Short- and long-term effects of intermittent social defeat stress on brain-derived neurotrophic factor expression in mesocorticolimbic brain regions

Abstract

Social defeat stress is an ethologically salient stressor which activates dopaminergic areas and, when experienced repeatedly, has long-term effects on dopaminergic function and related behavior. The mechanism for these long-lasting consequences remains unclear. A potential candidate for mediating these effects is brain-derived neurotrophic factor (BDNF), a neurotrophin involved in synaptic plasticity and displaying alterations in dopaminergic regions in response to various types of stress. In this study, we sought to determine whether repeated social defeat stress altered BDNF mRNA and protein expression in dopaminergic brain regions either immediately after the last stress exposure or four weeks later. Male Sprague-Dawley rats were subjected to social defeat stress consisting of brief confrontation with an aggressive male rat every third day for 10 days; control rats were handled according to the same schedule. Animals were euthanized either 2 h or 28 days after the last stress or handling episode. Our results show that 2 h after stress, BDNF protein and mRNA expression increased in the medial prefrontal cortex. At this time-point, BDNF mRNA increased in the amygdala and protein expression increased in the substantia nigra. Twenty-eight days after stress, BDNF protein and mRNA expression were elevated in the medial amygdala and ventral tegmental area. Given the role of BDNF in neural plasticity, BDNF alterations that are long-lasting may be significant for neural adaptations to social stress. The dynamic nature of BDNF expression in dopaminergic brain regions in response to repeated social stress may therefore have implications for lasting neurochemical and behavioral changes related to dopaminergic function. KeywordsMesolimbic; ventral tegmental area; prefrontal cortex; amygdala; dopamine; neurotrophin Social defeat stress is an ethologically salient stressor which provides a relevant model to investigate the etiology of stress-related disorders in humans (Koolhaas et al., 1997;Koolhaas et al., 1999 Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. is sufficient to alter behaviors such as exploratory activity and sensitivity to other stressors for several weeks (Koolhaas et al., 1999). NIH Public AccessVarious types of stressors can dramatically alter neurochemistry specifically within the mesocorticolimbic dopamine circuit (Fadda et al., 1978;Dunn and File, 1983;Deutch et al., 1985;Louilot et al., 1986;Abercrombie et al., 1989;Imperato et al., 1992;Tidey and Miczek, 1996;Nikulina et al., 1998Nikulina et al., , 2001Bland et al., 2005;, which mediates general rewa...

Stress-induced neuroinflammation is mediated by GSK3-dependent TLR4 signaling that promotes susceptibility to depression-like behavior

“…These disparate findings raise the possibility that stress induced by shock paradigms preferentially affect hippocampal cytokines whereas stress induced by non-shock paradigms affect cytokines in both the hippocampus and the prefrontal cortex. Other differential responses of the hippocampus and prefrontal cortex to stress have been reported previously, notably a variety of stresses have been reported to increase brain-derived neurotropic factor mRNA and or protein levels within the prefrontal cortex (Bland et al, 2007;Fanous et al, 2010), but they were unchanged or decreased in subregions of the hippocampus (Smith et al, 1995;Barrientos et al, 2004;Pizarro et al, 2004). The greater sensitivity of hippocampal cytokine increases to shock stresses may be related to the reportedly larger density of microglia in the hippocampus than in the prefrontal cortex (Lawson et al, 1990), although potential mechanisms underlying the differential inflammatory responses to stress in the hippocampus and the prefrontal cortex remain to be clarified.…”

Identification of a low–molecular weight TrkB antagonist with anxiolytic and antidepressant activity in mice

“…In these studies, preventing BDNF production in dopaminergic regions or inhibiting BDNF/TrkB signaling in the nucleus accumbens reduced the anxiety toward former aggressors and induces strong antidepressive effects in rodent, predicting that TrkB inhibition may lead to antidepressant action in humans (7,12). In line with this observation, mice susceptible to stress-related anxiety and depression exhibit high levels of BDNF in the ventral striatum (13) and acutely stressed mice show a rapid and sustained increase in BDNF expression in the prefrontal cortex and in the hippocampus (14,15). In consequence, while inhibiting BDNF signaling may not lead to depression-like behaviors (16)(17)(18), reports have suggested that inhibiting TrkB signaling may in contrast be a therapeutic strategy for treating human mood disorders (5,7,13,19).…”

“…Overactivity of the BDNF/TrkB signaling in the reward circuitry, including striatum and cortex, and in the hippocampus has been associated with the development of anxiety and depression in rodent animal models (7,(13)(14)(15). We therefore tested the hypothesis that injecting ANA-12 into mice would predict efficient anxiolytic and antidepressant properties of the compound.…”

“…In contrast, inhibition of BDNF and TrkB signaling in the reward system has shown strong antidepressant effects in rodent models of stress and depression (7,12). Given the dynamic activity of the BDNF/TrkB coupling in these disorders, it has been proposed that BDNF antagonists would provide a novel class of efficient therapeutic agents to treat anxiety and depression in humans (7,(11)(12)(13)(14)(15). Accordingly, we propose that ANA-12, antagonist of BDNF/TrkB signaling, may be effective for the treatment of anxiety disorders and depression in humans.…”

Social defeat protocol and relevant biomarkers, implications for stress response physiology, drug abuse, mood disorders and individual stress vulnerability: a systematic review of the last decade

“…BDNF and/or mRNA expression mPFC, AMY, substantia nigra, VTA Fanous et al 76 Reduced social behavior BDNF VTA Fanous et al 77 Reduced saccharin intake Furay et al 66 Increased cocaine self-administration…”