CELLULAR AND NETWORK MODELS IN PREFRONTAL WORKING MEMORY

这项研究计划的目标是在细胞水平上帮助解决工作记忆的神经机制这一长期存在的问题。为此，我们将采用基于皮层生理学的前额皮质回路生物物理模型，并从行为猴子中复制神经数据。建模项目将与实验数据分析相结合，并将与PI合作者的实验室中正在进行的实验并行进行。最终，这一领域的进展将有助于我们理解精神分裂症认知缺陷的细胞基础。本研究主要集中在三个方面：(a)持续活动的神经机制及其刺激选择性；(b)空间工作记忆存储在循环网络中的鲁棒性；(c)工作记忆在选择性注意中的作用。我们的研究项目旨在检验以下假设。(1)持久活动的产生。作为一种网络现象，混响产生稳定的持续活动，不仅需要高的突触循环连接效能，还需要特定的突触传递时间动态。NMDA受体在循环突触中起关键作用。突触产生的持续活动敏感地依赖于单个细胞固有的离子机制，并可以通过它们的神经调节来控制。(2)空间工作记忆的稳健性。在异质性存在的情况下，连续的“凹凸吸引子”（空间定位的活动模式）可能并不健壮。这个问题可以通过自适应机制来解决，如稳态突触缩放，它使工作记忆网络均匀化，从而赋予网络作为模拟量的空间位置的鲁棒记忆。(3)工作记忆和选择性注意。前额皮质具有选择性注意的“偏向竞争”机制：持续活动向感觉皮质区域提供持续的、特定位置或特征的、自上而下的偏向信号；然而，其内在抑制回路赋予前额叶皮层一种“赢者通吃”的竞争，以过滤掉与行为无关的刺激（干扰物）。

The goal of this research program is to help solve the long-standing problem of the neural mechanisms of working memory, at the cellular level. To this end, we will undertake a biophysical model of prefrontal cortical circuits that is based on cortical physiology and that reproduces neural data from the behaving monkey. Modeling projects will be combined with analysis of experimental data, and will be carried out in parallel with ongoing experiments in the laboratories of PI's collaborators. Ultimately, progress in this area will contribute to our understanding of the cellular substrate of cognitive deficits in schizophrenia. The proposal is focused on three major issues: (a) neural mechanisms of persistent activity and its stimulus selectivity; (b) robustness of spatial working memory storage in a recurrent network; (c) the role of working memory in selective attention. Our research projects are designed to test the following hypotheses. (1) Generation of persistent activity. The generation of a stable persistent activity by reverberation, as a network phenomenon, requires not only a high synaptic efficacy of recurrent connections, but also specific temporal dynamics of synaptic transmission. NMDA receptors at the recurrent synapses play a critical role. Synaptically-generated persistent activity depends sensitively on the intrinsic ionic mechanisms of single cells, and can be controlled by their neuromodulations. (2) Robustness of spatial working memory. A continuum of `bump attractors' (spatially localized activity patterns) may not be robust in the presence of heterogeneity. This problem can be solved by adaptive mechanisms, such as homeostatic synaptic scaling, which homogenize a working memory network and thereby endow the network with robust memory of spatial location as an analog quantity. (3) Working memory and selective attention. The prefrontal cortex is capable of a `biased competition' mechanism for selective attention: persistent activity provides a sustained, location- or feature-specific, top- down bias signal to the sensory cortical areas; whereas its intrinsic inhibitory circuit endows the prefrontal cortex with a `winner-take-all' competition for filtering out behaviorally irrelevant stimuli (distractors).