Linking Plasticity of Hippocampal Representation across the Single Neuron and Circuit Levels

内嗅皮层和海马体之间的功能相互作用对空间导航至关重要 以及与人、地点、物体和事件相关的情节记忆。经典地说，内侧内嗅器 大脑皮质(MEC)处理空间信息，而外侧内嗅皮层(LEC)处理非空间信息 上下文信息。这些“在哪里”和“什么”的信息然后被投射到海马体，以 形成与环境的感官和空间特征相联系的长期表征。 海马区表征的灵活性对产生适应性学习行为至关重要，并依赖于 可塑性。我们提出了内嗅皮层在调节海马可塑性和空间可塑性中的新作用。 申述。为了测试这一点，我们将分离出鲜为人知的远程和远程网络的组织和功能 在空间编码过程中，LEC与MEC和海马CA3区之间的局部回路对话。 PI(Basu)和co-Pi(Clopath)都是早期调查人员，正在结合他们的互补 在实验和计算方法方面的专业知识，以构建以集成电路为中心的 海马体中多个层次的可塑性。这项研究将检验这一假设，即 LEC输入在非空间编码、谷氨酸和新生的协同活动中的经典偏向作用 发现来自LEC和MEC的GABA能输入(Basu等人，2016)对于上下文相关是必要的 局部兴奋抑制动力学门控和树突整合对海马区细胞可塑性的影响。 为了测试这一想法，我们在实验和计算方面建立了一套创新的工具来 检查放置细胞在多个层次上的可塑性。我们将从SOMA进行细胞内电生理学 和急性脑片中CA3神经元的树突，以功能定位LEC-CA3回路(目标1)，并读出CA3 用CA3胞体和树突的体内双光子成像将细胞行为置于亚细胞分辨率 以及LEC轴突在头部固定的环境变形空间导航任务中的行为动物(目标2)。 与克利夫·肯特罗斯博士合作，我们将开发用于多重培养的LEC细胞类型特异性小鼠系。 谷氨酸和GABA能传入的光遗传激活和沉默同时或交替地和 读出这些操作如何影响CA3的可塑性。我们正在构建一种独特的计算模型 在单个神经元(目标1)和网络(目标2)水平上的海马区细胞编码结合了 树突激发抑制和长期可塑性(Bono和Clopath，2010)。格奥尔基·布萨基博士和 Dmitry Chklovskii将提供Place细胞和大规模成像数据分析方面的专家咨询。 我们的研究将为远程和局部电路动力学提供一个独特的视角，从而为 其他方面，基于环境需求的空间的稳定神经元表征。这会有更好的帮助 识别与创伤后应激障碍相关的感觉环境及其位置的不适应关联的潜在回路 在CA3是主要靶点的情况下，在阿尔茨海默病中，内嗅皮层在早期受到影响。

Functional interactions between the entorhinal cortex and hippocampus are critical for spatial navigation and episodic memories related to people, places, objects and events. Canonically, medial entorhinal cortex (MEC) processes spatial information while lateral entorhinal cortex (LEC) processes non-spatial contextual information. This ‘where’ and ‘what’ information is then projected to the hippocampus for formation of long-term representations associating the sensory and spatial features of the environment. Flexibility in hippocampal representations is critical for generating adaptive learnt behaviors and relies on plasticity. We propose a new role for entorhinal cortex in modulating hippocampal plasticity and spatial representations. To test this, we will dissociate the lesser known organization and function of long-range and local circuit dialogue between LEC vs. MEC and area CA3 of hippocampus during spatial coding. The PI (Basu) and co-PI (Clopath), both early stage investigators, are combining their complementary expertise in experimental and computational approaches to build an integrated circuit centric model of plasticity in the hippocampus across multiple levels. This study will test the hypothesis that beyond the classically biased role of LEC inputs in non-spatial coding, coordinated activity of glutamatergic and newly discovered GABAergic input (Basu et al., 2016) from both LEC and MEC is necessary for context-dependent plasticity of hippocampal place cells via gating of local excitation-inhibition dynamics and dendritic integration. To test this idea, we have established innovative set of tools on the experimental and computational fronts to examine place cell plasticity across multiple levels. We will perform intracellular electrophysiology from soma and dendrites of CA3 neurons in acute slices to functional map the LEC-CA3 circuit (Aim 1), and read out CA3 place cell behavior at sub-cellular resolution with in vivo two-photon imaging of CA3 soma and dendrites as well as LEC axons in behaving animals during a head-fixed context morphing spatial navigational task (Aim 2). In collaboration with Dr. Cliff Kentros, we will develop LEC cell type specific mouse lines for multiplexed optogenetic activation and silencing of glutamatergic and GABAergic inputs simultaneously or alternatingly and read-out how these manipulations impact CA3 plasticity. We are building a unique computational model of hippocampal place cell coding at single neuron (Aim 1) and network (Aim 2) levels incorporating modulation of dendritic excitation-inhibition and long-term plasticity (Bono and Clopath 2010). Drs. György Buzsáki and Dmitry Chklovskii will provide expert consultation on place cell and large-scale imaging data analysis. Our study will provide a unique perspective on long-range and local circuit dynamics that impart flexibility to otherwise stable neuronal representations of space based on environmental demands. This will help better identify circuits underlying maladaptive association of sensory contexts and their location, as seen in PTSD where CA3 is a major target, and in Alzheimer’s disease where entorhinal cortex is affected early on.