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Prelimbic to accumbal maladaptations in obesity and semaglutide-induced weight loss

Award Number: R03DK149009
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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Prelimbic to accumbal maladaptations in obesity and semaglutide-induced weight loss - Project summary Obesity is a leading cause of preventable death in the United States, yet there is no cure. The treatments we have to induce weight loss, either pharmacological, surgical, or lifestyle interventions, are not long-lasting, as most people who lose weight will reg-gain it within two years due to overeating. This suggests brain mechanisms that drive food seeking are strengthened in obesity and persist even beyond weight loss. This R03 proposal will test the function of a food-seeking neural circuit in the generation of diet induced obesity and uncover the extent to which this circuit underlies pharmacological-induced weight loss via GLP-1R agonists. The neurobiological underpinnings of enhanced food seeking in obesity have been challenging to test, in part due to restrictions posed by traditional rodent food motivation assays, which paradoxically report lower levels of food motivation in obese rodents. We developed a novel food seeking assay that uses instantaneous effort output to reveal that obese mice work harder for food than lean mice. Using this platform, we discovered that a pro-motivation population of neurons, Dopamine Receptor Type 1-Expressing Spiny Projection Neurons (D1SPNs) in the nucleus accumbens (NAc) exhibit enhanced activity during food seeking in obese mice, and are required for weight gain. Here we are leveraging this data to probe the course of such enhancements in excitatory activity in D1SPNs during food seeking, with the goal of revealing a neural target to induce weight loss. Preliminary data in this proposal demonstrates that inputs from prelimbic cortex (PL) to the NAc are overactive in obese mice, potentially due to deficient function of the endogenous mu opioid receptor (μOR). The role of NAc μOR in modulating palatable food seeking has been thoroughly demonstrated yet completely underexplored in obesity. The central hypothesis of this proposal is that enhanced activity in the PL-NAc pathway drives enhanced food seeking in obesity via deficient μOR function. The experiments here will use whole-cell patch clamp recordings, optogenetic stimulation, novel operant behavior, and synthetic GLP-1R agonism for brain circuit manipulation in a mouse-model of diet-induced obesity to test this hypothesis in two specific aims. Aim 1 will determine how diet-induced obesity enhances pre- and postsynaptic activity and μOR- driven plasticity mechanisms in the PL-NAc pathway as mice gain weight. Aim 2 will determine how synthetic satiety signaling induced by the GLP-1R agonist semaglutide (Ozempic) alters PL-NAc-D1- and D2SPN activity. By defining a neural circuit that enhances food seeking in obesity, this work will reveal a new brain focus for weight loss therapeutics, potentially via μOR targeting. This proposal will also uncover fundamental knowledge on PL-NAc mechanisms in food seeking in a healthy weight state. Ultimately, our findings may be a key node in crafting future obesity therapies, with a goal of inducing lasting weight loss and improving survival outcomes and enhanced quality of life for people with obesity.


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: 2026 ( Subtotal = $117,750 )
2026	2026	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/14/2026	NEW	$117,750
														Subtotal = $117,750

Grand Total All Awards = $117,750

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Prelimbic to accumbal maladaptations in obesity and semaglutide-induced weight loss

Award Number: R03DK149009

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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