The duality of tyrosine receptor kinase B in stress‐induced hypervigilant phenotypes

Post‐traumatic stress disorder (PTSD) is an anxiety disorder resulting from exposure to traumatic or life‐threatening events. In addition to anxiety and hypervigilant behavioral deficits (i.e. increased startle), PTSD is also an independent risk factor for the development of cardiovascular disease (CVD). While stress is recognized to promote the emergence of behavioral dysfunction and co‐morbid CVD, the mechanism by which this occurs is largely unknown. Stress has been shown to promote the activation of tyrosine receptor kinase (Trk) B in the amygdala, a major brain nucleus that promotes the onset of anxiety‐like and hypervigilant behaviors while simultaneously stimulating cardiac sympathetic activity. However it has yet to be determined whether TrkB activation of the CeA directly contributes to the behavioral and CV responses induced by stress. As such the aim of the current project was to determine whether social stress‐induced increases of CeA TrkB signaling is the initiating factor that leads to the subsequent development of a hypervigilant phenotype. In order to address this hypothesis, two distinct studies were conducted utilizing male Sprague Dawley rats in conjunction with the resident‐intruder paradigm of social defeat (30 min for 5 consecutive days). Study 1 was focused on determining whether direct CeA administration of the selective TrkB inhibitor ANA‐12 (25 ug in 40%DMSO and 0.9% Saline; administered on days 1, 3, and 5) was capable of inhibiting the emergence of a stress‐induced hypervigilant phenotype (enhanced startle, increased blood pressure and heart rate). Study 2 focused on investigating the activation of downstream signaling pathways (i.e. MAPK, Akt, or CamKII) to identify which TrkB‐initiated pathway is upregulated in susceptible individuals and determined whether ANA‐12 (25 ug; administered on days 1, 3 and 5 of stress) blocks the stress‐induced activation of these pathways. Based on preliminary data, direct CeA infusion of ANA‐12 30 minutes prior to the onset of social defeat stress on days 1, 3 and 5 was capable of inhibiting social defeat‐induced phosphorylation of the TrkB receptor. This inhibition of TrkB phosphorylation was functionally associated with reduced anxiety‐like behaviors in the elevated plus maze. Moreover, our preliminary data further suggests that TrkB phosphorylation may also be important for the emergence of defensive behaviors during defeat that underlie resilience. Based on these preliminary behavioral and molecular data, it is probable that ANA‐12 will further protect against the development of hypervigilant startle behaviors and may also protect against the emergence of stress‐induced CVD. Support or Funding Information These studies were supported by the National Institute of Mental Health (1R01MH113892‐01A1 to SKW), the Behavior Research Foundation NARSAD Young Investigator Grant (26809 to SKW), and the American Heart Association (17PRE33670106 to JEF). This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .