Dissecting a central amygdala-parasubthalamic nucleus circuitry underlying appetite control

点击翻译按钮获取中文摘要

Project Summary/Abstract Appetite suppressing agents secreted from the gut, such as cholecystokinin (CCK), play a critical role in regulating feeding behavior. However, drugs based on CCK or its receptors failed to effectively treat obesity. These drugs lack a specific neural target because the central neural mechanism underlying how peripheral CCK regulates appetite is not fully understood. Our long-term goal is to understand the neural mechanisms that regulate appetite and body weight, and to develop corresponding therapies to treat obesity and eating disorders. Using novel genetic methods, we identified a specific population of central amygdala (CEA) neurons, marked by the expression of protein kinase C delta (PKC-δ), that are necessary for the effect of CCK on appetite suppression. We demonstrated that CEA PKC-δ neurons suppress feeding through inhibitory synaptic connections with CEA PKC-δ negative neurons. However, the identity of CEA PKC-δ negative neurons and their downstream targets for CCK-induced anorexia are unknown. The objective of this application is to determine the neural circuits in the central brain areas that are downstream of CEA involved in regulating CCK-elicited feeding suppression. The central hypothesis is that the intersectional brain regions, i.e. disynaptically disinhibited by CEA PKC-δ neurons and activated by CCK, mediate CCK-induced feeding suppression and appetite control. The rationale for the proposed research is that the identification of the central brain neural circuits for appetite control will advance our understanding of the neural mechanisms of CCK-induced anorexia and feeding control, and suggest novel strategies for developing effective therapies to treat obesity and eating disorders. Guided by strong preliminary data, the hypothesis will be tested by pursuing three Specific Aims: (1) Establish functional circuitry connections from CEA PKC-δ neurons to the downstream targets. (2) Determine the role of the neurons downstream of CEA PKC-δ negative neurons in CCK-induced feeding suppression. We will test the working hypothesis that feeding is regulated by the neurons that are downstream of CEA PKC-δ negative neurons and activated by CCK. (3) Determine the specific neural pathways through which CEA PKC-δ negative neurons regulate the effect of CCK on feeding suppression. We will test the working hypothesis that neural circuits project from CEA PKC-δ negative neurons to their downstream neurons to regulate CCK-elicited feeding suppression. The innovation of the proposed research includes the intersectional approach of using unique genetic marker labeling of neurons combined with a well-established appetite suppression agent to map the central brain neural circuits for feeding regulation, and will develop and apply new tools to dissect functional-specific neural circuits. Finally, the proposed research is significant because it will provide novel neural targets in the central brain regions and determine their role in the neural axis of appetite control. Such knowledge has the potential to inform the development of novel therapies that include specific neural targets to treat obesity and eating disorders.