Melanocortin-4 receptor-expressing neurons in the nucleus accumbens and regulation of food preference

伏隔核中表达 Melanocortin-4 受体的神经元与食物偏好的调节

• 批准号: 409551513
• 负责人: Dr. Henning Fenselau, Ph.D.
• 金额: --
• 依托单位: Zentrum für Endokrinologie, Diabetologie und Präventivmedizin (ZEDP)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/409551513?language=en
• 关键词: Melanocortin; receptor; expressing; neurons; nucleus

The melanocortin system, working through melanocortin-4 receptors (MC4Rs), controls body weight homeostasis by regulating food intake. The MC4R-dependent control of homeostatic feeding is strongly supported by the development of hyperphagia and massive obesity in both mice and humans lacking MC4Rs. Strikingly, MC4R deficient individuals, in addition to being hyperphagic, exhibit a markedly increased preference for high fat food. Their preference for high sucrose food, in contrast, is strongly reduced. Thus, MC4Rs in addition to controlling homeostatic feeding critically influence the rewarding aspects of food. The brain site mediating this is unknown. MC4Rs are expressed on hypothalamic neurons, which regulate homeostatic feeding, and in extra-hypothalamic brain regions associated with reward-related behavior including the nucleus accumbens (NAc). This is of particular interest because the NAc has been implicated in regulating fat and sucrose consumption. However, it is unknown whether MC4R-expressing NAc (NAcMC4R) neurons are a control point for food preference. This is due to the fact that neuroscience tools to target NAcMC4R neurons were missing. In the current proposal, we will directly assess the role of NAcMC4R neurons using recently generated MC4R-t2a-Cre knock-in mice. Using these mice in combination with Cre-enabled viral technology, we will target NAcMC4R neurons to i) selectively monitor their activity in vivo, ii) stimulate and inhibit them during behavioral food preference assays, and iii) investigate their afferents and efferents. Collectively, these studies will determine the necessity and sufficiency of NAcMC4R neurons in controlling food preference and define the underlying neurocircuitry.

黑素皮质素系统通过黑素皮质素-4受体（MC4Rs）工作，通过调节食物摄入来控制体重稳态。在缺乏MC4Rs的小鼠和人类中，嗜食和大量肥胖的发生强烈支持mc4r依赖的稳态摄食控制。引人注目的是，缺乏MC4R的个体除了嗜食外，对高脂肪食物的偏好也明显增加。相比之下，他们对高蔗糖食物的偏好却大大减少了。因此，MC4Rs除了控制稳态喂养外，还对食物的奖励方面产生重要影响。大脑中起调节作用的部位尚不清楚。MC4Rs在调节稳态进食的下丘脑神经元和与奖励相关行为相关的下丘脑外脑区（包括伏隔核（NAc））表达。这是特别有趣的，因为NAc与调节脂肪和蔗糖的消耗有关。然而，目前尚不清楚表达mc4r的NAc （NAcMC4R）神经元是否是食物偏好的控制点。这是由于缺乏针对NAcMC4R神经元的神经科学工具。在目前的提案中，我们将使用最近生成的MC4R-t2a-Cre敲入小鼠直接评估NAcMC4R神经元的作用。将这些小鼠与cre激活的病毒技术相结合，我们将针对NAcMC4R神经元，i)选择性地监测它们在体内的活性，ii)在行为食物偏好测试中刺激和抑制它们，以及iii)研究它们的传入和传出。总的来说，这些研究将确定NAcMC4R神经元在控制食物偏好方面的必要性和充足性，并定义潜在的神经回路。