# Molecular principles of neuronal maturation and integration in the adult and aging brain

> **NIH NIH R01** · HARVARD UNIVERSITY · 2022 · $533,483

## Abstract

The hippocampus is a region of the brain that continues to produce new dentate granule cells (GCs)
throughout life. Development of adult-born GCs and their integration into preexisting circuits is modulated by
environment and by electrical activity of the local circuits, and is altered in the aging brain. To understand how
GC integration occurs and how it is modulated by activity and aging, it is crucial to dissect the precise
molecular mechanisms underlying these processes. The technology required for addressing these
fundamental problems is unavailable in Argentina, but routinely applied in the Arlotta lab at Harvard. Joining
efforts to address this specific problem is a natural next step. The overarching goal of this proposal is to exploit
the strategies for transcriptional profiling and bioinformatic analysis in brain development validated by the
Arlotta lab and the Schinder lab's expertise in functional characterization of adult-born GCs to build an
experimental pipeline for the discovery of new molecules controlling circuit plasticity in the adult and aging
brain, that includes assays for testing the roles of individual proteins to an unprecedented level of molecular
and functional detail. In Aim 1, we propose to generate a pipeline to reveal transcription factors, epigenetic
regulators, or effector genes controlling the developmental transitions along GC maturation and integration.
The proposed experimental pipeline is similar for all three Aims: (i) FACS-purify birth-dated adult-born GCs at
different stages; (ii) transcriptionally profile each population using two complementary forms of RNA
sequencing; (iii) bioinformatically identify transcription factors or epigenetic regulators that may control stage
progression; and (iv) functionally test candidate molecules through in vivo knock-down or overexpression.
Using this same approach, we will then investigate how stage-specific transcriptome dynamics are altered in
GCs from the aging hippocampus, to identify and functionally test changes in regulatory molecules that may be
responsible for their protracted development (Aim 2). Finally, we will seek to identify molecular mediators of
activity-mediated acceleration in GC development in the adult and the aging brain. (Aim 3). This grant will
further the aims of the Fogarty International Center in expanding the technical capacities of Dr Schinder's lab,
including availability of equipment, training of Argentinian graduate students and postdoctoral fellows, and
building collegial networks between members of the Leloir and Harvard research communities. This work will
significantly expand the capacity of Leloir to apply state-of-the-art transcriptomic profiling (currently limited,
throughout Argentina) to solve new problems related to brain function and disease, locally supported by a
bioinformatician who is co-investigator in the project. The workflow proposed will therefore not only enable a
new generation of molecular studies in the Schinder lab...

## Key facts

- **NIH application ID:** 10404657
- **Project number:** 5R01NS103758-05
- **Recipient organization:** HARVARD UNIVERSITY
- **Principal Investigator:** Paola Arlotta
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $533,483
- **Award type:** 5
- **Project period:** 2018-08-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10404657

## Citation

> US National Institutes of Health, RePORTER application 10404657, Molecular principles of neuronal maturation and integration in the adult and aging brain (5R01NS103758-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10404657. Licensed CC0.

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