Activation of CRHR1 receptors regulates social and depressive-like behaviors and expression of BDNF and TrkB in mesocorticolimbic regions following global cerebral ischemia

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Abstract

Increased HPA axis activation and CRH release characterize the brain's response to global cerebral ischemia. Recently, CRH via activation of CRH type 1 receptors (CRHR1) has been shown to regulate Brain Derived Neurotrophic Factor (BDNF) secretion and emotional behavior. The current study investigates the impact of CRHR1 blockade on BDNF/TrkB signaling expression in the mesolimbic circuitry, and social and depressive-like behavior following global ischemia. Adult male Wistar rats were injected with Antalarmin (2 μg/μl) or a vehicle 30 min prior to 10 min global cerebral ischemia (4VO model) or sham occlusion. The Three Chamber Social Approach Test (SIT) assessed sociability and preference for social novelty, and the novelty suppressed feeding test (NSFT), forced swim test (FST), and sucrose preference test characterized anxiety and depression. Corticosterone levels and organ (thymus, seminal and adrenal glands) weights were determined as additional physiological indices of stress. Immunohistochemistry, Western blot and Rt-PCR were used to assess BDNF and TrkB receptor levels in subregions of the medial prefrontal cortex (mPFC), nucleus accumbens (NAc) and ventral tegmental area (VTA) 30 days post-ischemia. Our findings indicate reduced BDNF and TrkB protein and mRNA expression in the mPFC post-ischemia, while heightened levels were found in the NAc. Ischemia increased immobility in the FST and reduced sucrose preference and led to reduced latency to feed in the NSFT and heightened sociability and social novelty preference in the SIT. Antalarmin treatment normalized post-ischemic biochemical/behavioral changes. Our findings support lasting effects of CRHR1 activation on brain plasticity markers, likely playing a role in emotional impairments following cardio- or cerebro-vascular accidents.

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