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

2019财年的进展包括： 为了研究BRS-3作用的特定细胞、部位、组织和递质，我们产生了一只有牙线的Brs3小鼠。在Cre驱动的重组过程中，通过选择性地丧失功能，小鼠可以确定特定细胞中Brs3的必要性。我们还产生了loxTB-Brs3小鼠，它们允许Cre选择性地重新激活Brs3，以确定特定细胞中Brs3的充分性。最后，我们培育了Brs3-Cre小鼠，其中Cre的表达模式与内源性Brs3相同。利用化学遗传学和光遗传学，Brs3-Cre小鼠被用来选择性地激活或抑制Brs3神经元的特定亚群。 2018年末，我们报道了急性激活下丘脑背内侧(DMHBrs3)表达Brs3的神经元，增加了体温(TB)、棕色脂肪组织温度、能量消耗、心率和血压，但对食物摄入量和体力活动没有影响。相反，激活下丘脑室旁核中的Brs3神经元对TB或能量消耗没有影响，但抑制了食物的摄入。DMHBrs3神经元的抑制减少了TB和能量消耗，表明在TB的调节中起着必要的作用。我们发现，视前区为DMHBrs3神经元提供了主要的输入(兴奋性和抑制性)。DMHBrs3投射到中缝苍白球的光遗传刺激增加了结核病。因此，DMHBrs3中缝苍白球神经元调节TB、能量消耗和心率，而下丘脑室旁核中的Brs3神经元调节食物摄入量。Brs3的表达是描述能量代谢调节回路的有用标记物。

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.