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      Manipulating Neural Circuits in Anesthesia Research

      , , , , ,
      Anesthesiology
      Ovid Technologies (Wolters Kluwer Health)

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          Abstract

          The neural circuits underlying the distinct endpoints that define general anesthesia remain incompletely understood. It is becoming increasingly evident, however, that distinct pathways in the brain that mediate arousal and pain are involved in various endpoints of general anesthesia. To critically evaluate this growing body of literature, familiarity with modern tools and techniques used to study neural circuits is essential. This Readers’ Toolbox article describes four such techniques: (1) electrical stimulation, (2) local pharmacology, (3) optogenetics, and (4) chemogenetics. Each technique is explained, including the advantages, disadvantages, and other issues that must be considered when interpreting experimental results. Examples are provided of studies that probe mechanisms of anesthesia using each technique. This information will aid researchers and clinicians alike in interpreting the literature and in evaluating the utility of these techniques in their own research programs.

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          Most cited references50

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          DREADDs for Neuroscientists.

          Bryan Roth (2016)
          To understand brain function, it is essential that we discover how cellular signaling specifies normal and pathological brain function. In this regard, chemogenetic technologies represent valuable platforms for manipulating neuronal and non-neuronal signal transduction in a cell-type-specific fashion in freely moving animals. Designer Receptors Exclusively Activated by Designer Drugs (DREADD)-based chemogenetic tools are now commonly used by neuroscientists to identify the circuitry and cellular signals that specify behavior, perceptions, emotions, innate drives, and motor functions in species ranging from flies to nonhuman primates. Here I provide a primer on DREADDs highlighting key technical and conceptual considerations and identify challenges for chemogenetics going forward.
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            Millisecond-timescale, genetically targeted optical control of neural activity.

            Temporally precise, noninvasive control of activity in well-defined neuronal populations is a long-sought goal of systems neuroscience. We adapted for this purpose the naturally occurring algal protein Channelrhodopsin-2, a rapidly gated light-sensitive cation channel, by using lentiviral gene delivery in combination with high-speed optical switching to photostimulate mammalian neurons. We demonstrate reliable, millisecond-timescale control of neuronal spiking, as well as control of excitatory and inhibitory synaptic transmission. This technology allows the use of light to alter neural processing at the level of single spikes and synaptic events, yielding a widely applicable tool for neuroscientists and biomedical engineers.
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              Which elements are excited in electrical stimulation of mammalian central nervous system: a review.

              J Ranck (1975)
              (1) There are data on the amount of current necessary to stimulate a myelinated fiber or cell body and/or its axon a given distance away from a monopolar electrode over the entire range of practical interest for intracranial stimulation. Data do not exist for other electrode configurations. (2) Currents from a monopolar cathode of more than 8 times threshold may block action potentials in axons. Therefore, only axons lying in a shell around the electrode are stimulated. Elements very close to the electrode may not be stimulated. Close to an electrode small diameter axons may be stimulated and larger ones may not be. (3) Most, and perhaps all, CNS myelinated fibers have chronaxies of 50-100 musec. When gray matter is stimulated, the chronaxie is often 200-700 musec. It is not clear what is being stimulated in this case. Current-duration relations should be determined for many more responses. (4) There are no current-distance or current-duration data for central finely myelinated or unmyelinated fibers. (5) It takes less cathodal current than anodal to stimulate a myelinated fiber passing by a monopolar electrode. When a monopolar electrode is near a cell body, on the opposite side from the axon, often the lowest threshold is anodal, but sometimes cathodal. Stimulation of a neuron near its cell body is not well understood, but in many cases the axon is probably stimulated. (6) Orientation of cell body and axons with respect to current flow is important. For an axon it is the component of the voltage gradient parallel to the fiber that is important. (7) The pia has a significant resistance and capacitance. Gray matter, white matter, and cerebrospinal fluid have different resistivities, which affect patterns of current flow. (8) More is known about stimulation of mammalian CNS than most workers are aware of. Much of what is unknown seems solvable with current methods.
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                Author and article information

                Journal
                Anesthesiology
                Ovid Technologies (Wolters Kluwer Health)
                0003-3022
                1528-1175
                July 01 2020
                July 01 2020
                : 133
                : 1
                : 19-30
                Article
                10.1097/ALN.0000000000003279
                32349073
                c2bae112-365e-413e-a9c6-593a4cd26b1b
                © 2020
                History

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