Synapse-type-specific plasticity in neocortical microcircuits

神经科学家认为，学习和记忆以及发育过程中神经元回路的完善是由于相互连接的神经元之间的突触连接的变化，称为突触可塑性。我的团队研究了新皮层的可塑性，重点是最近发现的尖峰时间依赖可塑性（STDP）范式，因为它具有出色的实验控制和生物可操作性。在经典的STDP中，突触前和突触后放电在几毫秒内会导致强化，而相反的时间顺序会导致弱化，这有效地使大脑能够学习因果关系。但是，突触可塑性是众所周知的，不同的突触类型-不同的机制和现象被发现在输入不同的神经元间类。突触可塑性为何以及如何变化？在这个发现补助金提案中，我们的目标是面对这个问题，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interneuronal细胞类型具有“逆转”STDP在他们的兴奋性输入，而其他人没有。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。我们将以此为出发点，追踪发育中视皮层关键突触类型的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分类。这项研究计划将阐明在新皮层发育过程中管理信息存储和重新布线的规则。我们的努力将产生尖端的科学成果，同时又是安全的。该提案将使三名研究生能够学习先进的光学和电生理技术，一名本科生能够学习成像、形态重建等，从而为从初级到相对高级的高素质人才的培训提供了理想的环境。

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 Our unpublished data indicate that some interneuronal cell types possess “reversed” STDP at their excitatory inputs, while others do not.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.