# Diet, Insulin, Dopamine, and Reward

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2022 · $600,844

## Abstract

Project Summary
Dopamine (DA) is an established neuromodulator in brain reward pathways. It is increasingly recognized that
regulatory factors acting within the striatum sculpt local DA release, complementing the role of midbrain DA
neuron activity in supplying DA to target regions. We have reported that glucose-induced increases in levels of
the metabolic hormone insulin acts as a reward signal in the nucleus accumbens (NAc). Using ex vivo striatal
slices, we discovered that insulin enhances DA release in the NAc and dorsal striatum, and that insulin
responsiveness is lost in rodents that are obese from a high-fat high-sugar (HF-HS) diet. Our companion
behavioral studies show that insulin action in the NAc is necessary for flavor-nutrient learning with glucose-
containing solutions, and for the escalation of glucose intake seen during training. Although understanding of
this reward pathway is far from complete, we have established the pivotal role of a striatal microcircuit involving
DA axons and striatal cholinergic interneurons (ChIs), both of which express insulin receptors (InsRs). An
abundant literature indicates that acetylcholine (ACh) from ChIs promotes DA release via β2-subunit containing
nicotinic ACh receptors (β2-nAChRs) on DA axons. We showed previously that insulin acting at InsRs increases
ChI excitability, and that the DA-boosting effect of insulin is prevented by β2-nAChR-selective antagonism, and
is absent in mice that lack striatal ACh synthesis (ChAT KO mice). However, key elements required to understand
and harness this pathway are missing, including: 1) cellular mechanisms by which insulin increases ChI activity;
2) specific components of flavor-nutrient learning influenced by insulin and whether they are blocked by β2-
nAChR antagonists and impaired by a HF-HS diet; and 3) patterns of insulin-dependent synaptic plasticity in
NAc medium spiny output neurons (MSNs) that underlie flavor-nutrient learning. These missing elements will be
addressed in three specific aims that capitalize on the complementary expertise of the PIs. Overall, our previous
and pilot data show that NAc insulin signaling is necessary for flavor-nutrient learning, which guides food choice
and consumption based on predicted nutritive yield. This insulin-dependent reward learning is impaired in
subjects with InsR subsensitivity induced by HF-HS feeding, leading to maladaptive consumption. By identifying
cellular mechanisms and pathway-specific plasticity that drive nutritive learning, this project will not only answer
key questions about NAc insulin, but also indicate targets that might bypass subsensitive NAc InsRs and restore
healthy eating.

## Key facts

- **NIH application ID:** 10440445
- **Project number:** 5R01DA050165-03
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Kenneth D Carr
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $600,844
- **Award type:** 5
- **Project period:** 2020-08-15 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10440445

## Citation

> US National Institutes of Health, RePORTER application 10440445, Diet, Insulin, Dopamine, and Reward (5R01DA050165-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10440445. Licensed CC0.

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