# The roles of anesthetics and neuroimmune interactions in postoperative cognitive dysfunction

> **NIH NIH R35** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2024 · $452,375

## Abstract

Project Summary
General anesthetics are routinely administered during surgical procedures to induce a reversible state of
unconsciousness, amnesia, analgesia, and immobility. However, it has become evident that anesthetics can
have detrimental effects on neurophysiological processes, including alterations in attention, sleep, and memory,
particularly in vulnerable populations such as neonates and older adults. Despite this knowledge, the precise
mechanisms underlying these undesired effects of anesthetics remain elusive. Our research aims to delve into
these mechanisms at the neural circuit, cellular, and molecular levels. Recent findings from our laboratory have
revealed the emergence of hyperactive neurons in the prefrontal cortex (PFC) following anesthesia as an early
functional indicator of subsequent neurocognitive changes. Building upon these findings, we will further
determine the involvement of local inhibitory circuits and deeper brain centers, such as the hippocampus, which
send long-range projections to the PFC. Using a combination of in vivo calcium imaging, virus-based circuit
tracing, and chemogenetics, we will elucidate the functional relevance of these circuits to the detrimental effects
induced by anesthetics and develop strategies to protect cognitive function after anesthesia. In addition, our
preliminary data suggest that astrocytes, the most abundant glial cells expressing GABAA receptors, respond to
GABAergic anesthetics and subsequently activate the unfolded protein response. We will test the hypothesis
that sustained activation of the unfolded protein response in astrocytes leads to reduced release of soluble
factors crucial for synaptogenesis, resulting in synapse loss and long-term memory decline. Additionally, we will
investigate whether restoring astrocytic function through a novel gene delivery strategy capable of permeating
the blood-brain barrier would alleviate neurocognitive deficits induced by anesthesia. Collectively, the proposed
research will contribute to a mechanistic understanding of the detrimental effects of anesthetics on the brain.
This knowledge is critical for optimizing anesthesia practices and mitigating potential adverse effects. By
unraveling the intricate interplay between anesthetics, neuro-immune-glial interactions, and brain plasticity, our
research holds promise for advancing perioperative care and promoting brain health.

## Key facts

- **NIH application ID:** 10842516
- **Project number:** 2R35GM131765-06
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Guang Yang
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $452,375
- **Award type:** 2
- **Project period:** 2019-05-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10842516

## Citation

> US National Institutes of Health, RePORTER application 10842516, The roles of anesthetics and neuroimmune interactions in postoperative cognitive dysfunction (2R35GM131765-06). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10842516. Licensed CC0.

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