Cortical feedback circuits for sensory integration and control of synaptic plasticity

神经科学面临的最大挑战之一是理解学习和记忆是如何工作的。长期记忆被认为储存在大脑皮层中。人类的大脑皮层特别发达。它几乎涉及行为和认知的每一个方面，从感官处理和行动计划，到逻辑推理和想象力。那么，学习和记忆是如何在如此多样化的结构中组织起来的呢？我们在这项工作计划中的目标是了解皮层回路的一个组成部分，它在大多数皮层区域形成一个循环模块，并可能为构成皮层剧目的各种形式的学习和长期记忆提供一个共同的基底。我们将研究接受来自高阶皮质区的反馈连接和携带感觉信息的上行前馈连接的锥体神经元。虽然反馈连接的目标顶端树突，前馈连接有利于锥体细胞的基底树突。所讨论的锥体神经元位于第2层和第3层（L2/3）。我们将在小鼠大脑皮层中一个相对简单但高度组织化的部分（称为桶皮层）中研究它们，该部分接收来自胡须的触觉信息。我们将观察当动物学习触觉纹理辨别任务时，来自高阶皮层区域的反馈信息如何与L2/3神经元相互作用，例如区分粗糙和光滑表面。我们将测试的假设，反馈连接门突触可塑性的前馈连接，从而编码功能的刺激有利于学习的歧视。此外，我们将测试的想法，抑制interneurones的目标顶端树突的一个子集能够控制反馈和前馈连接之间的相互作用，从而发挥控制突触plasticity.The工作方案包括实验，其中1。我们使用体外脑切片详细地探测了皮层回路的性质和操作，并通过观察被称为长时程增强（LTP）的突触过程来测量可塑性。我们测试了当动物在辨别任务中学习区分两种触觉纹理以获得奖励3时，整个动物（体内）回路的组件如何表现。我们测量了在有和没有正确反馈的学习过程中L2/3细胞的结构可塑性。初步研究表明，我们的纹理辨别任务依赖于桶皮质，可以在几天内被小鼠学习，并导致L2/3神经元的结构可塑性。来自高阶皮层区域的反馈连接可以表达可以被光激活的人工离子通道（光遗传学），使我们能够选择性地刺激反馈连接1。在皮层切片门控LTP在体外或2。在体内触觉学习过程中偏向于一种质地或另一种质地。我们的研究探索了我们认为是长期记忆系统的基本组成部分。它的正确运作依赖于顶端和基底树突上连接的分离。然而，在一个已知会导致人类精神健康状况的突变中（DISC 1 t（1;11）），我们发现锥体细胞的顶端和基底树突之间的平衡被改变（在桶状皮层和前额叶皮层）。正常情况下，基底树突的连接被发现刺激顶端树突，由于发育萎缩的基底树突。为了了解这种错误布线的程度及其对可塑性的影响，我们将使用光遗传学方法绘制突变体中的兴奋性和抑制性输入，并确定抑制控制可塑性的顶端门控的能力。这项研究的这一方面可以帮助解释认知缺陷是如何在精神分裂症等精神健康状况中出现的。

One of the great challenges in Neuroscience is understanding how learning and memory work. Long term memory is thought to be stored in the cerebral cortex. The cerebral cortex is particularly highly developed in humans. It is involved in almost every aspect of behaviour and cognition from sensory processing and planning for action, through to logical reasoning and imaginative thought. How therefore is learning and memory organised in such a diverse structure? Our aim in this programme of work is to understand a component of the cortical circuit that forms a recurring module throughout most cortical areas and may provide a common substrate for learning and long-term memory across the great variety of modalities that compose the cortical repertoire. We will study pyramidal neurones that receive both feedback connections from higher order cortical areas and ascending feedforward connections carrying sensory information. While feedback connections target apical dendrites, the feedforward connections favour the basal dendrites of the pyramidal cells. The pyramidal neurones in question are located in layers 2 and 3 (L2/3). We will study them in a relatively simple yet highly organised part of the mouse cerebral cortex (known as the barrel cortex) that receives tactile information from the whiskers. We will observe how feedback information from higher order cortical areas interacts with L2/3 neurones when the animal learns a tactile texture discrimination task, for example distinguishes between rough and smooth surfaces. We will test the hypothesis that feedback connections gate synaptic plasticity on the feedforward connections and thereby encode features of the stimulus advantageous for learning the discrimination. Furthermore, we will test the idea that a subset of inhibitory interneurones that target the apical dendrites are able to control the interaction between the feedback and feedforward connections and thereby exert control over synaptic plasticity.The programme of work comprises experiments where 1. we probe the nature and operation of the cortical circuit in some detail using in vitro brain slices and measure the plasticity by observing a synaptic process known as long-term potentiation (LTP) and 2. we test how the components of the circuit behave in whole animals (in vivo) when they learn to distinguish between two tactile textures in a discrimination task to gain a reward 3. we measure structural plasticity in the L2/3 cells during learning with and without the correct feedback. Preliminary studies show that our texture discrimination task depends on barrel cortex, can be learned by mice over a few days and causes structural plasticity in the L2/3 neurones. The feedback connections from higher order cortical areas can be made to express artificial ion channels that can be activated by light (optogenetics), allowing us to selectively stimulate feedback connections 1. in cortical slices to gate LTP in vitro or 2. during tactile learning in vivo to bias choices toward one texture or the other. Our studies probe what we believe is a fundamental component of the long-term memory system. Its correct operation relies on the separation of connections on apical and basal dendrites. However, in a mutation that is known to cause mental health conditions in people (DISC1 t(1;11)), we have found that the balance between apical and basal dendrites of pyramidal cells is altered (in barrel cortex and prefrontal cortex). Connections normally directed to basal dendrites are found to excite apical dendrites, due to developmental atrophy of the basal dendrites. To understand the extent of this mis-wiring and its consequences for plasticity we will map excitatory and inhibitory inputs in the mutants using optogenetics methods and determine the ability of inhibition to control apical gating of plasticity. This aspect of the study could help explain how cognitive deficits arise in mental health conditions like schizophrenia.