Neurogenetic analysis of value-based decision making

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Project Summary Dysfunctional decision making can have devastating impacts on individuals and on society. Many types of decision making are therefore under vigorous investigation. This proposal emphasizes value-based deci- sions, in which the chooser selects among options based on his subjective assessment of their value. A deeper understanding of this behavior is needed to develop the best possible treatments for decision making disorders, including the many forms of addiction and the cognitive deficits that accompany mental illness, brain injury, and neurodegenerative disease. Consumer choice is one of the best studied forms of value-based decisions. Studies reveal that our economic personalities have a significant genetic basis, but it is difficult to trace causal links between genes and behavior in humans. In response, geneticists often turn to simpler invertebrate organisms like the nema- tode worm C. elegans in which the functions of genes nearly identical to their human equivalents can be inves- tigated more rapidly, completely, and at a fraction of the cost. Until now, evidence that nematodes are truly ca- pable of value-based decision making has merely been suggestive. However, economists have developed mathematically rigorous testing procedures for determining whether decisions are based on subjective value. The PI's laboratory has developed microfluidic devices that enable this test to be done on nematodes deciding between high-quality food that is relatively abundant and low-quality food that is more scarce. The results meet all the criteria of value-based decision making. Previous work has identified a circuit of sensory neurons, interneurons, and motor neurons that controls head movements as the worm makes decisions about which food to eat. Using a combination of functional im- aging (Aim 1), optical manipulation of neuronal activity (Aim 2), and neuronal ablations (Aim 3), the proposed research will identify contribution each neuron makes to value-based decisions. A central question is how food value and abundance are represented in the circuit and how this representation is read-out in behavior. Aim 4 constructs a mathematical model based on data from Aim 1 and tests it using data from Aims 2 and 3. Successful completion of the proposed research yields a biologically realistic computational model of the neuronal mechanism of value-based decision making in a compact circuit than can, in principle, be under- stood completely. This work provides a foundation for understanding value-based decisions in more complex circuits. The work also lays the cornerstone for genetic analyses, at single-neuron resolution, of orthologs of human genes identified in association studies related to decision making. The research is broadly significant because it establishes a new biological system in which to analyze at single-neuron resolution the interaction of genes previously associated with decision making in humans, and to discover novel genetic pathways in- volved in this behavior.