The synapse is the principle active signaling component of the brain's neuronal circuitry. Synapses are highly complex, plastic, strongly modulated and deeply diverse entities, and their molecular complexity and diversity are fundamental to all synaptic circuit development and function. Moreover, many or most neurodevelopmental, psychiatric, and neurodegenerative disorders are rooted in abnormalities of the brain's vast and highly heterogeneous synapse populations. Unfortunately, such disorders are poorly understood and difficult to diagnose, prevent, and treat because we lack adequate tools to measure the brain's vast and highly diverse synapse populations, and because most of the limited tools in use today can be applied only to experimental animals such as mice. An interdisciplinary consortium comprising neurobiologists, biophysicists, clinicians, mathematicians and computer scientists here proposes development of a very ambitious "synaptomic" analysis pipeline that will transform the science of synaptic network function and disorders in both experimental animal and human brains. This novel high-throughput pipeline, based on powerful new array tomography methods, will enable measurement, analysis, and modeling of heterogeneous synapse and neuromodulatory fiber populations with unprecedented precision. The synaptomic pipeline will be demonstrated initially by developing "synaptomes" to model the heterogeneous synapse populations of mouse and human frontal and temporal lobes. Pipeline resources and data will then be shared via an Open Synaptome Project that will facilitate the development of synaptomes describing synapse populations of additional brain regions and species. These efforts are expected to provide a new foundation for understanding the basic mechanisms of mammalian brain function, and to offer new quantitative perspectives on both similarities and differences between mouse and human brain that will be critical to leveraging animal research opportunities for the improvement of human mental health. Because abnormalities of synapses and their neuromodulation are prime suspects in numerous human mental health disorders, the development and sharing of synaptomic pipeline resources and data proposed here are likely to catalyze rapid progress in clinical neuroscience.

Public Health Relevance

Many neurodevelopmental, psychiatric and neurodegenerative disorders are rooted in abnormalities of the brain's vast and diverse synapse populations. Unfortunately, such disorders are poorly understood and difficult to diagnose, prevent and treat because we lack adequate tools to measure these synapse populations, and because too many of today's limited tools can be applied only to experimental animals such as mice. The powerful new synaptomic resources proposed here will answer the need for faster and more precise analysis of heterogeneous synapse populations in both humans and experimental animals and thus will help to leverage the lessons from animal research much more directly to the improvement of human mental health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS092474-01
Application #
8755463
Study Section
Special Emphasis Panel (ZRG1-BCMB-A (51))
Program Officer
Talley, Edmund M
Project Start
2014-09-30
Project End
2019-06-30
Budget Start
2014-09-30
Budget End
2015-06-30
Support Year
1
Fiscal Year
2014
Total Cost
$1,918,904
Indirect Cost
$388,241
Name
Allen Institute for Brain Science
Department
Type
DUNS #
137210949
City
Seattle
State
WA
Country
United States
Zip Code
98103