Cortical mechanisms of learned spatial-temporal sequence coding

描述(申请人提供)：大脑不断地处理信息流，这些信息流是由尖峰活动的时间序列在神经水平上编码的。从这一活动中，大脑能够提取与行为相关的数据，并形成外部世界的内部表征，进而产生行为输出。大脑还使用其内部状态来预测外部刺激将如何变化；这些预测在执行行为规划中发挥着关键作用。目前尚不清楚这一过程是如何在大脑中完成的。建立活动序列、可塑性和这些内部表征的神经编码之间的关系将极大地帮助我们理解正常的大脑功能，并且对于理解与精神障碍相关的认知缺陷是必要的。由于动物不能自我报告其认知状态，因此利用动物模型来探索序列学习的高级神经机制是非常困难的。一般来说，新大脑皮层是按照单一的共同计划组织起来的，该计划赋予了一种独特的局部结构，有证据表明，大脑区域由于其特定的输入而获得功能分化。在这个框架中，视觉皮质是“视觉的”，主要是因为它连接到视网膜，皮质的所有区域都能够解决类似的信息处理问题。这表明，在“较高”的皮质区域学习序列所用的基本机制也应该存在于“较低的”区域，并导致假设主要感觉区域应该包含对序列表示进行局部编码所需的机制。一系列验证这一假设的实验表明，在初级视觉皮层中以时间和空间精度提取视觉序列是可能的。这项研究的目的是充分描述和理解这种学习的机制及其对大脑皮质加工的影响。这些实验旨在通过电生理观察、双光子显微镜、药物和光遗传操作以及计算模型的组合，验证视觉序列学习是由NMDAR介导的跨V1局部皮质层神经元群体之间的突触可塑性编码的假设。

DESCRIPTION (provided by applicant): The brain continually processes streams of information that are coded at the neural level by temporal sequences of spiking activity. From this activity, the brain is able to extract behaviorally relevant data and form internal representations of the external world used, in turn, to create behavioral output. The brain also uses its internal state to make predictions about how external stimuli will change; these predictions play a critical role in executive behavioral planning. It is not known how this processing is accomplished in the brain. Establishing the relationship between activity sequences, plasticity and the neural coding of these internal representations will greatly inform our understanding of normal brain function and is necessary to understand the cognitive deficits associated with mental disorders. Since animals cannot self-report their cognitive state it is ver difficult to explore the high-level neural mechanisms of sequence learning using animal models. Generally speaking, the neocortex is organized according to a single common plan that imparts a characteristic local architecture and there is evidence suggesting that brain regions acquire functional differentiation as a result of their specific inputs. In this framework, visual cortex i "visual" primarily because it connects to the retina and all regions of cortex are capable of solving similar information processing problems. This suggests that the same basic mechanisms used to learn sequences in "higher" cortical regions should exist within "lower" regions as well and leads to the hypothesis that primary sensory areas should contain the mechanisms necessary to locally encode sequence representations. A series of experiments testing this hypothesis demonstrate that it is possible to entrain visual sequences in primary visual cortex with both temporal and spatial precision. This research aims to fully characterize and understand the mechanistic nature of this learning and its consequences for cortical processing. The proposed experiments are designed to test the hypothesis that visual sequence learning is encoded by NMDAR mediated synaptic plasticity between populations of neurons spread across the cortical layers locally within V1 using a combination of electrophysiological observation, 2- photon microscopy, pharmacological and optogenetic manipulation, and computational modeling.