neural basis of neurobehavior disorders.ppt

NEURAL BASIS OF NEUROBEHAVIOR DISORDERS

Blok 162011

Learning Objectives

1. Describe the structures involved in psychiatric and neurobehavioral disorders

2. Describe and diagram the basic morphology of the structures comprising the limbic system

3. Describe and diagram the input-output relationships of limbic nuclei

4. Characterize the functions of limbic brain structures and their underlying mechanisms (where known)

5. Develop an understanding of the structural and functional bases for clinical and behavioral disorders associated with dysfunctions of the limbic system

OVERVIEW1. Anatomy of neurobehavior system

1. Overview of the human nervous system2. Anatomy of the brain

1. Cortex cerebri2. Anatomy of the Limbic system

2. Physiology of neurobehavior system1. Overview of the motoric system

1. Pyramidal system2. Extrapyramidal system

2. Overview of the sensoric system3. Higher functions of the brain

1. Intellectual functions of the brain2. Learning3. Memory

4. Emotion

FUNCTION OF THE NERVOUS SYSTEM

1. Sensory input. Sensory receptors present in skin and organs respond to external and internal stimuli by generating nerve impulses that travel to the brain and spinal cord.

2. Integration. The brain and spinal cord sum up the data received from all over the body and send out nerve impulses.

3. Motor output. The nerve impulses from the brain and spinal cord go to the effectors, which are muscles and glands. Muscle contractions and gland secretions are responses to stimuli received by sensory receptors.

Classification of The Human Nervous System

I. Anatomical I. Central Nervous SystemII. Peripheral Nervous System

II. PhysiologicalI. Motoric SystemII. Sensory SystemIII. Autonomic Nervous SystemIV. Higher Functions of the brainV. Emotion

DIVISIONS OF THE NERVOUS SYSTEM

1.Central Nervous System1.Brain (Cerebrum)2.Spinal cord

2. Peripheral Nervous System1.Cranial Nerves2.Spinal nerves

OVERVIEW OF THE FUNCTIONAL ANATOMY OF

THE BRAIN

Areas of the human cerebral cortex defined by Brodmann in his 1909 publication

The six layers of the neocortex, from the pial surface above layer 1 to the white matter below layer 6.

Diagram of the structure of the cerebral cortex. A: Golgi neuronal stain. B: Nissl cellular stain. C: Weigart myelin stain. D: Neuronal connections. Roman and Arabic numerals indicate the layers of the isocortex (neocortex); 4, external line of Baillarger (line of Gennari in the occipital lobe); 5b, internal line of Baillarger.

Spatial relationships between basal ganglia, thalamus, and internal capsule as viewed from the left side.

OVERVIEW OF THE LIMBIC SYSTEM

LIMBIC SYSTEM

• Is a system that concerns with specific motivated or goal-oriented behaviors, directly aimed at the maintenance of homeostasis and at the survival of the individual and of the species (Nieuwenhuys, 1996)

• Functions:– Maintenance of homeostasis– Motivated and goal-oriented behaviors– Survival of the individual– Survival of the species– Learning and memory

Stuctures of the Limbic System

1. Hypothalamus2. Amygdala3. Septal area4. Hippocampal formation5. Cingulate gyrus

Schematic illustration of the location of the limbic system between the diencephalon and the neocortical hemispheres

Schematic illustration of the concentric main components of the limbic sytem.

Schematic drawing of the major anatomical structures of the limbic system. Note: The cingulated and parahippocampal gyri form the limbic lobe, a rim of tissue located along the junction of the diencephalons and the cerebral hemispheres. n, nucleus.

Schematic illustration (left oblique view) of the position of the hippocampal formation within the left hemisphere

“Le Grande Lobe Limbique” as adapted from Broca’s original 1878 drawing of an otter’s brain. Broca’s “callosal gyrus” is now termed the cingulate gyrus.

Ref: Clinical Neuroanatomy.pdf

Ref: Clinical Neuroanatomy.pdf

Schematic showing some of the major limbic structures and pathways.

The limbic system receives inputs from sensory systems, including the cerebral cortex, and monoamine neuronal groups of the brainstem reticular formation.

Primary outputs of the limbic system are directed to the hypothalamus. This arrangement allows the limbic system to alter the activity of the hypothalamus in response to sensory input.

Because the hypothalamus provides the integrating mechanism for different forms of emotional behaviors as well as for other visceral and autonomic responses, the limbic system serves as a key modulating region of these processes by virtue of its inputs into the hypothalamus.

Inputs to the limbic system from monoamine pathways can provide the substrates underlying mood changes.

Information flow to and from the limbic system

HIPPOCAMPAL FORMATION

Structures constitute the Hippocampal Formation

1. Subiculum2. Dentate gyrus 3. Hippocampus proper

Hippocampal formation in relation to other limbic structures. A, amygdala; AC, anterior commissure; AN, anterior nucleus of the thalamus; B-F, basofrontal region;CC, corpus callosum (b, body; g, genu; s, splenium); CG, cingulate gyrus; E-RC, entorhinal cortex;F, fornix; Fm, fimbria; HF, hippocampal formation; IG, indusium griseum; MB, mammillary bodies;MTT, mammillothalamic tract; S, septal area; T, thalamus.

Diagram illustrates the histological appearance of the cell layers within the hippocampus and loci of the hippocampal fields, dentate gyrus, and subicular cortex. CA1-CA4 denote the four sectors of the hippocampus

Semischematic diagram illustrates: (1) inputs from the entorhinal region, which include the perforant and alvear pathways; (2) internal circuitry, which includes the connections of the mossy fibers and Schaffer collaterals; and (3) efferent projections of the hippocampal formation through the fimbria-fornix system of fibers.

Major projection targets of the hippocampal formation. The primary output is through the fornix to diencephalon (i.e., medial hypothalamus, mammillary bodies, and anterior thalamic nucleus) via the postcommissural fornix and to the septal area via the precommissural fornix. Other connections shown include efferent fibers that synapse in entorhinal cortex, which, in turn, project to amygdala and cingulate gyrus

HIPPOCAMPAL FIBERS project to the MAMMILLARY BODIES, which, in turn, project through the MAMMILLOTHALAMIC TRACT to the ANTERIOR NUCLEUS. The anterior thalamic nucleus then projects to the CINGULATE GYRUS, and the axons of the cingulate gyrus then project back to the HIPPOCAMPAL FORMATION.

Papez circuit

HYPOTHALAMUS

A. The approximate boundaries of the anterior, middle, and posterior divisions of the Hypothalamus

B. The medial and lateral zones of the hypothalamus(shaded). Hypothalamic cells adjacent to the third ventricle is paraventricular zone.

Abbreviations: A, amygdala; AC, anterior commissure; AcN, accumbens nucleus; CN, caudate nucleus; CP, cerebral peduncles; Fc, columns of the fornix; Fcrus, crus of fornix; Inf, infundibulum; MB, mammillary body; OC, optic chiasm; ON, optic nerve; OT, optic tract; P, putamen; Pit, pituitary gland; S, septal nuclei; SN, substantia nigra; SubT, subthalamus; T, thalamus.

HYPOTHALAMIC–PITUITARY CONNECTIONS.

The posterior portion of the pituitary (neurohypophysis) is innervated by hypothalamic neurons that transport the hypothalamic hormones (oxytocin and vasopressin) down their axons to be released into capillary beds of the posterior pituitary from where they enter the general circulation. By contrast, the capillary beds of the anterior pituitary (adenohypophysis) are supplied with hypothalamic hormones (either “releasing” or “inhibitory factors”) via a blood portal system from capillary beds in the hypothalamus itself. Once released into the adenohypophysis, these hypothalamic hormones then stimulate pituitary cells to synthesize and secrete their own (pituitary) hormones, which then are released into the bloodstream. Note: Some hypothalamic hormones inhibit the production/secretion of pituitary hormones.

SEPTAL AREA

Topographically organized projections from the hippocampal formation to the septal area (left side) and topographically arranged efferent projections from the diagonal band of Broca to the hippocampal formation (right side).

Diagram illustrates other projections from the septal area to the medial hypothalamus, mammillary bodies, medial thalamus, prefrontal cortex, and anterior cingulate gyrus.

AMYGDALA

the organization of the nuclei of the amygdala

The major efferent projections of the amygdala. One principal output includes the stria terminalis, which projects to the bed nucleus of the stria terminalis and to the rostro-caudal extent of the medial hypothalamus. Fibers from the bed nucleus also supply similar regions of the hypothalamus. Another important output to the hypothalamus and midbrain PAG uses the ventral amygdalofugal pathway. Other fibers pass rostrally from the amygdala to the prefrontal cortex.

Neuroscience of Clinical Psychiatry, The: The Pathophysiology of Behavior and Mental Illness, 1st Edition

NEUROTRANSMITTER


• A neurotransmitter is technically defined by meeting three criteria:1. The substance must be stored in the presynaptic

neuron.2. It must be released with depolarization of the

presynaptic neuron induced by the influx of Ca2+.3. The substance must bind with a specific receptor

on the postsynaptic neuron


CLASSIFICATION OF NEUROTRANSMITTER

1. The classic neurotransmitters:1. Amino acids:

1. Glutamate2. GABA and Glycine

2. Monoamines1. Catecholamines

1. Dopamine2. Norepineprhine3. Epinephrine

2. Indoleamines 1. Serotonin2. Melatonin 3. Histamine

3. Acetylcholine

2. Neuropeptides.3. Unconventional neurotransmitters

1. Gases : Nitric oxide (NO)2. Endocannabinoids


Neuropeptides

Neuropeptides Example

Gut-brain peptides Substance PCholecystokininGalanin

Pituitary peptides Adrenocorticotropic hormone (ACTH)Luteinizing hormone (LH)OxytocinVasopressin

Hypothalamic releasing peptides Corticotropin-releasing factor (CRF)Gonadotropin-releasing hormone (GnRH)Thyroidtropin-releasing hormone (TRH)Somatostatin

Opioid peptides EndorphinEnkephalins

Other peptides AngiotensinBradykinin


Unconventional neurotransmitters

1. Gases2. Endocannabinoids


The synthesis of catecholamines from tyrosine.

Catecholamines are synthesized from the essential amino acid tyrosine that must be obtained from the diet. Note that L-dopa is synthesized into DA. This shows why L-dopa can be given as a treatment for Parkinson's disease. The trick is to allow the synthesis in the CNS, but inhibit the enzyme dopa decarboxylase in the periphery so that the patient is not too nauseated.


The relative size of -A : the amino acids-B : two of the amines -C : neuropeptide


Glutamate• This is the major workhorse of the brain, with glutamate neurons

making up more than half of the excitatory neurons. Without glutamate the brain does not get started or keep running.

• Glutamate and another excitatory transmitter aspartate are nonessential amino acids that do not cross the blood-brain barrier. Consequently, glutamate must be synthesized in the brain from glucose and other precursors.

• Glial cells assist in the reuptake, degradation, and resupply of glutamate for neurons.

• Disorders:– Too much glutamate (as in stroke) is toxic to the nerve cells– glutamatergic dysregulation may be present in patients with

schizophrenia


GABA and Glycine

• GABA is the major inhibitory transmitter in the brain and is used by approximately 25% of the cortical neurons.

• Glycine is the other inhibitory amino acid, but is less common.

• GABA puts the brakes on the brain: not enough GABA and one can have seizures.

• The GABA neurons are primarily the interneurons in the gray matter providing local constraint over cortical circuitry.


Dopamine (DA)There are 3 dopaminergic system in the brain:1. Nigrostriatal system or Mesostriatal system :– From Substantia nigra to striatum (nucleus Caudatus and

Putamen)Parkinson disease

2. Mesolimbocortical DA system:1. Mesolimbic : from ventral tegmental area (VTA) to nucleus

accumbens, amygdala, and hippocampus.2. Mesocortical : from VTA to prefrontal cortex

3. Tuberoinfundibular DA system :– From Arcuate nucleus to hypophysis inhibit synthesis and

release of prolactin.– antipsychotic medications that block the DA receptor can

cause an increase in prolactin (hyperprolactinemia)


Dopamine (cont.)

• The branches to the nucleus accumbens are involved with reward and substance abuse.

• The branches to the prefrontal cortex are involved with attention and cognition, and seem to be impaired in patients with attention deficit hyperactivity disorder (ADHD).

• Some speculate that problems with the mesolimbic system cause the positive symptoms of schizophrenia whereas negative symptoms are caused by impairment in the mesocortical system.


The dopaminergic systemThe substantia nigra forms the nigrostriatal pathways to the caudate and putamen. The ventral tegmental area projects to the nucleus accumbens and cortex. The arcuate nucleus of the hypothalamus projects to the tuberoinfundibular area of the hypothalamus


Norepinephrine (NE)

• NE neurons contain an additional enzyme in their terminals that converts DA to NE.

• Approximately 50% of the NE neurons are located in the locus coeruleus. There are approximately 12,000 neurons in each nucleus.

• The remainder of the NE neurons is found in loose clusters in the medullary reticular formation .

• Plays an important role in anxiety and depression.


Norepinephrine (cont.)

• The NE neurons play an important role in alertness. • The firing of the locus coeruleus increases along a

spectrum from drowsy to alert, with the lowest found when we sleep and the highest when we are hypervigilant.

• The noradrenergic neurons are important in handling danger. In a threatening situation, the locus coeruleus is active as are the sympathetic neurons of the autonomic nervous system (ANS) where the peripheral noradrenergic neurons are found.


The noradrenergic system. With projections to almost every area of the brain and spinal cord, the NE

system plays an important role in alertness and anxiety.


Epinephrine• The epinephrine (or adrenaline) neurons are

few and play a minor role in the CNS. • Most of the epinephrine in the body is

produced in the adrenal medulla and excreted with sympathetic stimulation.

• Therefore, epinephrine plays a much greater role outside of the brain as a hormone, than within as a neurotransmitter


Serotonin synthesis


Serotonin (5-hydroxytryptamine)• Serotonin is found in many parts of the body outside of the CNS, such as

platelets and mast cells. Only approximately 1% to 2% of the body's serotonin in located in the brain.

• The most closely associated neurotransmitter with modern neuropsychopharmacology.

• Serotonin is synthesized from tryptophan that must be obtained in the diet .

• In the pineal gland there are two additional enzymes that convert serotonin to melatonin.

• The serotonin neurons are relatively few in number (approximately 200,000) and reside in the raphe nuclei in the brain stem.

• As with NE, the serotonin neurons project to virtually all areas of the brain.

• Plays an important role in depression and anxiety, and also in the sleep-wake cycle.


The serotonergic systemThe cluster of Raphe nuclei along the brainstem has projections to most of the brain and spinal cord. These neurons play an important roll in mood, anxiety, and with the

sleep-wake cycle


Histamine• Histamine in the brain is involved in arousal and attention. • Most of the cell bodies start in the tuberomammilary

nucleus of the posterior hypothalamus, with sparse but widespread projects to all regions of the brain and spinal cord.

• When animals are alert, the histamine neurons are active. Histamine neurons are quiet when animals are sleeping.

• More recently, there has been increased interest in activating the histamine neurons as a treatment for fatigue. Modafinil, the only agent in the class, indirectly activates the histamine neurons and has been used successfully as a treatment for narcolepsy, excessive sleepiness, and ADHD.


Acetylcholine• Acetylcholine (ACh) was the first neurotransmitter identified (1920)• ACh is a small molecule transmitter but it is not an amino acid nor a

monoamine.• ACh plays a prominent role :

– in the peripheral autonomic nervous system (ANS)– at the neuromuscular junction.

• In the CNS arises from cell bodies in the brain stem and forebrain with prominent projects to the cortex and hippocampus.

• Projections to the hippocampus are involved with learning and memory and are disrupted in Alzheimer's disease.

• ACh, unlike the catecholamines and indoleamines, is also synthesized in interneurons in the CNS.

• In the striatum, the ACh neurons balance the dopaminergic input from the substantia nigra to coordinate extrapyramidal motor control. Disruption of this balance with DA-blocking antipsychotic agents can result in extrapyramidal side effects. The anticholinergic agents are administered to restore the ACh/DA balance and allow normal movement.


Neuropeptides• The neuropeptides are small chains of amino acids but larger than the classic

neurotransmitters. Peptides are synthesized in nerve cells and have effects on behaviors such as learning, attachment, mood, and anxiety.

• Some have important endocrine functions in the body, such as the regulation of reproduction, growth, water intake, salt metabolism, temperature control.

• The formation, release, and inactivation of the neuropeptides differ from that of the monoamines. Peptides must be transcribed from mRNA on the ribosomes of the endoplasmic reticulum. Initially the peptide is a large propeptide precursor, which is cleaved into an active neuropeptide as it is moved from the Golgi apparatus into large dense core vesicles that are stored at the terminal bud of the neuron.

• Unlike the monoamines, neuropeptides are not recycled by the neuron, but are rather broken down by degradative enzymes (peptidases) on the receptor membrane.


Neuropeptides

Neuropeptides Example

Gut-brain peptides Substance PCholecystokininGalanin

Pituitary peptides Adrenocorticotropic hormone (ACTH)Luteinizing hormone (LH)OxytocinVasopressin

Hypothalamic releasing peptides Corticotropin-releasing factor (CRF)Gonadotropin-releasing hormone (GnRH)Thyroidtropin-releasing hormone (TRH)Somatostatin

Opioid peptides EndorphinEnkephalins

Other peptides AngiotensinBradykinin


Unconventional Neurotransmitters

• Nitric oxide (NO) : – most commonly associated with erectile dysfunction, – is a gas that is formed in glutamate neurons when arginine is converted into

citrulline and NO. – NO has the ability to diffuse (without obstruction) out of the originating cell,

through the extracellular medium and into any neighboring cell that it meets.– NO converts guanosine triphosphate (GTP) into cyclic guanosine

monophosphate (GMP) that acts as a second messenger. – Cells containing the NO synthase (the enzyme that creates NO) constitute

only approximately 1% of neuronal cells in the brain, but reach out so extensively that nearly every cell in the brain may encounter NO.

– NO may be involved with aggression and sexual behavior, as well as migraine headaches. NO may restrain aggressive and sexual behavior.

– It is worth noting that the medications for erectile dysfunction have not been associated with any adverse effects on mental function. This may be due to the inability of these medications in their current form to cross the blood-brain barrier.


Unconventional Neurotransmitters (cont.)• Endocannabinoids:– The cannabinoid receptor (CB1) is widely expressed

throughout the brain on presynaptic terminals. – The effect of activating CB1 receptors results in

inhibition of that neuron and in a simple way explains the calming effect of marijuana.

– Blocking the CB1 receptor can inhibit appetite. – Rimonabant, a potent and selective blocker

(antagonist) of the CB1 receptor, has been shown in clinical studies to facilitate weight loss.

neural basis of neurobehavior disorders.ppt

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