The Central Nervous System

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The Central Nervous System

• The CNS consists of the brain the spinal cord,
  immersed in the cerebrospinal fluid (CSF)
• The brain consists of three main structures the
  cerebrum, the cerebellum the brainstem
• Cerebrum composed of 2 cerebral hemispheres each
  made up of the cerebral cortex (grey matter), the
  basal nuclei diencephalon (white matter)
• Each hemisphere (left and right), consists of
  four lobes (frontal, parietal, occipital 
  temporal)

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cerebral cortex

• The outer layer of grey matter, approximately 2
  mm thick, covering the entire surface of the
  cerebral hemispheres
• It is made up of neurons supporting glial cells
• It functions to correlate information
• from many sources to control
• cognitive function (all aspects of
• perceiving, thinking remembering)

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Basal Nnuclei (Ganglia)

• The basal nuclei is a group of cell bodies deep
  in the white matter of the cerebral hemispheres
  beneath the cerebral cortex
• Major components include the caudate, putamen,
  globus pallidus substantia nigra
• The basal nuclei functions to sensorio-motor
  integration motor control

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Cerebellum

• The walnut-shaped structure situated at the base
  of the brain
• The cerebellum is responsible for motor
  co-ordination, posture maintaining equilibrium
• It ordinates sensory input from the inner ear and
  the muscles to provide accurate control of
  position movement

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Brain Stem

• The stalk-like part of the brain connecting
• the cerebral cortex, white matter the spinal
  cord
• Made up of the pons, the medulla oblongata the
  midbrain
• The brainstem acts as an important relay station
• The brainstem contributes to the control of
  breathing, sleep circulation
• Every nerve impulse passing between the brain
  the spinal cord must pass through the brainstem
  to allow the body to function normally

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Other Parts of the Brain

• Thalamus and Hypothalamus
• The thalamus has wide connections with the cortex
  the basal ganglia, hypothalmus brainstem
• It is capable of perceiving pain
• The hypothalamus has several functions, including
  control of the bodys appetite, sleep patterns,
  sexual drive response to anxiety

• Ventricles
• Ventricles are a number of cavities within the
  brain
• Ventricles are filled with CSF, which is produced
  within the ventricle wall
• The CSF also surrounds the outer surfaces of the
  brain and cushions the brain against trauma,
  maintains and control the extracellular
  environment, and circulates endocrine hormones

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The limbic system

• It a group of nerve pathways including structures
  deep within the temporal lobes, as the
  hippocampus the amygdale
• It is connected with the cerebral cortex, white
  matter brainstem
• the limbic system is involved in the control and
  expression of mood and emotion, in the processing
  and storage of recent memory, and in the control
  of appetite and emotional responses to food
• The limbic system has been implicated in the
• pathogenesis of depression schizophrenia
• The limbic system is linked with parts of
• the neuro-endocrine autonomic
• nervous systems

hippocampus
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Reticular Activating System

• It is a collection of nuclei at the core of the
  brainstem
• They receive input from the bodys sensory
  systems (sight, smell, taste, etc), the
  cerebellum and cerebral hemispheres
• Some neurons from the reticular formation project
  to meet motor neurons of the spinal cord and
  influence functions like CVS respiratory
  control
• In addition, there are also neurons projecting
  into most of the rest of the brain
• The ascending fibers of the reticular formation
  form a network called the reticular activating
  system, which influence wakefulness, overall
  degree of arousal and consciousness (depression!)

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Neurotransmission Processing of Information

• Two signaling mechanisms action potentials
  synaptic signals are the basis for all the
  information-processing in the brain
• An action potential is initiated at a synapse and
  travels along the axon to the axonal terminal
• The electrical signal is converted to a chemical
  signal a neurotransmitter
• It diffuses out of the neuron, across the
  synapse, to its neighboring neuron
• At the postsynaptic neuron the chemical signal is
  converted back into an electrical signal once
  again

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The Action Potential

• Resting neurons have a negative
• membrane potential, caused by
• a steady outflow of potassium ions an
  impermeability to sodium ions
• The action potential represents transient changes
  in this resting membrane potential
• For most axons de-polarisation initiates the
  action potential
• It causes a transient change in the membrane
  allowing the passage of sodium ion

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The Synaptic Signal
50 nm

• Once the action potential  reaches the axonal
  terminal,
• the changed membrane potential triggers the
  activation of calcium channels
• This allows elevation of the concentration of
  calcium ions in the pre-synaptic neuron 
• Thereafter, synaptic vesicles fuse with the
  presynaptic membrane and one or more
  neurotransmitters are released into the synaptic
  cleft 
• Neurotransmitters bind to specific receptors on
  the membrane of the postsynaptic neuron, or to an
  autoreceptor

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Small Molecule Neurotransmitters
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Neuropeptide Neurotransmitters

• Corticotropin releasing hormone
• Corticotropin (ACTH)
• Beta-endorphin
• SubstanceP
• Neurotensin
• Somatostatin
• Bradykinin
• Vasopressin
• Angiotensin II

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Serotonin

• CNS contains only less than 2 of the total
  serotonin in the body
• Serotonin is localized mainly in nerve pathways
  emerging from the raphe nuclei, a group of nuclei
  at the centre of the reticular formation
• These serotonergic pathways spread extensively
  throughout the brainstem, the cerebral cortex and
  the spinal cord
• In addition to mood control, serotonin has other
  functions, including the regulation of sleep,
  pain perception, body temperature, blood pressure
  hormonal activity

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Serotonin Receptors

• Seven classes, 5-HT1- 5-HT7
• All 5-HT1A,1B,1D,1E,1F are inhibitory Gi-coupled
• 5-HT1A is a somatodentritic auto-receptor
• 5-HT1B,1D are postsynaptic pre-synaptic auto-Rs
• 5-HT2 5-HT4 are excitatory receptors linked to
  Gq/11-PLC and Gs-AC respectively
• 5-HT3 is the only inotropic 5-HT receptor

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Noradrenaline

• Noradrenergic neurons are found in the locus
  coeruleus, the pons the reticular formation
• These neurons project to the cortex, hippocampus,
  thalamus  midbrain
• The release of NA tends to increase the level of
  excitatory activity within the brain
• Noradrenergic pathways are thought to be involved
  in the control of functions such as attention
  arousal

locus coeruleus A small area in the brainstem
consisting of a pair of identical nuclei in the
pons from which all brain connections, using NA,
arise
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Dopamine Acetylcholine

• Dopamine
• It is of high density in the basal ganglia
• Dopaminergic neurons are widely distributed
  throughout the brain in three important dopamine
  pathways
• The nigrostriatal,
• The mesocorticolimbic,
• The tubero-hypophyseal
• DA deficit in Parkinsons disease, DA over
  activity in schizophrenia

• Acetylcholine
• Cholinergic pathways are concentrated mainly in
  the brainstem
• They are believed to be involved in cognitive
  functions, especially memory
• Severe damage to these pathways is the probable
  cause of Alzheimers disease

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Dopamine Receptors

• DA receptors are 7-TM G-protein coupled
• D1-like (D1, D5) receptors are linked to Gi-AC
• D1-like receptors mediate excitatory DA activity
• D5 is abundant in limbic system, D1 in striaum,
  little in limbic system
• D2-like (D2, D3, D4) are linked to Gs-AC
• D2-like receptors mediate inhibitory activity of
  DA
• D3, D4 receptors are located mainly in limbic s,
  not in motor structures, unlike D2 receptors
• Atypical neuroleptics (clozapine) have affinity
  of D3, D4gt D2 ? less extra-pyramidal side effects

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Exciatatory Amino Acid NeurotransmissionGlutamate
Aspartate

• Exciatatory amino acid neurotransmitters,
  especially glutamate, are abundant in the CNS
• Glutaminergic neurons in cerebral cortex provide
  the main excitatory cortical output to
  hippocampus, basal ganglia, thalamus amygdala
• Hippocampal glutaminergic neurons project to
  limbic structures possibly controling learning
• Retinal glutaminergic neurons are the major
  excitatory pathways linked to photoreceptors
• NMDA receptor antagonists including
  glycine-binding site blockers are investigated as
  potential antiepileptic agents or drugs that
  prevent ischemic brain damage after stroke/trauma

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Exciatatory Amino Acid ReceptorsNMDA
(N-Me-D-aspartate) Non-NMDA Receptors

• NMDA Receptors
• Inotropic tetrameric receptor permeable to
  monovalent cations, high permeability to Ca2
• Binding to glutamate? ?Ca2 ? Activation of
  Ca2-dependent enzymes (PKC, NOS)? response
• It has 6 binding sites, 2 excitatory
• Glutamate binding sites
• Glycine binding sites
• and 4 inhibitory sites
• Phencyclidine (PCP), voltage-gated Mg2, Zinc,
  and polyamine binding site

• Non-NMDA Receptors
• 4 subtypes named after their selective agonist
• Kainate R Na, K-inotropic receptor, abundant
  in hippocampus
• Quisqualate/AMPA iontropic Na, K- regulating
  receptor
• L-AP4 metabotropic mGluR4,6,7,8 presynaptic
  receptors
• They cause inhibition of pre-synaptic neurons
• ACPD metabotropic receptors linked to PLC
  mediating excitatory effects

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NMDA RECEPTOR
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Inhibitory Amion Acid TransmissionGama-aminobutyr
ic Acid (GABA)

• GABA, the main inhibitory transmitter CNS in GABA
  pathways GABA inter-neurones
• 50 of the inhibitory synapses in the brain are
  GABA mediated
• Synthesized by glutamate decarboxylation
• Pre- post-synaptic GABA transporters terminate
  effect
• GABAergic inter-neurons in retina, cortex,
  hippocampus, spinal cord, cerebellum

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Inhibitory Anion Acid TransmissionGlycine

• Formed from serine by hydroxyMe-transferase
• Glycine receptors are inotropic Cl--channels,
  blocked by strychnine
• Glycine is removed by uptake using two
  transporters GLYCT-1 -2
• Limited distribution
• in spinal cord as inhibitory control over motor
  neurons
• In brainstem, reticular formation retina

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Neuropeptides

• Most important ones include opioid peptides,
  angiotensin II, oxytocin, cholecystokinin, and
  vasopressin
• All aforementioned peptides are excitatory except
  for opioid peptides that are inhibitory
• Opiods will be discussed in detail later in
  separate session

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Dopamine and Serotonin Pathway
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Noradrenaline and GABA Pathway