# Hilar mossy cells and dentate gyrus function

> **NIH NIH R01** · NATHAN S. KLINE INSTITUTE FOR PSYCH RES · 2020 · $392,004

## Abstract

ABSTRACT
 Mossy cells (MCs) of the dentate gyrus (DG) are glutamatergic neurons that are considered to be
important to normal function and their injury has been suggested to contribute to neurological and
psychiatric disorders, as well as deficits after traumatic brain injury. Anatomical and slice
electrophysiology studies have described MCs in detail, but there is a gap between these studies and
understanding how MCs contribute to DG-dependent behavior in vivo. To address this issue, we
began with a simple approach: mice were engaged in behaviors related to DG function, and MCs
were examined afterwards using the neural activity marker c-fos. We quickly found that simply
exploring novel objects led to a large increase in MC c-fos immunoreactivity (ir). Interestingly, most c-
fos-ir did not increase in most of the other DG neurons, suggesting preferential activation of MCs by
novelty. However, there was one area of the DG where c-fos-ir was consistent: a subset of GCs in
dorsal DG. In contrast, the majority of MCs with c-fos-ir were ventral. Because the main projection of
ventral MCs is to dorsal GCs, these data suggest that ventral MCs excite dorsal GCs. This circuitry
helps explain how normally quiescent GCs become activated in dorsal DG, which is considered
essential for cognitive functions of the DG. In Aim 1 we will use optogenetics to test this hypothesis,
taking advantage of new mouse lines that have targeted Cre recombinase to MCs. We will also ask if
dorsal MCs have effects analogous to ventral MCs, i.e., dorsal MCs contribute to ventral DG
functions. In Aim 2 the underlying circuitry will be addressed. We suggest that optogenetic excitation
of MCs in a normal adult mouse will recapitulate the results with c-fos: MCs excite proximal GCs
weakly but distal GCs in a more robust manner. This idea has been supported by data from slices
that were cut at an angle to preserve MC axons, and will be tested further in Aim 2 using voltage
imaging and microelectrodes. In Aim 3 we will address the hypothesis that a large number of the
distal GCs that are activated by MCs are immature. That hypothesis supports a previously published
study showing that MCs are a primary source of afferent input to young GCs that are born in
adulthood. This is potentially important because immature GCs are considered central to DG
functions. Therefore, we will address the additional hypothesis that MCs activate adult-born GCs
primarily in distal locations, leading to stronger excitation of distal GCs than proximal GCs. By
providing afferent input to immature GCs, MCs could play a critical role in behaviors associated with
adult DG neurogenesis. Together these experiments will significantly advance our understanding of
DG circuitry and its contribution to behavior. Because MC injury is associated with several disorders,
these experiments will also shed light on impairments in DG functions in those pathological
conditions.

## Key facts

- **NIH application ID:** 9934273
- **Project number:** 5R01MH109305-05
- **Recipient organization:** NATHAN S. KLINE INSTITUTE FOR PSYCH RES
- **Principal Investigator:** Helen E Scharfman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $392,004
- **Award type:** 5
- **Project period:** 2016-08-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9934273

## Citation

> US National Institutes of Health, RePORTER application 9934273, Hilar mossy cells and dentate gyrus function (5R01MH109305-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9934273. Licensed CC0.

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