R35GM141802

In vivo dual color imaging of neuronal networks during anesthesia - 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 multiple but specific proteins on neuronal membranes, and different ligand-gated and voltage-gated ion channels have received 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 the 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., hippocampal formation).

Importantly, our previous studies have established that the 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 hippocampal 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 existing 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 medically significant because it describes the importance of drugs that target voltage-gated calcium channels for potential development of safer practices in clinical anesthesia.

The Regents Of The University Of Colorado

NOT APPLICABLE

93.859 - Biomedical Research and Research Training

National Institute of General Medical Sciences (NIGMS) [HHS - NIH]

Aurora, Colorado 800452530 United States

Single Zip Code

Maximizing Investigators' Research Award (R35 - Clinical Trial Optional) (PAR-22-180)

Amendment Since initial award the End Date has been extended from 05/31/26 to 06/30/31 and the total obligations have increased 574% from $462,742 to $3,117,019.