Neural Mechanisms and Neuromodulation of Affective States

PROJECT SUMMARY Violations of our expectations result in prediction-error signals in the brain. When these prediction errors are repeatedly experienced, they can influence our current affective state, mood, and ultimately behavior. Despite this understanding, the brain circuits and patterns of activity within the circuits that translate these prediction error signals into affective state fluctuations is unknown. Uncovering this is fundamental to gaining insight into the neural basis of moods in healthy people, what becomes dysfunctional in pathological states like depression, and for the development of new treatments that focally target these circuits. The experiment in this proposal will combine high-density, multi-region, neurophysiology with state-of-the-art computational models to determine neural and physiological biomarker of mood-like states in macaques. During the K99 phase of this proposal, I will train with Drs. Rudebeck (primary mentor), Mayberg (co-mentor) at the Icahn School of Medicine at Mount Sinai and Dr Rutledge (co-mentor) at Yale to test the hypothesis that a recent history of negative or positive prediction errors will cause changes in affect through different subgenual cingulate cortex circuits that are specific to the type of prediction violation encountered. This will be achieved by combining computational models of affect with the simultaneous recording of activity across multiple limbic and prefrontal brain circuits while awake non- human primates perform multiple different reward-based tasks that manipulate the recent history of prediction errors. Next, I will focally target activity in these brain circuits using non-invasive transcranial focused ultrasound aimed at subgenual cingulate cortex while concurrently recording activity from its interconnected brain areas. The NIH K99/R00 Pathway to Independence Award will give me the unique opportunity to receive a multi- disciplinary and technical training under the K99 portion. This will include training in the acquisition and analysis of single-neuron and population activity, computational modeling, and how insights from basic research can influence the clinic. In addition, during this phase I will receive career-shaping training in how to lead my own laboratory (i.e. managing people, writing a grant and networking), translate research from the laboratory to clinical settings, apply to and obtaining a tenure rack position at a top-tier academic research institution. In the R00 phase of the proposal I will combine neurophysiology with transcranial focused ultrasound to test the hypothesis that causal manipulation of the history of reward prediction error in subgenual cingulate cortex stabilize affective state fluctuations. The work proposed will provide strong preliminary data on the neural and computational mechanisms of affect and a non-invasive ultrasound protocol to modulate neural activity within these circuits data. This will be foundational for my lab’s first grant applications and to establish myself as a successful principal investigator causally investigating the neural basis of affective states in healthy brains as well as in disease.