# Pan-neuronal functional imaging and anesthesia

> **NIH NIH R35** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $358,968

## Abstract

Volatile anesthetics, such as isoflurane, produce all stages of general anesthesia including unconsciousness,
amnesia, analgesia and muscle relaxation. Despite their ubiquity, the fundamental mechanisms of action of
these drugs remains unknown. Elucidating the mechanisms by which clinical anesthesia is produced is the
foundational unanswered research question in the specialty of anesthesiology. The routine use of volatile
anesthetics is not without clinical risk. Multiple exposures to anesthetics in infancy leads to possible behavioral
problems in later life, and persistent post-operative cognitive dysfunction is seen in the elderly after anesthesia.
Historically, research in this field has proceeded along two tracks: either molecular analysis looking for specific
receptors for the volatile anesthetics (an approach that has largely foundered due to diffuse interactions with
many receptors whose effects do not combine appropriately), or the gross measurement of neuronal activity in
entire regions of the brain using EEG and fMRI (which are fundamentally limited by resolution). Clearly, there is
an enormous gap in length resolution between synaptic-scale and EEG-scale. We hypothesized that the onset
of anesthesia, and hence the loss of consciousness, is due to disruption in the communication between
neurons at the level of small neuronal networks that lie well below the resolution limit of EEG and fMRI. We
study the effect of anesthetic agents on intercommunication within intact, living neural networks, with single
neuron resolution. We use C. elegans, the creature with the simplest, most tractable neuronal architecture in
which anesthesia is known to be inducible. Using light-sheet microscopy, a combination of fixed and calcium-
sensitive fluorophores expressed under neuronal promoters, and our customized supercomputing toolchain for
image analysis and signal extraction, we track and capture the activity of essentially the entire nervous system
and examine its behavior under varying levels of anesthetic exposure normalized to comparable levels used in
human surgery. Using two-photon imaging, we are able to perform similar experiments in the mouse and
extract activity from selected regions of the somatosensory cortex in both awake and anesthetized states.
We will use a system of differential expression of fixed neuronal fluorophores in C. elegans to allow the precise
identification of individual neurons under light-sheet imaging. In combination with the C. elegans connectome,
we will determine the neuronal pathways that underlie anesthetized vs conscious states, how anesthetics alter
chemical and electrical synaptic connections to induce these states, the changes in neuronal connectivity that
permit the anesthetized state to resolve back into consciousness, and hence delineate the mechanisms of
clinical post-operative cognitive dysfunction in the old and neurodevelopmental impairment in the young. We
will extend our imaging and analysis techniques i...

## Key facts

- **NIH application ID:** 10906134
- **Project number:** 5R35GM145319-03
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Christopher W Connor
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $358,968
- **Award type:** 5
- **Project period:** 2022-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10906134

## Citation

> US National Institutes of Health, RePORTER application 10906134, Pan-neuronal functional imaging and anesthesia (5R35GM145319-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10906134. Licensed CC0.

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