Hypothalamic Pathways of Age Related Homeostatic Dysregulation

PROJECT SUMMARY This project is designed to determine the role of hypothalamic neurons in the progression of physiological decline with age. During summer heat waves, older adults are extremely vulnerable to hyperthermia and dehydration leading to higher risk of morbidity and mortality. Understanding the cellular mechanisms responsible for increased frailty with age is critical for improving heathspan in older adults. The goal of this proposal is to establish a novel role for supraoptic hypothalamic neurons in causing age-dependent physiological disturbances which disrupt neuroendocrine homeostasis. Guided by our recent finding that arginine-vasopressin (Avp) transcription in supraoptic hypothalamic neurons is dramatically increased in aged mice, the proposed experiments leverage state-of-the-art methods for monitoring and manipulating vasopressin neurons in mice with the goal to elucidate their role in thermoregulation and fluid balance. This proposal will also explore the role of brain inflammation in altering physiological homeostasis through dysregulation of vasopressin neuronal function. Finally, the therapeutic potential of gene therapies focusing on vasopressin neurons will be investigated in the context of behavioral and physiological frailty with age. The proposed studies will lay the groundwork for imputing a causal role of supraoptic vasopressin neurons in the onset of age-dependent frailty.