Feedforward-feedback integration in the posterior parietal cortex

项目概要/摘要 复杂的行为依赖于感官线索和内部因素的结合，如目标，期望， 记忆和注意力。这些相互作用的崩溃被认为是许多 神经精神障碍感官信息是由前馈输入，而内部因素是 通过反馈传入传递。来自人类、灵长类动物和啮齿类动物的有力证据表明， 和反馈神经元通路会聚在后顶叶皮层（PPC）。事实上，PPC被认为是 是一系列认知过程的基础，包括工作记忆和决策。这些 数据表明PPC神经元在整合感觉和认知信息流中起关键作用。然而， 我们对整合前馈神经元的突触机制的认识还存在一个关键的空白， 输入与PPC中的反馈信号。这种缺乏洞察力限制了我们理解神经元 电路相互作用驱动行为以及受损的整合如何导致神经精神疾病。 在初步实验中，我们使用双色光遗传学来独立控制皮质传入通路。 我们发现，PPC神经元接受直接的，单突触神经支配，从前馈和 反馈源。此外，我们发现第5层的功能不同的子类 锥体神经元整合来自离散长距离传入的输入。特别是端脑内 投射（IT）细胞表现出非线性反应增强，而皮质下投射 端脑外（ET）神经元线性地对输入求和。这些数据激发了我们的核心假设，即细胞- 前馈和反馈突触的类型特异性整合驱动输入/输出转换 在PPC。为了验证这一假设，我们提出了一个互补使用的光和化学发生电路 操作，脑切片电生理学和计算建模。首先，我们将确定时间 在不同的第5层投射神经元中控制反馈和前馈传入的相互作用的规则（目的 1）。然后，我们将联合收割机双色光遗传学与电路特异性化学遗传沉默（DREADD）相结合， 确定细胞类型特异性突触整合如何驱动PPC网络的功能输出（目标2）。 最后，我们将利用计算方法来确定什么是离子电导的基础， 前馈-反馈整合的细胞类型特异性（Aim 3）。这项研究的完成将提供新的 深入了解支持感官和反馈信息相互作用的细胞机制 溪流这些知识将进一步加深我们对指导信息处理的原则的理解， 新皮层，并为未来的基础和转化研究提供基础。

PROJECT SUMMARY / ABSTRACT Complex behaviors rely on the combination of sensory clues and internal factors like goals, expectations, memories, and attention. A breakdown of these interactions is thought to be at the core of many neuropsychiatric disorders. Sensory information is carried by feedforward inputs while internal factors are conveyed via feedback afferents. Robust evidence from humans, primates, and rodents indicates that sensory and feedback neuronal pathways converge in the posterior parietal cortex (PPC). Indeed, the PPC is thought to be fundamental to an array of cognitive processes including working memory and decision-making. These data suggest that PPC neurons play a key role in integrating sensory and cognitive information streams. Yet, we have a critical gap in our knowledge regarding the synaptic mechanisms integrating feedforward inputs with feedback signals in the PPC. This lack of insight limits our ability to understand how neuronal circuit interactions drive behavior and how impaired integration leads to neuropsychiatric disorders. In preliminary experiments, we used two-color optogenetics to independently control cortical afferent pathways. We discovered that PPC neurons receive direct, monosynaptic innervation from both feedforward and feedback sources. Furthermore, we found marked differences in how functionally distinct subclasses of layer 5 pyramidal neurons integrate inputs from discrete long-range afferents. Specifically, intratelencephalically projecting (IT) cells exhibited nonlinear response enhancement while subcortically projecting extratelencephalic (ET) neurons summed inputs linearly. These data motivate our central hypothesis that cell- type specific integration of feedforward and feedback synapses drives input / output transformations in the PPC. To test this hypothesis, we propose a complementary use of opto- and chemogenetic circuit manipulation, brain slice electrophysiology and computational modelling. First, we will determine the temporal rules governing the interaction of feedback and feedforward afferents in distinct layer 5 projection neurons (Aim 1). Then we will combine two-color optogenetics with circuit specific chemogenetic silencing (DREADDs) to determine how cell-type specific synaptic integration drives the functional output of the PPC network (Aim 2). Finally, we will take advantage of computational methods to determine what ionic conductances underlie the cell-type specificity of feedforward-feedback integration (Aim 3). Completion of this research will provide novel insights into the cellular mechanisms underpinning the interaction of sensory and feedback information streams. This knowledge will further our understanding of the principles that guide information processing in the neocortex and provide the foundation for future basic and translational research.