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

定义后区神经元细胞类型在食物摄入和恶心中的作用

• 批准号: 10582220
• 负责人: Paulette B. Goforth
• 金额: $ 68.82万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-10 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10582220
• 关键词: Affect; Agonist; Anorexia; Appetite Depressants; Aversive Stimulus; Behavioral; Behavioral Assay; Biological Assay; Blood - brain barrier anatomy; Body Weight decreased; Brain; Cells; Chronic Disease; Complex; Data; Desire for food; Development; Dorsal; Eating; Electrophysiology (science); GDF15 gene; GIPR gene; Genetic; Glutamates; Human; Image; Individual; Injections; Mammalian Genetics; Mediating; Medical; Methods; Modeling; Mus; Nausea; Nausea and Vomiting; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Obesity Epidemic; Pathologic; Pattern; Pharmaceutical Preparations; Physiological; Population; RAMP3; Rattus; Regulation; Reporter; Risk; Role; Satiation; Signal Transduction; Structure of area postrema; System; Therapeutic; amylin receptor; cell type; combat; design; designer receptors exclusively activated by designer drugs; detection of nutrient; feeding; gamma-Aminobutyric Acid; improved; islet amyloid polypeptide; neural; novel; obesity treatment; parabrachial nucleus; pharmacologic; rational design; receptor; response; single cell analysis; weight loss intervention

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.

抽象的 肥胖会导致 2 型糖尿病和其他慢性疾病的发生，而减肥可以降低这些疾病的风险，然而，目前的药物疗法仍然不足以对抗美国持续存在的肥胖流行病，部分原因是一些最有前途的肥胖药物会促进肥胖。为了设计改进的肥胖疗法，我们必须了解控制食物摄入和介导恶心的回路的作用机制和相互关系。单细胞分析表明，AP 包含两个主要的谷氨酸 (GLU) 神经元群：第一个 (GLU10) 包含表达 Calcr (CalcrAP) 的神经元。也包含 RAMP3（因此称为 AmyR），另一种（称为 GLU4）由多个亚群组成，其中一个由 Prlhr（PrlhrAP 细胞）标记，另一个由 Gfral（受体）标记。 GDF15；GfralAP 细胞）；两个亚群都表达 Glp1r。病理信号刺激 GLU4 细胞（包括 Glp1rAP、PrlhrAP 和 GfralAP 神经元）以促进厌恶结合 GIPR 激动剂减弱某些厌恶反应的能力，AP GABA 神经元的主要局部投射模式使我们认为营养反应性 GiprAP 细胞代表抑制 GLU4 细胞的“抗恶心”神经元，从而减弱其厌恶作用。我们还假设 GiprAP 神经元仅抑制特定的 GLU4 亚群，因此仅修改 AP 介导的厌恶信号的子集，而小鼠代表最常见的信号。与哺乳动物遗传系统相比，大鼠提供了更丰富的行为分析，并允许通过立体定位方法精确操纵 AP 神经元，因此，我们开发了一组针对 AP 神经元的转基因大鼠系。这些研究的结果将允许合理设计针对这些神经元中最有利成分的肥胖治疗药物。电路。