To date, researchers have gained substantial knowledge about microscopic components of the brain, such as proteins, cells and microcircuits, and about macroscopic patterns of human brain area activation across a wide variety of tasks. However, neuroscientists studying the mammalian brain presently lack credible explanations for how tens to thousands of cells - typically distributed across multiple, distant regions of the brain - act in concert to create mammalian cognition and behavior. This gap in understanding is due to the lack of data regarding the mechanisms by which cells in multiple brain areas coordinate their spiking dynamics, which in turn stems from a lack of technology that can visualize how cells interact across brain regions. We seek novel technology to watch how information is transformed between brain areas, e.g. from sensory to motor areas. Inventing ways to observe how cells interact across brain areas is essential if we are to comprehend global brain dynamics and disorders thereof. Understanding of brain malfunction is shifting towards increasingly sophisticated views, in which neurons of specific types exhibit improper patterns of ensemble activity. In principle, there are enormous opportunities for new therapies aimed at correcting aberrant patterns of circuit activity. A key dilemma is that we cannot take ful advantage of these opportunities until we know what are normal patterns of activity across brain areas and how these patterns go awry in disease or disorder. There are many rodent models of human brain disorders, but we cannot yet visualize how cells interact across brain areas in these models. Obtaining such large-scale data sets is key to identifying neurophysiologic signatures of brain malfunction and is a prerequisite for developing therapeutic ways to re-tune aberrant activity patterns. To study how large ensembles of neurons interact across multiple brain areas, we will build a robotic microscope, the 'Octopus', with 8 optical arms, each a two-photon microscope that can be flexibly positioned around the brain, to record neural dynamics in up to 8 brain areas concurrently in a head-restrained, awake behaving rodent. Octopus imaging will provide the first glimpses of how neural ensembles in multiple areas coordinate their dynamics during animal behavior. For the first time, we will be able to watch computational processing and the flow of information through multiple brain areas concurrently. The 8 regions under view could include multiple sensory or motor neocortical regions, cerebellar cortex, and sub-cortical areas. We will be able to visualize simultaneously the multiple stages of a sensorimotor transformation, how different regions contribute to a cognitive decision, or how brain areas work differently together across various stages of life or in different brain states. W will also be able to follow individual cells in the 8 areas over weeks and months, to observe the long-term dynamics of neural coding and plasticity. Overall, Octopus microscopy is a game-changing new approach and ideally suited for the EUREKA program.

Public Health Relevance

Today, for lack of appropriate technology there is scant information on how multiple brain areas coordinate their collective neural circuit dynamics. To break this barrier, we will build a robotic microscope, 'the Octopus', with eight remotely controlled movable arms, each arm a two-photon microscope, for imaging neuronal dynamics in up to eight brain areas (deep or superficial) concurrently in behaving rodents. The Octopus microscope will yield new knowledge about the intercommunications between brain areas that will be critical to understanding how healthy and diseased brains operate and malfunction.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Special Emphasis Panel (ZMH1)
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Buhring, Bettina D
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Stanford University
Biomedical Engineering
Schools of Medicine
United States
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Lecoq, Jérôme; Savall, Joan; Vu?ini?, Dejan et al. (2014) Visualizing mammalian brain area interactions by dual-axis two-photon calcium imaging. Nat Neurosci 17:1825-9