Functional and Physiological Role of Extra-Hypothalamic Corticotropin Releasing Hormone Neurons in the Nucleus of the Hippocampal Commissure in Regulation of Stress Response

Corticotropin releasing hormone (CRH) neurons located within the paraventricular nucleus (PVN) are known to be involved in regulation of stress responses. Recently, CRH neurons were identified above the PVN within the nucleus of the hippocampal commissure (NHpC) that located in the septum. We hypothesized that CRH neurons in the NHpC play a critical role in the stress response due to their rapid activation and could be a part of the traditional hypothalamo-pituitary-adrenal (HPA) axis. The dissertation addresses the role of 1) CRH expressing neurons in the NHpC compared with those within the PVN utilizing two different stressors, food deprivation (FD) and immobilization stress, 2) arginine vasotocin (AVT) neurons in the late phase of stress responses to sustain CRH neuron activities, 3) CRH and AVT receptors within the NHpC, PVN, and anterior pituitary (APit), 4) brain derived neurotrophic factor, BDNF, in the regulation of the stress response, particularly, interactions of CRH and AVT and their, major receptors, CRHR1 and V1aR, and 5) the glucocorticoid receptor (GR) and its role in regulating CRH neurons in the NHpC and PVN, and POMC transcripts within the APit. Results showed that CRH neurons in the NHpC are activated rapidly and help initiate the general response of both types of stressors investigated, namely, FD and immobilization. rapid activation of CRH neurons in the NHpC indicated that the NHpC contributes significantly in the initial upregulation of POMC transcripts and plasma CORT concertation increase; however, persistence of high CORT levels seemed to be attributed to both CRH and AVT activation in the PVN demonstrating that the two neuropeptides are working together to maintain a response to continued stress. Additionally, a delayed increase of AVT expression in the PVN is associated with upregulation of its major receptor, V1aR, showing a positive feedback indicating that AVT and V1aR are involved when a stressor persists. CRH and AVT receptors within the two structures, NHpC and PVN, are regulated differentially during the stress response. Specifically, CRH and its major receptor, CRHR1, are regulated negatively in the NHpC and positively within the PVN; however, CRHR2 has a positive feedback with its ligand in both neural structures. Importantly, BDNF appeared to play a critical role in the upregulation of CRH followed by AVT activation in the PVN as well as for the positive feedback relationship between CRH and CRHR1 and AVT and V1aR within the PVN. Additionally, the V1bR mRNA was detected and shown upregulated within the NHpC and PVN. Increased neuronal secretion during stress downregulated CRHR1 and V1aR gene expression in the APit resulting in an absence of stimulating POMC transcripts thereby reducing their effect on CORT release. In contrast, upregulation of the V1bR in the APit maintains a significant CORT release when stressors persist. Upregulation of GR within the brain functions to inhibit CRH neurons in the NHpC followed by those in the PVN in order to decrease peak plasma levels of CORT. Hence, CRH neurons in the NHpC function to assist in initiating the stress response and, therefore, play a significant role in the early phase of HPA axis activation. CRH and AVT in the PVN sustain the stress response as evidenced by plasma CORT levels. The GR functions to dampen peak levels of CORT thereby effecting a homeostatic response to persistent stressors