Brain-derived neurotrophic factor signaling mitigates the impact of acute social stress

Abstract

Brain-derived neurotrophic factor (BDNF) is known to promote fear learning as well as avoidant behavioral responses to chronic social defeat stress, but, conversely, this peptide can also have antidepressant effects and can reduce depressant-like symptoms such as social avoidance. The purpose of this study was to use a variety of approaches to determine whether BDNF acting on tropomyosin receptor kinase B (TrkB) promotes or prevents avoidant phenotypes in hamsters and mice that have experienced acute social defeat stress. We utilized systemic and brain regiondependent manipulation of BDNF signaling before or immediately following social defeat stress in Syrian hamsters, TrkB F616A knock-in mice, and C57Bl/6J mice and measured the subsequent behavioral response to a novel opponent. Systemic TrkB receptor agonists reduced, and TrkB receptor antagonists enhanced, behavioral responses to social defeat in hamsters and mice. In the neural circuit that we have shown mediates defeat-induced behavioral responses, BDNF in the basolateral amygdala, but not the nucleus accumbens, also reduced social avoidant phenotypes. Conversely, knockdown in the basolateral amygdala of TrkB signaling in TrkB F616A mice enhanced defeat-induced social avoidance. These data demonstrate that systemic administration of BDNF-TrkB drugs at the time of social defeat alters the behavioral response to the defeat stressor. These drugs appear to act, at least in part, in the basolateral amygdala and not the nucleus accumbens. These findings were generalizable to two rodent species with very different social structures and, within mice, to a variety of strains providing converging evidence that BDNF-TrkB signaling reduces anxiety-and depression-like symptoms following short-term social stress.

The role of SIRT1 in the basolateral amygdala in depression‐like behaviors in mice

“…BDNF is a member of the neurotrophin family of growth factors, which is involved in neuronal homeostasis and brain plasticity‐related process 40 . A previous study put forward that BDNF–TrkB signaling reduced anxiety‐ and depression‐like symptoms following short‐term social stress 41 . Another study reported that SIRT1 activation could ameliorate spatial memory deficits by altering hippocampal BDNF–TrkB signaling 42 .…”

BDNF Therapeutic Mechanisms in Neuropsychiatric Disorders

“…This further supports the BDNF stress-sensitivity hypothesis that BDNF dysregulation, as with the Val66Met polymorphism, predicts vulnerability to stress [ 217 ]. Indeed, TrkB receptor blockade enhances defeat-induced avoidance and PTSD-like symptoms in models of acute social and single-prolonged stress, which were mitigated by TrkB activation [ 218 , 219 ]. It should be stressed that secondary modulation of dopaminergic and serotonergic transmission by BDNF represents one mechanism affecting anxiety, depression, and schizophrenia as previously described mechanisms such as neuroinflammation, oxidative stress, and plasticity impairments are also involved and modulated by BDNF.…”

A salience hypothesis of stress in PTSD

“…Similar delayed effects are also reported after exposure to other types of acute stressors including acute predator stress and one‐time injection of the stress hormone corticosterone (Cohen et al, 2006; Kim et al, 2014, 2015; Zohar et al, 2008) and can be detected even 30 days afterwards (Kozlovsky, Matar, Kaplan, Kotler, Zohar, & Cohen, 2007). Rodents also show enhanced social anxiety (a symptom often reported in PTSD patients; Collimore et al, 2010) which is quantified by a decrease in social interaction of a stressed animal with an unfamiliar conspecific (Chakraborty et al, 2020; Lehmann et al, 2016; Rosenhauer et al, 2019; Saxena et al, 2020; Varlinskaya & Spear, 2008) (Table 1). So while stress does alter salience processing of both social and non‐social cues, could social and asocial anxiety divergently evolve over time after the same stressful experience?…”