CAREER: A cortex-basal forebrain loop enabling task-specific cognitive behavior

About This Grant

Cognitive flexibility, or the ability to make different decisions to meet ever-changing demands from the environment, is essential for the survival of humans and other animals. To support this key ability, the brain needs to reorganize its activity patterns depending on the current behavioral context, but we still understand little about how this functional reorganization is accomplished. This project will investigate this fundamental question by asking how multiple mouse brain regions act in concert to support task switching, a common type of flexible cognitive behavior. Beyond leading to better understanding of basic brain mechanisms, this research could inform future work that aims to treat cognitive inflexibility, which is pervasive in brain disorders like autism, schizophrenia, and dementia. The project will also have other broader societal impacts. First, it will provide numerous opportunities for undergraduate and graduate education in neuroscience. Second, it will include outreach to schoolteachers and children to raise awareness about the detriments of excessive task switching, which has vastly increased with pervasive digital technologies like smartphones and particularly affects learning in school-aged children. The central goal of this proposal is to contrast two competing models of how the brain reorganizes its activity patterns task dependently: in the intracortical model, task-specific activity is fully generated within the cerebral cortex. In the external input model, extra-cortical input is required to actively reorganize cortical activity, enabling new cognitive computations. Based on preliminary studies, the hypothesis is that a loop between the prefrontal cortex, the cholinergic basal forebrain and the rest of the cortex is a key multi-region circuit that enables the generation of cortex-wide activity patterns depending on cognitive demands, compatible with the external input model. The project will use mice as the model organism due to their unique combination of sufficiently complex cognitive behavior and availability of experimental tools. It will leverage a new behavioral paradigm for head-fixed mice making navigational decisions in virtual reality, in which they switch between a simple and a complex task dozens of times within a behavioral session. This paradigm will be combined with cutting-edge genetic and optical tools to record and perturb different nodes of the hypothesized circuit loop, with cell-type and projection specificity. Further, statistical and mechanistic modeling will be employed to link neural activity patterns to task-specific behavior and extract generalizable computational principles from this specific circuit. Thus, this project will bring together recent developments in behavioral, computational, and circuit-dissection technologies to gain mechanistic insight into task switching, a canonical form of flexible cognitive behavior. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.