Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Science. 2011 Jul 29;333(6042):637-42. doi: 10.1126/science.1205295.
Physiological homeostasis is essential for organism survival. Highly responsive neuronal networks are involved, but their constituent neurons are just beginning to be resolved. To query brain serotonergic neurons in homeostasis, we used a neuronal silencing tool, mouse RC::FPDi (based on the synthetic G protein-coupled receptor Di), designed for cell type-specific, ligand-inducible, and reversible suppression of action potential firing. In mice harboring Di-expressing serotonergic neurons, administration of the ligand clozapine-N-oxide (CNO) by systemic injection attenuated the chemoreflex that normally increases respiration in response to tissue carbon dioxide (CO(2)) elevation and acidosis. At the cellular level, CNO suppressed firing rate increases evoked by CO(2) acidosis. Body thermoregulation at room temperature was also disrupted after CNO triggering of Di; core temperatures plummeted, then recovered. This work establishes that serotonergic neurons regulate life-sustaining respiratory and thermoregulatory networks, and demonstrates a noninvasive tool for mapping neuron function.
生理内稳态对于生物体的生存至关重要。涉及高度响应的神经元网络，但它们的组成神经元才刚刚开始被解析。为了在体内稳态中查询脑 5-羟色胺能神经元，我们使用了一种神经元沉默工具，即小鼠 RC::FPDi（基于合成 G 蛋白偶联受体 Di），它专为细胞类型特异性、配体诱导和可恢复的动作电位发射抑制而设计。在表达 Di 的 5-羟色胺能神经元的小鼠中，通过系统注射给予配体氯氮平-N-氧化物（CNO）可减弱通常会增加呼吸的化学感受器反射，以响应组织二氧化碳（CO2）升高和酸中毒。在细胞水平上，CNO 抑制了由 CO2 酸中毒引起的放电率增加。在 Di 被 CNO 触发后，室温下的体温调节也被打乱；核心温度骤降，然后恢复。这项工作确立了 5-羟色胺能神经元调节维持生命的呼吸和体温调节网络，并展示了一种用于映射神经元功能的非侵入性工具。
