# genetic mechanisms controlling serotonergic function across life span

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2020 · $585,570

## Abstract

New findings suggest intrinsic gene regulatory programs are needed throughout life for the maturation and
health of postmitotic neurons. Although tremendous progress has been made in elucidating the regulatory
mechanisms that control early neuronal specification far less is known about the regulatory programs that act
later in life in specific neuron-types. In many instances transcription factors (TFs) that play crucial early roles in
neuronal differentiation, i.e. in the acquisition of transmitter identity, continue to be expressed in the mature
neurons they helped to generate. This project is aimed at investigating the regulatory factors that act across
the lifespan to build and sustain the serotonin (5-HT) neurotransmitter system. Serotonergic regulatory
mechanisms are of particular interest as 5-HT has wide-ranging modulatory effects on central neural circuitry
and altered 5-HT gene expression has been implicated in several neuropsychiatric disorders. We will use our
validated conditional targeting approaches to test specific hypotheses about the structure and function of
regulatory networks that are continuously active in 5-HT neurons. Our working hypothesis is that 5-HT neuron
TFs, Pet-1 and Lmx1b, which are directly involved in acquisition of 5-HT transmitter identity, continue to
perform critical regulatory functions that build 5-HT neuron connectivity and sustain their identity. In aim 1, we
will test the hypothesis that continuous Pet-1 expression is required to build 5-HT connectivity and prevent
progressive decay of 5-HT gene regulatory networks and 5-HT neuron cell state identity. These studies will be
performed with Pet-1 targeted mice using our constitutive 5-HT specific cre line, ePet-Cre, floxed Pet-1 allele
and the Ai9 (RCL-tdT) reporter to mark 5-HT neurons with Td-tomato and enable sorting of postnatal neurons
for RNA-seq studies at different life stage. In aim 2, we will investigate the importance of Pet-1 and Lmx1b in
sustaining the health of adult 5-HT neurons. We will individually target these TFs with our tamoxifen-inducible
5-HT neuron-type approaches to eliminate expression in adulthood. We will determine whether adult loss of
these TFs causes progressive decay in 5-HT neuron identity, function, connectivity, and 5-HT modulated
behaviors. We will also investigate whether these two TFs perform distinct functions and whether their targets
switch later in life. In aim 3, we will investigate two mechanistic hypotheses about how continuously expressed
TFs control postmitotic neuron gene expression. In the first set of experiments we will study how Pet-1
temporally switches targets and test the hypothesis Pet-1 occupancy in 5-HT chromatin is dynamic and
changes at specific genes as 5-HT neurons progress through postmitotic life. The second set of experiments
will test the hypothesis that Pet-1 is a regulatory master of a postmitotic TF network that performs specific
regulatory functions in 5-HT neurons. We will investigate ex...

## Key facts

- **NIH application ID:** 9858418
- **Project number:** 5R01MH062723-19
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** EVAN S DENERIS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $585,570
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9858418

## Citation

> US National Institutes of Health, RePORTER application 9858418, genetic mechanisms controlling serotonergic function across life span (5R01MH062723-19). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9858418. Licensed CC0.

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