Grant: Operating Grant

Vasopressin (VP, the antidiuretic hormone) is produced by a small group of neurons in the hypothalamus. The electrical activity of VP neurons (and thus its secretion into the blood) normally increases when body water is low (a condition termed hyperosmolality) to promote water conservation by the kidney. Hyperosmolality is detected by other neurons, termed osmoreceptors, that excite VP neurons via synaptic connections. The endocrine response mediated by this simple neuronal circuit is vital for body fluid balance and changes in its performance are linked to significant pathological conditions. For example, an exaggerated response of osmoreceptors contributes to hyponatremia and pulmonary congestion following a heart attack, and may be involved in the development of hypertension linked to excessive salt intake. Conversely, inadequate (i.e. weak) osmoreceptor control of VP neurons causes night time polyuria and enuresis (overfilling of the bladder and bed-wetting). More importantly, weak osmoreceptor control of VP neurons also contributes to the increased risk of mortality of elderly individuals during summertime heat waves, and in patients hospitalized with septic shock. Although defects in osmoreceptor signaling clearly contribute to disease, virtually nothing is known about the molecular and cellular mechanisms that mediate these functions in either normal or pathological conditions. In this project Dr. Bourque and his collaborators will use in-vitro models of rodent brain to investigate how neurons in the biological clock (the suprachiasmatic nucleus) interact with osmoreceptor neurons and VP neurons to increase in the electrical activity of VP neurons during late sleep. Bourque's team will also investigate how a peptide neurotransmitter called angiotensin II may increase in osmoreceptor signaling during dehydration. The findings of these studies could help define important new approaches for the treatment of conditions related to impaired osmoreceptor signaling.