Neurobiology 404 Depression, mood disorders Schizophrenia

Two components: Emotion/feelings peripheral/physicalcentral/mental Moods - sustained/emotional/feeling states Affect - momentary/emotional/feeling states

Disorders of Mood exaggerated or maladaptive emotions Unipolar depression Bipolar disorder Dysthymia

Depression

Andrew Solomon Anatomy of Melancholy

Depression is present in all cultures Demographics 10-20% of the population will experience at least one episode X more common in women - really 50%? Increasing occurrence since 1940 Decreasing age of onset since 1940 First episode often preceded by life stress

Occurrence of depression is higher among people with primary relatives who have been depressed. Genetics 40-60% concordance in identical twins 10% concordance in dizygotic twins Bipolar disorder vs. unipolar depression 80% concordance in identical twins

Reserpine - produced depression Drug effects on mood provided the first indication that depression is a disorder of nervous system functioning. Iproniazid - improved mood Tricyclics (imipramine) alleviated depression

Antidepressants alter amine neurotransmitter levels Biogenic amines - neuromodulators

Serotonin Affect/Mood Sleep Appetite Sexual behavior Endocrine function Synthesized from tryptophan Precursor of melatonin - sleep rhythms

Serotonergic projections

Norepinephrine (Noradrenaline) Affect Attention Reward Endocrine function Synthesized from the amino acid tyrosine

Noradrenergic projections

Antidepressants act at three locations in amine synapses MAOinhibitors TricyclicsSSRIsNSRIsAtypicals

Monoamine oxidase Amine transmitter concentrations Amine transmitter degradation NOTSPECIFIC

Amine reuptake Amine in synapse Reuptakeinhibitors

The re-uptake transporters for NE, 5HT and DA comprise a gene family of similar molecules. a gene family of similar molecules. *12 TM domains *Conserved residues

Reuptake transporters are specific to a single neurotransmitter Serotonin Norepinephrine Dopamine

NE transport activity

NE 5HT DA

SSRIs Selective reuptake inhibitors

NSRI - Reboxetine

Depression is a common disorder that affects multiple neural and endocrine pathways. Drugs that alter amine neurotransmission alleviate the symptoms of depression Drugs that inhibit the transport of transmitter back into the presynaptic terminal are the most commonly used anti-depressants. Amines act largely as neuromodulators. They are released by a Small subset of neurons that have broad projections. Clinical use of antidepressants is tailored to the individual. Summary

Amine hypothesis of depression Depression is due to a depletion of amine neurotransmitter. But drug effects on transporters are almost immediate yet anti-depressant action is not noticeable for several weeks.

Long term tricyclic administration leads to decreased receptor response to neurotransmitter.

Receptor internalization Receptor desensitization Chronic receptor activation leads to decreased response to neurotransmitter Chronic receptor activation leads to internalization of receptors or changes in receptor expression.

Amine transmitters activate G-protein-coupled receptors    GDP Receptor Trimeric G protein Ion channel RE Effector e.g. cyclase

   GDP Receptor Trimeric G protein Ion channel GTP RE Effector e.g. cyclase

   Receptor Effector e.g. cyclase Ion channelGTP Generation of 2nd messengers e.g. cAMP opened or closed ER

   Receptor Effector e.g. cyclase Ion channelGTP Generation of 2nd messengers e.g. cAMP opened or closed ER P Activation of receptors reveals a site that is phosphorylated by G Receptor Kinases (GRKs) GRK kinase

   GDP Receptor Trimeric G protein effector Ion channel arrestin P Phosphorylation of receptors by G Receptor Kinase (GRK) leads to uncoupling from the G protein and recruitment of the protein arrestin

Arrestin promotes receptor internalization    GDP Receptor Trimeric G protein effector Ion channel endosome P arrestin

   Receptor G protein effector Ion channel A    Receptor G protein effector Ion channel endosome Two effects of receptor occupation desensitization internalization P P A

Mammalian CNS contains over 10 different serotonin receptors which demonstrate differential expression and cellular localization

Revised Amine Hypothesis of Depression Changes in amine levels lead to structural changes that bias the neural/endocrine system towards normalcy or depression.

Antidepressants increase synthesis of neurotrophic factors in the hippocampus.

Infusion of BDNF into the dentate gyrus of the hippocampus produces similar behavioral effects to antidepressants. J. Neurosci. 22:3251

Reduced hippocampal volume in depressed individuals PNAS, 93:3908, 1996

Volume is inversely correlated with length of depression J. Neurosci. 19:5034, 1999

Fluoxitine increases neuronal proliferation in the hippocampus. Science, 301:805

Trophic factor hypothesis of antidepressant action

Antidepressants alter levels of neuronal trophic factors. Neuronal survival and proliferation are associated with the behavioral effects of antidepressants. Summary

The HPA Stress Axis Stressors Hypothalamus Cortisol Corticosterone (-) Pituitary Corticotropin-release factor (CRF) (+) Adrenals Adrenocorticotropin hormone (ACTH) (+) Cortisol Corticosterone (+) Liver, fat, muscle, lymphycytes, etc

Secretion of the stress hormone cortisol is elevated in depressed individuals.

The HPA Stress Axis Stressors Hypothalamus Pituitary Corticotropin-release factor (CRF) (+) Adrenals Adrenocorticotropin hormone (ACTH) (+) Cortisol Corticosterone (+) Liver, fat, muscle, lymphycytes, etc Cortisol Corticosterone (-) dexamethasone This negative feedback path- way is reduced in depression.

The HPA Stress Axis Stressors Hypothalamus Cortisol Corticosterone (-) Pituitary Corticotropin-release factor (CRF) (+) Adrenals (+) Liver, fat, muscle, lymphycytes, etc

CorticotropinReleasingFactor

CRF levels are elevated in depressed individuals Science 226:

CorticotropinReleasingFactor Receptors CRF1 pituitary neocortex CRF2a,b Raphe Periphery VTM

CRF 1and 2 are differentially expressed in CNS

Consideration of CRF receptor knockouts HPA axis response Effects on measures of anxiety Are changes in CRF action the primary event in the etiology of anxiety and depression?

CRF R1 knockouts display reduced blood cortisol levels

CRF R1 mutants show decreased anxious behavior Smith et al. Neuron, 20:1093

..and a decreased HPA axis response to stress

Experiment: Vary ease of obtaining food for parents when baby monkeys are weeks old.

PNAS, 93:1619 Maternal neglect is associated with elevated CRF levels in adulthood.

Stress effects on the brain Stressors Hypothalamus Pituitary Corticotropin-release factor (CRF) (+) Adrenals Adrenocorticotropin hormone (ACTH) (+) Cortisol Corticosterone (+) Liver, fat, muscle, lymphycytes, etc Cortisol Corticosterone Hippocampus (-) Glucocorticoid receptors

Epigenetic modeling of anxiety Handling INCREASED “licking & grooming” Variations in maternal care allow separation of HIGH nursing mothers from LOW nursing mothers. Handling INCREASED “arched-back” nursing as opposed to “blanket” or “half-moon” nursing

Rats differ in their mothering style PNAS 95:

Adult offspring of low- nurturing dams exhibit more anxious behavior

Science 277: And increased HPA axis activation

Science 277: Decreased glucocorticoid receptor expression in less nurtured rats

Nat Neurosci 7: GR gene contains a non-coding region that can be methylated, which blocks transcription

Nat Neurosci 7: Reduced methylation of GR gene in high nurtured rats

Nat Neurosci 7: Persistence of reduced methylation of GR gene in high nurtured rats

Nat Neurosci 7: Cross-fostering can change methylation patterns

The HPA axis plays an essential role in stress responses and the development of anxiety/depression. HPA axis signaling is sensitive to environmental input. Life experiences can induce long-term, epigenetic changes in HPA axis functioning. Summary

Maternal Care and GR Expression Maternal nurturing increases GR gene expression in offspring hippocampus GR gene expression is accompanied by an increased hippocampal expression of nerve growth factor-inducible protein A (NGFI-A) The non-coding exon 1 region of hippocampal GR includes a promoter region, exon 1 7, which contains a binding site for NGFI-A Splice variants of the GR mRNA containing the exon 1 7 sequence are found predominantly in the brain Expression of GR mRNAs containing exon 1 7 is increased in offspring of high nurturing mothers or following manipulations that increase maternal licking and grooming.