Measurements of cortical field potentials are widely used throughout basic and clinical neuroscience, including in electroencephalography (EEG), electrocorticography (ECoG) and local field potential (LFP) recordings. However, the neural origins of field potentials remain poorly understood, due to a lack of techniques for dissecting how different classes of cells contribute to field potential signals. To overcome this longstanding barrier, our project applies fluorescent voltage-indicators and instrumentation for optical voltage-imaging that our team created earlier in the NIH BRAIN Initiative. These new tools will enable us to systematically identify the contributions of 12 different cell-types to neocortical field potential activity. To perform cell-type specific recordings of neural transmembrane voltage dynamics, we will express red and green genetically encoded voltage indicators in a wide set of different transgenic mouse lines, each of which allows selective gene expression in one of the pyramidal neuron or interneuron classes of the neocortex. Concurrent with optical recordings, we will perform traditional electrical recordings of cortical LFPs. These joint optical and electrical measurements will be the first of their kind and will yield important insights into how each neuron-type influences spontaneous and stimulus-evoked cortical field potential activity. Across our collection of mouse lines, we will conduct 3 novel types of recordings, each of which uses cutting-edge instrumentation for optical voltage-imaging in up to 2 cell-types at once in awake behaving mice: a) Fiber-optic voltage-sensing, for tracking the voltage dynamics of genetically defined neural populations; b) Wide-field voltage-imaging of voltage oscillations and waves across the cortex in specific cell-types; c) High-speed (1 kHz) optical voltage imaging of spiking dynamics in up to 2 neuron-types at a time. Further, to test the causal role of each neuron class in shaping cortical field potentials, we will also perform chemogenetic inhibition studies in each of the mouse lines. In these studies, we will silence each of the individual neuron-types and observe how the effective removal of this cell-type from cortical circuitry impacts both LFP activity and the population voltage dynamics of other neuron classes. Together, these groundbreaking studies will propel understanding of cortical field potentials in basic and applied neuroscience by providing fundamental insights into how different cell-types shape field potential dynamics. To help assure that our experiments optimally advance conceptual understanding in the field, our team includes 2 computational neuroscientists whose expertise lies in modeling the biophysics of cortical field potentials. To promote transparency and open-science, we will deposit all of the extensive datasets and analyses from our experiments into public repositories.

Recordings of cortical field potentials are widely used in basic and clinical neuroscience and include electroencephalography (EEG), electrocorticography (ECoG) and local field potential (LFP) recordings, which all provide time-varying voltage signals reflecting neural population activity. However, the neural origins of field potential dynamics remain poorly understood, due to a lack of techniques for dissecting how different classes of cells contribute to field potential signals. To break this longstanding impasse, our project applies recently developed voltage-indicators and optical instrumentation for imaging the transmembrane voltage dynamics of genetically defined neuron classes; these techniques will enable us to systematically identify the contributions of 12 different cell- types to neocortical field potential activity.