# Nucleus Accumbens RAGE and Diet-Induced Anhedonia

> **NIH NIH R21** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $466,125

## Abstract

Project Summary
Nearly half of the US adult population are type 2 diabetic (T2D) or pre-diabetic, and there is increasing evidence of
a link between T2D and depression, particularly the core clinical feature of anhedonia. A known mechanistic
overlap between T2D and major depression is increased inflammatory activity. In the case of T2D, a key role has
been established for advanced glycation end products (AGEs) and their receptor (RAGE) in pro-inflammatory gene
activation and insulin resistance. AGEs form endogenously, but also originate exogenously, with dietary sugar and
high fat foods being rich sources. We have previously observed that a high fat, high sugar diet decreases evoked
dopamine (DA) release in nucleus accumbens (NAc) and induces NAc insulin receptor (InsR) subsensitivity.
Although RAGE is expressed in brain, there has been very little investigation of diet effects on brain RAGE
expression, and almost nothing is known about brain RAGE effects on CNS function and behavior. New
preliminary data indicate that the high fat, high sugar diet, found previously to diminish DA and InsR function,
increases expression of RAGE and its key intracellular signaling effector molecule, DIAPH1 in NAc but not caudate
putamen. We propose to investigate whether diet-induced RAGE expression and signaling in the NAc induce
behavioral signs of anhedonia in rats. We predict that a high-fat, high-sugar diet elevates circulating levels of
AGEs, increases expression of RAGE and DIAPH1 in the NAc, and induces behavioral signs of anhedonia in
brain stimulation reward and conditioned place preference assays. To assess the causal connection between
brain RAGE and behavioral changes, a recently available small-molecule high-affinity RAGE inhibitor will be
continuously infused into the brain ventricular system. Our findings might identify a mechanistic basis for the
link between T2D and depression and, perhaps, diet-induced anhedonic effects that drive escalating
consumption of energy-dense palatable food aimed at achieving reward homeostasis.

## Key facts

- **NIH application ID:** 10054550
- **Project number:** 1R21MH121239-01A1
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Kenneth D Carr
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $466,125
- **Award type:** 1
- **Project period:** 2020-06-02 → 2023-06-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10054550

## Citation

> US National Institutes of Health, RePORTER application 10054550, Nucleus Accumbens RAGE and Diet-Induced Anhedonia (1R21MH121239-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10054550. Licensed CC0.

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