Computational and experimental investigation of heterosynaptic plasticity and pattern separation in adult-born dentate granule cells

成年齿状颗粒细胞异质突触可塑性和模式分离的计算和实验研究

• 批准号: 467764793
• 负责人: Professor Dr. Peter Jedlicka
• 金额: --
• 依托单位: Institut für Medizinische Informatik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/467764793?language=en
• 关键词: Computational; experimental; investigation; heterosynaptic; plasticity

Adult-born granule cells (abGCs) possess unique electrophysiological features and play a special role in hippocampal memory formation and pattern separation. Young abGCs display a critical phase starting at 4 weeks of cell age when they exhibit increased excitability, enhanced synaptic plasticity, and decreased inhibitory input. Moreover, we have recently shown that from the 5th week on, young abGCs show homo- and heterosynaptic structural plasticity. However, the interplay between these properties of abGCs and their contribution to pattern separation is not sufficiently understood and has never been modeled in biologically realistic simulations. Therefore, we will address the following major questions: How do characteristic properties of young abGCs shape their input-output transformation and thereby affect pattern separation at the single cell level? The principal goal is to better understand the biophysical and computational rules, which drive the establishment of young abGCs as efficient pattern separators in the dentate gyrus. Our specific questions are: What are the functional consequences of observed lower synapse density combined with higher excitability in young abGCs for their input-output function? How do characteristic features of young abGCs affect the sparseness of their firing? How does unique ion channel expression in young abGCs modulate their input-output function, synaptic plasticity and pattern separation? Can the known differences in ion channel expression, inhibition and NMDA-receptor subunit expression in young abGCs fully explain enhanced homosynaptic plasticity in young abGCs as compared to mature abGCs? How does homosynaptic synaptic strengthening (LTP) and heterosynaptic weakening (LTD) in young abGCs affect their pattern separation performance? Are homosynaptic LTP and heterosynaptic LTD balanced at the level of individual young abGCs? Is there a synergy or degeneracy (i.e. partial redundancy) between intrinsic and extrinsic (synaptic) parameters with respect to sparse granule cell firing and pattern separation? What is a realistic range of variability in the parameter space, which would explain experimentally observed variability? To answer these questions, we have the following objectives. Using a combination of computational and electrophysiological methods we aim to: (1) improve and extend existing compartmental models of mature GCs and young abGCs; (2) develop models of enhanced homosynaptic plasticity in young abGCs and analyze its underlying mechanisms; (3) develop models of heterosynaptic plasticity in young abGCs; (4) study the computational role of unique intrinsic/extrinsic properties of young abGCs and their heterosynaptic plasticity for sparse firing and pattern separation; (5) develop reduced cellular and circuit models of pattern separation; (6) validate computational models experimentally and test their predictions. New and greatly improved models of dentate GCs will be freely available.

成年颗粒细胞（abGC）具有独特的电生理特征，在海马记忆形成和模式分离中发挥特殊作用。年轻的 abGC 从细胞龄 4 周开始就表现出一个关键阶段，此时它们表现出兴奋性增加、突触可塑性增强和抑制输入减少。此外，我们最近发现，从第 5 周开始，年轻的 abGC 表现出同源和异源突触结构可塑性。然而，abGC 的这些特性及其对模式分离的贡献之间的相互作用尚未得到充分理解，并且从未在生物学现实模拟中进行建模。因此，我们将解决以下主要问题：年轻的 abGC 的特性如何塑造其输入输出转换，从而影响单细胞水平的模式分离？主要目标是更好地理解生物物理和计算规则，这些规则推动年轻 abGC 的建立，作为齿状回中的有效模式分离器。我们的具体问题是：观察到的较低突触密度与年轻 abGC 的输入输出功能较高的兴奋性相结合会产生什么功能后果？年轻 abGC 的特征如何影响其发射的稀疏性？年轻 abGC 中独特的离子通道表达如何调节其输入输出功能、突触可塑性和模式分离？年轻 abGC 中离子通道表达、抑制和 NMDA 受体亚基表达的已知差异能否充分解释年轻 abGC 与成熟 abGC 相比同突触可塑性增强？年轻 abGC 中的同源突触强化 (LTP) 和异源突触减弱 (LTD) 如何影响其模式分离性能？同源突触 LTP 和异源突触 LTD 在个体年轻 abGC 水平上是否平衡？就稀疏颗粒细胞放电和模式分离而言，内在和外在（突触）参数之间是否存在协同或简并（即部分冗余）？参数空间中可变性的实际范围是多少，这可以解释实验观察到的可变性？为了回答这些问题，我们有以下目标。结合计算和电生理学方法，我们的目标是：（1）改进和扩展现有的成熟 GC 和年轻 abGC 的区室模型； (2) 建立年轻abGC同突触可塑性增强的模型并分析其潜在机制； (3) 开发年轻 abGC 的异质突触可塑性模型； (4) 研究年轻 abGC 独特的内在/外在特性及其异质突触可塑性对稀疏放电和模式分离的计算作用； (5) 开发模式分离的简化蜂窝和电路模型； (6) 通过实验验证计算模型并测试其预测。新的和经过大幅改进的齿状 GC 模型将免费提供。