Role of prefrontostriatal circuits in effort-based, cost-benefit decision making

项目摘要 在适应性决策过程中，对成本效益权衡的持续评估指导行动选择。当 结果发生变化时，重新评估潜在行动的效用，以确定是否坚持或偏离 现有的战略。在成本效益决策背后的神经机制的干扰可能导致 病理行为（例如，成瘾、强迫症、抑郁/焦虑）。基于努力的决策具体来说是 在抑郁症、精神分裂症和物质使用障碍患者中被破坏。虽然病态 在这些情况下的行为与前额叶皮层和纹状体的功能障碍有关，我们缺乏详细的 神经生物学的理解，设计有针对性的治疗干预措施。我们将解决这一赤字 使用尖端工具测量和操纵自由行为动物的神经活动。我们将测试 前扣带皮层（ACC）向丘脑核（NAc）投射神经元特异性假说 根据新的努力-回报权衡，对行动选择策略的更新进行编码，并将其输入到NAc 实例化新的、有效的选择策略。在目标1中，我们将使用小型化的头戴式显微镜， 确定ACC和ACCàNAc投射神经元活动是如何组织的，以表示与努力相关的成本。 影响行动选择的利益计算。在目标2中，我们将操纵ACCàNAc的活性， 投射神经元与光遗传学，在灵活的决策过程中，由努力相关的价值变化驱动。 最后，在目标3中，我们将重点关注前额叶向NAc的投射，测量和抑制ACCàNAc的活动 终端和比较输入眶额皮质（OFC）。我们将在决策过程中这样做 在努力和延迟成本的背景下，作为进一步完善我们对NAC如何集成的理解的工具， 前额叶输入并将其转化为行动选择。这一建议直接解决了迫切需要， 了解细胞类型和电路特定的机制，介导成本效益决策。我们 研究可以为各种药物、心理治疗和脑刺激干预提供信息， 以无序的成本效益评估和决策为特征的精神疾病。

PROJECT SUMMARY Ongoing evaluation of cost-benefit tradeoffs guides action selection during adaptive decision making. When outcomes change, the utility of potential actions is re-evaluated to determine whether to persist or deviate from an existing strategy. Disturbances in the neural mechanisms underlying cost-benefit decision making can lead to pathological behavior (e.g., addiction, OCD, depression/anxiety). Effort-based decision making is specifically disrupted in patients with depression, schizophrenia and substance use disorders. Although pathological behavior in these conditions is linked to dysfunction in the prefrontal cortex and striatum, we lack the detailed neurobiological understanding necessary to design targeted therapeutic interventions. We will address this deficit using cutting edge tools for measuring and manipulating neural activity in freely behaving animals. We will test the specific hypothesis that anterior cingulate cortex (ACC) to nucleus accumbens (NAc) projection neurons encode updates to action selection policies based on new effort-reward tradeoffs, and that inputs to the NAc instantiate new, effortful choice strategies. In Aim 1, we will use miniaturized head-mounted microscopes to determine how ACC and ACCàNAc projection neuron activity is organized to represent effort-related cost- benefit computations influencing action selection. In Aim 2, we will manipulate the activity of ACCàNAc projection neurons with optogenetics, during flexible decision making driven by changes in effort-related value. Finally, in Aim 3, we will focus on prefrontal projections to the NAc, measuring and inhibiting activity at ACCàNAc terminals and comparing with inputs from the orbitofrontal cortex (OFC). We will do this during decision making in the context of both effort and delay-costs as a tool to further refine our understanding of how NAc integrates prefrontal inputs and translates these into action selection. This proposal directly addresses a pressing need to understand the cell-type and circuit-specific mechanisms that mediate cost-benefit decision making. Our research can inform pharmacological, psychotherapeutic and brain stimulation interventions for a variety of psychiatric conditions characterized by disordered cost-benefit evaluations and decision making.