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)

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)

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

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

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

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 body’s 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

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

Reticular Activating System It is a collection of nuclei at the core of the brainstem They receive input from the body’s 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!)

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

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

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

Small Molecule Neurotransmitters

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

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

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

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

Dopamine & Acetylcholine 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 Parkinson’s 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 Alzheimer’s disease

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, D4> D2 → less extra-pyramidal side effects

Exciatatory Amino Acid Neurotransmission Glutamate & 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

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

NMDA RECEPTOR

Inhibitory Amion Acid Transmission Gama-aminobutyric 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

Inhibitory Anion Acid Transmission Glycine 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

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

Dopamine and Serotonin Pathway

Noradrenaline and GABA Pathway