Modern Methods for Unraveling Cell- and Circuit-Level Mechanisms of Neurophysiological Biomarkers in Psychiatry

Methods for studying the mammalian brain in vivo have advanced dramatically in the past two decades. State-of-the-art optical and electrophysiological techniques allow direct recordings of the functional dynamics of thousands of neurons across distributed brain circuits with single-cell resolution. With transgenic tools, specific neuron types, pathways, and/or neurotransmitters can be targeted in user-determined brain areas for precise measurement and manipulation. In this chapter, we catalog these advancements. We emphasize that the impact of this methodological revolution on neuropsychiatry remains uncertain. This stems from the fact that these tools remain mostly limited to research in mice. And while translational paradigms are needed, recapitulations of human psychiatric disease states (e.g., schizophrenia) in animal models are inherently challenging to validate and may have limited utility in heterogeneous disease populations. Here we focus on an alternative strategy aimed at the study of neurophysiological biomarkers—the subject of this volume—translated to animal models, where precision neuroscience tools can be applied to provide molecular, cellular, and circuit-level insights and novel therapeutic targets. We summarize several examples of this approach throughout the chapter and emphasize the importance of careful experimental design and choice of dependent measures.