工作记忆中持续性发放的机制研究

项目名称： 工作记忆中持续性发放的机制研究

项目编号： No.31471049

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 神经、认识与心理学

项目作者： 李澄宇

作者单位： 中国科学院上海生命科学研究院

项目金额： 87万元

中文摘要： 前额叶皮层在工作记忆任务的延迟期间存在持续性发放，被认为是大脑存储和操纵信息的媒介，但其产生机制不明。目前有单细胞兴奋性和网络回环连接两种假说可以解释持续性发放，并且具有明确而不同的预期实验结果。我们在小鼠中开发了基于嗅觉的工作记忆行为范式，将综合应用在体全细胞记录、在体胞外记录、光遗传、药理学等手段，尝试验证哪种假说更接近于生物学现实。我们将观察单个前额叶皮层神经元在工作记忆的延迟期间的膜电位，从而了解持续性发放中的突触输入特性；通过直接注入去极化或超极化电流，我们将观察撤销电流后神经元持续性发放的可能调控，从而直接验证两种假说预期正确与否；通过光遗传实验，我们将操控群体神经元的兴奋性，并观察对后续发放的影响；通过药理学研究，我们将特异性的阻断单细胞假说中的核心离子通道，从而验证假说的合理性。本项目将有助于阐明工作记忆中持续性发放产生的机制。

中文关键词： 光遗传学；神经环路；电生理；前额叶；工作记忆

英文摘要： Working memory is a crucial brain process that temporally stores and manipulates information for active control of cognitive behavior. Delay related persistent activity has been observed in prefrontal cortex (PFC) in working memory and was thought to mediate the maintenance and manipulation of information. Currently two models are competing to explain the mechanism for persistent activity in working memory. One is the intrinsic excitability hypothesis, which claims that positive feedback mechanism of ion channels can lead to self-sustained plateau potential and persistent firing in the absence of sensory inputs. The other is recurrent network theory, which stresses the importance of synaptic recurrent connections among local and global networks in maintaining the positive feedback for persistent activity. Intrinsic excitability hypothesis predicts that temporarily enhancing or suppressing neural excitability by depolarizing or hyperpolarizing current injection will further enhance or suppress the excitability, therefore boost or decrease the subsequent firing even after ceasing of current injection, respectively. In contrast, recurrent network hypothesis predicts that perturbing single neurons' excitability will not modulate the subsequent firing. The two hypotheses also differ in prediction of synaptic noise in delay period, effects of perturbing global excitability, and sensitivity to pharmacological manipulations. We will test these predictions by combined efforts from in vivo whole-cell recording, extracellular recording, optogenetic, and pharmacological means in head-fixed mice performing working memory task. We have already measured membrane potential by whole cell recording while mice were performing a delayed non-match to sample task. The membrane potential modulation during delay period was measured and compared to neuronal firing. The results show that neuronal firing was sensitive to small fluctuations in membrane potential, as predicted by recurrent network hypothesis. We applied depolarizing or hyperpolarizing currents during delay period, but failed to observe autonomous modulation in membrane potential and firing rates following the ceasing of current injection. In future, we will further collect more neurons to corroborate our results. We will also use optogenetics to manipulate global neural excitability to test the two hypotheses. Furthermore, we will apply pharmacological method to block calcium activated non-selective cation channels (CAN) and L-type calcium channels, which are predicted to be critical by intrinsic excitability hypothesis but not by recurrent network hypothesis. Our results will illustrate which of the two hypotheses is closer to the reality of the underlying mechanism for persistent activity in working memory.

英文关键词： optogenetics;neural circuits;electrophysiology;prefrontal cortex;working memory