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.

摘要