Hippocampal and Hypothalamic CRH Neurons in Mood Related Behaviors

Abstract

Stressful experiences lead to important changes in physiology and behavior, including the release of corticosteroid stress hormones and engagement of behavioral states like vigilance. While normally important for survival, these aspects of the stress response can cause detrimental effects if they are dysregulated and become exaggerated or blunted. It is important to understand how this system is engaged by stressful stimuli and how the magnitude of the stress response is tuned to fit the circumstances that triggered it. 

The ventral hippocampus (vHPC) has long been described as an inhibitory regulator of the corticosteroid stress response, part of a system that controls the size of stress responses. Downstream, the hypothalamic CRH-expressing neurons are known to be gatekeepers 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 to 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 then introduce more recent findings that imply this pathway could also be involved in non-neuroendocrine stress responses through neural 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 PVN^CRH 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 PVN^CRH cells and their responses to stressful stimuli. I establish the first in vivo recordings of PVN^CRH cells during vHPC chemogenetic perturbation. By inhibiting vHPC activity during the stressful experiences from Chapter 3, I find that vHPC selectively modulates activity of PVN^CRH cells during a subset of behavioral responses to immediate, uncontrollable threat and ambiguous, self-controlled threat.  

In Chapter 5, I integrate these experimental findings with knowledge in the field about the roles of vHPC and PVN^CRH cells and the regions’ contributions to engaging and controlling the stress response as a whole.