Sex-specific differences in adult cognition and neuroplasticity following repeated combinatory stress and TrkB receptor antagonism in adolescence

Abstract

Evidence supports brain-derived neurotrophic factor (BDNF)and its primary receptor tyrosine-related kinase B (TrkB)as targets in the treatment of mood disorders. This study characterized the impact of a 10-day combinatory stress paradigm (alternating days of restraint stress and forced swim)and administration of the selective TrkB antagonist ANA-12 (0.5 mg/kg, i.p.)during adolescence in male and female Wistar rats on adulthood behavioral and neurochemical responses. The social interaction/preference (SIT/SP), and Y maze conditioned place preference (YMCPP)and passive avoidance tests (YMPAT), initiated on PND 62, served to determine sex-related behavioral responses. Results support reduced sociability in females in the SIT/SP, but no impact of ANA-12 to regulate sociability or social memory. Blockade of TrkB during adolescence facilitated YMCPP-related reward behavior in both sexes, and reduced YMPAT fear conditioning in females. Following behavioral testing, rats were exposed to 5-min acute forced swim and brains collected 2 h post swim to determine effects of adolescent TrkB blockade and stress exposure on neurochemical regulators of stress and plasticity. Findings show elevated glucocorticoid receptor (GR-)and TrkB-immunoreactivity (ir)in the amygdalar central nucleus, and GR-ir in the hypothalamic paraventricular nucleus of females compared to males. In the hippocampal CA1, BDNF-ir was lower in females versus males, and GR-ir was elevated in stress versus non-stress males. Together, we demonstrate that inherent sex-specific differences, which may modulate impact of adolescence stress exposure and TrkB inhibition, differentially affect male and female adulthood behavior and biochemical response profiles, suggesting that these responses are in part conditioned by prior experience.