Sex‐ and region‐specific consequences of chronic nicotine in the murine hippocampus during fear extinction

Abstract

In the United States 90% of people experience at least one event in their lifetime that meets the DMS‐5 criteria for a traumatic event, but only 8.3% of Americans develop Post‐Traumatic Stress Disorder (PTSD). While severity and frequency of trauma impact the development of PTSD, there is an increasing emphasis on biological factors explaining why only a subset present with PTSD. We know sex is a major risk factor for PTSD, with women being twice as likely to develop PTSD than men. Additionally, people suffering from PTSD are twice as likely to smoke daily than healthy controls. However, while nicotine dependence is positively correlated with PTSD symptoms in men, this is not true in women, suggesting sex divergence in the neurobiological response to trauma and the resulting increased susceptibility to nicotine use disorder. The hippocampus has a well‐defined regiospecific role in both contextual memory and affective responding, the dorsal hippocampus (DHIPP) and ventral hippocampus (VHIPP) respectively. This places the hippocampus as a nexus point for both memory and emotion, suggesting these subregions are potential targets for mechanistic evaluation of comorbid PTSD and nicotine dependence. In these studies, we chronically treated male and female 7 to 8‐week‐old mice with either saline or intermittent nicotine (18 mg/kg/day) via osmotic minipumps (Alzet 1002 model). On the twelfth day of treatment, the subjects were trained in a fear conditioning paradigm with two CS‐US pairings (CS 89 dB tone and US 0.35 mA shock), then underwent 6 contextual fear extinction sessions. Following behavioral testing, the DHIPP and VHIPP were collected and assessed for genomic, transcriptomic, and proteomic changes. Preliminary results from these experiments suggest that the behavioral sex differences observed likely relate to differences in transcriptional control mechanisms. Further examination of treatment by sex effects in extinction behavior and the genomic and functional alterations underpinning these effects are ongoing.