2. Presented by Justin P. Smith
Deficit in BDNF does not increase vulnerability to stress but dampens antidepressant-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: /j.psyneuen

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