Cortical mechanisms of learned spatial-temporal sequence coding

描述（由申请人提供）：大脑不断处理信息流，这些信息流在神经水平上通过脉冲活动的时间序列进行编码。从这种活动中，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。大脑还利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起着至关重要的作用。目前尚不清楚大脑是如何完成这一过程的。建立这些内部表征的活动序列、可塑性和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，因此利用动物模型探索序列学习的高级神经机制非常困难。一般来说，新皮层是根据一个单一的共同计划组织的，这赋予了一个独特的局部结构，有证据表明，大脑区域因其特定的输入而获得功能分化。在这个框架中，视觉皮层之所以是“视觉的”，主要是因为它与视网膜相连，所有的皮层区域都有能力解决类似的信息处理问题。这表明，用于“高级”皮质区域学习序列的相同基本机制也应该存在于“低级”皮质区域，并导致了主要感觉区域应该包含局部编码序列表征所需的机制的假设。一系列测试这一假设的实验表明，在初级视觉皮层中同时具有时间和空间精度的视觉序列是可能的。本研究旨在充分表征和理解这种学习的机制性质及其对皮层处理的影响。本实验旨在通过电生理观察、双光子显微镜、药理学和光遗传学操作以及计算模型的结合，验证视觉序列学习是由NMDAR介导的突触可塑性编码的这一假设。

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.