Reward Encoding and Anxiety

项目 总结/摘要 焦虑 是 一 大多数精神疾病的衰弱症状，包括创伤后应激障碍，重度抑郁症， 精神分裂症自闭症和成瘾焦虑症的治疗主要限于苯二氮卓类药物， 滥用的可能性，并产生多种认知和行为副作用，包括增加倾向， 患上痴呆症替代治疗或预防策略的设计取决于更好的 理解焦虑的神经基础。虽然动物研究已经告诉我们， 恐惧和焦虑的功能神经解剖学，现实生活中焦虑的负面影响超出了厌恶 情绪和涉及中断正在进行的目标导向的行为。例如，焦虑与 缺乏灵活的控制奖励驱动的行动和表达的动机行为时，它是受 一个令人厌恶的结果的风险这些行为缺陷的神经基础在很大程度上是未知的。因此 驱动本申请实验目标的首要研究问题是：焦虑如何影响 目标导向行为的神经元编码为了解决这个问题，实验的一个主要挑战是 一种方法是创造一种焦虑的背景状态，这种状态不会阻止动物进行目标导向的行为， 在多个区域的电生理记录期间奖励任务。有见及此，我们建议 使用两种互补的焦虑实验模型，结合创新和临床相关的 行为任务，同时测量涉及奖励的两个区域的神经元之间的动态协调 处理和灵活控制行为：腹侧被盖区（VTA）和背内侧前额叶皮层 （dmPFC）。具体的目标是基于计算式模型设计的，其假设是 初步数据支持：（1）行为差异（控制和焦虑状态之间）是特定于 冲突或厌恶结果风险下的行为选择条件;（2）差异 在冲突/厌恶结果期间观察到神经元活动的（控制和焦虑状态之间）， 包括减少募集的行动编码神经元在dmPFC和破坏协调之间 dmPFC神经活动和VTA多巴胺神经元。这种方法是新颖的和有意义的，因为 神经计算对与焦虑等症状相关的异常神经活动的理解， 确定生物标志物和临床测量，描述这些症状的病因和生理。

PROJECT SUMMARY/ABSTRACT Anxiety is a debilitating symptom of most psychiatric disorders including PTSD, major depression, schizophrenia, autism and addiction. Treatment of anxiety is mostly limited to benzodiazepines, which have abuse potential and produce multiple cognitive and behavioral side effects, including increased propensity to develop dementia. Design of alternative treatments or prevention strategies is contingent upon a better understanding of the neuronal basis of anxiety. While animal studies have so far informed us about the functional neuroanatomy of fear and anxiety, the negative impact of real-life anxiety extends beyond aversive feelings and involves disruptions in ongoing goal-directed behaviors. For example, anxiety is associated with deficits in flexible control of reward-driven actions and expression of motivated behavior when it is subject to the risk of an aversive outcome. The neural basis of these behavioral deficits is largely unknown. Thus, the overarching research question that drives the experimental aims of this application is: How does anxiety affect neuronal encoding of goal-directed behaviors? To address this question, a major challenge of the experimental approach is to create a background state of anxiety that does not prohibit animals to perform goal-oriented and rewarded tasks during electrophysiological recordings from multiple regions. With this in mind, we propose to use two complementary experimental models of anxiety in combination with innovative and clinically relevant behavioral tasks while measuring dynamic coordination between neurons of two regions implicated in reward processing and flexible control of behavior: ventral tegmental area (VTA) and dorsomedial prefrontal cortex (dmPFC). Specific aims are designed based on a computational-style model with assumptions that are supported by preliminary data: (1) behavioral differences (between control and anxiety states) are specific to conditions that involve action selection under conflict or the risk of an aversive outcome; (2) differences (between control and anxiety states) in neuronal activity are observed during conflict/aversive outcomes and involve diminished recruitment of action encoding neurons in dmPFC and disrupted coordination between dmPFC neural activity and VTA dopamine neurons. This approach is novel and significant because a neurocomputational understanding of aberrant neural activity relevant to symptoms such as anxiety can help identify biological markers and clinical measures that delineate etiology and physiology of those symptoms.