Defining roles for area postrema neuron cell types in food intake and nausea

摘要 肥胖会导致2型糖尿病和其他慢性疾病的发生，而减肥则会改善这些疾病的风险。然而，目前的医学疗法仍然不足以对抗正在进行的美国肥胖流行病-部分原因是一些最有前途的肥胖药物促进了厌恶反应（例如，恶心），这限制了它们的治疗效用。为了设计更好的肥胖治疗方法，我们必须了解控制食物摄入和调节恶心的回路的作用机制和相互关系。最后区（AP）感知营养物质和潜在的有害物质，并含有代表肥胖治疗重要靶点的受体。单细胞分析显示，AP包含两个主要的谷氨酸能（GLU）神经元群体：第一个（GLU 10）包含表达钙铬（CalcrAP）的神经元，也包含RAMP 3（因此AmyR）。另一个（称为GLU 4）由多个亚群组成，包括一个由Prlhr（PrlhrAP细胞）标记，另一个由Gfral（GDF 15的受体; GfralAP细胞）标记;两个亚群都表达Glp 1 r。GABA能AP神经元的单个群体含有Gipr表达（GiprAP）细胞。我们假设CalcrAP神经元对胰淀素和其他营养刺激信号做出反应，并促进非厌恶性饱腹感，而病理信号刺激GLU 4细胞（包括Glp 1 rAP，PrlhrAP和GfralAP神经元），以促进厌恶性厌食。连同GIPR激动剂钝化一些厌恶反应的能力，AP GABA神经元的主要局部投射模式使我们假设营养响应性GiprAP细胞代表抑制GLU 4细胞的“抗恶心”神经元，减弱其厌恶作用。我们还假设GiprAP神经元仅抑制特定的GLU 4亚群，从而仅修改AP介导的厌恶信号的子集。虽然小鼠代表了最常见的哺乳动物遗传系统，但大鼠提供了更丰富的行为测定，并允许通过立体定位方法精确操纵AP神经元。大鼠也更接近模拟人类对AmyR激动剂的反应。因此，我们开发了一组基因修饰的大鼠细胞系，以靶向表达关键药理学药物受体的AP神经元，使我们能够定义AP神经元不同子集的功能和作用机制。这些研究的结果将允许合理设计用于治疗肥胖症的药剂，其靶向这些回路的最有利的组分。

Abstract Obesity contributes to the development of type 2 diabetes and other chronic diseases, while weight loss ameliorates the risk for these maladies. Current medical therapies remain inadequate to combatting the ongoing US obesity epidemic, however- in part because some of the most promising obesity drugs promote aversive responses (e.g., nausea) that limit their therapeutic utility. To design improved obesity therapies, we must understand the mechanisms of action for and relationships among circuits that control food intake and that mediate nausea. The area postrema (AP) senses nutrients and potentially harmful substances and contains receptors that represent important targets for obesity therapy. Single-cell analysis reveals that the AP contains two major populations of glutamatergic (GLU) neurons: The first (GLU10) contains Calcr-expressing (CalcrAP) neurons that also contain RAMP3 (and thus AmyR). The other (termed GLU4) consists of multiple subpopulations, including one marked by Prlhr (PrlhrAP cells) and another marked by Gfral (the receptor for GDF15; GfralAP cells); both subpopulations express Glp1r. A single population of GABAergic AP neurons contains Gipr-expressing (GiprAP) cells. We hypothesize that CalcrAP neurons respond to amylin and other nutrient-stimulated signals and promote non-aversive satiation, while pathologic signals stimulate GLU4 cells (including Glp1rAP, PrlhrAP, and GfralAP neurons) to promote aversive anorexia. Together with the ability of GIPR agonists to blunt some aversive responses, the predominantly local projection pattern of AP GABA neurons leads us to hypothesize that nutrient-responsive GiprAP cells represent “anti-nausea” neurons that inhibit GLU4 cells, attenuating their aversive effects. We also postulate that GiprAP neurons inhibit only specific GLU4 subpopulations and thus modify only a subset of AP-mediated aversive signals. While the mouse represents the most common mammalian genetic system, rats provide richer behavioral assays and permit the precise manipulation of AP neurons by stereotaxic methods. Rats also more closely model the human response to AmyR agonists. Hence, we have developed a panel of genetically-modified rat lines to target AP neurons that express receptors for key pharmacologic agents, enabling us to define the functions and mechanisms of action for distinct subsets of AP neurons. The results of these studies will permit the rational design of agents for the therapy of obesity that target the most advantageous components of these circuits.