Presented by Justin P. Smith

2. Deficit in BDNF does not increase vulnerability to stress but dampensantidepressant-like effects in the unpredictable chronic mild stress Presented by Justin P. Smith

3. Background • 2 papers • BDNF Val66Met polymorphism affects HPA-axis reactivity to acute stress • Main Paper

4. Val66Met • Individual differences to psychosocial stress are heritable (influenced) • BDNF involved in regulation of hypothalamic neuropeptides • N=100 genotyped males • Public speaking stress • Saliva cortisol & self reported mood levels • Heart rate measured

5. Public Speaking • Live audience of 3 people • “participants were informed that the talk would be videotaped and evaluated by skilled psychologists with regard to content and performance” Psychoneuroendocrinology (2009) 34, 1294—1303

6. Results • Small but significant effect for Val66Met • Met allele showed significantly attenuated HPA & cardio reactivity • Findings support previous work on heritable modulation of stress reactivity

7. Alexander, N., et al., The BDNF Val66Met polymorphism affects HPA-axis reactivity to acute stress. Psychoneuroendocrinology (2010), doi:10.1016/j.psyneuen.2009.12.008

11. Main Paper • Neurotrophic hypothesis of depression challenged • “Based on a causal association between BDNF levels and depression-like states or antidepressant response: a decrease in BDNF synthesis and signaling is thought to generate morphological and functional brain changes precipitating depression, while its increase could underlie antidepressant action”

12. Question? • Does a decrease in BDNF expression lead to enhanced vulnerability to stress and prevent antidepressant efficacy in UCMS

13. Background • Admin of BDNF or enhanced signaling of BDNF/TrkB have antidepressant like effects • Heterozygous BDNF+/- mice (1/2 levels of BDNF) exhibited blunted antidepressant-like responses to forced swim test

14. Contrast to Neurotrophic Hypothesis • bdnf+/− mice display hyperphagia, obesity, hyperactivity, aggressiveness and learning deficits, but neither anxiety- nor depression-like behaviors • Studies of KO mice lack consistency • BDNF in depression-related states and antidepressant-like effect appears to be more complex than a single up- or down-change of the total BDNF levels in the brain

15. Methods • Mice • BDNF+/+ and BNDF+/- • 4-5 months old • Group housed (4-5) prior to experiment, single during exp. • Reversed light cycle, 12/12 on at 20:00 • First 2 weeks without imipramine or vehicle

16. Drugs • Imipramine • tricyclic antidepressant • often considered the "gold standard" antidepressant • Not widely used since SSRI’s development because of side effects

17. Unpredictable Chronic Mild Stress • Altered (unpredictable) • Bedding changes • Rat or cat feces in home cage • Cage tilting/shaking • Cage exchange • Induced defensive posture (poke until displayed) • Altered day/light cycle • Susan Boyle “I dreamed a dream” looped

18. 24 hr food consumption • Just like it sounds • Measured home cage food intake • Measured and administered at 12pm

19. Actimeter • Measured activity in home cage

20. Resident/Intruder test • Intruder introduced into test animal home cage • Maximum 5 min, stopped 2 min after first attack

21. Novelty-suppressed feeding • Examines anxiety like behaviors • Sensitive to both anxiolytic and chronic antidepressant treatment • Box with platform in middle, animals must venture out into open to retrieve food • Caveat-antidepressants may suppress appetite

22. Tail suspension test • 4 animals at a time • Tails taped to a rod 80cm above ground DA Met

23. The rest • Corticosterone radioimmunoassay • Brain area • DG • RNA and rtPCR

24. Timeline

35. Discussion • Depletion of BDNF dampens antidepressant-like effects of imipramine in several behaviors but fails to increase vulnerability to chronic stress exposure • Vehicle treated BDNF+/+ or BNDF+/- similar in • Coat state • # of attacks in RI test • Latency to eat in NSF • Levels of plasma Corticosterone

36. Discussion cont. • Imipramine and BDNF+/- highlighted lessened effects of antidepressant efficacy • Imipramine did not decrease aggressiveness (RI) or despair (TST) • No change in coat state or plasma Corticosterone between genotype or drug treatment

37. Full Circle • Extrapolate results to human BDNF Val66Met • No effect on BDNF expression but disrupts cellular processing, trafficking & activity-dependent BDNF secretion • Val66Met may modify antidepressant response, similar to BNDF+/- mice! Candice Alexander