A 5-dimensional connectomics approach to the neural basis of behavior

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Project Summary / Abstract This project is a collaboration between researchers at four universities to examine how the brain makes decisions. When a human or any animal moves through the world, it must make constant decisions about what to do next. These decisions are based on the state of the animal, its past history, and its future goals. In most animals, it is difficult or impossible to examine the neural mechanisms underlying the translation of a decision into an actual motor act because of the complexity of the neural computation, the number of neurons involved, and the complexity of the physical change produced by the movement of the animal. To reduce all three of these complexities, this project examines foraging decisions made by the brain of a nudibranch mollusc, Berghia stephanieae. This sea slug has fewer than 7000 neurons and they are identifiable as individuals or as members of particular classes. This project will map out all of the synaptic connectivity of the brain (the connectome) by serially sectioning the brain and reconstructing neurons and synapses from electron microscopic images. The RNA expressed by each of the neurons in the brain will sequenced and their transcriptomes mapped onto each neuron in the connectome. This will allow neuromodulatory connectivity to be inferred and overlaid on the synaptic connectivity, producing a “neuromodulome”. The project will develop CRISPR/cas9 gene editing techniques for this “non-model” organism, allowing genetically-encoded sensors and activators to be expressed in neuron classes. The decision-making process will be observed in a closed-loop semi-intact preparation where the brain of the animal controls a virtual environment that the brain navigates through using its own neural commands. Multiple neurons at a time will be recorded from using voltage-sensitive dyes or genetically-encoded sensors. This real-time neural spike activity will be mapped onto the connectome, allowing the dynamics of the circuitry to be observed. Mathematical and statistical methods will be used to analyze these dynamic networks. The result will be the algorithm and its implementation in the brain of the sea slug. The project will then examine how this circuit changes as the brain and the body grow and add neurons. Understanding how neural circuits add neurons while continuing to function is an important basic research question that links directly to human disease because adult neurogenesis in humans has been linked to many cognitive and mood disorders.