1. http://depts.washington.edu/stellalb/nbio.shtml

2. Neurobiology 404 Depression, mood disorders Schizophrenia

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

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

5. Depression

6. Andrew Solomon Anatomy of Melancholy

7. Depression is present in all cultures Demographics 10-20% of the population will experience at least one episode 1.5 - 2X more common in women - really 50%? Increasing occurrence since 1940 Decreasing age of onset since 1940 First episode often preceded by life stress

8. 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

9. 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

10. Antidepressants alter amine neurotransmitter levels Biogenic amines - neuromodulators

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

12. Serotonergic projections

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

14. Noradrenergic projections

16. Antidepressants act at three locations in amine synapses MAOinhibitors TricyclicsSSRIsNSRIsAtypicals

18. Monoamine oxidase Amine transmitter concentrations Amine transmitter degradation NOTSPECIFIC

19. Amine reuptake Amine in synapse Reuptakeinhibitors

20. 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

21. Reuptake transporters are specific to a single neurotransmitter Serotonin Norepinephrine Dopamine

23. NE transport activity

24. NE 5HT DA

25. SSRIs Selective reuptake inhibitors

26. NSRI - Reboxetine

27. 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

28. 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.

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

30. 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.

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

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

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

34.    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

35.    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

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

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

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

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

42. Antidepressants increase synthesis of neurotrophic factors in the hippocampus.

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

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

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

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

48. Trophic factor hypothesis of antidepressant action

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

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

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

52. 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.

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

54. CorticotropinReleasingFactor

55. CRF levels are elevated in depressed individuals Science 226:1342 1984

56. CorticotropinReleasingFactor Receptors CRF1 pituitary neocortex CRF2a,b Raphe Periphery VTM

57. CRF 1and 2 are differentially expressed in CNS

58. 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?

59. CRF R1 knockouts display reduced blood cortisol levels

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

61. ..and a decreased HPA axis response to stress

63. Experiment: Vary ease of obtaining food for parents when baby monkeys are 17-29 weeks old.

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

65. 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

66. 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

67. Rats differ in their mothering style PNAS 95:5335 1998

68. Adult offspring of low- nurturing dams exhibit more anxious behavior

69. Science 277:1659 1997 And increased HPA axis activation

70. Science 277:1659 1997 Decreased glucocorticoid receptor expression in less nurtured rats

71. Nat Neurosci 7:847 2004 GR gene contains a non-coding region that can be methylated, which blocks transcription

72. Nat Neurosci 7:847 2004 Reduced methylation of GR gene in high nurtured rats

73. Nat Neurosci 7:847 2004 Persistence of reduced methylation of GR gene in high nurtured rats

74. Nat Neurosci 7:847 2004 Cross-fostering can change methylation patterns

75. 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

76. 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.