The ability to estimate the probabilities of different outcomes is a cognitive function critical for decision- making in uncertain environments. A pervasive feature of human decision-making is probability distortion: humans tend to overweight small probabilities and underweight large probabilities. For example, when individuals decide to purchase insurance or play the lottery, these decisions are influenced by how likely they perceive low probability outcomes to be. Decision-making is disrupted in psychiatric disorders including schizophrenia and bipolar disorder. Therefore, a circuit-level understanding of how the brain represents probabilistic outcomes during decision-making has enormous consequences for human health. I will use high-throughput behavioral training to develop behavioral paradigms for studying probability distortion in rats, enabling application of powerful tools to monitor and manipulate neural circuits (Aim 1, K99 phase). I have recently developed a system that enables cellular resolution imaging of large populations of neurons in rats performing cognitive behaviors during voluntary head-restraint. I will use this system, combined with newly developed transgenic rats expressing the calcium indicator GCaMP6f, to record from 100s-1000s of cortical neurons as behaving rats estimate probabilities (Aim 2, K99 phase). I will develop and apply decoding methods to explicitly test hypotheses about how neural populations represent probabilities. Combining the imaging data and decoding methods, I will determine the stage of cortical processing at which probability distortion emerges (Aim 2, K99 phase). Finally, I will perform optogenetic and pharmacological perturbation experiments to delineate the functional causal circuits underlying probability distortion (Aim 3, R00 phase). I will then combine optogenetics and two-photon imaging of interconnected brain regions, to evaluate how representations of probability propagate across and are represented by multiple brain regions. Together, these experiments will establish the rat as a cost-effective, tractable mammalian model for studying probability distortion, and will produce well-informed working models of the relevant circuits and mechanisms by which animals compute, represent, and distort estimates of probabilities. The rat voluntary head-restraint imaging system has been exclusively developed as part of a collaboration between the Tank and Brody laboratories, making Princeton the only place for me to learn these techniques. In addition, the strong, collaborative environment at the Princeton Neuroscience Institute makes it an ideal place for me to pursue these research goals. My training plan provides a detailed strategy for acquiring the necessary skills in the K99 phase from a team of co-mentors with extensive, proven expertise in the relevant techniques. Technical training, as well as frequent data presentations, attendance of professional courses, seminars, and conferences, and development of my writing and leadership skills, will allow me to transition to an independent position. In the independent R00 phase, I will use these acquired skills to complete the proposed aims and build a laboratory focused on the study of probability distortion and decision- making using innovative behavioral, imaging, computational, and optogenetic approaches.
Humans exhibit distorted estimates of probabilities. This proposal will combine novel behavioral, computational, circuit perturbation and two-photon imaging techniques in rats to gain a mechanistic understanding of how the probabilities of different outcomes are computed, represented, and ultimately distorted in the brain. The system I will develop in this proposal will provide a platform for understanding a key aspect of decision-making, estimation of outcome probabilities and evaluation of risk, that is severely disrupted in psychiatric disorders such as schizophrenia and bipolar disorder.
