Cortical interactions underlying memory and decision making in rodent models

支持认知的神经生物学机制仍然缺乏特征。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层区域和分布在中脑皮层-纹状体-边缘回路中的其他相互关联区域的活动。我的实验室最近在大鼠模型中进行了结合行为测试、药理学和体内细胞外记录的研究，以了解这些相互作用。目前的发现基金申请将集中于推进我们对行为范式中皮层处理的理解，以评估我实验室优化的工作记忆。这些实验的结果有望从综合行为和生理的角度显著增加对高级认知功能（如学习和记忆）的理解。在我的指导下，HQP的本科生、研究生和博士后将继续进行实验，旨在了解内侧前额叶皮层（mPFC）和纹状体的活动模式，这些活动模式与气味广度任务中测量的工作记忆容量有关。在最近对大鼠体内细胞外记录的研究中，我们已经表明，在气味跨越任务的延迟期，mPFC神经元的活动预测了任务的后续表现。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额外的记录，以检查控制广度表现的额纹状体活动模式。我相信这些实验的发现将有助于完善关于认知过程中皮层-纹状体相互作用的理论。我们还将描述mPFC，后顶叶皮层（PPC）的作用，以及它们与背纹状体在视觉空间工作记忆任务中的相互作用，即在配备触摸屏的操作性条件反射室中执行的“试验-唯一-不匹配-位置”（TUNL）任务。拟进行的实验将描述：1)TUNL期间各皮质区域的神经活动模式；2)皮层区域在任务的取样、延迟和测试阶段的参与；3)光遗传学抑制任务特异性活动模式是否会损害TUNL的功能。由于在啮齿类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层在认知中的功能的理解。最后，我们将评估眼窝额叶皮层与PPC相互作用的作用，我们最近优化了一系列物体奇异性测试，以使我们能够控制可用刺激的模式。预计该研究计划将从根本上有助于理解皮层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.