Presented By: Justin Felice Chief Technical Director FINANCIAL INVESTIGATIONS DIVISION.
Presented by Justin P. Smith
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Transcript of 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
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