Deficit in BDNF does not increase vulnerability to stress but dampens antidepressant-like effects in the unpredictable chronic mild stress

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Deficit in BDNF does not increase vulnerability
to stress but dampensantidepressant-like effects
in the unpredictable chronic mild stress

• Presented by Justin P. Smith

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Background

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

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Val66Met

• Individual differences to psychosocial stress are
  heritable (influenced)
• BDNF involved in regulation of hypothalamic
  neuropeptides
• N100 genotyped males
• Public speaking stress
• Saliva cortisol self reported mood levels
• Heart rate measured

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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, 12941303
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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

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Alexander, N., et al., The BDNF Val66Met
polymorphism affects HPA-axis reactivity to acute
stress. Psychoneuroendocrinology (2010),
doi10.1016/j.psyneuen.2009.12.008
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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

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Question?

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

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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

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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

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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 2000
• First 2 weeks without imipramine or vehicle

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Drugs

• Imipramine
• tricyclic antidepressant
• often considered the "gold standard"
  antidepressant
• Not widely used since SSRIs development because
  of side effects

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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

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24 hr food consumption

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

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Actimeter

• Measured activity in home cage

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Resident/Intruder test

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

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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

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Tail suspension test

• 4 animals at a time
• Tails taped to a rod 80cm
• above ground
• DA Met

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The rest

• Corticosterone radioimmunoassay
• Brain area
• DG
• RNA and rtPCR

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Timeline
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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

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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

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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
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