Changes

'''Big picture:''' understand the temporospatial and mechanistic changes in neural activity induced by various anesthetics. Can we recapitulate those with steerable, low latency, closed-loop non-invasive neuromodulation or use this knowledge to drive discovery of novel drugs?

'''Big picture:''' understand the temporospatial and mechanistic changes in neural activity induced by various anesthetics. Can we recapitulate those with steerable, low latency, closed-loop non-invasive neuromodulation or use this knowledge to drive discovery of novel drugs?

*High-throughput screen of anesthetics (and anesthetic reversal agents) in C.elegans. I could work in parallel in a different organism (e.g. yeast, jellyfish, hydra, sea anemones, corral, bacteria, plants, neuronal explants).

*High-throughput screen of anesthetics (and anesthetic reversal agents) in C.elegans. I could work in parallel in a different organism (e.g. yeast, jellyfish, hydra, sea anemones, corral, bacteria, plants, neuronal explants).

*Based on 30 years of in vitro studies (n>300), most anesthetics exhibit similar potency across a range of receptors. Most receptors are non-selective for ligands. What this paper addresses but doesn't answer is whether the receptors are present at the correct locations and necessary to the anesthetic behavioral response.

*[https://scholar.googleusercontent.com/scholar.bib?q=info:dK96wvRnWFAJ:scholar.google.com/&output=citation&scisdr=CiBKb9IEEIjgixESwUs:ACTRDVEAAAAAasUU2UsAEqSgPmvYJRTMHcZKb4s&scisig=ACTRDVEAAAAAasUU2a34RqVYzDaWRdbVsL76Mk4&scisf=4&ct=citation&cd=-1&hl=en 2026 A&A paper] argues that classifying anesthetics as, say, GABAergic vs. NMDAergic is misleading. Propofol for instance actually has higher potency at the α4β2 nAChR and HCN1 receptors than at the "classic" GABA_AR receptor. Based on 30 years of in vitro studies (n>330), most anesthetics exhibit similar potency across a range of receptors. Most receptors are non-selective for ligands. What this paper addresses but doesn't answer is whether the receptors are present at the correct locations and necessary to the anesthetic behavioral response.

*Some anesthetics ('''ketamine, dexmedetomidine, etomidate, benzos''') are fairly selective, but are rarely used as sole anesthetics. Below, I list each of the ''in vitro'' binding affinities of these "selective" anesthetics, up until there is a change of one order of magnitude or greater for the next receptor.

*According to this paper, some anesthetics (i.e. ketamine, dexmedetomidine, etomidate, benzos) are fairly selective, but are rarely used as sole anesthetics. Below, I list each of the ''in vitro'' binding affinities of these "selective" anesthetics, up until there is a change of one order of magnitude or greater for the next receptor.

**Ketamine binds to α4β4 nAChR w/ IC₅₀ of 0.144 uM, but has an IC₅₀ for the GluN1/N2C NMDAR of 0.338 uM.

**Ketamine binds to α4β4 nAChR w/ IC₅₀ of 0.144 uM, but has an IC₅₀ for the GluN1/N2C NMDAR of 0.338 uM.

**Dexmedetomidine binds to α_2A AR w/ K_D of 0.0014 uM and the M₃ mAChR w/ IC₅₀ of 0.001 uM.

**Dexmedetomidine binds to α_2A AR w/ K_D of 0.0014 uM and the M₃ mAChR w/ IC₅₀ of 0.001 uM.

**Etomidate binds to α1β2γ2 GABA_AR w/ an EC₅₀ of 1.08 uM, but to I_K(dr) with an IC₅₀ of 4.59 uM, and the α1 GlyR w/ an IC₅₀ of 5.37 uM.

**Etomidate binds to α1β2γ2 GABA_AR w/ an EC₅₀ of 1.08 uM, but to I_K(dr) with an IC₅₀ of 4.59 uM, and the α1 GlyR w/ an IC₅₀ of 5.37 uM.

**Midazolam binds to α1β2γ2 GABA_AR w/ EC₅₀ of 0.041 uM, Na_V (neuron) IC₅₀ of 0.074 uM, and nAChR (muscle) w/ IC₅₀ of 0.143 uM.

**Midazolam binds to α1β2γ2 GABA_AR w/ EC₅₀ of 0.041 uM, Na_V (neuron) IC₅₀ of 0.074 uM, and nAChR (muscle) w/ IC₅₀ of 0.143 uM.

**Diazepam binds to α1β2γ2 GABA_AR w/ EC₅₀ of 0.07 uM.

**Diazepam binds to '''α1β2γ2 GABA_AR''' w/ EC₅₀ of 0.07 uM.

**Sevoflurane binds to K_v1.2 w/ EC₅₀ of 0.0097 mM.

**Sevoflurane binds to '''K_v1.2''' w/ EC₅₀ of 0.0097 mM.

*'''Are there pharmacological inhibitors with receptor specificity? When given together with "promiscuous" anesthetics, what happens? For instance, is propofol equally effective when given with a specific HCN1 receptor inhibitor? What about a GABA_AR inhibitor? Could you do optogenetic location-specific inducible receptor knockdowns? Do model organisms already exist?'''

*'''Are there pharmacological inhibitors with receptor specificity? When given together with "promiscuous" anesthetics, what happens? For instance, is propofol equally effective when given with a specific HCN1 receptor inhibitor? What about a GABA_AR inhibitor? Could you do optogenetic location-specific inducible receptor knockdowns? Do model organisms already exist?'''

*Hamilton has a gap junction (network of gap junctions?) and some specific neurons that he think are a conserved mechanism of anesthesia. He wants to test this by doing a screen of a bunch of different anesthetics in WT and KO worms with a behavioral screening assay. He has a behavior rig that basically automatically records swimming speed. He wants to look for the EC50 of various anesthetics and see if that number is shifted with KO or KD of different gap junctions.

*Hamilton has a gap junction (network of gap junctions?) and some specific neurons that he think are a conserved mechanism of anesthesia. He wants to test this by doing a screen of a bunch of different anesthetics in WT and KO worms with a behavioral screening assay. He has a behavior rig that basically automatically records swimming speed. He wants to look for the EC50 of various anesthetics and see if that number is shifted with KO or KD of different gap junctions.