EFFECTS OF TRAUMATIC STRESS EXPOSURE ON THE COMPONENTS OF THE REWARD SYSTEM: ALTERATIONS AT CELLULAR, STRUCTURAL, AND FUNCTIONAL LEVELS

Abstract

Traumatic stress exposure can lead to post-traumatic stress disorder (PTSD), which often co-occurs with substance use disorders (SUDs), including opioid use disorder (OUD). Prolonged opioid use significantly affects the brain's reward circuit, altering the volume of reward circuit nodes, their functional connectivity, and the expression and function of opioid receptors. Besides affecting fear learning and memory, PTSD also involves symptoms related to the reward system, such as emotional numbing and anhedonia. Understanding the reward system's role in PTSD symptomatology can help address PTSD and tackle co-occurring disorders like OUD. This dissertation investigates the effects of traumatic stress exposure on reward system components using a rodent model of PTSD (i.e., single prolonged stress, SPS). The focus is on the expression and dynamics of mu-opioid receptors (MORs), functional connectivity within the brain's reward system, and the volume of reward system nodes. Traumatic stress exposure caused sex-specific effects on MOR phosphorylation (p-MOR) within the anterior cingulate cortex (ACC) and CA2 subregion of the ventral hippocampus (vCA2). In female rats, SPS increased p-MOR levels within the ACC and vCA2, while in male rats, it decreased p-MOR levels in the ACC and had no significant effect on p-MOR levels within the vCA2. SPS did not significantly affect MOR expression in these regions. Neuroimaging data collected before and 7 to 10 days after SPS exposure showed a decrease in overall functional connectivity within the default mode network (DMN) in both sexes. SPS affected intrahippocampal functional connectivity, including dCA1-vCA1 and CA2-dDG, and connectivity between StriVM and thCM in both sexes. Additionally, SPS had sex-specific effects on functional connectivity between hippocampal subregions and thalamic nuclei: in male rats, it inhibited the increase in connectivity between vCA1-thMD, while in female rats, it increased connectivity between vCA1-PV and dDG-thMD. Structural MRI analysis revealed that traumatic stress exposure inhibited the expansion of the dDG in both sexes. This study identified brain regions within the reward system affected by traumatic stress in male and female rats and highlighted pathways and networks with sex-specific responses. Future research should determine the behavioral correlates of these changes, particularly in fear and addictive behaviors, to provide insights into the mechanisms of PTSD and PTSD-OUD comorbidity. This could lead to targeted treatments that consider sex-specific responses to traumatic stress, ultimately improving outcomes for individuals with PTSD or PTSD-OUD.