# Cellular and circuit mechanisms of the therapeutic action of inhaled nitrous oxide in rodent models of chronic stress

> **NIH NIH R35** · UNIVERSITY OF PENNSYLVANIA · 2024 · $406,250

## Abstract

Project Summary/Abstract
Depression is the leading cause of disability worldwide and new treatments are needed. This therapeutic
challenge stems from the fact that depression involves deficits distributed among neuronal subtypes and multiple
brain regions. A growing body of clinical research demonstrates that a single dose of N-methyl-D-aspartate
receptor , induce rapid and durable
improvements in depressive symptoms persisting for days to weeks in patients refractory to conventional
antidepressant therapies. Despite nitrous oxide being the oldest and one of the safest anesthetics in current
 (NMDA-R) antagonists, inhaled nitrous oxide or intravenous ketamine
clinical practice, our understanding of how nitrous oxide modulates neuronal activity and circuit function to
produce its clinical effects is extraordinarily limited. While it has been hypothesized that the therapeutic effect of
NMDA-R antagonists is related to their ability to induce plasticity, the mechanisms that initiate and sustain this
plasticity remain unclear. By combining in vivo imaging of synaptic structure, functional calcium imaging,
electrophysiology, and behavioral recordings, this proposal will test an innovative hypothesis that
changes in neuronal activity imposed by nitrous oxide acutely, automatically give rise to sustained
plasticity through activity-dependent mechanisms. This hypothesis is based on extensive work on activity-
dependent plasticity in the neocortex and on our own novel preliminary results showing that nitrous oxide
specifically and directly activates layer 5 pyramidal neurons, which mediate cortico-cortical and cortico-
subcortical connectivity, through a novel mechanism. All animal models and techniques have been established
in the studies that generated the preliminary results, making the proposal highly achievable. In line with the
mission of the NIGMS, the immediate goal of this proposal is to lay the foundation for advances in the
treatment of depression by understanding the mechanisms of action of nitrous oxide in cortical circuits.
Such an understanding may explain how acute pharmacologic interventions can lead to sustained therapeutic
benefits in the setting of depression and potentially other neuropsychiatric diseases.

## Key facts

- **NIH application ID:** 10900748
- **Project number:** 5R35GM151160-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** JOSEPH CICHON
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $406,250
- **Award type:** 5
- **Project period:** 2023-08-15 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10900748

## Citation

> US National Institutes of Health, RePORTER application 10900748, Cellular and circuit mechanisms of the therapeutic action of inhaled nitrous oxide in rodent models of chronic stress (5R35GM151160-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10900748. Licensed CC0.

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