# A translational approach to understand hippocampal neural circuitry regulating impulsive aggression

> **NIH NIH K23** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2021 · $185,104

## Abstract

PROJECT SUMMARY/ABSTRACT
There are few treatments for persistent impulsive aggression in individuals with severe neuropsychiatric
disorders, and existing treatments are of limited efficacy yet confer the potential for significant side effects.
Aggression contributes to repeat institutionalization and significant costs to healthcare and criminal justice
systems. As a neuroscientist and board-certified psychiatrist, this mentored patient-oriented research career
development award (K23) will provide training to support Dr. Lewis's goal of becoming an independent
translational investigator focused on the development of novel therapeutic approaches informed by the neural
circuitry regulating impulsive aggression. To accomplish his career and research goals, Dr. Lewis will receive
training in translational neuroscience by acquiring new skills to manipulate neural circuitry in mice and humans,
identify effects on behaviors related to impulsive aggression, and rigorously analyze resulting data. Training
will be guided by a team of mentors and contributors who are leaders in the basic and translational science of
neural circuits underlying behavior relevant to neuropsychiatric disorders as well as in statistical analysis. The
research plan is supplemented by coursework at Yale in translational neuroscience and statistical modeling, as
well as participation in relevant seminars and national scientific meetings. The proposed experiments build
upon preliminary data in mouse models demonstrating that activation of α7 nicotinic receptors in the dentate
gyrus (DG) reduces aggressive behavior, while reduction of α7 receptors increases aggressive behavior.
Because α7 receptors are highly enriched on local inhibitory interneurons of the DG and their activation
enhances DG and hippocampal inhibition, the hypothesis will be tested that hippocampal excitatory-inhibitory
(E/I) balance governs the expression of aggressive behavior in mice and humans. In Aim 1, activity of
excitatory or inhibitory neurons in the mouse DG will be recorded using fiber photometry and manipulated
using optogenetics to determine how DG E/I balance influences aggression onset in real time during resident-
intruder tests. In Aim 2, this circuit mechanism will be translated to human subjects with schizophrenia using a
pharmacological probe. The α7 partial agonist GTS-21 will be orally administered to enhance hippocampal
inhibition, and an Emotional Go/NoGo Task used to determine effects on impulsive responding to negative and
neutral valence stimuli. This behavioral task is mediated by prefrontal-temporolimbic circuitry, including the
hippocampus, and performance correlates with a history of impulsive aggression in schizophrenia patients.
These focused experiments take an innovative translational approach in mice and humans to understand how
hippocampal activity influences behavioral measures related to impulsive aggression in neuropsychiatric
disorders. Training in contemporary techniques of t...

## Key facts

- **NIH application ID:** 10151475
- **Project number:** 5K23MH116339-05
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Alan Seth Lewis
- **Activity code:** K23 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $185,104
- **Award type:** 5
- **Project period:** 2018-09-15 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10151475

## Citation

> US National Institutes of Health, RePORTER application 10151475, A translational approach to understand hippocampal neural circuitry regulating impulsive aggression (5K23MH116339-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10151475. Licensed CC0.

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