Endocannabinoid Regulation of Homeostatic Feeding

为了维持生存的最佳生物条件，生物体内的能量平衡是一个严格调节的稳态过程，其中食物的剥夺或能量储存的损失将促进食物摄入，以确保存在适当的能量储存。这种进食的稳态调节在很大程度上依赖于下丘脑内的离散细胞群，这些细胞群对代谢激素和营养状态的变化做出反应，以促进寻食行为和摄取。也就是说，在这些下丘脑细胞网络中，能量状态的动态变化如何调节神经活动的机制还没有完全理解。内源性大麻素（eCB）系统是一个候选系统，它在连接这些过程的能力方面获得了越来越多的兴趣。eCB系统首先被确定为大麻的精神活性成分THC对大脑功能和行为产生影响的生物靶点。考虑到THC的食欲刺激作用，eCB信号本身已被证明是进食行为的重要调节剂也就不足为奇了。该领域的证据表明eCB信号在摄食调节中的重要性，但eCB信号影响稳态摄食的“如何”和“在何处”还没有很好地建立。** 这项发现资助将检验以下假设：在离散的下丘脑核团和细胞类型中，eCB信号传导的动态变化响应于营养状态的变化，是由外周代谢激素介导的，并驱动食物消耗的稳态变化。我的实验室采用的方法是创造性的和独特的，并利用了复杂的药理学，病毒和生化方法的组合。通过本研究计划中提出的目标，我们将确定下丘脑内的细胞类型和细胞核，eCB信号通过这些细胞核调节稳态摄食。更重要的是，我们还将确定外周激素信号（向大脑传达有关能量储备和营养状况的信息）改变eCB信号以控制摄食行为的具体机制。该研究计划中采用的方法的多样性是培养高素质人才的理想途径，从本科到博士后。重要的是，这项工作将填补我们对摄食行为神经生物学理解的知识空白，并有助于巩固我们对eCB信号传导如何有助于摄食稳态控制的理解。

To maintain optimal biological conditions for survival, energy balance within an organism is a tightly regulated homeostatic process where deprivation of food, or loss of energy stores, will promote food intake to ensure that appropriate energy reservoirs are present. This homeostatic regulation of feeding is heavily dependent upon discrete cell populations within the hypothalamus that respond to changes in metabolic hormones and nutritional status to promote food-seeking behaviour and ingestion. That being said, the mechanisms subserving how dynamic changes in energy status modulate neural activity within these hypothalamic cell networks are not entirely understood. One candidate system that has gained increasing interest with respect to its ability to link these processes is the endocannabinoid (eCB) system. The eCB system was first identified as the biological target through which THC, the psychoactive constituent of cannabis, exerted its effects on brain function and behaviour. Given the appetite stimulating effects of THC, it is not surprising that eCB signaling itself has proven to be an important regulator of feeding behaviour. Converging evidence in the field demonstrates the importance of eCB signaling in the regulation of feeding, but the "how" and the "where" by which eCB signaling influences homeostatic feeding is not well established. ******This Discovery grant will test the hypothesis that dynamic changes in eCB signaling, within discrete hypothalamic nuclei and cell types, in response to changes in nutritional status are mediated by peripheral metabolic hormones and drive homeostatic shifts in food consumption.******The approach taken by my lab is creative and unique, and utilizes a combination of sophisticated pharmacological, viral and biochemical approaches. Through the objectives proposed in this grant we will determine the cell types and nuclei within the hypothalamus through which eCB signaling modulates homeostatic feeding. More so, we will also determine the specific mechanism by which peripheral hormonal signals, which convey information regarding energy reserves and nutritional status to the brain, alter eCB signaling to govern ingestive behaviour. The diversity of the methodologies employed within this research program functions as an ideal avenue for the training of highly qualified personnel, from undergraduate to postdoctoral. Importantly, this work will fill knowledge gaps in our understanding of the neurobiology of feeding behaviour and help consolidate our understanding of how eCB signaling contributes to the homeostatic control of feeding.