Cross-Species comparison of cholinergic neuromodulation in mice and primates

Baylor College Of Medicine, Houston TX

Investigators

Abstract

Project Summary / Abstract The brain continuously regulates its internal states in order to efficiently and flexibly interact with the environment. Brain states vary at a global scale due to changes in arousal, whereas local changes are typically observed during selective attention. Although arousal and attention operate at different spatial scales, they have similar physiological signatures. However, the major limitation of our understanding of the impact of brain states on neuronal circuits is the fact that arousal and attention have mostly been studied separately and in different species. Indeed, despite clear similarities between neural correlates of arousal in the mouse and attention in the primate, research on brain states in the two species has proceeded largely in parallel, with very few direct collaborations between primate and rodent labs. Therefore, whether and how the mechanisms regulating brain states on different spatial scales intersect to jointly influence neuronal function and behavior is unknown. Furthermore, with few exceptions, attention and arousal have been typically examined in one brain area at a time, hence precluding our understanding of the coordination of brain states at global and local spatial scales, their neural mechanisms, and their influence on behavioral performance. Here, we propose to develop several technical capabilities that will allow us to study multiple features of brain state changes across quiescence, arousal, and attention in mice and monkeys. We will develop a workflow for performing large-scale electrophysiological and optical recordings from multiple cortical areas relevant for visual behavior, establish a complementary behavioral paradigm in both species, and validate an optogenetic approach to silencing feedback. These capabilities will allow us to test three central hypotheses in a subsequent R01: (1) brain state changes in the mouse are a subset of changes in the primate, with similar underlying mechanisms but different spatial scales (Aim 1 ); (2) selective attention is built on top of mechanisms that mediate fast changes in global arousal (Aim 2), and (3) feedback from higher areas onto specific neural cell types mediates selective attention and is gated by global neuromodulation (Aim 3). These experiments a will generate a potentially transformative multi-modal dataset for understanding the mechanisms of attention and arousal at single cell resolution, which will also advance our understanding of dysfunctional brain states and their impact on neurological disorders.