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

二零一九财年的进展包括以下各项： 为了研究BRS-3作用的特异性细胞、位点、组织和递质，我们产生了一种floxed Brs 3小鼠。floxed小鼠允许通过Cre驱动重组后选择性丧失功能来确定特定细胞中Brs 3的必要性。我们还产生了loxTB-Brs 3小鼠，其允许Cre选择性地再激活Brs 3以确定特定细胞中Brs 3的充足性。最后，我们产生了Brs 3-Cre小鼠，其中Cre以与内源性Brs 3相同的模式表达。Brs 3-Cre小鼠被用于使用化学遗传学和光遗传学选择性地激活或抑制Brs 3神经元的特定子集。 在2018年底，我们报告了下丘脑背内侧（DMHBrs 3）中Brs 3表达神经元的急性激活增加了体温（Tb），棕色脂肪组织温度，能量消耗，心率和血压，对食物摄入或身体活动没有影响。相反，激活下丘脑室旁核中的Brs 3神经元对Tb或能量消耗没有影响，但抑制了食物摄入。抑制DMHBrs 3神经元减少Tb和能量消耗，这表明Tb调节的必要作用。我们发现，视前区提供了主要的输入（兴奋性和抑制性）DMHBrs 3神经元。光遗传刺激DMHBrs 3投射到中缝苍白肌增加Tb。因此，DMHBrs 3中缝苍白神经元调节Tb，能量消耗和心率，下丘脑室旁核中的Brs 3神经元调节食物摄入。Brs 3表达是描述能量代谢调节回路的有用标记。

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.