Distributed Representation of Working Memory in Prefrontal Cortex

描述（由申请人提供）：工作记忆是当信息不再存在于环境中时保留和操纵信息的能力，并且是许多认知能力（如决策和语言理解）的基本要求。前额叶皮层在工作记忆中起着至关重要的作用，并且已经表明，神经元选择性地对必须记住的线索进行放电，当它们被移除时，这提供了工作记忆可能在大脑的这个区域中“保持”的证据。最近的研究表明，在延迟期间神经元的放电模式显示出复杂的动力学，这是许多经典的前额叶皮层功能理论所不能解释的。我推测，工作记忆是由小的、空间上聚集的细胞亚群维持的，这些亚群在激活另一个亚群之前暂时激活，就像一系列多米诺骨牌一样，顺序反映了记忆的内容，多米诺骨牌象征着亚群。这个猜想是基于最近的研究和我的初步结果，这些研究表明，大多数神经元只是短暂地代表记忆，而且在试验期间，成对的神经元似乎会短暂地相互作用。我提出了两个具体的目标，旨在测试这一猜想，并提供信息对一个更机械的理解如何前额叶皮层电路保持活动在工作记忆任务。第一个具体的目的是测试的假设，即工作记忆是由一系列离散的状态，其中一个状态是与一个小的神经元亚群，激活短暂的延迟期间，不同的记忆唤起不同的序列的状态，他们的首选刺激。第二个具体的目的是测试的假设，类似调谐的神经元在前额叶皮层或神经元与一个国家显示空间聚类。这些特定的目标将通过长期植入的四极阵列和体内双光子成像的组合，而猴子从事工作记忆任务。这些研究将提供一个机制的洞察，谁的工作记忆内容是代表和维持在一个群体的神经元。这一点很重要，因为工作记忆功能障碍与精神分裂症和注意力缺陷/多动症有关。通过更好地理解工作记忆的维持，它可能会为更有针对性的药理学打开大门，改善副作用。

DESCRIPTION (provided by applicant): Working memory is the ability to retain and manipulate information when it is no longer present in the environment, and is a fundamental requirement for numerous cognitive abilities like decision-making and language comprehension. The prefrontal cortex plays a critical role in working memory, and it has been shown that neurons fire selectively to cues that must be remembered when they are removed, providing evidence that working memory may be "held" in this region of the brain. Recent work has shown that the firing patterns of neurons during the delay period shows complex dynamics that are not accounted for by many classical theories of prefrontal cortex function. I conjecture that working memory is maintained by small, spatially clustered, sub-populations of cells that activate temporarily before activating another sub- population, like a series of dominos, where the sequence reflects what is remembered and the domino symbolizes the sub-population. This conjecture is based upon recent studies and my preliminary results showing that the majority of neurons represent the memory only transiently and that pairs of neurons seem to interact briefly during a trial. I propose two specific aims designed to test this conjecture and provide information towards a more mechanistic understanding of how prefrontal-cortical circuits maintain activity during working memory tasks. The first specific aim is to test the hypothesis that working memory is represented by a sequence of discrete states, where a state is associated with a small neuronal subpopulation that activates transiently during the delay period, and that different memoranda evoke different sequences of states, their preferred stimulus. The second specific aim is to test the hypothesis that similarly tuned neurons in prefrontal cortex or neurons associated with a state show spatial clustering. These specific aims will be addressed through a combination of chronically implanted arrays of tetrodes and in vivo two-photon imaging while monkeys are engaged in a working memory task. These studies will provide a mechanistic insight into who working memory contents are represented and maintained across a population of neurons. This is important because dysfunctions of working memory are associated with schizophrenia and attention-deficit/hyperactivity disorder. By better understanding working memory maintenance, it may open the door for more targeted pharmacology with improved side-effect profiles.