The National Institutes of Health (NIH) Brain Research Through Advancing Innovative Neurotechnologies® (BRAIN​) Initiative Cell Census Network (BICCN) has developed an atlas of cell types and an anatomical neuronal wiring diagram for the mammalian primary motor cortex, derived from detailed studies of mice, monkeys, and humans. More than 250 scientists at more than 45 institutions across three continents have collaborated to make the resource available. The atlas provides a foundation for more in-depth study of cell types in the rest of the mammalian brain. The findings appear as 17 associated papers published in a dedicated issue of the journal Nature.

“Thanks to this groundbreaking collaboration, we now have a comprehensive understanding of the brain cells found in the motor cortex of the brain and their basic functional properties,” said NIH director Francis S. Collins, MD, PhD. “The atlas will provide a springboard for future research into the structure and function of the brain within and across species.”

“There is an urgent need to develop therapies for brain-based disorders. Research conducted as part of BICCN will provide scientists with tools that enable precise targeting of cell types and neural networks by genomic therapy for disorders that affect thinking, memory, mood, and movement,” said Walter Koroshetz, MD, director of the National Institute of Neurological Disorders and Stroke.

One of the new studies, “The mouse cortico–basal ganglia–thalamic network,” by University of California, Los Angeles (UCLA) researchers demonstrates new insights into the wiring of a crucial brain circuit affected by Huntington’s and Parkinson’s disease. Their mouse study may lead to new therapeutic targets.

“The cortico–basal ganglia–thalamo–cortical loop is one of the fundamental network motifs in the brain,” write the researchers. “Revealing its structural and functional organization is critical to understanding cognition, sensorimotor behavior, and the natural history of many neurological and neuropsychiatric disorders. Classically, this network is conceptualized to contain three information channels: motor, limbic and associative.

Yet this three-channel view cannot explain the myriad functions of the basal ganglia. We previously subdivided the dorsal striatum into 29 functional domains on the basis of the topography of inputs from the entire cortex. Here we map the multi-synaptic output pathways of these striatal domains through the globus pallidus external part (GPe), substantia nigra reticular part (SNr), thalamic nuclei and cortex.”

The researchers sought to determine how the mouse brain is wired. They analyzed 600 pathways and cataloged nerve-cell connectivity to create a wiring diagram of critical brain circuits.

“Like any explorer traveling deep into uncharted territory, we make maps to guide future visitors,” explained Hong-Wei Dong, PhD, professor of neurobiology at the David Geffen School of Medicine at UCLA and lead senior author of the study. “My lab mapped out the circuitry of the mouse brain to enable other scientists to conduct more accurate experiments in mouse models of diseases like Parkinson’s or Huntington’s disease.”

Dong and his colleagues labeled a small number of individual neurons with a green dye, enabling the team to track their connections with other neurons through arm-like projections called axons and dendrites. These connections, called circuits, process and communicate distinct types of sensory information in the brain.

“We identified smaller circuits within the cortico-basal ganglia-thalamic loop that process information for specific functions,” explained Nicholas Foster, PhD, the study’s first author and a project scientist in Dong’s lab. “Some of these subcircuits enable the brain to control movement of the arms, legs, and mouth. Other circuits process emotional input or complex cognitive processes, such as learning the consequences of actions.”

The new findings can help scientists pinpoint smaller circuits that could go awry when neurological diseases progress.

“These subcircuits could reveal new treatment targets and serve as physiological benchmarks to measure the effectiveness of new drug treatments in preclinical experiments,” Foster said.

“Our results illuminate clearer paths for future studies to follow by illustrating how different brain structures organize into networks and communicate with one another,” concluded Dong. “These findings will enable scientists to better understand how dysfunction in one small brain region can undermine the function of its larger neural circuit.”

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