CRCNS Research Proposal: Cortico-amygdalar substrates of adaptive learning

CRCNS 研究提案：适应性学习的皮质杏仁核基质

• 批准号: 10598322
• 负责人: Alicia Izquierdo
• 金额: $ 31.42万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10598322
• 关键词: Adaptive Behaviors; Amygdaloid structure; Anterior; Area; Behavioral; Brain; Calcium; Clinical; Computer Models; Data; Environment; Exhibits; Failure; Future; Human; Image; Individual; Learning; Measurement; Modeling; Neurons; Outcome; Pathway interactions; Prefrontal Cortex; Psychiatry; Research Proposals; Resolution; Reversal Learning; Rewards; Rodent; Role; Stimulus; Substance Use Disorder; System; Testing; Uncertainty; Work; adaptive learning; base; behavior change; cingulate cortex; flexibility; improved; network models; neuromechanism; neuropsychiatry; nonhuman primate; preference; response; therapeutic target; therapeutically effective

PROJECT SUMMARY Individuals with Substance Use Disorders (SUD) often exhibit preferences for risky, uncertain outcomes and demonstrate inflexible learning. The neural mechanisms of adaptive learning under uncertainty, however, have been predominantly investigated in human and nonhuman primates with limited capacity for microcircuit measurements and/or systems-level causal manipulations. Guided by mechanistic computational models, here we propose precise systems-level manipulation of interactions between multiple brain areas and imaging of stable neuronal ensembles in rodents, to reveal circuit- level mechanisms underlying adaptive learning. Previous studies point to the role of basolateral amygdala (BLA) and several interconnected subregions of the prefrontal cortex (PFC), including orbitofrontal (OFC) and anterior cingulate cortex (ACC), in adaptive behavior. Based on our recent modeling and experimental work, we hypothesize that OFC and ACC provide stable representations of stimulus-outcome (state values) and action-outcome associations (action values), respectively. BLA uses input from OFC and ACC to estimate volatility in both state and action values to destabilize these representations, which in turn enables faster adjustments in response to real changes in the environment. To test this hypothesis we will chemogenetically inhibit projection neurons between these regions during probabilistic reversal learning of state and action values, and record neuronal ensemble activity via calcium imaging in each cortical region during learning. The results from manipulating different pathways and high temporal- and spatial- resolution of calcium imaging data will be used to identify the relative strength and types of projections, and the representations of reward value in order to refine our models and subsequently develop circuit-level, spiking network models for adaptive learning under uncertainty. Given that SUDs are characterized by uncertain, rapidly-changing, and often extreme reward environments, our proposed aims are pertinent to clinical observations in SUDs and especially deficits in behavioral adjustments. Altogether, using a combination of detailed computational modeling and a sophisticated experimental approach, we will reveal the contributions of cortico- amygdalar circuits to adaptive behavior under uncertainty.

项目摘要 患有物质使用障碍（SUD）的人通常表现出对风险，不确定结果的偏好 并表现出不灵活的学习。不确定条件下自适应学习的神经机制， 然而，主要在人类和非人类灵长类动物中进行了研究， 微电路测量和/或系统级因果操作的能力。指导 机械计算模型，在这里，我们提出了精确的系统级操纵的相互作用 在啮齿动物的多个大脑区域和稳定的神经元集合成像之间，以揭示电路- 适应性学习的层次机制。以前的研究指出基底外侧的作用， 杏仁核（BLA）和前额叶皮层（PFC）的几个相互关联的子区域，包括 眶额皮层（OFC）和前扣带皮层（ACC），在适应行为。根据我们最近的 模型和实验工作，我们假设OFC和ACC提供了稳定的表征， 刺激-结果（状态值）和动作-结果关联（动作值）。BLA用途 OFC和ACC的输入，用于估计状态和行动值的波动性，以使其不稳定 表示，这反过来又使得能够响应于图中的真实的变化而进行更快的调整。 环境为了验证这一假设，我们将化学发生抑制这些神经元之间的投射神经元。 在状态和动作值的概率反向学习期间，记录神经元集合 在学习过程中通过钙成像在每个皮层区域的活动。操纵的结果 不同的途径和高时间和空间分辨率的钙成像数据将被用来 识别预测的相对强度和类型，以及奖励值的表示， 完善我们的模型，并随后开发电路级，尖峰网络模型， 在不确定性下学习由于SUD的特点是不确定的，快速变化的，经常 极端的奖励环境，我们提出的目标是相关的临床观察SUD和 尤其是行为调整方面的缺陷总之，使用详细的计算组合， 模型和复杂的实验方法，我们将揭示皮质的贡献， 杏仁核回路在不确定性下的适应行为。