# Neural activity and circuitry-mediated hippocampal stress responses

> **NIH NIH K99** · NORTHWESTERN UNIVERSITY · 2022 · $98,659

## Abstract

Project Summary/Abstract
Major depressive disorder (MDD) is a leading cause of disability and lost productivity, but we do not know its
underlying causes, nor do we have adequate treatments. Development of more effective therapies will require
better understanding of the cellular and molecular mechanisms of antidepressants (AD). Newly generated
(immature) neurons within the dentate gyrus (DG) have been linked to AD action in addition to their association
with hippocampus-dependent cognition, pattern separation, social memory, and stress-induced anxiety.
Increased numbers of newborn DG neurons are associated with improved hippocampal function, while
decreased numbers are associated with impaired hippocampal function. Moreover, my recent publication showed
that suppressing excitability of newborn neurons without altering neuronal number leads to MDD-related
phenotypes and abolishes AD effects. Conversely, enhancing activity of immature neurons without altering
neurogenesis is sufficient to alleviate effects of unpredictable chronic mild stress (uCMS), a well-validated, widely
used model of depression. Since newborn neurons form synapses more readily, are more excitable, and have
greater synaptic plasticity, understanding the complex effects of neurogenesis on behavior requires knowledge
of the synaptic connectivity of newborn neurons, the level of DG activity, the information streams within the DG,
and how these properties are changed by experience. Thus, I propose to establish an input-defined circuit map
of mature and immature DG neurons, and to identify the changes in this map, together with activity-dependent
changes in transcription, in the context of AD treatment and uCMS. In Aim 1, I will establish a presynaptic input
map of distinctly dorsal-ventral, mature and immature DG neurons in everyday life by combining transgenic
mouse technology with monosynaptic rabies virus retrograde tracing in the intact brain. Then, I will test the impact
of AD treatment and chronic chemogenetic neuronal silencing on these anatomically identified circuits. In Aim 2,
I will examine the effects of uCMS, which produces MDD-related behavioral phenotypes, with and without chronic
AD treatment and with acute chemogenetic neuronal activation on DG circuitry. In both Aims, I also will examine
synaptic, molecular and behavioral changes, and activity-dependent single-cell transcriptomics. By combining
gene expression data and DG connectivity with behavioral phenotypes in the light of changes produced by
uCMS, AD treatment and chemogenetic manipulations, I will be able to construct a biologically relevant DG
network model that can be used to test functional hypotheses, including dorsal-ventral DG dichotomy. Studying
chronic AD treatment and acute/chronic chemogenetic manipulations also will be valuable for identifying
signaling pathways underlying AD action, especially fast-acting ADs. Development of this DG network model will
help to clarify the critical role of the DG ...

## Key facts

- **NIH application ID:** 10455684
- **Project number:** 5K99MH125016-02
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Elif Tunc-Ozcan
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $98,659
- **Award type:** 5
- **Project period:** 2021-07-22 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10455684

## Citation

> US National Institutes of Health, RePORTER application 10455684, Neural activity and circuitry-mediated hippocampal stress responses (5K99MH125016-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10455684. Licensed CC0.

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