# In vivo dual color imaging of neuronal networks during anesthesia

> **NIH NIH R35** · UNIVERSITY OF COLORADO DENVER · 2022 · $161,750

## Abstract

From Parent Award
One of the remaining fundamental challenges we face in pharmacology is deciphering the mechanisms of
action of general anesthetics (GAs). A complete anesthetic state involves loss of consciousness (hypnosis)
and movement (immobilization), as well as loss of pain sensation (analgesia) and recollection of the event
(amnesia). It is believed that GAs act through the multiple but specific proteins on neuronal membrane and
different ligand-gated and voltage-gated ion channels have received a significant consideration. One of the
compelling reasons to study voltage-gated calcium channels (VGCCs) in the mechanisms of anesthetic
actions is that these channels are essential in regulation of synaptic transmission and excitability in the
neuronal sleep pathway (e.g. thalamus) and in the brain regions involved in learning/memory (e.g. hippo-
campal formation). Importantly, our previous studies have established that low-voltage-activated subtype of
VGCCs or T-type calcium channels (T-channels) are inhibited by different classes of GAs within the clinically
relevant concentration range. For the past two decades our work has established the role of the family of T-
type VGCCs in acute and chronic pain processing, including post-surgical pain. However the role of VGCCs
in the mechanisms of GA-induced hypnosis and amnesia remains elusive. Furthermore, despite substantial
progress that has been made in the last two decades towards our understanding of how GAs act at the
molecular level, much less is known about how GAs cause hypnosis and memory deficit at the level of intact
neuronal networks. Hence, this proposal aims to elucidate the contribution of specific subtypes of T-channels
to anesthetic effects in the thalamocortical (Research area 1) and hippo- campal circuitry (Research area 2).
We will take advantage of mouse genetics, selective knock-down of different T-channel isoforms ex vivo and
in vivo electrophysiology, optical recordings, as well as a battery of behavioral tests to address these key
challenges. Our proposed work has the potential to overturn ex- isting dogma about anesthetic mechanisms
and to shift the focus to underappreciated targets, such as neuronal T-channels. We posit that understanding
the neurophysiological mechanisms of action of GAs that target T-channels may be used as a starting point
to develop novel and potentially safer approaches and practices in clinical anesthesia. MIRA mechanism is
well suited to achieve our stated goals because of flexibility to pursue new avenues within the research area
of interest to NIGMS. Consistent productivity of our lab and our ability to collaborate with others in the field of
anesthetic pharmacology strongly suggest that our approach will be fruitful. The proposed work is innovative
in that new mechanisms of useful clinical effects of general anesthetics such as loss of consciousness and
amnesia will be characterized. It is med- ically significant because it describes the importan...

## Key facts

- **NIH application ID:** 10582000
- **Project number:** 3R35GM141802-02S1
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Slobodan M. Todorovic
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $161,750
- **Award type:** 3
- **Project period:** 2021-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10582000

## Citation

> US National Institutes of Health, RePORTER application 10582000, In vivo dual color imaging of neuronal networks during anesthesia (3R35GM141802-02S1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10582000. Licensed CC0.

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