Uncovering the Brain Circuits that Govern the Behavioral and Neuroendocrine Acute Stress Responses

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The body employs various tactics to face and overcome acute or short-term stress. These processes include behavioral and accompanying fine-tuned neuroendocrine responses to help individuals adapt to stress. Consequently, in instances wherein these systems are not functioning correctly, physical and psychological disease states ensue. The neural circuitry that controls both the behavioral response, in the form of anxiety-like behavior, and the neuroendocrine response, activation of the hypothalamic-pituitary-adrenal (HPA) axis, to stress has yet to be understood entirely. Previous work showed that the ventral hippocampus (vHPC) can control anxiety-like behavior and HPA axis activity. Therefore, we hypothesized that a shared neural pathway from the vHPC may simultaneously control behavioral and neuroendocrine stress responses. One candidate for this shared pathway is the ventral subiculum (vSub), the primary output structure of the vHPC. In the present work, we used chemogenetic manipulation of neural activity to investigate the role of the vSub in anxiety-like behavior and HPA axis responses to acute stress in male and female mice. We hypothesized that vSub activation would decrease anxiety-like behavior and HPA axis reactivity. Instead, we found that chemogenetic activation of the vSub increased anxiety-like behavior, as measured by center exploration in a bright, novel open field (OF), and increased the HPA axis response to the OF. We next used chemogenetic activation to test the effect of the downstream projections from the vSub to the anterior bed nucleus of the stria terminalis (aBNST) in these stress responses. Interestingly, we found that chemogenetic activation of the vSub-aBNST projection decreased anxiety-like behavior, as measured as open area exploration in the elevated zero maze and increased the HPA axis response to the OF. Overall, these results show that vSub neurons control both behavioral and neuroendocrine stress responses. We identified a novel role for the vSub in activating the HPA axis via the aBNST. Additionally, the finding of differential modulation of anxiety-like behavior with vSub vs vSub-aBNST activation suggests that the vSub differentially controls anxiety-like behavior via downstream projections. Finally, in preparation for future experiments, we sought to establish a technique using Ca2+ imaging that may be employed to assess the relationship between vSub-aBNST neural activity levels and anxiety-like behavior. We successfully expressed a retrograde Ca2+ indicator in aBNST neurons. This development provides a basis for the future recording of dynamic cell activity in vSub-aBNST neurons in freely behaving mice during exposure to an acutely stressful environment such as the OF.

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