Corticostriatal and Corticoinsular Circuit Mechanisms Underlying Stress Effects on Effort-based Reward Processing

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Project Summary The ability to effectively weigh costs and benefits for action selection is integral to survival. Many environmental and internal factors influence the decision to pursue reward in the face of costs such as energy expenditure. This type of decision making, referred to as “effort valuation” allows individuals to navigate circumstances in which effort and reward contingencies change and to maximize the utility of actions. Effort valuation is often impaired in individuals suffering from disorders of motivation including depression and schizophrenia, whereby they may perceive the anticipated effort cost to outweigh the value of expected rewards. Disrupted signaling in the anterior cingulate cortex (ACC) is known to impair effort valuation and bias individuals toward suboptimal behavioral responses, however, the precise function of discrete ACC circuits in encoding reward- and effort-related information and enabling this behavior remains unknown. We will integrate in vivo 2-photon calcium imaging (Aim 1), and optogenetics (Aim 2) to delineate the roles of two projection-defined ACC subtypes - corticostriatal and corticoinsular neurons – in encoding of task features including reward- and effort-predictive cues. Clinical and preclinical evidence suggests that these subcortical structures (the nucleus accumbens and insular cortex) are critically involved in driving goal-directed behavior and monitoring internal state, respectively, processes that may support different aspects of effort valuation. To facilitate these experiments, we have developed and validated an imaging-compatible effort valuation task which enables measurement of motivational (anticipatory) and hedonic (consummatory) reward seeking behavior in low- and high-effort conditions. Using this task, we will determine the effects of chronic psychosocial stress, a risk factor for depressive symptoms, on effortful reward seeking and circuit function (Aim 3). Importantly, only a subset of individuals who experience stress develop depression while many remain `resilient.' Uncovering the neurobiological bases for individual differences in susceptibility to stress is important to understanding the etiology of psychiatric disorders. In the independent phase, we will explore these differences through single-cell transcriptomic interrogation of corticostriatal and corticoinsular neurons in stress-susceptible and resistant animals in the hope of uncovering novel molecular pathway candidates to inform therapeutic targets. Training in circuit dissection and individual and population- level neural activity data analysis will be provided by the primary mentor, Dr. Liston, and complemented by Drs. Victor and Rajasethupathy with all available resources in their labs at Weill Cornell Medicine and Rockefeller University. As co-mentor, Dr. Macosko (Harvard Medical School), will train the candidate in single-cell RNA- sequencing methods with local support from Dr. Anrather. Dr. Nestler (Mt. Sinai) will provide additional guidance on animal models of stress. The candidate's mentors and External Advisory Committee will facilitate her transition to an independent research program focused on circuit mechanisms of motivated behavior in healthy and disease states, through the implementation of a structured and comprehensive training plan.