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

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Progress in FY2019 includes the following: In order to study the specific cells, sites, tissues, and transmitters by which BRS-3 acts, we have generated a floxed Brs3 mouse. The floxed mice allow determination of necessity of Brs3 in the particular cells by selective loss of function upon Cre-driven recombination. We have also generated loxTB-Brs3 mice, which allow selective re-activation of Brs3 by Cre to determine the sufficiency of Brs3 in the particular cells. Last, we have generated Brs3-Cre mice, in which Cre is expressed in the same pattern as endogenous Brs3. Brs3-Cre mice are being used to selectively activate or inhibit specific subsets of Brs3 neurons using chemogenetics and optogenetics. In late 2018, we reported that acute activation of Brs3-expressing neurons in the dorsomedial hypothalamus (DMHBrs3) increased body temperature (Tb), brown adipose tissue temperature, energy expenditure, heart rate, and blood pressure, with no effect on food intake or physical activity. Conversely, activation of Brs3 neurons in the paraventricular nucleus of the hypothalamus had no effect on Tb or energy expenditure, but suppressed food intake. Inhibition of DMHBrs3 neurons decreased Tb and energy expenditure, suggesting a necessary role in Tb regulation. We found that the preoptic area provides major input (excitatory and inhibitory) to DMHBrs3 neurons. Optogenetic stimulation of DMHBrs3 projections to the raphe pallidus increased Tb. Thus, DMHBrs3 raphe pallidus neurons regulate Tb, energy expenditure, and heart rate, and Brs3 neurons in the paraventricular nucleus of the hypothalamus regulate food intake. Brs3 expression is a useful marker for delineating energy metabolism regulatory circuitry.