Synapse-type-specific plasticity in neocortical microcircuits

神经学家认为，学习和记忆以及发育过程中神经元电路的细化是由于相互连接的神经元之间的突触连接发生了变化，这被称为突触可塑性。我的团队研究新大脑皮层的可塑性，重点是最近发现的依赖于峰的可塑性(STDP)范式，因为它具有出色的实验控制和生物学上的合理性。对于经典的STDP，在突触后几毫秒内放电之前的前几毫秒会导致增强，而相反的时间顺序会导致减弱，这有效地使大脑能够学习因果关系。但众所周知，突触的可塑性随着突触类型的不同而不同--在不同神经元间类的输入端发现了不同的机制和现象学。为什么以及如何改变突触的可塑性？在这份探索基金提案中，我们的目标是解决这个问题，使用一系列最先进的方法，如配对记录、双光子成像、光遗传学和计算机建模。 我们未发表的数据表明，一些神经元间细胞类型在其兴奋性输入时具有“反向”的STDP，而其他类型的细胞则不具有。STDP的这种突触类型特异性不太可能是巧合，但对大脑功能很重要。我们将以此为起点，追踪视觉皮质发育过程中关键突触类型的STDP学习规则，同时根据它们的形态、内在放电模式和遗传标记对这些中间神经元进行仔细的分类。这项研究计划将阐明在大脑皮层发育过程中管理信息存储和重新连接的规则。我们的努力将产生尖端的科学成果，同时又是安全的。该建议将使3名研究生学习先进的光学和电生理技术，1名本科生学习成像、形态重建等，从而为培养从初级到相对高级的高素质人才提供理想的环境。

Neuroscientists believe that learning and memory as well as the refinement of neuronal circuits during development are due to changes in synaptic connections among interconnected neurons, known as synaptic plasticity. My team investigates plasticity in neocortex, with a focus on the more recently discovered Spike-Timing-Dependent Plasticity (STDP) paradigm, because of its excellent experimental control and biological plausibility. With classical STDP, pre before postsynaptic firing within a few milliseconds results in strengthening, whereas the opposite temporal order elicits weakening, which effectively enables the brain to learn causal relationships. But synaptic plasticity is known to vary with synapse type -- different mechanisms and phenomenology are found at inputs to different interneuronal classes. Why and how does synaptic plasticity vary? In this Discovery Grant proposal, we aim to confront this issue, using a battery of state-of-the-art methods such as paired recordings, 2-photon imaging, optogenetics, and computer modeling. Our unpublished data indicate that some interneuronal cell types possess “reversed” STDP at their excitatory inputs, while others do not. This synapse type specificity of STDP is not likely to be coincidental, but important for brain functioning. We will use this as a starting point, and trace out the STDP learning rules of key synapse types in developing visual cortex, while carefully classifying these interneurons based on their morphology, intrinsic firing patterns, and genetic markers. This research program will clarify the rules that govern information storage and rewiring during development of the neocortex. Our efforts will produce cutting-edge scientific results, while at the same time being safe. The proposal would enable three graduate students to learn advanced optical and electrophysiological techniques, and an undergraduate to learn imaging, morphological reconstructions, etc., thus providing an ideal setting for training of highly qualified personnel ranging from the junior to the relatively senior.