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Dissecting a central amygdala-parasubthalamic nucleus circuitry underlying appetite control

Award Number: R01DK124501
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Dissecting a central amygdala-parasubthalamic nucleus circuitry underlying appetite control - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $337,554 )
2025	2025	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	2/21/2025	NON-COMPETING CONTINUATION	$337,554
														Subtotal = $337,554

Issue Date FY: 2024 ( Subtotal = $360,677 )
2024	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	5/20/2024	NON-COMPETING CONTINUATION	$22,543
2024	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	2/27/2024	NON-COMPETING CONTINUATION	$338,134
														Subtotal = $360,677

Issue Date FY: 2023 ( Subtotal = $376,301 )
2023	2023	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	2/15/2023	NON-COMPETING CONTINUATION	$376,301
														Subtotal = $376,301

Issue Date FY: 2022 ( Subtotal = $376,852 )
2022	2022	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	4/6/2022	NON-COMPETING CONTINUATION	$37,685
2022	2022	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/23/2022	NON-COMPETING CONTINUATION	$339,167
														Subtotal = $376,852

Issue Date FY: 2021 ( Subtotal = $377,363 )
2021	2021	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/23/2021	NEW	$377,363
														Subtotal = $377,363

Grand Total All Awards = $1,828,747

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Dissecting a central amygdala-parasubthalamic nucleus circuitry underlying appetite control

Award Number: R01DK124501

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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