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Defining the neural basis for persistent obesity

Award Number: K01DK134804
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/01/2023
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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Defining the neural basis for persistent obesity - Project Summary/Abstract. Despite the prevalence of obesity in the United States, how obesity strengthens brain circuits that reinforce feeding is not known. This K01 proposal will identify specific neural circuits and subcircuit mechanisms that enhance feeding and are co-opted in obesity. While prior research has focused on obesity-linked adaptations in brain regions that drive homeostatic feeding, adaptations in brain regions involved in hedonic, motivated feeding may be dysregulated in obesity and contribute to ongoing food seeking and weight gain. For instance, the nucleus accumbens (NAc) is a brain region that regulates feeding and reward, and human and rodent literature have revealed alterations in NAc activity in obesity, along with disrupted NAc synaptic plasticity mechanisms. Preliminary data in this proposal demonstrates that NAc activity was selectively increased in a subpopulation of neurons known to invigorate reward, D1-receptor expressing neurons (D1SPNs), in obese mice during food seeking. Further, inhibiting NAc D1SPNs output decreased food seeking and prevented diet-induced weight gain. Enhanced D1SPN activity was driven by increased intrinsic excitability and pre-synaptic glutamatergic drive. Together these data suggest a model in which enhanced excitatory NAc inputs drive food seeking in obesity. Yet it remains unclear which input(s) is/are responsible for increased NAc activity in obese mice, whether all NAc D1SPNs are aberrantly activated or if select ensembles drive food seeking, and lastly, what synaptic mechanisms underlie these adaptations. The central hypothesis of this proposal is that enhanced excitatory input to NAc D1SPNs drives food seeking and obesity through attenuated synaptic depression of glutamatergic inputs. The experiments outlined here will use in vivo optogenetics, electrophysiology, genetic manipulations, novel operant behavioral paradigms, and a mouse model of diet- induced obesity to test this hypothesis in the following Aims: Aim 1 will determine which NAc input(s) drive food seeking and weight gain in obese mice. Aim 2 will investigate how select ensembles of NAc D1SPNs that are activated during food seeking drive enhanced feeding in obesity. Aim 3 will define a potential mechanism underlying changes in NAc plasticity in obese mice, and determine how such plasticity underlies food seeking and weight gain. Together, these experiments represent a major step forward towards understanding how obesity alters brain circuits, and why it so difficult for people to lose weight and keep it off.


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 = $151,492 )
2025	2025	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	7/14/2025	NON-COMPETING CONTINUATION	$151,492
														Subtotal = $151,492

Issue Date FY: 2024 ( Subtotal = $151,492 )
2024	2024	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	8/6/2024	NON-COMPETING CONTINUATION	$151,492
														Subtotal = $151,492

Issue Date FY: 2023 ( Subtotal = $152,992 )
2023	2023	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	8/18/2023	NEW	$152,992
														Subtotal = $152,992

Grand Total All Awards = $455,976

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Defining the neural basis for persistent obesity

Award Number: K01DK134804

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/01/2023

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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