IzBen C. Williams, MD, MPH Instructor. BIOLOGY OF BEHAVIOR GENETICS, ANATOMY, & BIOCHEMISTRY OF...

BEHAVIORAL SCIENCE

IzBen C. Williams, MD, MPHInstructor

BIOLOGY OF BEHAVIOR

GENETICS, ANATOMY, &

BIOCHEMISTRY OF BEHAVIOR

Genetics of BehaviorDefinition of common terms:For fullest appreciation of this presentation

students may wish to refresh their memory on some basic principles of genetics; particularly on such terms as:Genotype and Phenotype, Heritability, Penetrance, ExpressivityHomozygosity and HeterozygosityDominance and Recessivity

Genetics of Behavior -2

There are basically three methods of studying behavioral genetics. A. Family StudiesB. Twin StudiesC. Adoption Studies


Methods of studying behavioral Genetics. A. Family Studies: These assess the pattern of affliction in the

relatives of an affected individual, who is called the index case, propositus, or proband

The family tree showing the occurrence of certain traits and diseases in different members is called the pedigree. By studying the pedigree the likely mode of inheritance may be inferred


Methods of studying Genetics:B. Twin Studies: These assess the degree to which both members

of a pair of twins manifest a given trait or disease. If both twins have a certain trait, they are termed concordant for that trait. If only one twin of the pair has the trait, the pair is said to be discordant

Twin studies may be carried out on monozygotic (identical) or dizygotic (fraternal) twins


Methods of studying Genetics:C. Adoption Studies: Offer an opportunity to distinguish between

genetic and environmental influences on behavior. The prevalence of specific traits or conditions in

the biological versus the adoptive relatives of probands is compared.

A genetic condition is characterized by a significantly higher prevalence of the condition among biological relatives when compared with adoptive relatives

Specific Disorders

Looking at the genetics of some specific disorders: A. SchizophreniaB. Affective DisordersC. Other Psychiatric Disorders

Genetics of Psychiatric Disorders

A. SCHIZOPHRENIA:A severe mental illness that is marked by:

Hallucinations (which are chiefly auditory)DelusionsDisorganization of thought and speech, andEmotional blunting


Schizophrenia (cont’d)1. Family studies: Worldwide lifetime

incidence of Schizophrenia ranges from 0.3% to 3.0% with a mean incidence of about 0.9%.

The risk for parents is about 4% to 5%The risk for full siblings is 7% to 8%Children of a schizophrenic proband, risk of

10% to 12%If both parents have schizophrenia, risk is

35% to 46%


Schizophrenia (cont’d)2. Twin studies: Concordance rate for schiz.

is significantly higher in monozygotic than in dizygotic twins (35-58% for mono; 9-26% for di)

3. Adoption studies: Prevalence of schiz and related disorders significantly higher in biological relatives compared to adoptive relatives


Schizophrenia (cont’d)4. Inheritance of Schizophrenia:

a. The exact mode of transmission of Schiz is unknown but clearly, in addition to genes, environmental factors are contributory

It is likely that there are several subtypes of schiz (schizophrenia spectrum disorders) and that genes are more important in some than in others


Schizophrenia (cont’d)4. Inheritance of Schizophrenia:

b. Exactly what is inherited in schiz is not known. Some investigators have hypothesized that specific biochemical defects are transmitted.

Alternatively, only the predisposition to develop schiz under certain situations may be transmitted


B. AFFECTIVE DISORDERS:Conditions marked by pervasive pathologic

change in mood. There are two major forms:Unipolar disorder (pure depressive disorder)

characterized by a single episode of repeated episodes of depression

Bipolar disorder (manic depressive illness) characterized by episodes of mania and depression


Affective Disorders (cont’d)1. Family studies

a. Unipolar disorder: Lifetime incidence in the general population is 15%

to 20% 40% to 60% have a first-degree relative with an

affective disorder Morbidity risk for an affective disorder is: 13% for

parents; 15% for siblings, and 21% for children Relatives of unipolar patients are at much higher

risk of developing unipolar than bipolar illness


Affective Disorders (cont’d)1. Family studies

b. Bipolar disorder:Lifetime incidence in the general population is 1%

to 2%, however 80% risk for affective disorder in first degree relative

Morbidity risk: for an affective disorder is: 22% for parents; 25% for siblings, and 39% for children

Relatives of unipolar patients are at much higher risk of developing either unipolar or bipolar illness


Affective Disorders (cont’d)2. Twin studies

Monozygotic twins reared either apart of together have a 75% rate of concordance compared to dizygotic twins who have a 20% concordance rate

Twins of unipolar probands are likely to be unipolar

Twins of bipolar probands are likely to be bipolar or unipolar


Affective Disorders (cont’d)3. Adoption studies

There is (as in schiz) a higher prevalence of affective disorders in biological relatives than in adoptive relatives of affected individuals


4. Inheritance of affective disorders: Studies strongly suggest that genetic factors contribute to the etiology of major affective disorders. There is (as in schiz) a higher prevalence of

affective disorders in biological relatives than in adoptive relatives of affected individuals

An X-linked mode of inheritance suggestedDepressive spectrum disease proposed on the

basis of high prevalence of sociopathy and alcoholism in male members of families of probands with major depression


C. OTHER PSYCHIATRIC DISORDERS:1. Personality Disorders: Conditions marked

by chronic patterns of maladaptive behavior and the patients are usually unaware of their own role in the continuing difficulties that arise.Concordance rate several times higher on mono-

than in dizygotic twins The most conclusive evidence for inherited traits

are antisocial, histrionic, schizoid, schizotypal, and obsessive compulsive personality disorders


C. OTHER PSYCHIATRIC DISORDERS:2. OCD & other anxiety disorders: No

established evidence for genetic links 3. Alcohol and tobacco use: Adoption

studies indicate genetic link for alcoholism. Little evidence for genetic link in tobacco use

4. Attention deficit disorder: Twin studied and adoption studies confirm strong genetic link

Biochemistry & Behavior -1

This presentation assumes the prior knowledge, which I am sure you possess, of:Neuronal transmission and Intra-neuronal transport

And begins with a brief introduction to aspects of Inter-neuronal transport


Aspects of Inter-neuronal transport Neuroregulators: Chemicals that carry

information between neurons. They include Neurotransmitters: transfer of information

lasts 1-2 msec Neuromodulators: effect lasts up to minutesNeurohormones: released into systemic

circulation


Aspects of Inter-neuronal transport Types of neurotransmitters

Excitatory neurotransmitters increase the likelihood of the firing of the postsynaptic neurons

Inhibitory neurotransmitters decrease the likelihood of firing of the postsynaptic neuron


Aspects of Inter-neuronal transport Some neurotransmitters appear to be

solely excitatory eg glutamateSome others appear to be solely inhibitory

eg GABA and glycineAnd others may function either way, eg

dopamine and acetyl choline (ACh)


Neurotransmitter criteria -11. The transmitter must be present at nerve

terminals.2. Stimulation of the nerve must cause the

release of the transmitter in sufficient amounts to exert its action at the post synaptic terminal

3. Effects of the transmitter on the post synaptic membrane must be similar to those of transmitter stimulation of presynaptic nerve


Neurotransmitter criteria -24. Pharmacologic agents should alter the dose- response curve of the applied transmitter in the same magnitude and direction that they alter the naturally occurring synaptic potential 5. A mechanism of inactivation or metabolism of the transmitter must exist in the vicinity of the synapse


Neurotransmitter criteria -3 Proven or definite neurotransmitters meet

all the criteria (ACh, dopamine, Epi & NEpi, GABA, Serotonin and glycine)

Putative neurotransmitters meet a few of the criteria (glutamate, aspartate, substance P)

Neurotransmitter candidates meet one or two criteria (adenosine, cAMP, prostaglandins, and most peptides)

Neurotransmitters -1

THREE CLASSES OF NEUROTRANSMITTER SUBSTANCES:

1. BIOGENIC AMINES2. AMINO ACIDS3. NEUROPEPTIDES

4. Other Non-Peptide Neurotransmitter Candidates

Neurotransmitters -3

1. BIOGENIC AMINESa) Dopamineb) Norepinephrinec) Epinephrine d) Serotonin (5-HT)e) Histaminef) Acetylcholine

Neurotransmitters Biogenic Amines

1. DOPAMINE • Synthesis: tyrosine hydroxylation is the rate-

limiting step in the synthesis of all of the major catecholamines (ie, dopamine, Nor Epi, and Epi)

• Metabolism: Two enzymes are important for the inactivation of catecholamines (MAO and COMT)

• Receptors: Action may be excitatory or inhibitory but inhibition appears to be the more common. There are at least two, and possibly four types of Dopamine receptors (D1-4)


DOPAMINE: Important brain tracts in the CNS1. Nigrostriatal tract (movement)2. Mesolimbic and mesocortical tracts (affect,

cognition and motivation in man)3. Tuberohypophyseal (pituitary, prolactin

release)4. Medullary periventricular tract (?function)5. Incertohypothalamic tract (? function)In addition dopaminergic neurons are located in the retina and in the olfactory bulb


DOPAMINE: Behavioral functions 1From a behavioral perspective the three most important tracts are the nigrostriatal, mesolimbic and mesocortical The nigrostriatal pathway degenerates in

Parkinson’s diseaseNeuroleptic drugs, because they block post

synaptic dopamine receptors, and reserpine because it depletes dopamine, also cause parkinsonism


DOPAMINE: Behavioral functionsXS of dopamine transmission is thought to

be important in some disorders of XSive movement (hyperkinetic disorders) eg tardive dyskinesia

Dopamine also important for the organization of thought and feeling (the dopamine hypothesis of schizophrenia)


DOPAMINE: Behavioral functions The psychotic symptoms of schiz are

believed to result from a hyperdopaminergic stateNeuroleptic drugs block dopamine receptors.

This correlates with their anti psychotic effectDopamine agonist drugs such as

amphetamine and L-dopa make schiz symptoms worse

Dopamine & Serotonin Tracts


SEROTONIN: synthesis


SEROTONIN (5-HT): Receptors: Two types of serotonergic

receptorsS1 bind serotonin, are affected by guanineS2 bind spiperone and are less affected by

guanine nucleotides than S1

The predominant action of serotonin on receptors is inhibition

LSD acts as a receptor blocker and partial agonist


SEROTONIN (5-HT): Important brain tracts: The most important

serotonergic neurons in the brain are located in clusters in or around the midline (or raphe) of the pons and mesencephalon, including the median and dorsal raphe nuclei

Median raphe neurons innervate limbic structures

Dorsal raphe innervates striatum, cerebral cortex, thalamus and cerebellum


SEROTONIN (5-HT): Behavioral functions:

Important in many central processesInvolved in the pathophysiology of both

affective disorders and schizophreniaAffective disorders: permissive

serotonin hypothesis (low in depression, high in mania)

Transmethylation hypothesis of schizophrenia


2. NOREPINEPHRINE • Synthesis: tyrosine hydroxylation is the

rate-limiting step in the synthesis of all of the major catecholamines (ie, dopamine, Nor Epi, and Epi)

• Metabolism: Two metabolites of nor-epi are commonly measured in plasma or urine: 3-methyl-4-hydroxyphenylglycol and Vanillymandelic acid (HMPG and VMA)


2. NOREPINEPHRINE Receptors: four types α1, α2, β1 and β2

• α1 post synaptic receptors, blocked by prazocin

• α2 presynaptic receptors, decrease the synthesis of NEpi when stimulated

• β1 post synaptic, linked to atenolol, albutalol etc are selective antagonists

• β2 post synaptic, linked to adenylate cyclase. Terbutaline and albutalol are selective agonists


2. NOREPINEPHRINE Important brain tracts. Two major groupsI. The first group arises from the locus

ceruleus with projections going to the cerebellum and spinal cord, and to the hippocampus ventral striatum and entire cerebral cortex

II. The second group originates from the ventral tegmental area and projects to basal forebrain areas such as the septum and amygdala

Norepinephrine tracts


2. NOREPINEPHRINE Behavioral functions Projects to most areas of the brain and is

an important neuromodulator (eg, sleep-wake, pain, arousal, orientation)

Genesis of mood and anxiety disorders (catecholamine theory of mood disorders)

Implicated in some movement disorders, eg Tourette’s, Parkinson’s, torsion dystonia, tardive dyskinesia


ACETYLCHOLINE (ACh): Synthesis:

Choline cannot be synthesized in neurons hence high and low affinity transport processes transports it into the brain.

The high affinity process is the regulating factor


ACETYLCHOLINE (ACh): Metabolism:

ACh is inactivated by cholinesterases (including both acetylcholinesterase and pseudocholinesterase)

It is reversibly inhibited by physostigmine and almost irreversibly inhibited by organophosphorus compounds (found in insecticides)


ACETYLCHOLINE (ACh): Receptors:

Nicotinic receptors: are excitatoryIn the PNS their cell bodies lie in the spinal

cord or brainstem. They innervate skeletal muscle

Nicotine receptor agonists include nicotine and antagonists include curare drugs, gallamine, decamethonium


ACETYLCHOLINE (ACh): Receptors:

Muscarinic receptors: are excitatory or inhibitory

Their cell bodies lie primarily outside the CNS.

They innervate smooth muscle and glandsAgonists include muscarine, pilocarpineAntagonists include atropine

Acetylcholine brain tracts


ACETYLCHOLINE (ACh): Behavioral functions: in humans, the

most important known effects involve movement and memoryACh involved in movement peripherally

(skeletal muscles) and centrally (balancing the extrapyramidal motor system.

Ach important in memory and cognition. Associated with dementing illness

AMINO ACIDS

GABAGlycineGlutamate and Aspartate

Amino Acids

Amino AcidsGABA:

Receptors: GABA was the first amino acid demonstrated to be a receptor

GABA, unlike most other transmitters, is dedicated to the CNS

It is purely inhibitoryIt is the most abundant neurotransmitter X

plenty

Amino Acids

GABA:Two kinds of GABAergic receptors in

the CNSGABA-A receptors, muscinol is a selective

agonist GABA-B receptors, bacolfen is a selective

agonistSome GAGA receptors are coupled to a

third recognition site for benzodiazepines which potentiate the inhibitory action of GABA

GABA Brain Tract

GABA is the neurotransmitter for Purkinje cells, the only efferent neurons for the entire cerebral cortex

Inhibitory interneurons in all areas of the brain contain GABA

IzBen C. Williams, MD, MPH Instructor. BIOLOGY OF BEHAVIOR GENETICS, ANATOMY, & BIOCHEMISTRY OF...

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