# Mechanisms of emergence from general anesthesia

> **NIH NIH R35** · UNIVERSITY OF WASHINGTON · 2022 · $374,828

## Abstract

Project Summary
Cellular mechanisms mediating the transition from a state of general anesthesia to an awake state are not
understood. Patients emerge from anesthesia passively without the use of mechanistically targeted
interventions, creating an unpredictable clinical outcome marked by behavioral phenomena like emergence
agitation and delirium. Many anesthetics act either directly or indirectly to change excitatory/inhibitory balance
in the brain, highlighting the importance of understanding inhibitory networks in emergence. My research
program focuses on the effects of general anesthesia on inhibitory plasticity during the transition from
anesthetized to awake state in mice. My prior work examines neuroligin-2, a central organizer of the inhibitory
synapse, using cell-type and circuit specific manipulations. Neuroligin-2 is a cell adhesion protein that acts as a
scaffold to regulate general inhibitory synaptic function and is recently implicated as an independent regulator
of intracellular signaling and disease. I demonstrated that neuroligin-2 manipulation modulates agitation and
related behaviors in mouse models. My established expertise in stress-induced inhibitory synaptic plasticity
provides a strong foundation for the following three complementary research areas investigating general
anesthesia emergence. (1) Inhibitory cell plasticity in emergence from anesthesia: Research area 1 will
focus on effects of general anesthesia emergence on inhibitory cell plasticity, starting with an investigation of
key inhibitory postsynaptic genes, like neuroligin-2, using targeted knockdown and electrophysiology studies.
Single cell sequencing transcriptomic investigations will characterize all cell types and synaptic constituents
modified by emergence. (2) Brain-wide cell type-specific circuit activity in emergence: Research area 2
will investigate whole brain circuit changes induced by general anesthesia emergence using activity mapping
and light sheet microscopy at single cell resolution, along with recordings of neuronal activity using genetically
encoded optical sensors expressed in anesthesia-regulated circuits. (3) Preclinical models for emergence
delirium across the lifespan: Research area 3 will develop and validate preclinical rodent models of
emergence delirium using machine learning approaches, in order to study vulnerability to anesthesia-induced
delirium across the lifespan. Together, these three projects form an overarching research program to
understand mechanisms of emergence from the inhibitory cellular to circuit to behavioral levels of analysis,
providing a holistic view of emergence. We must understand the mechanisms of anesthetic emergence across
all levels in order to design pharmaceutical interventions to bring about safer and predictable emergence.

## Key facts

- **NIH application ID:** 10497470
- **Project number:** 1R35GM146751-01
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Mitra Heshmati
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $374,828
- **Award type:** 1
- **Project period:** 2022-09-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10497470

## Citation

> US National Institutes of Health, RePORTER application 10497470, Mechanisms of emergence from general anesthesia (1R35GM146751-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10497470. Licensed CC0.

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