# The role of the lateral hypothalamus in the balance of learning and behavior towards relevant stimuli

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2022 · $412,383

## Abstract

PROJECT SUMMARY
Relapse is a major hurdle for treating substance use disorder (SUD). Relapse results in part from drug-paired
cues exerting strong control over drug-seeking behavior. Indeed, the reactivity to drug-paired cues is predictive
of subsequent likelihood of relapse, and this vulnerability does not go away with time; the effects of drug-paired
cues over behavior increases progressively with time since drug exposure. Importantly, this is not specific to
drug-paired cues. Behavioral and physiological responses to reward-paired cues is also related to likelihood of
relapse, and is even correlated with a propensity to develop SUDs in rodent models. This points to an underlying
change in learning and behavior to reward-paired cues, which may be exacerbated by drug exposure, to make
individuals with SUDs particularly vulnerable to the effect of drug-paired cues over behavior.
We have recently discovered that GABAergic neurons in the lateral hypothalamus (LHGABA) neurons are
important for learning about reward-paired cues. What’s more is that this region appears to actively oppose
learning about non-reward related information. This suggests that LHGABA neurons bias learning towards cues
that are directly related to rewards (proximal cues) and away from information that is not directly related to
rewards (distal cues). Under normal circumstances this is good. We should pay more attention to information
that is directly relevant to what we need right now. However, prior research has shown that drug exposure
strengthens function in LH circuits. It is easy to see how this could produce a vulnerability to reward-paired cues
seen in SUDs. Increases in LH function seen following drug exposure could potentiate learning and behavior
directed to proximal cues (e.g. drug-paired cues), even while trying to remain abstinent, hijacking the adaptive
function of LH to focus on cues that help predict rewards that likely promote survival under normal circumstances.
We will test a novel reinforcement-learning theory of LH function, and how this function might be strengthened
by drug exposure to produce a vulnerability to reward-paired cues. We have developed an innovative task taken
from the cognitive neuroscience literature based on human participants. In tandem with optogenetics and fiber
photometry of a genetically-encoded calcium sensor, this will allow us to isolate behavior and neural activity
during proximal or distal predictors in the same animal. We will also uncover the nature of learning about proximal
cues supported by LH function. Our preliminary data shows this involves a sensory-specific representation of
reward, which allows LH to influence behavior in flexible and specific ways. Finally, we have found that
methamphetamine self-administration enhances behavioral control by proximal cues in a manner that requires
a specific reward representation. We will record calcium activity in LHGABA neurons during learning after exposure
to drugs to test if th...

## Key facts

- **NIH application ID:** 10522247
- **Project number:** 1R01DA054967-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Melissa Sharpe
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $412,383
- **Award type:** 1
- **Project period:** 2022-09-30 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10522247

## Citation

> US National Institutes of Health, RePORTER application 10522247, The role of the lateral hypothalamus in the balance of learning and behavior towards relevant stimuli (1R01DA054967-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10522247. Licensed CC0.

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