# Genomic mechanisms of firing rate homeostasis

> **NIH NIH R01** · HARVARD MEDICAL SCHOOL · 2021 · $576,752

## Abstract

PROJECT SUMMARY/ABSTRACT
Neuronal Firing Rate Homeostasis (FRH) describes the ability of neurons to maintain their average firing rates
at precise set points in the long-term, even in the face of changing synaptic inputs. The stability provided by
FRH enables learning and memory. Achieving FRH requires an FRH control circuit that is akin to a thermostat
that compares desired to actual room temperatures or an autopilot that compares desired to actual trajectories.
Identifying this control circuit will require direct measurement of FRH by perturbing firing rates and observing
homeostatic recovery, which has rarely been done. A promising candidate FRH control circuit is the neuronal
Activity-Regulated Gene (ARG) program, in which activity-dependent increases in calcium lead to transcription
of genes whose mRNA levels remain elevated for many hours. The ARG program is a promising candidate
because individual activity-regulated genes protect against seizures, and they also regulate homeostatic
effector mechanisms like synaptic scaling that may mediate FRH. However, the molecules that comprise the
FRH control circuit are unknown. We hypothesize that the ARG program is the core control mechanism of
FRH. Our extensive preliminary data reinforce the importance of testing this hypothesis at genome-scale. The
genome-scale approach is important not only because of the sheer number of ARGs but also because different
ARGs appear to “interpret” firing rate error in very different -- but as yet undefined -- ways. Relying on our
extensive knowledge of the ARG program, we will evaluate its contribution to FRH. For ARG induction to be a
core mechanism of FRH, it must be specified quantitatively by firing rates. We will therefore map the coupling
of firing rates to ARG expression levels, by controlling firing rates optogenetically and detecting gene
expression with RNA-Seq. We will also directly assess the functional contribution of ARG induction to FRH by
perturbing firing rates pharmacologically in cortical neurons and observing homeostatic recovery using multi-
electrode arrays, with or without perturbation of ARGs. Our approach is innovative because it is a genome-
wide investigation of the activity-sensing control system for homeostasis rather than the far better-studied
homeostatic effector mechanisms. Our work is significant because it will advance basic knowledge of the
control circuit mediating FRH and produce tools for manipulating FRH that will help connect this control circuit
to candidate homeostatic mechanisms.

## Key facts

- **NIH application ID:** 10094256
- **Project number:** 5R01MH116223-04
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Susan M. Dymecki
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $576,752
- **Award type:** 5
- **Project period:** 2018-03-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10094256

## Citation

> US National Institutes of Health, RePORTER application 10094256, Genomic mechanisms of firing rate homeostasis (5R01MH116223-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10094256. Licensed CC0.

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