Brain Structure Function Carl Sagan Overview Lobes of

Brain Structure & Function

Carl Sagan

Overview Lobes of the brain (forebrain) Midbrain/ Hindbrain Protection and Blood Supply Structure and Functions of a Neuron Synaptic Transmission Neurotransmitters

Central Nervous System The central nervous system consists of the brain and the spinal cord and is responsible for our basic functions, personality and behaviour.

Forebrain Cerebrum and Cerebral cortex Left and Right Hemispheres Left hemisphere for most people is the dominant hemisphere- responsible for production of language, mathematical ability, problem solving, logic Right hemisphere thought to be responsible for creativity and spatial ability

The Brain Most complex organ in the body Weighs 1, 300 grams Contains billions of neural networks that interact to create human behaviour

The Lobes of the Brain The major sections of the cerebral hemispheres are divided up into lobes. The lobes are named after the bones of the skull that overlie them Frontal Lobe Temporal Lobe Parietal Lobe Barlow and Durand 2005 Occipital Lobe

Frontal Lobe �Located at the front of both cerebral hemispheres �Primary motor cortex �Pre-motor cortex �Broca’s Area- Motor Production of speech �Complex Functioning �Personality � judgement � Insight � Reasoning � problem solving, � abstract thinking � working memory

Parietal Lobe Located behind the temporal lobe Sensory information Temperature Pain Texture Spatial orientation Perception Recognising object by touch Links visual and sensory information together Neglect

Temporal Lobe �Auditory information �Higher order visual information �Complex memory � Memory of faces �Comprehension of language (Wernicke’s area)

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Occipital Lobes Rearmost portion of the brain Visual processing area Corpus Callosum- Fibre bundle in the brain that connects the two hemispheres together.

Other Important Structures Hypothalamus Thalamus Cerebellum Pons Medulla Oblongata Reticular formation Basal Ganglia Substantia Nigra Amygdala Hippocampus

Diencephalon �Thalamus � filters sensory information, controls mood states and body movement associated with emotive states (http: //training. seer. cancer. gov/module_anato my/unit 5_3_nerve_org 1_cns. html) �Hypothalamus � Central control’ for pituitary gland. Regulates autonomic, emotional, endocrine and somatic function. Has a direct involvement in stress and mood states.

Hindbrain Cerebellum regulates equilibrium, muscle tone, postural control, fine movement and coordination of voluntary muscle movement. Pons Relay station between cerebrum and cerebellum www. deryckthake. com/psychim ages/hindbrain.

Medulla oblongata Conscious control of skeletal muscles, balance, co-ordination regulating sound impulses in the inner ear, regulation of automatic responses such as heart rate, swallowing, vomiting, coughing and sneezing Reticular Formation Important in arousal and maintaining consciousness, alertness attention and Reticular Activating System which controls all cyclic functions i. e. respiration, circadian rhythm.

Basal Ganglia Control of muscle tone, activity, posture, large muscle movements and inhibit unwanted muscle movements. Substatia Nigra Produces dopamine, is connected to the basal ganglia – EPSE’s

Limbic System Amygdala mediates and controls major affective mood states such as friendship , love, affection, fear, rage and aggression. Hippocampus Memory, particularly the ability to turn short term memory into long term memory. Alzheimer's disease.

Pituitary and Pineal Glands

Protection and Blood Supply � Meninges Ø Ø Dura mater Arachnoid Mater Subarachnoid space Pia mater � CSF Ø 2 main functions; shock absorption and mediation of blood's vessels and brain tissue in exchange of nutrients. � Circle of Willis Ø carotid arteries and baliser arteries � Blood Brain Barrier Ø Protect the brain from chemicals http: //training. seer. cancer. gov/module_anatomy/unit 5_3_n erve_org 1_cns. html in the blood. Made up of tightly packed endothelial cells/capillaries making it difficult to penetrate.

Neurons

Structure of a Neuron

Resting Potential

Function of a Neuron Resting potential Positive/negative charge Voltage Gated channels Sodium/ potassium pump Action potential Threshold Depolarisation

Action Potential

Action Potential

Synaptic Transmission � Calcium ion channels stimulate the release of neurotransmitters � Vesicles fuse to the cell membrane and release into the synapse � Lock and key effect � Reuptake of neurotransmitters into the cell or broken down by enzymes in the synaptic cleft

Neurotransmitters

There are two kinds of neurotransmitters – INHIBITORY and EXCITATORY. stimulate the brain calm the brain

Neurotransmitters Neurotransmitter is a chemical Its released from the synaptic cleft Another term for neurotransmitter is a ligand Three main groups of neurotransmitters Amines Amino Acids Peptides Others

�Amines � Dopamine � Noradrenaline � Adrenaline � Serotonin �Amino Acids � Glutamate and GABA � Aspartate and glycine �Peptides � Cholecystrokinin � Neuropetide Y � Vasoactive intestinal Peptide � Substance P & Substance K � Somatosatin �Others � Acetylcholine � Histamine

Neurotransmitters Small molecule neurotransmitters Type Neurotransmitter Postsynaptic effect Other Acetylcholine Excitatory Amino acids Gamma aminobutyric acid (GABA) Inhibitory Glycine Inhibitory Glutamate Excitatory Aspartate Excitatory Dopamine Excitatory Noradrenaline Excitatory Serotonin Excitatory Biogenic amines

Neural Communication

AMINES

Dopamine (DA) � Almost a million nerve cells in the brain contain dopamine. � Role in � complex movement � cognition � motor control � emotional responses such as euphoria or pleasure. � Newer antipsychotic medication focus on particular dopaminergic pathways in the brain. Lessening EPSE’s.

Dopamine Theory � The dopamine hypothesis of psychosis – overactivity of dopamine neurons in the mesolimbic pathway of the brain may mediate the positive symptoms of psychosis � Mesolimbic pathway responsible for pleasure, effects of drugs and alcohol and hallucinations and delusions

Dopamine Receptors Five subtypes – D 2 most important in terms of psychosis Blockade of mesolimbic receptors leads to reduced psychotic symptoms Blockade of the mesocortical pathway leads to increased negative symptoms

Dopamine Receptors Dopamine and acetylcholine have a reciprocal relationship- Blockade of dopamine receptors increases the activity of acetylcholine Over activity of acetylcholine causes EPSE Blockade of dopamine causes movement disorders in the nigostriatal pathway Long term blockade causes “upregulation” and leads to Tardive Dyskinesia

D 2 ANTAGONIST Nigrostriatal pathway extrapyramidal side effects (EPS) and tardive dyskinesia Mesocortical pathway enhanced negative and cognitive psychotic symptoms Tuberoinfundibular pathway hyperprolactinemia (lactation, infertility, sexual dysfunction) Mesolimbic pathway dramatic therapeutic action on positive psychotic symptoms

Dopamine Receptors Type Distribution Postulated Roles D 1, 5 -like Brain, smooth muscle Stimulatory, role in schizophrenia? D 2, 3, 4 -like Brain, Inhibitory, role in cardiovascular schizophrenia? system, presynaptic nerve terminals www. lundbeck. com. au

Serotonin (5 ht) � Believed to be one of the great influences on behaviour. � Complex neurotransmitter. � Surprisingly only 2% of serotonin is found in CNS. � Roles include � Vasoconstriction, gastrointestinal regulation. � Low serotonin associated with aggression, suicide, impulsive eating, anxiety and low mood. � Regulates general activity of the CNS, particularly sleep. � Delusions, hallucinations and some of the negative symptoms of schizophrenia. www. rodensor. com/images/site_gra phics/Dopamineseratonin

Serotonin Receptors Type Distribution Postulated Roles 5 -HT 1 Brain, intestinal nerves Neuronal inhibition, behavioural effects, cerebral vasoconstriction 5 -HT 2 Brain, heart, lungs, Neuronal excitation, smooth muscle control, vasoconstriction, behavioural GI system, blood effects, depression, anxiety vessels, platelets 5 -HT 3 Limbic system, ANS Nausea, anxiety 5 -HT 4 CNS, smooth muscle Neuronal excitation, GI 5 -HT 5, 6, 7 Brain Not known www. lundbeck. com. au

Amino Acids

Glutamate is found in all cells of the body control the opening of ion channels that allow calcium to pass into nerve cells producing impulses Blocking of glutamate receptors produces psychotic symptoms ( eg. By PCP) schizophrenic like symptoms Over exposure of neurons to glutamate cause cell death seen in stroke and Huntington’s disease (PN).

GABA Gamma-aminobutyric acid Inhibitory and its pathways are only found within the CNS. control excitatory neurotransmitters in the brain and controlling spinal and cerebral reflexes. anxiety disorders decreased GABA can lead to seizure activity Benzodiazepines and barbiturates sedative medication act on GABA Benzo. org. au

Others

Histamine Found in the posterior hypothalamus. Believed to be involved in the regulation of the sleeping and waking states. Histaminergic cells fire rapidly during waking and slowly during periods of relaxation and tiredness. Cease transmission during REM and non-REM sleep

Type H 1 Histamine Receptor H 2 histamine receptor H 3 histamine receptor H 4 histamine receptor Location Found on smooth muscle, endothelium, and CNS tissue Located on parietal cells and vascular smooth muscle cells Function bronchoconstriction, bronchial smooth muscle contraction, separation of endothelial cells (responsible for hives), pain and itching due to insect stings; receptors involved in allergic rhinitis symptoms motion sickness; sleep regulation. vasodilatation. stimulate gastric acid secretion Found on central nervous system Decreased neurotransmitter release: and to a lesser extent peripheral histamine, acetylcholine, nervous system tissue norepinephrine, serotonin Found primarily in the basophils and in the bone marrow. It is also Plays a role in chemotaxis. found on thymus, small intestine, spleen, and colon.

Acetylcholine (ACh) • Cholinergic pathways • thought to be involved in cognition (esp. memory) and our sleep/wake cycle • parasympathetic nervous system regulating bodily functions such as heart rate, digestion, secretion of saliva and bladder function • Alzheimer’s disease and myathesia gravis (weakness of skeletal muscles) • Anti-cholinergic effects

Acetylcholine Receptors Type Distribution M 1 Nerves M 2 M 3 M 4 M 5 NM NN Postulated Roles CNS excitation, gastric acid secretion Heart, nerves, smooth muscle Cardiac inhibition, neural inhibition Glands, smooth muscle, Smooth, muscle contraction, endothelium vasodilation ? CNS? Not known Skeletal muscles Neuromuscular transmission neuromuscular junction Postganglionic cell body dendrites Ganglionic transmission www. lundbeck. com. au

Noradrenaline Norepinephrine (NE) Found mainly in 3 areas of the brain; � the locus coeruleous, � the pons � reticular formation. Main role; Deprexchart. gif Scienceblogs. com � attention, alertness, arousal � sleep/wake cycle � regulating mood

Noradrenaline Receptors Type Alpha 1 Distribution Brain, heart, smooth muscle Alpha 2 Brain, pancreas, smooth Vasoconstriction, muscle presynaptic effect in GI (relaxant) Heart, brain Heart rate (increase) Beta 1 Postulated Roles Vasoconstriction, smooth muscle control Beta 2 Lungs, brain, skeletal muscle Bronchial relaxation, vasodilatation Beta 3 Postsynaptic effector cells Stimulation of effector cells www. lundbeck. com. au

The 3 Neurotransmitters song

Pharmacogenetics The variability in response to modern multi-target drugs suggests a complex trait in which several genes may play a part in the bodies response to drugs. Reported associations between polymorphic receptors for metabolic enzymes and treatment response confirm this hypothesis These results can be taken as evidence of the genomic influence in drug response

Polymorphisms in genes associated with metabolic enzymes & neurotransmitters 5 -HTs, 5 -HTT, H 2 - Clozapine response prediction Arranz et al. (2000) 5 -HT 6 - Clozapine response Yu et al. (1999) 5 -HTT - Response to SSRIs Smeraldi et al. (1998) Kim et al. (2000) APOE, PS 1 and PS 2 - Alzheimer’s disease treatment response Cacabelos et al. (2000)

CYP 1 A 2 - Movement disorders Basile et al. (2000) CYP 2 D 6 - Tardive dyskinesia Kapitany et al. (1998) & Extra-pyramidal side-effects Scordo et al. (2000) CYP 2 C 19 - Mephenytoin blood levels Ferguson et al. (1998) D 2 Short-term neuroleptic response Malhotra et al. (1999) Schafer et al. (2001) D 3 - Clozapine response Scharfetter et al. (1998) D 3 - Tardive dyskinesia Steen et al. (1997) Kapitany et al. (1998) Segman et al. (2000) Ozdemir et al. (2001) D 4 - Clozapine response Shaikh et al. (1993) 5 -HT 2 A - Clozapine response Arranz et al. (1995, 1998 b) 5 -HT 2 C - Clozapine response Sodhi et al. (1995) Tardive dyskinesia Segman et al. (2000)

Pharmacogenomics

Pharmacokinetics

Pharmacokinetics The study of the movement of a drug through the body Absorption Distribution Metabolism Elimination

Pharmacokinetics Absorption The rate at which a drug gets out of the G. I tract and into the blood stream Distribution Process of drug molecules leaving the blood stream to reach tissues and organs

Body membranes affecting drug distribution: Capillaries � General body capillaries allow drug molecules to pass freely into the surrounding tissue.

Blood Brain Barrier BBB Brain capillaries have a dense walled structure & are surrounded by glial cells (lipid). This prevents many drug molecules from entering the surrounding tissue. Glial cells Capillary wall

Termination of drug action. Metabolism: Detoxification or breakdown. Enzymes (Cytochrome P 450) in liver cells transform drug from fat soluble to water soluble. Elimination: removal of drug from body. Most via kidney’s, lungs & G. I. Tract (small amounts) nature. com

Pharmacokinetics clip

Pharmacodynamics. How drugs act on body Drug receptor interaction: drug concentrated at the site of action. Effect (body responses): Therapeutic effects, intoxication & side effects. The effect will vary depending on age, gender & health of person, plus the route, frequency of use, duration of use and the environment in which the drug is consumed.

Mechanism of action � Blockade of receptors � Receptor sensitivity changes � Reuptake inhibition � Interference with storage vesicles � Pre-curser chain interference � Synaptic enzyme inhibition � Second messenger cascade

Neurotransmitter Re-uptake pump Receptor Axon Dendrite Synapse Presynaptic storage vesicles

Agonist = Mimic

Agonist = Facilitate binding

Blocking = Antagonist

Up-regulation

Down-regulation

Acetylcholine GABA Serotonin Dopamine Glutamate Noradrenaline

Normal Fine muscle movement, decision making, stimulates the hypothalamus to release hormones Stimulates the ANS – Fright & Flight Dopamine Noradrenaline = Serotonin sleep regulation, hunger, mood states, pain perception, aggression and sexual behaviour Acetylcholine Learning & Memory

Depression Acetylcholine Noradrenaline & Serotonin

Mania Glutamate, Noradrenaline Dopamine Acetylcholine

Schizophrenia Dopamine Acetylcholine

Parkinsons Acetylcholine Dopamine

Dementia Dopamine Norepinephrine Acetylcholine Serotonin

References � Boyd (2002). Psychiatric Nursing , contemporary practice. Lippincott, USA � Rosenweig, Breedlove and Leiman (2002) Biological Psychology: an introduction to cognitive, behavioural and clinical neuroscience 3 rd Edition. Sineur Associates , Inc USA. � Stuart and Laraia (2005) Prinicples and Practice of Psychiatric Nursing. Mosby, USA. � Barlow and Durand (2005). Abnormal Psychology, and intergrated approach. Thompson/Wadsworth, Australia. � Leonard BE (1997). Fundamentals in Psychopharmacology. 2 nd ed. Chichester: Wiley & Sons. � Purves DE, Augustine GJ, Fitzpatrick D, et al. (eds). Neuroscience. Sunderland, MA: Sinauer Associates, Inc; 1997. � Lundbeck Institute, www. brainexplorer. com � Blakemore & Frith (2005). The Learning Brain. Blackwell Publishing � Begley (2005). The blood brain Barrier. Gauchers News May 2005 c Staddon S, Arranz MJ, Mancama D, Mata I, Kerwin RW (2002) Clinical applications of pharmacogenetics in psychiatry, Psychopharmacology 162: 18– 23