Abstract

A central goal of neuroscience is to understand how populations of neurons coordinate and cooperate in order to give rise to perception, cognition, and action. Nonhuman primates (NHPs) are an attractive model with which to understand these mechanisms in humans, primarily due to the strong homology of their brains and the cognitively sophisticated behaviors they can be trained to perform. Using electrode recordings, the activity of one to a few hundred individual neurons may be measured electrically, which has enabled many scientific findings and the development of brain-machine interfaces. Despite these successes, electrophysiology samples sparsely from neural populations and provides little information about the genetic identity and spatial micro-organization of recorded neurons. These limitations have spurred the development of all-optical methods for neural circuit interrogation. Fluorescent calcium signals serve as a reporter of neuronal responses, and when combined with post-mortem optical clearing techniques such as CLARITY, provide dense recordings of neuronal populations, spatially organized and annotated with genetic and anatomical information. Here, we advocate that this methodology, which has been of tremendous utility in smaller animal models, can and should be developed for use with NHPs. We review here several of the key opportunities and challenges for calcium-based optical imaging in NHPs. We focus on motor neuroscience and brain-machine interface design as representative domains of opportunity within the larger field of NHP neuroscience.

Highlights

  • Neuroscientists seek to understand the function and dysfunction of the nervous system, with an eye towards comprehending and supporting the health of the human brain

  • We focus here on the use of calcium imaging in the study of the cortical motor system, both in the realm of basic science and the development of brain-machine interfaces, but certainly similar opportunities for optical imaging exist in other brain regions and across the spectrum of perception, cognition, and action (Belmonte et al, 2015; Miller et al, 2016)

  • Electrophysiology provides a wealth of information about the types of responses neurons exhibit and the oscillatory electrical rhythms that accompany neural computation in neural circuits

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Summary

Introduction

Neuroscientists seek to understand the function and dysfunction of the nervous system, with an eye towards comprehending and supporting the health of the human brain. Whereas electrical measurements accurately capture neuronal spiking, optical methods can provide a complementary view of neural activity that is substantially richer in many ways, contextualizing patterns of neural activity within a genetically annotated, spatially localized, dense map linking circuit structure with function (Deisseroth and Schnitzer, 2013; Peron et al, 2015; Emiliani et al, 2015) These tools have already transformed the study of neural circuits in small animal models, including worms, zebrafish, flies, and rodents, and promise to open new avenues of research to probe a variety of neuropathologies in nonhuman primate models of Experimental Pipeline a b Chamber geometry. We proceed by exploring the limitations of electrophysiology, explore the avenues of scientific inquiry we feel would be especially well-served by optical approaches within the cortical motor system, and highlight some of the challenges in developing the primate optical experimental approach we envision

Limitations of electrophysiology and the development of optical methods
Relating dynamics of neural populations to circuit organization
Clarifying the functional macroscopic organization of motor cortex
Optical dissection of therapeutic neural stimulation and sensory write-in
Insights from optical methods for brain-machine interface design
Decoding algorithms for large neuron counts
Challenges of optical measurement in NHPs
Imaging in monkeys: data collection challenges
Concluding remarks
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