Women are twice as likely as men to develop Post-Traumatic Stress Disorder (PTSD) after a trauma, but the neurobiological basis for this discrepancy is poorly understood. One hallmark symptom of PTSD is a re- experiencing of the trauma in safe situations, a ?generalization? phenomenon that can be studied using preclinical rodent models like Pavlovian fear conditioning. Because both women and female rodents exhibit a greater tendency to generalize fear in safe contexts, better insight into potential sex-dependent factors that disrupt aversive context processing could lead to the development of novel treatments for PTSD. Preliminary data from our lab points to a novel role for the endocannabinoid system in conferring a sex-specific susceptibility to contextual fear generalization. Specifically, we observe a TRPV1-mediated increase in contextual fear generalization in females, but not males. A deeper investigation into this provocative finding may open new avenues for therapeutic development for women with PTSD. But in order to identify key areas and mechanisms to target for manipulation, we must first conduct exploratory studies to help guide the direction of larger-scale interrogations. The work we propose here will first determine whether our behavioral effects are selectively mediated by either the dorsal or ventral hippocampus (Aim 1), and then examine potential sex differences in mechanisms of eCB- and fear conditioning-related synaptic plasticity (Aim 2). We will carry out these Aims using a combination of behavioral pharmacology, fluorescent microscopy, biochemistry, and high resolution neuronal structural analysis. Together, these experiments will identify potential mediators of our behavioral effects, opening up our model for more focused interrogation and providing insight into sex-specific mechanisms of fundamental learning and memory processes.

Public Health Relevance

Women are twice as likely as men to develop Post-Traumatic Stress Disorder, but the neurobiology underlying this discrepancy is poorly understood. The proposed work will investigate a novel role for the endocannabinoid system in conferring susceptibility to contextual fear generalization in females, providing insight into potential new therapeutic targets for women.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21MH122914-02
Application #
10091528
Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Winsky, Lois M
Project Start
2020-02-01
Project End
2021-12-31
Budget Start
2021-01-01
Budget End
2021-12-31
Support Year
2
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Northeastern University
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
001423631
City
Boston
State
MA
Country
United States
Zip Code