Cortical interactions underlying memory and decision making in rodent models

支持认知的神经生物学机制仍然没有得到充分的描述。越来越多的证据表明，包括学习、记忆和决策在内的认知过程依赖于皮质区域和分布的中皮质-纹状体-边缘回路中其他相互连接的区域的活动。我的实验室最近进行了一项结合了行为测试、药理学和活体细胞外记录的研究，在大鼠模型中进行了研究，以努力了解这些相互作用。目前的发现资助申请将专注于促进我们对行为范式中的皮质处理的理解，以评估我实验室优化的工作记忆。这些实验的结果预计将从行为和生理的综合角度显著增加对高级认知功能的理解，如学习和记忆。在我的指导下，本科生、研究生和博士后水平的HQP将继续进行实验，旨在了解气味广度任务中测量的工作记忆容量在内侧前额叶皮质(MPFC)和纹状体的活动模式。在最近使用大鼠体内细胞外记录的工作中，我们已经表明，在气味跨度任务的延迟期，mPFC神经元的活动可以预测随后在该任务中的表现。因此，我计划结合多巴胺受体药理学、光遗传学和急性应激进行更多的记录，以检查支配广度表现的额叶-纹状体活动模式。我相信，这些实验的发现将有助于完善关于认知过程中皮质-纹状体相互作用的理论。我们还将描述mPFC、顶叶后皮质(PPC)以及它们与背侧纹状体在视觉空间工作记忆任务中的作用(S)，这是在配备触摸屏的操作条件室中执行的试验唯一不匹配到位置(TUNL)任务。拟议的实验将表征：1)TUNL过程中每个皮质区域的神经活动模式；2)大脑皮层区域参与任务的样本、延迟和测试阶段；3)用光遗传学抑制任务特定的活动模式是否会损害TUNL的性能。由于在啮齿动物中使用的工作记忆范式很少显示PPC参与，这些结果将增加我们对这一未被研究的啮齿动物皮质在认知中的功能的理解。最后，我们将在最近优化的一系列对象奇异性测试中评估眶前皮质与PPC相互作用的作用，以允许我们控制可用刺激的形态。预计拟议的研究计划将从根本上有助于理解皮质-纹状体神经活动促进学习、记忆和决策的详细机制。

The neurobiological mechanisms supporting cognition remain poorly characterized. Converging lines of evidence suggest that cognitive processes including learning, memory, and decision making rely on activity in cortical regions and other interconnected areas of the distributed meso-cortico-striatal-limbic circuitry. Recent research in my laboratory involving a combination of behavioural testing, pharmacology, and in vivo extracellular recordings has been conducted in rat models in an effort to understand these interactions. The present Discovery Grant Application will focus on advancing our understanding of cortical processing in the behavioural paradigms to assess working memory optimized in my laboratory. The results of these experiments are expected to significantly increase the understanding of advanced cognitive functions such as learning and memory from an integrated behavioural and physiological perspective. HQP under my supervision at the undergraduate, graduate, and postdoctoral levels will continue experiments designed to understand the patterns of activity in medial prefrontal cortex (mPFC) and striatum for working memory capacity as measured in the odour span task. In recent work using in vivo extracellular recordings in rats, we have shown that activity of mPFC neurons during the delay period of the odour span task predicts subsequent performance on the task. Thus, I plan to conduct additional recordings in combination with dopamine receptor pharmacology, optogenetics, and acute stress to examine patterns of frontal-striatal activity that govern span performance. I believe that the findings from these experiments will be useful in refining theories regarding cortical-striatal interactions during cognition. We will also characterize the role(s) of mPFC, posterior parietal cortex (PPC), and their interactions with dorsal striatum in a visuospatial working memory task, the trial-unique-nonmatching-to-location (TUNL) task performed in touchscreen-equipped operant conditioning chambers. The proposed experiments will characterize: 1) the patterns of neural activity in each cortical area during TUNL; 2) involvement of the cortical areas in the sample, delay, and test phases of the task; 3) whether inhibiting task-specific activity patterns with optogenetics impairs performance of TUNL. As few working memory paradigms used in rodents show PPC involvement, these results will increase our understanding of the function of this understudied area of rodent cortex in cognition. Finally, we will assess the roles of orbitofrontal cortex interactions with the PPC in an array of object oddity tests we have recently optimized to allow us to control the modality of the available stimuli. It is expected that the proposed program of research will fundamentally contribute to understanding the detailed mechanisms through which cortical-striatal neural activity enables learning, memory, and decision making.