High-throughput Physiological Micro-connectivity Mapping in Vivo

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PROJECT SUMMARY Mapping the synaptic connectivity of brain circuits is essential for obtaining a mechanistic understanding of the neural basis of behavior, learning, and cognition. While anatomical approaches can reveal the physical architecture of neural circuits, only a functional approach can reveal the strength and dynamics of each synapse in a network. These parameters are crucial for building any type of quantitative and explanatory model for how neural circuits compute, encode, and store information. This proposal brings together three teams with complementary expertise in holographic optogenetics and electrophysiology (Adesnik), high resolution volumetric imaging (Ji) and statistical modeling and real-time experimental design (Paninski), to develop two new technologies that will be able reveal much of the physiological connectome of single neurons in the brain. The first approach combines high resolution multiphoton photo-stimulation in vivo with single cell intracellular electrophysiology in the intact brain, and statistical algorithms that permit high-throughput mapping of the targeted neuron's presynaptic connectome. The second approach employs the same photo-stimulation system, but leverages optical reporters of activity in individual synapses to achieve the all-optical measurement of synaptic connectivity in a cortical network chronically over time. These two new technologies will allow neuroscientists to obtain the quantitative data on the physiological micro-connectivity of cortical networks across large fractions of the cortex. The first approach provides unparalleled measurements of synaptic strength and dynamics of each identified synaptic connections. The second approach permits the repeated assessment of the micro-connectivity of the same neurons in the same animal over many days, finally opening up the opportunity to map the reorganization of brain circuitry over the course of development, learning, or the progression of brain disease.