Physiology and Pharmacology of BRS3 (Bombesin Receptor Subtype-3)

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

Progress in FY2025 includes the following: We have identified preoptic area neurons expressing BRS3 (POA-BRS3) as a population whose activation increased body temperature; inversely, acute inhibition of these neurons reduced body temperature. POA-BRS3 neurons that project to either the paraventricular nucleus of the hypothalamus or the dorsomedial hypothalamus increased body temperature, heart rate, and blood pressure via the sympathetic nervous system. Long-term inactivation of POA-BRS3 neurons caused increased body temperature variability, overshooting both increases and decreases in body temperature set point, with RNA expression profiles suggesting multiple types of POA-BRS3 neurons. Thus, POA-BRS3 neuronal populations regulate body temperature and heart rate, contribute to cold defense, and fine-tune feedback control of body temperature. These findings advance understanding of homeothermy, a defining feature of mammalian biology. We have generated and are now characterizing Brs3-FlpO and Brs3-Dre recombinase driver mouse lines. These enable combinatorial approaches to identifying and determining the functions of smaller populations of neurons that are better defined. In a collaboration with Michael Krashes, we discovered that ARCAgRP neurons directly inhibit bombesin receptor subtype-3 (BRS3) neurons in the MPOA, a population that governs both parenting and satiety. Selective activation of this ARCAgRP to MPOABRS3 circuit shifted behaviors from parenting to food-seeking. Thus, hypothalamic networks are modulated by physiological states and work antagonistically during the prioritization of competing motivated behaviors.