# Elucidating the mechanisms underlying ketamine-induced protection against fear overgeneralization

> **NIH NIH F31** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $45,520

## Abstract

PROJECT SUMMARY / ABSTRACT
Though stress is necessary for the adaptive survival of a species, stress exposure can also elicit maladaptive
physiological and behavioral responses. Chronic stress in particular often leads to maladaptive responses, and
subsequent development of psychiatric disorders such as post-traumatic stress disorder (PTSD) and major
depressive disorder (MDD). A core symptom observed in these disorders is increased fear generalization, as
defined by the overgeneralization of fear from a conditioned, fear-inducing stimulus to novel, neutral stimuli.
We have previously discovered that a single injection of (R,S)-ketamine, a rapid-acting antidepressant,
protects mice against stress-induced depressive-like behavior (Brachman et al., 2016) and attenuates learned
fear following contextual fear conditioning (CFC) (McGowan et al., 2017). We have also found that, using a
contextual fear discrimination (CFD) protocol, (R,S)-ketamine decreases fear generalization (Mastrodonato et
al., 2018). The Denny laboratory has reported that the ventral hippocampus (vHPC), specifically ventral CA3
(vCA3), mediates (R,S)-ketamine's effects on attenuating learned fear in the CFC paradigm. However, how
exactly (R,S)-ketamine modulates the ensembles in vCA3 to decrease fear generalization is yet to be explored.
This research plan will lay the groundwork to uncover the effects of (R,S)-ketamine administration on fear
generalization throughout CFD using a combination of in vivo microdialysis and in vivo Ca2+ imaging in vCA3.
Both of these in vivo techniques will allow for chronic assessment of underlying changes throughout (R,S)-
ketamine administration and during behavioral expression (e.g., fear overgeneralization). In Aim 1, I will test
the hypothesis that neurochemical changes in glutamate, gamma-aminobutyric acid (GABA), and serotonin (5-
HT) in vCA3 potentially mediate (R,S)-ketamine's effects on fear generalization in male and female mice. By
using in vivo microdialysis, I will determine how neurotransmitters relevant to learning and memory are
contributing to fear generalization in both saline (control)-injected and (R,S)-ketamine-injected mice. I will test
the hypothesis that glutamate and 5-HT in vCA3 are persistently increased, while GABA is decreased, during
expression of fear in saline-treated mice, but that this persistent increase is mitigated by (R,S)-ketamine
treatment. In Aim 2, I will utilize nVoke minimicroscopes developed by Inscopix to perform in vivo Ca2+ imaging
and will test the hypothesis that (R,S)-ketamine prevents the heightened excitatory Ca2+ activity in vCA3
induced by stress, and thus, decreases fear generalization in male and female mice. For Aim 2A, I will
visualize Ca2+ transients in excitatory cells of vCA3. For Aim 2B, I will visualize Ca2+ transients in inhibitory
cells of vCA3. To date, no longitudinal studies utilizing in vivo Ca2+ imaging or in vivo microdialysis studies
have yet been performed for fear generalizatio...

## Key facts

- **NIH application ID:** 9911605
- **Project number:** 1F31MH122187-01
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Josephine McGowan
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 1
- **Project period:** 2020-09-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9911605

## Citation

> US National Institutes of Health, RePORTER application 9911605, Elucidating the mechanisms underlying ketamine-induced protection against fear overgeneralization (1F31MH122187-01). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/9911605. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*