ – the four lobes of the cerebral cortex and a fifth lobe, the insula, deep within the brain, as shown on the slide.[Martin, 2003; Tortora & Derrickson, 2009; Price & Wilson, 2003] The lobes of the cerebral cortex are named after the cranial bones that overlie them (frontal, parietal, occipital, and temporal).[Martin, 2003]

The lobes have distinct functions. The frontal lobe has a diverse range of behavioural functions, including movement, speech, cognition, and emotion.[Martin, 2003] The parietal lobe mediates perceptions of touch, pain, and proprioception.[Martin, 2003] The occipital lobe can be thought of as the visual processing centre, containing the primary visual cortex.[Martin, 2003] Finally, the temporal lobe controls a range of sensory functions, and is important in memory and emotion.[Martin, 2003]

Martin JH. Neuroanatomy Text and Atlas. 3rd edition. McGraw-Hill, 2003.

Price SA, Wilson LM. Pathophysiology: Clinical Concepts of Disease Processes. 6th edition. Mosby, 2003.

Tortora GJ, Derrickson B. Principles of Anatomy and Physiology. 12th edition. John Wiley & Sons, 2009.

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Neurosynaptic transmission
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Neurotransmission
Slide information
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Information moves through the nervous system via two integrated forms of communication – electrical neurotransmission and chemical neurotransmission, as shown on the slide.[Kandel et al., 2000]

An action potential is generated at the origin of the axon following sufficient excitatory stimulation of the neurone. The action potential is created by movement of electrically charged particles (ions) in and out of the neurone through pores (ion channels) in the cell membrane in a particular pattern, travelling along the length of the axon.[Kandel et al., 2000] When the action potential reaches the axon terminal it stimulates the release of chemical neurotransmitters.[Kandel et al., 2000] After the action potential has induced the release of chemical neurotransmitters, the neurotransmitters pass information to the next neurone.[Kandel et al., 2000]

Kandel ER, Schwartz JH, Jessell TM (eds). Principles of Neural Science. 4th edition. McGraw-Hill, 2000.

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The synapse
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Neurones do not physically touch one another; two neurones are separated by a gap, known as a synaptic cleft.[Kandel et al., 2000] Because neurones do not touch, and an action potential cannot ‘jump’ across a synaptic cleft, the signal must be converted to a chemical signal to enable communication between neurones to occur.[Kandel et al., 2000] The presynaptic neurone uses chemical signals (neurotransmitters) to increase (excite) or decrease (inhibit) the generation of action potentials in the postsynaptic neurone. It is also possible to effect other biochemical processes, such as cell signalling pathways, in the postsynaptic neurone. This complex interconnectivity gives rise to the rich functional communication network that is the central nervous system.[Kandel et al., 2000]

Presynaptic neurone – a neurone from which an electrical impulse is transmitted across a synaptic cleft to a postsynaptic neurone by the release of a chemical neurotransmitter.
Postsynaptic neurone – a neurone to which an electrical impulse is transmitted across a synaptic cleft by the release of a chemical neurotransmitter from the axon terminal of a presynaptic neurone.

Kandel ER, Schwartz JH, Jessell TM (eds). Principles of Neural Science. 4th edition. McGraw-Hill, 2000.

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Process of chemical neurotransmission
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The idea that neurotransmission occurs at synapses and is mediated by chemicals was, at first, a contentious issue.[Purves et al., 2008] It was in the first half of the 1900s that experiments proved chemical neurotransmission occurred.[Purves et al., 2008]

The process is outlined in brief on the slide.[Purves et al., 2008; Kandel et al., 2000; Tortora & Derrickson, 2009; Sadock et al., 2009] Briefly, an action potential arrives at the terminal end of the presynaptic neurone, which means that the membrane potential at the terminal is altered.[Purves et al., 2008] This altered potential causes voltage-gated ion channels to open, leading to a rapid influx of calcium (detail not shown on slide).[Purves et al., 2008] The increased calcium within the neurone terminal (which is just a transient effect) causes vesicles to fuse with the membrane, and release their contents into the synaptic cleft.[Purves et al., 2008] Among the released contents are neurotransmitters, which bind to specific receptors on the postsynaptic neurone.[Purves et al., 2008] The effect of this binding varies, but usually leads to altered conductance of the postsynaptic neurone, and the propagation of the action potential.[Purves et al., 2008]

Vesicle – a membrane-enclosed sac that stores or transports substances.
Receptor – a protein molecule on a cell membrane that binds to a specific chemical, such as a neurotransmitter or drug, and produces a specific physiological effect.
Reuptake – a mechanism by which a neurotransmitter is taken back into the axon terminal that released it; the most common mechanism for removal and inactivation of neurotransmitters.
Astrocyte – a class of glial cells; functions include maintenance of extracellular ionic environment, and structural and metabolic support of neurones.
Diffusion – in regard to neurotransmission, a mechanism by which neurotransmitters drift out of the synaptic cleft.

Kandel ER, Schwartz JH, Jessell TM (eds). Principles of Neural Science. 4th edition. McGraw-Hill, 2000.

Purves D, Augustine GJ, Fitzpatrick D, et al. (eds). Neuroscience. 4th edition. Sinauer Associates, 2008.

Sadock BJ, Sadock VA, Ruiz P (eds). Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th edition. Vol 1–2. © Lippincott Williams & Wilkins, 2009.

Tortora GJ, Derrickson B. Principles of Anatomy and Physiology. 12th edition. John Wiley & Sons, 2009.

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Neurotransmitters
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Neurotransmitters and receptors
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There are many different neurotransmitters in the CNS, each binding to a specific receptor type which has a distinct distribution and role within the CNS.[Purves et al., 2008; Kandel et al., 2000; Stahl, 2013] Some common neurotransmitters are listed in the table on this slide. Defects in many neurotransmitter pathways have been implicated in psychiatric disorders.

The variety of neurotransmitters that operate within the CNS adds to the functional complexity of the brain.[Purves et al., 2008] Different neurotransmitters can produce different responses on the same neurone; e.g., a neurone might be excited by serotonin but inhibited by the binding of GABA.[Purves et al., 2008]

Exactly what constitutes a neurotransmitter has been the subject of some disagreement but, generally, a neurotransmitter must:[Purves et al., 2008]

  • be present within the presynaptic neurone
  • be released in response to presynaptic depolarisation, and the release must be calcium-dependent
  • have specific receptors on the postsynaptic neurone.

Kandel ER, Schwartz JH, Jessell TM (eds). Principles of Neural Science. 4th edition. McGraw-Hill, 2000.

Purves D, Augustine GJ, Fitzpatrick D, et al. (eds). Neuroscience. 4th eition. Sinauer Associates, 2008.

Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 4th edition. © Cambridge University Press, 2013.

 

Other references used on slide

Grieg NH, Reale M, Tata AM. New advances in pharmacological approaches to the cholinergic system: an overview on muscarinic receptor ligands and cholinesterase inhibitors. Recent Pat CNS Drug Discov 2013; 8 (2): 123–141.

Sadek B, Stark H. Cherry-picked ligands at histamine receptor subtypes. Neuropharmacology 2016; 106: 56–73.

Wierońska JM, Zorn SH, Doller D, Pilc A. Metabotropic glutamate receptors as targets for new antipsychotic drugs: Historical perspective and critical comparative assessment. Pharmacol Ther 2016; 157: 10–27.

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Glutamate
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Control of the CNS can be thought of in terms of a balance between ‘go’ (excitatory) and ‘stop’ (inhibitory) signals.[Purves et al., 2008; Stahl, 2013] If the sum of the ‘go’ signals that a neurone receives outweighs the sum of the ‘stop’ signals, then that neurone will exist in an active state, and will continue to signal to the downstream neurone.[Purves et al., 2008; Stahl, 2013] The main excitatory neurotransmitter in the CNS is glutamate; the main inhibitory neurotransmitter is gamma-aminobutyric acid (GABA).[Purves et al., 2008]

Glutamate is arguably the most important neurochemical for normal brain function.[Purves et al., 2008] Nearly all excitatory neurones in the CNS are glutamatergic – more than half of the neurones in the brain.[Purves et al., 2008] It is noteworthy, though, that high concentrations of glutamate are neurotoxic.[Purves et al., 2008] There are three types of receptor to which glutamate can bind (named after the agonists that activate them), each of which has slightly different properties:[Purves et al., 2008]

  • NMDA (N-methyl-d-aspartate)
  • AMPA (α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate)
  • kainate (kainic acid).

Purves D, Augustine GJ, Fitzpatrick D, et al. (eds). Neuroscience. 4th edition. Sinauer Associates, 2008.

Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 4th edition. © Cambridge University Press, 2013.

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GABA – gamma-aminobutyric acid
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GABA is the main inhibitory neurotransmitter found in the brain.[Purves et al., 2008] GABA is synthesised predominantly from glutamate, by the enzyme glutamic acid decarboxylase that is found almost exclusively in GABAergic neurones.[Purves et al., 2008] The ionotropic GABA receptors are usually inhibitory, because when activated they allow the flow of negative chlorine ions across the membrane – reducing the potential for neuronal signalling.[Purves et al., 2008]

Chemicals that function as GABA agonists have been used to treat various conditions, and include anticonvulsants, anxiolytics, benzodiazepines, and hypnotics.[Stahl, 2013]

Purves D, Augustine GJ, Fitzpatrick D, et al. (eds). Neuroscience. 4th edition. Sinauer Associates, 2008.

Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 4th edition. © Cambridge University Press, 2013.

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Serotonin
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Serotonin (also known as 5-HT) is a neurotransmitter that is found throughout the body.[Brunton et al., 2006; Stahl, 2013; Purves et al., 2008] The wide dispersal of serotonergic neurones throughout the brain enables serotonin to be involved in modulating diverse body functions. Body functions modulated by serotonin include:[Brunton et al., 2006]

  • mood
  • sleep
  • cognition
  • sensory perception
  • pain perception
  • movement
  • regulation of internal temperature
  • appetite
  • sexual behaviour
  • hormone secretion.

Brunton LL, Lazo JS, Parker KL (eds). Goodman & Gilman’s the Pharmacological Basis of Therapeutics. 11th edition. McGraw-Hill, 2006.

Purves D, Augustine GJ, Fitzpatrick D, et al. (eds). Neuroscience. 4th edition. Sinauer Associates, 2008.

Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 4th edition. © Cambridge University Press, 2013.

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Noradrenaline
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Noradrenaline acts on two classes of adrenergic receptor, α and β.[Purves et al., 2008] Noradrenergic neurones project widely throughout the brain, and there are many brain areas where serotonin, noradrenaline and dopamine projections overlap, allowing interactions.[Stahl, 2013]

Noradrenaline and the locus coeruleus are thought to have important input into the control the CNS exerts over mood, cognition, stress, arousal, pain, and other functions.[Stahl, 2013; Dunn & Swiergiel, 2008] Malfunction of the locus coeruleus is thought to underlie disorders such as depression, anxiety, and disorders of attention and information processing.[Stahl, 2013]

Low or abnormal noradrenaline activity is, theoretically, characterised by impaired attention; concentration, working memory and information processing difficulties; as well as psychomotor retardation, fatigue, and apathy.[Stahl, 2000] In addition, abnormalities in the noradrenergic projection to the hypothalamus, which mediates stress response, are indicated in depressive and anxiety disorders.[Dunn & Swiergiel, 2008]

Dunn AJ, Swiergiel AH. The role of corticotropin-releasing factor and noradrenaline in stress-related responses, and the inter-relationships between the two systems. Eur J Pharmacol 2008; 583 (2–3): 186–193.

Purves D, Augustine GJ, Fitzpatrick D, et al. (eds). Neuroscience. 4th edition. Sinauer Associates, 2008.

Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 2nd edition. © Cambridge University Press, 2000.

Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 4th edition. © Cambridge University Press, 2013.

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Dopamine
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Dopamine is believed to be involved in motivation, reward, and reinforcement.[Purves et al., 2008] Dopamine also plays an essential role in the control and coordination of movement.[Purves et al., 2008]

Dopamine receptors all influence the activity of the second messenger, cyclic AMP, which is involved in many biochemical processes within a neurone.[Kandel et al., 2000] Dopamine receptor subtypes D1 and D5 increase the levels of cyclic AMP, whereas D2, D3, and D4 subtypes decrease the levels of cyclic AMP.[Kandel et al., 2000] Thus, depending on which receptor subtype the neurotransmitter binds with on the postsynaptic neurone, dopamine can increase or decrease cellular activity.[Kandel et al., 2000]

Dopamine, and its actions within the CNS, is critical to the underlying disease state of many conditions, including Parkinson’s disease, which is characterised by a dearth of dopamine, and schizophrenia, which appears to be caused by an overactivity of dopamine within certain brain regions.[Stahl, 2013] Furthermore, many addictive substances work by altering the effect of dopamine within the brain.[Purves et al., 2008] For instance, the drug cocaine appears to act by inhibiting the reuptake of dopamine, which leads to an increased concentration of dopamine in the synapse, prolonging its action.[Purves et al., 2008]

Delusion – a disturbance in thought leading to false beliefs.
Hallucination – a false sensory perception, such as hearing voices or seeing things that are not there.
Prolactin – a hormone, produced and released into the bloodstream by the pituitary gland, that is involved in the secretion of milk and breast growth; unusually high amounts are responsible for impotence and loss of libido in both men and women.

Kandel ER, Schwartz JH, Jessell TM (eds). Principles of Neural Science. 4th edition. McGraw-Hill, 2000.

Purves D, Augustine GJ, Fitzpatrick D, et al. (eds). Neuroscience. 4th edition. Sinauer Associates, 2008.

Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 4th edition. © Cambridge University Press, 2013.

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