Cortical feedback circuits for sensory integration and control of synaptic plasticity

用于感觉统合和突触可塑性控制的皮层反馈电路

• 批准号: MR/W004844/1
• 负责人: Kevin Fox
• 金额: $ 187.83万
• 依托单位: CARDIFF UNIVERSITY
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW004844%2F1
• 关键词: Cortical; feedback; circuits; sensory; integration

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.

神经科学的巨大挑战之一是理解学习和记忆的工作原理。长期记忆被认为存储在大脑皮层中。人类的大脑皮层特别发达。它几乎涉及行为和认知的各个方面，从感觉处理和行动计划，到逻辑推理和想象力。那么，学习和记忆是如何以如此多样化的结构组织起来的呢？我们这个工作计划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，并可能为构成皮层指令的各种模式的学习和长期记忆提供共同的基础。我们将研究锥体神经元，它们接收来自高阶皮质区域的反馈连接和携带感觉信息的上升前馈连接。反馈连接针对的是顶端树突，而前馈连接则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（称为桶状皮层）相对简单但高度组织的部分中研究它们，该部分从胡须接收触觉信息。当动物学习触觉纹理辨别任务时，例如区分粗糙和光滑的表面，我们将观察来自高阶皮质区域的反馈信息如何与 L2/3 神经元相互作用。我们将测试这样的假设：反馈连接门控前馈连接上的突触可塑性，从而编码有利于学习辨别的刺激特征。此外，我们将测试这一想法，即针对顶端树突的抑制性中间神经元的子集能够控制反馈和前馈连接之间的相互作用，从而对突触可塑性进行控制。工作计划包括实验，其中 1. 我们探究使用体外脑切片详细了解皮质回路的性质和操作，并通过观察称为长时程增强 (LTP) 的突触过程来测量可塑性，2. 我们测试回路的组件如何当整个动物（体内）在辨别任务中学习区分两种触觉纹理以获得奖励时，它们会表现出行为。 3. 我们在有或没有正确反馈的学习过程中测量 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取决于桶状皮层，小鼠可以在几天内学会并导致 L2/3 神经元的结构可塑性。来自高阶皮质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. 在皮质切片中以在体外门控 LTP 或 2. 在触觉学习过程中vivo 将选择偏向一种纹理或另一种。我们的研究探讨了我们认为的长期记忆系统的基本组成部分。其正确的操作依赖于顶端和基底树突上连接的分离。然而，在已知会导致人类心理健康状况的突变中（DISC1 t(1;11)），我们发现锥体细胞的顶端和基底树突之间的平衡发生了改变（在桶状皮层和前额叶皮层）。由于基底树突的发育萎缩，通常针对基底树突的连接被发现会激发顶端树突。为了了解这种错误接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心理健康状况下出现的。

项目成果

Differentiation of Hebbian and homeostatic plasticity mechanisms within layer 5 visual cortex neurons.

第 5 层视觉皮层神经元内 Hebbian 和稳态可塑性机制的分化。

• DOI: http://dx.10.1016/j.celrep.2022.110892
• 发表时间: 2022
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Pandey A

Hebbian and homeostatic plasticity mechanisms are segregated in sub-types of layer 5 neuron in the visual cortex

赫布可塑性机制和稳态可塑性机制在视觉皮层第 5 层神经元的亚型中是分离的

• DOI: http://dx.10.1101/2022.02.11.480060
• 发表时间: 2022
• 作者: Pandey A