# Lateral Habenula and Memory Guided Response Flexibility

> **NIH NIH R21** · UNIVERSITY OF WASHINGTON · 2020 · $188,585

## Abstract

PROJECT SUMMARY
Since hippocampal (HPC) neural activity does not reliably and accurately predict future choices in context-
dependent tasks, experience-dependent and intentional behaviors must be enabled downstream of HPC,
perhaps where information about one’s internal state (e.g. level of motivation, stress, and emotion) has an
opportunity to bias cortical instructions for future behaviors. Indeed often one may ‘know’ what to do in a given
situation, yet the condition of one’s internal state often prevent even desired responses from occurring. The
present application tests the novel hypothesis that the lateral habenula (LHb) is pivotally important for
determining the expression of HPC/mPFC-dependent memory and decisions because it integrates
current internal state information with HPC/mPFC output to enable (or not) responses (60). This
hypothesis is not predicted by the more common but narrower view that LHb directs choice behavior because it
signals negative task conditions (11,23-26). AIM 1 will test whether interactions across the HPC-mPFC-
LHb circuit are necessary to perform accurately on a HPC and mPFC-dependent spatial delayed
alternation task that requires flexible decision making. Exp. 1: Since there are no known direct
connections between HPC and LHb, their interactions will be studied using an established (muscimol-induced)
disconnection paradigm. Preliminary data show that HPC-LHb interactions are necessary for accurate
performance on the delayed alternation task. Exp. 2: Direct connections between mPFC and LHb have been
described (4). Thus, optical inhibition of mPFC terminals in LHb will test the necessity of mPFC-LHb
interactions for accurate task performance. Aim 2 will characterize the nature of HPC-LHb theta coherence
during spatial delayed alternation task performance. Then we will determine the relative contributions
of memory (via mPFC input) and internal state information (via lateral hypothalamus, or LH, input) to
HPC-LHb coherence. Coordinated theta phase and power relationships across structures will be studied to
better understand the direction of information flow, and the nature of information shared during bouts of theta
coherence. Using the same animals, we will then determine the relative influence of memory system input (via
PFC) and internal state input (via LH) on HPC-LHb theta coherence using retroviral and optogenetic methods.
In summary, this R21 application seeks ‘proof of concept’ evidence for a novel hypothesis that could lead to
new therapeutic approaches to improve lateral habenula-mediated disorders of behavioral control.

## Key facts

- **NIH application ID:** 9872215
- **Project number:** 5R21MH119391-02
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** SHERI J. Y. MIZUMORI
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $188,585
- **Award type:** 5
- **Project period:** 2019-02-15 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9872215

## Citation

> US National Institutes of Health, RePORTER application 9872215, Lateral Habenula and Memory Guided Response Flexibility (5R21MH119391-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9872215. Licensed CC0.

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