PROJECT SUMMARY A goal of the BRAIN initiative is to develop and validate novel tools to map and manipulate neural circuits. The definition and control of behaviorally relevant circuits requires both retrograde and anterograde trans-synaptic technologies that perform well in vivo.
Project Summary Neuroscience stands at the precipice of a new depth of understanding about how the brain works thanks to recent advances in imaging data acquisition technologies such as light-sheet fluorescence microscopy (LSFM). How- ever, the lack of analytic tooling to mine this rich information's relationship across samples, timepoints, and data acquisition technologies prevents researchers from unlocking quantitative relationships. We propose the creation of an easy-to-use, distributed-computation image registration tools that will map large images into a common reference frame.
PROJECT SUMMARY Tools for exclusively targeting neuronal and glial subtypes are needed to advance our understanding of the brain. “Intersectional” systems improve targeting by restricting “reporter/effector” transgenes to a subdomain defined by the expression overlap between two activating factors. “Split-driver” systems have enhanced targeting precision in flies and are operable in fish, but have yet to be systematically deployed in vertebrate systems.
Abstract The brain is remarkably complex, and our understanding of this organ is still in its infancy. Many fundamental questions about brain development and function remain. Single cell genomics promises new ways to answer these questions, but nearly all single-cell methods share shortcoming – cells are destroyed when their molecular states are measured.
PROJECT SUMMARY Methods for regulating cellular processes within distinct populations of neurons are needed to elucidate relationships between molecular mechanisms, circuits, and behavior; and to develop cell type- or circuit- selective treatments for neurological disorders. We propose a novel, non-genetic, small molecule method— transcription factor-chemically induced proximity (TF-CiP)—that harnesses the cell type- and circuit-specificity of endogenous transcription factors to regulate gene expression in subsets of neurons.
Project Summary Despite the rapid advances in the neuroimaging research workflow over the last decade, the enormous variability between and within data types and specimens impedes integrated analyses. Moreover, the availability of a comprehensive portfolio of software libraries and tools has also resulted in a concerning degree of analytical variability.
PROJECT SUMMARY/ABSTRACT Critical advances in the treatment of human brain disorders are hindered by our inability to specifically target dysfunctional circuitry in a safe and noninvasive manner. Existing noninvasive techniques (e.g., transcranial magnetic, electrical, and ultrasound neuromodulation) activate many brain circuit components within the targeted region, and their efficacies are difficult to control.
PROJECT SUMMARY Although genetic tools have dramatically advanced our understanding of brain function, they have largely been confined to mice. While mice are essential models for many areas of neuroscience, there are also many aspects of higher brain function that cannot be adequately modeled in rodents. Similarly, many brain disorders affect higher cognitive functions that have no clear parallels in rodents. Furthermore, recent large- scale single cell transcriptomic analyses have revealed many neuron types, connections and gene expression patterns that are unique to primates.
Primate brains contain cortical areas that exhibit selective engagement in high-level sensory or behavioral operations. The functional specialization of these regions is thought to be central to primate-specific cognitive faculties and to associated disorders. Deciphering the origins of functional specialization in primate brain regions has been an enormously challenging task, however, due in large part to the absence of suitable experimental tools.
Project Summary/Abstract The goal of this work is to facilitate synaptic level analysis of neurons and their interconnecting microcircuits in neurosurgical cerebral cortex biopsies from human patients. These full-thickness human cerebral cortex biopsies will be provided by neurosurgical colleagues from patients undergoing resective surgery or surgical implantation of leads for deep brain stimulation (DBS).
