UCSF

Stressful experiences lead to important changes in physiology and behavior, including the release of corticosteroid stress hormones and engagement of vigilance behaviors. While normally important for survival, these aspects of the stress response can exert detrimental effects if they are dysregulated and become exaggerated or blunted. The ventral hippocampus (vHPC) has long been depicted as an inhibitory regulator of the corticosteroid stress response, part of a negative feedback loop that controls the size of stress responses. Downstream, the hypothalamic CRH-expressing neurons are known to be the gatekeeper of the cortisol stress response, but recent studies also implicate a non-hormonal role for these cells in anxiety-related behavior. What is still unknown is how these two regions respond in the same animals to different stressors like approach-avoidance assays used in the study of anxiety-related behavior, and how the ventral hippocampus may be involved in regulating CRH activity in these behaviors. In Chapter 1, I introduce the hippocampal-hypothalamic circuitry that is implicated in emotion-related behaviors from the stress and anxiety fields. I discuss how this indirect projection has been modelled as a regulator of the neuroendocrine stress response, with respect to the corticosteroid response. I also introduce more recent findings that imply this pathway could also be involved in non-neuroendocrine stress responses through direct control of stress-induced behaviors. In Chapter 2, we review recent work on how vCA1 contributes to a network that associates external stimuli with internal motivational drive states to promote the selection of adaptive behavioral responses. This leads us to propose a model of vHPC function that emphasizes its role in the integration and transformation of internal and external cues to guide behavioral selection when faced with multiple potential outcomes. In Chapter 3, I present evidence that PVNCRH and vHPC cells respond independently to fear- and anxiety-related stimuli. Immediate, uncontrollable threats and freezing responses to these threats evoke activity in both regions. However, this is not true for exploratory behaviors in an approach-avoidance assay and self-controlled transitions between levels of potential threat; these events reliably evoke activity only in vHPC cells. In Chapter 4, I investigate the influence of the vHPC on PVNCRH cells and their responses to stressful stimuli. I establish the first in vivo recordings of PVNCRH cells during vHPC chemogenetic perturbation. By inhibiting vHPC activity during stressful experiences, I find that vHPC selectively modulates activity of PVNCRH cells during a subset of behavioral responses to immediate, uncontrollable threats and ambiguous, self-controlled threat. In Chapter 5, I integrate these experimental findings with knowledge in the field about the roles of vHPC and the PVNCRH cells and the regions’ contributions to engaging and controlling the stress response as a whole.