Chronic dynamic behavioral changes and upregulation of glutamatergic signaling proteins following traumatic brain injury in females.

Abstract

Traumatic brain injury (TBI) is a leading cause of disability worldwide, with approximately 50 % of individuals with mild TBI experiencing persistent, debilitating symptoms. Clinical findings have demonstrated that females are more likely than males to develop chronic symptoms and tend to report greater symptom severity. Despite this, the pathophysiological mechanisms underlying these sex-specific chronic outcomes remain poorly understood. Using a clinically-relevant preclinical model of closed-head controlled impact in adult female rats, we examined affective-like behavior alterations up to twelve weeks post-injury. Injured animals exhibited early increases in risk-taking and disinhibition behaviors, followed by decreased social novelty preference and evidence of increased grooming behavior at eight weeks. Glutamatergic protein expression was measured in the frontal cortex and hippocampus at twelve weeks to assess glutamatergic alterations associated with chronic behavioral outcomes. TBI resulted in elevated expression of N-methyl-D-aspartate receptor subunits GluN1, GluN2A, and GluN2B, along with a decreased GluN2A:GluN2B ratio in the frontal cortex. Additionally, glutamate transporters GLT-1 and GLAST were upregulated in the hippocampus and frontal cortex, respectively. Together, these findings demonstrated that females exhibited dynamic behavioral changes accompanied by region-specific upregulation of glutamatergic signaling proteins. Further investigations are warranted to investigate circuit-level glutamatergic dysfunction and its potential role as a mechanistic driver of chronic TBI-related deficits in females.