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

Background

• 2 papers– BDNF Val66Met polymorphism affects HPA-axis

reactivity to acute stress– Main Paper

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

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

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

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

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”

Question?

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

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

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

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

Drugs

• Imipramine– tricyclic antidepressant– often considered the "gold standard"

antidepressant – Not widely used since SSRI’s development

because of side effects

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

24 hr food consumption

• Just like it sounds• Measured home cage food intake• Measured and administered at 12pm

Actimeter

• Measured activity in home cage

Resident/Intruder test

• Intruder introduced into test animal home cage

• Maximum 5 min, stopped 2 min after first attack

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

Tail suspension test

• 4 animals at a time– Tails taped to a rod 80cm

above ground

DA Met

The rest

• Corticosterone radioimmunoassay• Brain area– DG

• RNA and rtPCR

Timeline

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

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

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