Effects of cumulative trauma on hippocampal activity and gene function

Accumulation of trauma throughout the lifespan is more strongly associated with the development of threat-related disorders and suicidality than exposure to a single trauma. As a large proportion of veterans are exposed to abuse and neglect in childhood in addition to deployment-related trauma in adulthood, it is critical to determine how cumulative trauma affects the brain in order to develop more effective treatments for veterans suffering from resultant psychiatric symptoms. In this proposal I aim to better characterize the activity and gene expression changes at the neural circuit level that result from cumulative trauma. Using a mouse model of physical trauma in both early life and adulthood, I will determine how activity and gene expression in the hippocampus changes with cumulative trauma and how gene expression and neurosteroid treatment can be shaped to ameliorate these changes. I have recently collected preliminary data in the hippocampus of mice exposed to cumulative trauma that shows increased hippocampal excitatory cell activity and abnormal upregulation and downregulation of the genes Slc6a15 and Tesc, respectively, both known to regulate neural excitability. In Aim 1, I will use in vivo local field potential recordings and in vivo single cell calcium imaging to determine how hippocampal neural activity in response to stress- inducing stimuli differs in mice exposed to cumulative trauma compared to those exposed to no trauma or a single trauma. In Aim 2, I will use circuit-specific CRISPR to decrease Slc6a15 and increase Tesc in the hippocampus of mice exposed to cumulative trauma to determine if gene manipulation can restore normal behavioral responses to stressful stimuli. I have also collected preliminary data that shows mice that are more susceptible to early life trauma show decreased allogrenanolone levels in the hippocampus. In Aim 3, I will determine if local hippocampal infusion of allopregnanolone, an FDA-approved neurosteroid known to fine tune inhibitory processes, can restore more normal circuit function and behavior after cumulative trauma. Overall, this proposal will both enhance my training in cutting edge electrophysiologic and gene manipulation techniques as well as to provide preliminary data for future Merit Reviews to support my career as an independent VA researcher studying the effects of cumulative trauma on neural circuits. Project Number: 1IK2BX006528-01A2 | Fiscal Year: 2026 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: Erin Hisey | Institution: VA BOSTON HEALTH CARE SYSTEM, BOSTON, MA | Activity Code: IK2 | Study Section: Special Emphasis Panel[ZRD1 MHBA-U (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11186499