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Introduction

THE PREVIOUS CHAPTER focused on the neuroanatomy of the brain and the connections between different brain regions. An understanding of how these connections mediate behavior requires insight into how the information represented by the activity of different populations of neurons is communicated and processed. Much of this understanding has come from recordings of the minute electrical signals generated by individual neurons.

Although much has been learned by recording from just one or a few neurons at a time, advances in miniaturization and electronics technology now make it possible to record action potentials simultaneously from many hundreds of individual neurons across multiple brain areas, often in the context of a sensory, motor, or cognitive task (Box 5–1). Such advances, together with computational approaches for managing and making sense of large data sets, promise to revolutionize our understanding of neural function.

Box 5–1 Optical Neuroimaging

Optical imaging methods are a rapidly advancing field of technology for large-scale monitoring of neural circuit dynamics. Most of these approaches use fluorescent sensors—synthetic dyes or genetically engineered and encoded proteins—that signal changes in neural activity via changes in the magnitude or the wavelength of their emitted light following excitation. Various florescence imaging approaches have been developed, depending on the source of fluorescence excitation, including single-photon, multiphoton, and super-resolution fluorescent microscopic imaging.

The most commonly used fluorescence indicators signal changes in intracellular calcium levels as a proxy for the electrical activity of neurons. While the temporal resolution of fluorescence calcium imaging is generally lower than that of electrophysiology, fluorescent imaging with genetically encoded calcium indicators enables simultaneous monitoring of many thousands of individually identified neurons in the behaving animal over several days to weeks and months.

In addition to calcium imaging, synthetic and genetically encoded fluorescent indicators of electrical activity (eg, genetically encoded voltage indicators [GEVIs]), neurotransmitter concentration reporters (eg, glutamate-sensing fluorescent reporter [GluSnFR]), activity states of intracellular signaling molecules, and gene expression provide rapidly expanding and versatile techniques for monitoring neural activity on multiple spatial and temporal scales.

At the same time, modern genetic approaches based on mRNA sequencing from individual neurons are revealing the numerous types of cells that contribute to population activity. Genetic-based approaches also allow defined types of neurons to be activated or silenced during an experiment, supporting tests of causality (Box 5–2).

Box 5–2 Optogenetic and Chemogenetic Manipulation of Neuronal Activity

Functional analysis of neural circuits relies on the ability to accurately manipulate identified circuit elements to elucidate their roles in physiology and behavior. Genetically encoded neural perturbation tools have been developed for remotely controlling neuron function using light (optogenetics) or small molecules (chemogenetics) that activate engineered receptors.

Genetically encoded foreign proteins can be expressed in molecularly, genetically, or spatially specified subsets of neurons using viruses or transgenic animals for subsequent selective perturbations of these cell populations. Optogenetic approaches involve the expression of light-sensitive proteins and subsequent light ...

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