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Social Isolation and Metabolic Homeostasis: Investigating the Role of Oxytocin in Modulating Hypothalamic Glucose Sensing

Award Number: K00MH147882
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/08/2024
PERIOD OF PERFORMANCE END DATE: 06/30/2030

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Social Isolation and Metabolic Homeostasis: Investigating the Role of Oxytocin in Modulating Hypothalamic Glucose Sensing - PROJECT SUMMARY/ABSTRACT Perceived loneliness is an independent risk factor for both diabetes and dementia. Older adult populations are a high-risk group for the metabolic and cognitive consequences of social isolation due to frailty, loss of mobility and lack of affordable transportation. However, the neural mechanism underlying the relationship between social connection, glucose homeostasis, and cognitive health is poorly understood. To address this gap, my F99/K00 proposal builds on preclinical and clinical evidence demonstrating that social isolation negatively impacts glucose homeostasis. Glucose regulation is critical in the progression of both diabetes and dementia. Oxytocin is a neurohormone which modulates social behavior and energy balance. The oxytocin receptor (OTR) is highly expressed in the ventromedial hypothalamus (VMH), a brain area critical to glucose homeostasis. VMH glucose sensing neurons respond to fluctuations in extracellular glucose to regulate peripheral glucose homeostasis. However, the role of oxytocin in modulating VMH glucose sensing and the extent to which social isolation disrupts VMH glucose sensing has never been investigated. Our preliminary data demonstrate that:1) single-housed mice are hyperglycemic compared to co-housed mice; 2) VMH OTR neurons are inhibited by glucose; 3) VMH OTR neurons co-express neuronal nitric oxide synthase (nNOS), a marker for glucose-inhibited (GI) neurons. Together, this evidence supports our central hypothesis that oxytocin modulates VMH glucose sensing neurons, and that social isolation amplifies this modulation leading to a hyperglycemic phenotype. AIM 1 F99 Phase: I will investigate the mechanism by which social isolation induces hyperglycemia. I will perform whole-cell patch clamp electrophysiology in brain slices to determine whether oxytocin modulates GI neurons. I will use in vivo fiber photometry calcium recordings to determine if VMH-OTR activity increases during induced hypoglycemia. I will use CRISPR/Cas9 to selectively knock down the VMH OTR receptor in co-housed mice and determine glycemic differences compared to controls. These F99 experiments will contribute mechanistic insights regarding the role of oxytocin in social isolation-induced glucose dysregulation. My training plan will provide the conceptual and technical neuroscience foundation necessary for the K00 phase of my career development plan. AIM 2 K00 Phase: I will determine if social contexts affect cognitive aging via oxytocin control of glycemia AIM 2A will use an aging rodent model to determine how different patterns of endogenous oxytocin release affect glucose homeostasis and memory performance. These experiments will allow me to build on my F99 skillset and gain expertise in optogenetics, social behaviors, and cognitive testing assays. AIM 2B will use secondary analysis methods to model human longitudinal data and identify the specific social relationships that mediate the link between loneliness, diabetes, and cognitive function in diverse patient sub-populations


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 = $87,631 )
2026	2026	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Mental Health Research Grants	000	2	9/7/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$87,631
2026	2026	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Mental Health Research Grants	001	2	9/9/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $87,631

Grand Total All Awards = $87,631

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Social Isolation and Metabolic Homeostasis: Investigating the Role of Oxytocin in Modulating Hypothalamic Glucose Sensing

Award Number: K00MH147882

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/08/2024

PERIOD OF PERFORMANCE END DATE: 06/30/2030

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