# Gene regulatory network control of olfactory cortex cell type specification

> **NIH NIH R01** · BROWN UNIVERSITY · 2024 · $505,570

## Abstract

Project summary
Understanding brain function critically depends on knowing the identities of neural cell types. The olfactory
(piriform, PCx) cortex is the main recipient of afferent inputs from the olfactory bulb and plays key roles in odor
perception and memory. However, we lack a detailed molecular description of piriform cell types and the
molecular machinery that defines their functional properties. Furthermore, and in contrast to sensory and motor
areas in the neocortex, the genetic programs underlying PCx cell lineage specification during development
remain largely unknown. A comparative analysis of cell types in the PCx and neocortex will reveal piriform-
specific cell types and molecular features.
Here, we propose to determine the gene expression and chromatin accessibility states of PCx neurons in the
adult mouse, and to characterize the dynamic interaction of domains of regulatory chromatin and transcription
factor activity that drive cell lineage specification during development. Our central hypothesis is that cell type
identity in PCx is specified during development by the activity of piriform-specific gene regulatory network (GRN)
activity. We further posit that GRN activity in piriform is distinct from neocortex due to the scarcity of epigenetic
mechanisms for transcriptional repression.
Aim 1: to identify molecularly distinct cell types in the adult olfactory cortex of mice. We will
simultaneously measure gene expression and chromatin accessibility states of single cells in the mouse PCx.
We predict that the molecular diversity of piriform neurons matches the diversity of their functional properties.
Aim 2: to determine epigenetic mechanisms of piriform cell lineage specification during development.
We will measure changes in gene expression and chromatin accessibility in developing piriform neurons and
computationally reconstruct their differentiation trajectories. We predict that cell lineage specification in PCx is
driven by piriform-specific dynamic interactions between domains of regulatory chromatin and associated
transcription factor activity. Aim 3: to reverse engineer a gene regulatory network model for piriform cell
type specification. We will infer data-driven, mechanistic GRN models for piriform and neocortex
(somatosensory cortex S1) development. We will compare GRNs for PCx and neocortex using dynamical
systems theory to test our model that the scarcity of repressive interactions between transcription factors drives
the specification of piriform cell types.
Our work will provide mechanistic insight into the epigenetic control of TF activity during neuronal differentiation
and test the role of TF cross-repression in cell type specification. By integrating experimental data across PCx
and neocortex, we will reveal piriform-specific cell types and the molecular features that specify the functional
properties of the olfactory cortex.

## Key facts

- **NIH application ID:** 10791864
- **Project number:** 5R01DC020478-02
- **Recipient organization:** BROWN UNIVERSITY
- **Principal Investigator:** Alexander Fleischmann
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $505,570
- **Award type:** 5
- **Project period:** 2023-03-01 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10791864

## Citation

> US National Institutes of Health, RePORTER application 10791864, Gene regulatory network control of olfactory cortex cell type specification (5R01DC020478-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10791864. Licensed CC0.

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