1535-P: Physiological Role of Stress-Activated Neurons in the Paraventricular Hypothalamus

• Published in: Diabetes (New York, N.Y.) Vol. 72; no. Supplement_1; p. 1
• Main Authors: ESPINOZA, DIEGO G., ALVARSSON, ALEXANDRA, JIMENEZ GONZALEZ, MARIA, HAMPTON, ROLLIE F., LI, ROSEMARY Y., DEVARAKONDA, KAVYA, CHOUDHURY, JESLYN, WAXMAN, TALIA S., STANLEY, SARAH
• Format: Journal Article
• Language: English
• Published: New York American Diabetes Association 20.06.2023
• Subjects: Anxiety; Autonomic nervous system; Behavior; Corticosterone; Energy metabolism; Food intake; Glucose tolerance; Homeostasis; Hormones; Hypophagia; Hypothalamic-pituitary-adrenal axis; Hypothalamus; Immunohistochemistry; Metabolic response; Metabolism; Neural networks; Neurons; Neuropeptides; Oxytocin; Paraventricular nucleus; Stress response; Tyrosine 3-monooxygenase; Vasopressin
• DOI: 10.2337/db23-1535-P
• ISSN: 0012-1797

Psychological stimuli that disrupt homeostasis - stressors - lead to acute and chronic metabolic disturbance but the underlying neural circuits are incompletely understood. The paraventricular nucleus of the hypothalamus (PVH) plays a significant role in behavioral, autonomic and hormonal responses to stress. The PVH contains multiple cell types including neurons expressing tyrosine hydroxylase (TH). However, the contributions of PVHTH neurons to the acute stress response are largely unknown. We aim to determine the roles of PVHTH neurons in the metabolic and behavioral responses to acute stress. We first generated mice with tdTtomato expression in TH+ neurons (TH-tdTomato) by crossing validated TH-cre mice to mice with cre-dependent expression of tdTomato. Using immunohistochemistry for PVH neuropeptides linked to energy metabolism and stress in TH-Tdtomato mice, we quantified overlap of PVHTH neurons with CRH, oxytocin and vasopressin. We found small fractions of PVHTH neurons co-express CRH, oxytocin and vasopressin suggesting PVHTH neurons are a distinct population. Next, we assessed activation of PVHTH in response to acute stress by examining Fos expression in TH-tdTomato mice. Acute stress significantly increased the number of FOS+ PVHTH neurons. Finally, we examined whether chemogenetic activation of PVHTH neurons mimicked behavioral, hormonal and metabolic adaptations to stress using PVH injection of AAV with cre-dependent hM3DGq-mCherry or mCherry (control) in TH-cre mice. Chemogenetic activation of PVHTH neurons acutely suppressed dark-phase food intake and impaired glucose tolerance without effects on plasma corticosterone or anxiety-like behavior. These findings suggest acute stress may recruit PVHTH neurons to elicit hypophagia and impair glucose tolerance, independent of HPA axis activation and anxiety-like behavior. Future studies using chemogenetic inhibition will determine if PVHTH neurons are required for the full metabolic response to acute stress.