# Mechanisms of Stress-Enhanced Aversive Conditioning

> **NIH NIH R01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2022 · $652,048

## Abstract

ABSTRACT
Cognitive dysfunction, including the inappropriate generalization (i.e., overgeneralization) of negative episodic
memories, is a core diagnostic criterion of major depression, and is recognized as a key determinant of severe
affective symptoms. For this reason, we believe that studying the neurobiology of memory generalization could
have considerable translational impact for depression. We propose to identify the cellular and circuit
mechanisms subserving generalization of negative context (episodic-like) memories using a newly developed
paradigm of stress-induced generalization (SIG). Aim 1 will rely on most recent approaches that allow us to
visualize and manipulate neuronal populations coding either specific and general features of context
memories. Through these techniques, we expect to determine whether stress promotes or disrupts the
reactivation of these neuronal populations during memory retrieval. Aim 2 will utilize chemogenetic and
optogenetic approaches, alone or in combination with neuronal labeling, to determine whether excitatory
ventral tegmental area (VTA) to dorsal hippocampus (DH) projections, which signal negative valence,
contribute to SIG. Inhibition of these projections is expected to reduce generalization, especially in females.
Aim 3 will focus on the role of MS to DH projections, which we suspect play a more prominent role in SIG in
males than in females. In addition to the approaches used in Aim 2, we will determine the effects of stress and
cholinergic neuromodulation on hippocampal oscillations and acetylcholine release, and we will explore the
stress-mediated changes of global brain activity using manganese-enhanced magnetic resonance imaging.
Upon competition of this project, we expect to have identified the main cellular and circuit (mal)adaptations
induced by stress that result in lasting generalization of negative context memories. Approaches that prove
effective in reversing SIG could be the foundation for novel treatments of cognitive deficits associated with
depression and affective disorders.

## Key facts

- **NIH application ID:** 10378150
- **Project number:** 5R01MH078064-17
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Jelena Radulovic
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $652,048
- **Award type:** 5
- **Project period:** 2007-09-30 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10378150

## Citation

> US National Institutes of Health, RePORTER application 10378150, Mechanisms of Stress-Enhanced Aversive Conditioning (5R01MH078064-17). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10378150. Licensed CC0.

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