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The organismal stress response is an integrated physiological and behavioral response to actual or perceived threat to homeostasis. The brain plays a central role in orchestrating these stress responses via many interacting circuits in the forebrain, hypothalamus, and brainstem. While stress responses are intrinsically adaptive reactions and have evolved to reestablish homeostasis, they can become dysregulated and contribute to numerous stress-related diseases. Consequently, it is imperative to understand the neural regulation of stress responses to gain new insight into potential circuit pathology in stress-related disorders. This dissertation investigated the role of the nucleus of solitary tract (NTS) of the brainstem in the regulation of stress responses. Stress activates the hypothalamo-pituitary-adrenal (HPA) axis, culminating in the synthesis and release of glucocorticoids by the adrenal cortex. The magnitude and duration of the HPA axis response are mediated in large part by the glucocorticoid receptors (GRs). Importantly, the NTS abundantly expresses GRs and is well positioned to modulate the HPA axis activation. Accordingly, studies presented in Chapter 2 were designed to elucidate the role of NTS GRs in the control of the stress adaptation and pathology. We found that rats with local inhibition of GRs signaling within the NTS, when subjected to either acute restraint stress (a psychogenic stress) or chronic variable stress (CVS) had more exaggerated HPA axis responses than controls, indicating that GRs signaling in the NTS is necessary for inhibiting the neuroendocrine response to stress. Furthermore, NTS GRs inhibition decreased open arm exploratory behavior in the elevated plus maze and increased immobility in the forced swim test. Together, these findings reveal that NTS GRs signaling is necessary for inhibiting both endocrine and behavioral responses to stress and suggest that the NTS is an important regulatory focus for the organismal response to stress.The NTS is also the primary locus of glucagon-like peptide-1 (GLP-1) production. GLP-1 is increasingly recognized for its excitatory role in the neural coordination of stress responses. Exogenous central infusion of GLP-1 activates the HPA axis, increases heart rate and blood pressure, and activates hypothalamic and brainstem neurons innervating sympathetic preganglionic neurons. Additionally, GLP-1 receptor (Glp1r) is highly expressed in the hypothalamic paraventricular nucleus (PVN), and GLP-1 immunoreactive fibers innervate hypophysiotrophic corticotropin-releasing hormone (CRH) neurons in the PVN, placing GLP-1 in prime position to integrate stress responses. Accordingly, studies presented in Chapter 3 of this thesis tested the necessity of the central GLP-1 signaling in the neural integration of stress reactivity. In agreement with our hypothesis, we found that Glp1r knockdown in neurons expressing single-minded 1 (Sim1) transcription factor decreased HPA axis responses to both acute and chronic stress and reduced anxiety-like behavior. Furthermore, Sim1 Glp1r knockdown attenuated stress-induced cardiovascular responses, demonstrating that GLP-1 signaling in the brain is required for autonomic regulation of the stress responses. Collectively, my dissertation work demonstrates that both NTS GRs and GLP-1 signaling are important elements of the neural circuit that mediates autonomic, endocrine, and behavioral stress responses. |
