Project Summary/AbstractAppetite suppressing agents secreted from the gut such as cholecystokinin (CCK) play a critical role inregulating 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 CCKregulates appetite is not fully understood. Our long-term goal is to understand the neural mechanisms thatregulate 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 bythe expression of protein kinase C delta (PKC-) that are necessary for the effect of CCK on appetitesuppression. We demonstrated that CEA PKC- neurons suppress feeding through inhibitory synapticconnections with CEA PKC- negative neurons. However the identity of CEA PKC- negative neurons and theirdownstream targets for CCK-induced anorexia are unknown. The objective of this application is to determine theneural circuits in the central brain areas that are downstream of CEA involved in regulating CCK-elicited feedingsuppression. The central hypothesis is that the intersectional brain regions i.e. disynaptically disinhibited byCEA PKC- 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 appetitecontrol will advance our understanding of the neural mechanisms of CCK-induced anorexia and feeding controland suggest novel strategies for developing effective therapies to treat obesity and eating disorders. Guided bystrong preliminary data the hypothesis will be tested by pursuing three Specific Aims: (1) Establish functionalcircuitry connections from CEA PKC- neurons to the downstream targets. (2) Determine the role of the neuronsdownstream of CEA PKC- negative neurons in CCK-induced feeding suppression. We will test the workinghypothesis that feeding is regulated by the neurons that are downstream of CEA PKC- negative neurons andactivated by CCK. (3) Determine the specific neural pathways through which CEA PKC- negative neuronsregulate the effect of CCK on feeding suppression. We will test the working hypothesis that neural circuits projectfrom CEA PKC- 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 markerlabeling of neurons combined with a well-established appetite suppression agent to map the central brain neuralcircuits 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 brainregions and determine their role in the neural axis of appetite control. Such knowledge has the potential to informthe development of novel therapies that include specific neural targets to treat obesity and eating disorders.