Aligning Circuit-Directed Rehabilitation with HPA Axis for Improved TBI Recovery

About This Grant

Project Summary/Abstract: Traumatic brain injury (TBI) affects over 2.87 million people annually, with nearly 50% reporting chronic psychological health conditions (PHCs), including sensory, cognitive, and sleep deficits, which often differ between men and women. The most common pathology associated with TBI is diffuse axonal injury (DAI), leading to chronic neurodegeneration and maladaptive circuit reorganization. PHCs are strongly linked to dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, which regulates corticosterone (CORT) in rats. Dysregulation of brain glucocorticoid receptors (GR) impairs HPA axis feedback, disrupting neuroplasticity and reducing the efficacy of rehabilitation (Rehab). While the connection between HPA axis dysregulation and neuroplasticity is known, the specific impact of TBI-induced HPA axis dysregulation on neuroplasticity, Rehab efficacy, and sex differences remains poorly understood. Published and preliminary data from our lab indicate that early circuit-directed Rehab reduces the severity of late-onset sensory deficits and addresses chronic HPA axis dysregulation. The goal of this proposal is to evaluate how TBI-induced HPA axis dysregulation affects neuroplasticity and the long-term efficacy of Rehab initiated after sensory deficits are established, focusing on sex differences. We hypothesize that TBI causes sex-dependent HPA axis fluctuations, resulting in temporal shifts in circulating CORT and brain GR levels, which influence neuroplasticity and Rehab efficacy. We will test this hypothesis in the following proposed aims using a midline fluid percussion injury (mFPI) model in male and female Sprague-Dawley rats. Aim 1: Establish a comprehensive profile of sex-dependent HPA axis dysregulation and neuroplasticity between 1- and 3-months post-injury. Aim 2: Quantify the short-term efficacy of circuit-directed Rehab administered during HPA axis fluctuations on the upregulation of BDNF in sensory circuits. Aim 3: Assess the long-term efficacy of Rehab, administered during HPA axis fluctuations, on the severity of sensory sensitivity and associated circuit structure and function. These experiments will elucidate how TBI-induced HPA axis fluctuations impact neuroplasticity and Rehab outcomes. By examining sex differences in these processes, this study aligns with NIH’s focus on women’s health research (NOT-OD-24-079) and will guide the development of more effective, sex-specific rehabilitation strategies for TBI patients. Impact: The findings have broad implications for improving patient outcomes and quality of life, providing a foundation for future studies aimed at optimizing Rehab for TBI-related conditions.