# Effects of anesthetics on thalamic  excitability

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2020 · $325,000

## Abstract

Project Summary
The thalamus is the major gateway for the flow of sensory information from the periphery to the cortex and the
disruption of thalamocortical connectivity may be an essential common feature of the hypnotic effects of
many general anesthetic (GAs). Furthermore, recent studies have identified important roles of the central
medial nucleus (CeM) and ventrobasal (VB) nucleus of the thalamus in control of arousal and natural sleep.
Although the role of thalamic T-type calcium channels (T-channels) in natural sleep is reasonably well
established, the role of these channels in anesthesia remains poorly understood. In addition, in the past
cycle of this grant we established that exposure of rat pups to clinically-relevant GAs causes increased T-
current densities in the reticular thalamic nucleus (nRT), which in turn contributes to lasting hyperexcitabil- ity
and pathological oscillations in thalamocortical networks in vitro and in vivo. These changes in neuronal
function were reversed by selective antagonism of T-channels.
We postulate that the use of pharmacological inhibitors that target T-channels may facilitate GA-induced loss
of consciousness and hence may reduce usage of potent volatile GAs needed for surgery. The overall
objective of this application, is to test the central hypothesis that the CaV3.1 isoform of T-channels in the
CeM and VB thalamic nuclei is important for anesthetic-induced hypnosis.
To test this hypothesis, we will use in vitro patch-clamp recordings from acute brain slices and recombinant
cells in vitro and electroencephalographic (EEG) recordings in vivo from the CeM and VB nuclei, selective
pharmacological T-channel inhibitors, and mouse genetics with global and region-specific silencing of
CaV3.1 channels in the thalamus to pursue the following specific aims:
Aim 1: To determine the biophysical and molecular mechanism of recombinant and native CaV3.1 channel
inhibition in vitro by two common GAs, isoflurane (ISO) and sevoflurane (SEVO), and their effect on neu-
ronal excitability of CeM. We will also use new approach with photoaffinity ligands of ISO (AZI-ISO) and
SEVO (AZI-SEVO) to identify specific molecular binding sites on CaV3.1 channels for volatile GAs.
Aim 2: To determine whether CaV3.1 channels in the CeM contribute to the alterations in thalamocortical
network function during sedation/hypnosis with volatile GAs and administration of the selective T-channel
inhibitor TTA-P2, as assessed by in vivo EEG recordings.
Aim 3: To determine if region-specific silencing of CaV3.1 channels in the CeM and VB thalamus will have
differential effects on sedation/hypnosis and thalamocortical oscillations in vivo induced by ISO and SEVO.
The proposed work is innovative in that new mechanisms of anesthetic-induced loss of consciousness will be
characterized. It is medically significant because it describes the importance of drugs that target voltage- gated
calcium channels for potential development of safer practices i...

## Key facts

- **NIH application ID:** 9993532
- **Project number:** 5R01GM102525-06
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Slobodan M. Todorovic
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $325,000
- **Award type:** 5
- **Project period:** 2014-01-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9993532

## Citation

> US National Institutes of Health, RePORTER application 9993532, Effects of anesthetics on thalamic  excitability (5R01GM102525-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9993532. Licensed CC0.

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