Cooperative Agreements

ABSTRACT Recent years have seen a boon in the development of new molecular, genetic and imaging tools designed to dissect brain circuits that give rise to behavior in live animals. Although investment in these efforts is yielding fantastic returns, an accounting of the definition and function of neuronal circuits underlying higher mental function requires that these tools be extending into animal models capable of performing more sophisticated cognitive tasks. Ideally, this would be an animal model with a brain that most closely resembles that of the human brain.

Project Abstract/Summary The brains of mammals contain an extraordinarily large number of neurons whose activity and interconnections determine the function of circuits that monitor our sensory environment, dictate our motor choices, form memories, and guide all behavior. However, we do not understand how the activity of these circuits governs brain activity. A fundamental limitation has been the inability to monitor and control the activity of a genetically and anatomically known brain cells.

One of the central goals of the BRAIN initiative is to develop and disseminate methods for imaging activity in large populations of neurons at high speeds. Of the available techniques, one of the most promising is light sheet microscopy.

Abstract Swept confocally aligned planar excitation (SCAPE) microscopy is a method for high-speed, cellular level imaging of living, intact tissues.

Project Abstract This project is a pilot clinical trial of a new brain stimulation treatment for obsessive-compulsive disorder. OCD is a mental illness that affects 4-7 million people in the US. Of those, 50-70% still have substantial symptoms after being treated with medication or talk therapy. Recently, clinicians have started trying to treat OCD with deep brain stimulation (DBS). DBS involves surgically placing electrodes into the brain, then sending electrical stimulation currents through those electrodes.

 DESCRIPTION (provided by applicant): The goal of this proposal is to develop new methods for high speed monitoring of sensory-driven synaptic activity across all inputs to single living neurons in the context of the intact cerebral cortex. Although our focus is on understanding how synaptic inputs are integrated across a single neuron embedded in an intact circuit, the next generation random access imaging technology we propose is more broadly applicable for monitoring multi-cellular activity representing large intra-and inter areal neuronal networks.

 DESCRIPTION (provided by applicant): We propose to combine whole brain 2-photon imaging of neural activity in behaving larval zebrafish with detailed anatomical and connectivity information extracted from the same animals. The final goal is to generate quantitative models of brain wide neural circuits that explain the dynamic processing of sensory information as well as the generation of motor output by these circuits. Anatomical data will be generated by two complementary technologies: 1) whole brain EM data sets will be prepared from the same fish that were used for calcium imaging.

 DESCRIPTION (provided by applicant): Perceptual decision-making involves multiple cognitive components and diverse brain regions. To perform a perceptual decision, an individual must process an incoming sensory percept, retain this information in short- term memory, and choose an appropriate motor action. Research using delayed-response tasks in nonhuman primates has revealed that sensory and choice information is distributed across a hierarchy of cortical areas, with task-relevant information flowing from sensory to association to motor regions.

 DESCRIPTION (provided by applicant): Two-photon microscopy is a widely used, key method for functional imaging of cellular activity in living animals. Most recently, in vivo calciu imaging experiments have started to reveal the spatiotemporal activity patterns that occur in various areas of the neocortex during head-fixed mouse behavior. Typically, however, the field-of- view for imaging cellular activity is fairly small, on the order of a few hundred micrometers.

 DESCRIPTION (provided by applicant): Two of the most fundamental questions of sensory neuroscience are: 1) how is stimulus information represented by the activity of neurons at different levels of information processing? And 2) what features of this activity are read by the higher brain areas to guide behavior? The first question has been the subject of a large body of work across different sensory modalities. To answer the second question, one needs to establish a causal link between neuronal activity and behavior.