The Role of the Basolateral Amygdala Projections to the Bed Nucleus of the Stria Terminalis in Anxiety‐like Behaviors in Male and Female Rats

Abstract

Men and women display different symptomology in anxiety disorders, yet our understanding of the sex differences in the neurobiology related to these disorders is limited. The basolateral amygdala (BLA) is a critical component of the neurocircuitry involved in anxiety, is hyperactive in patients with anxiety disorders and displays a sexual dimorphism with respect to neural activity. Differences in BLA activity may be a contributing factor to sex differences in the pathophysiology of anxiety disorders. Prior studies have demonstrated that sex differences in BLA neuronal activity exist; however, it is not known whether specific subsets of BLA neurons exhibit this disparity. BLA outputs to the lateral bed nucleus stria terminalis (BSTL) play a critical role in the expression of prolonged cued fear and general anxiety‐like behavior with female rats expressing less general anxiety‐like behaviors compared to males. The purpose of this study was to determine if BLA‐BSTL neurons in female rats are less active than in males. We utilized in vivo single‐unit extracellular electrophysiological recordings to record anti‐dromically identified BLA‐BSTL neurons in anesthetized male and cycling female rats. We found that BLA‐BSTL neurons in females have lower firing frequencies compared to males, despite females having greater spontaneous BLA neuronal activity overall. We also examined whether prolonged cued fear conditioning, which is dependent, in part, on BLA‐BSTL connections, is less robust in female rats compared to males. Rats were conditioned to an 8 min tone, during which footshocks (0.3mA) were delivered at random. Four days later (when females were in the same estrous stage as training), rats were tested in a novel context and time spent freezing during the presentation of the tone was measured. No sex differences were observed during training, but proestrous females froze less during training compared to males and metestrous females. However, during extinction, females extinguished freezing behavior more quickly than males, and proestrous females froze less than metestrous females. To determine if our electrophysiological data suggesting decreased BLA‐BSTL activity in females leads to a decreased freezing behavior during prolonged cued fear, we utilized a chemogenic approach to selectively inhibit BLA‐BSTL neurons. We performed bilateral Cre‐dependent designer receptor exclusively activated by designer drug (DREADD) injections then assessed anxiety‐like behavior and freezing responses during prolonged cued fear. Preliminary results suggest that inhibition of BLA‐BSTL neurons during the open field task has opposite effects in male and female rats. Specifically, we found that BLA‐BSTL inhibition reduced latency to enter the center in males, but increased latency to enter center in females. Together this suggests that in addition to BLA‐BSTL neurons displaying sex differences in activity, these same neurons may also mediate different behaviors in male and female rats. These results may help explain the apparent disconnect between overall sex differences in BLA neuronal firing and its relation to particular anxiety behaviors.Support or Funding InformationR01MH100536This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.