Feedforward-feedback integration in the posterior parietal cortex

项目摘要/摘要 复杂的行为依赖于感官线索和内部因素的组合，如目标，期望， 回忆和关注。这些相互作用的破裂被认为是许多 神经精神障碍。感官信息由前馈输入携带，而内部因素是 通过反馈传入传递。来自人类、灵长类和啮齿动物的有力证据表明，感官 反馈神经元通路汇聚在后顶叶皮质(PPC)。事实上，购买力平价被认为是 是包括工作记忆和决策在内的一系列认知过程的基础。这些 数据表明，PPC神经元在整合感觉和认知信息流方面发挥着关键作用。然而， 我们对整合前馈的突触机制的了解有一个严重的差距 PPC中带有反馈信号的输入。这种洞察力的缺乏限制了我们理解神经元如何 电路相互作用驱动行为，以及整合受损如何导致神经精神障碍。 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神经元接受来自前馈和前馈的直接、单突触神经支配 反馈来源。此外，我们还发现，第5层子类在功能上的不同之处显著不同 锥体神经元整合来自离散的远程传入的输入。具体地说，就是脑内 投射(IT)细胞在皮质下投射时表现出非线性反应增强 脑外(ET)神经元对输入进行线性求和。这些数据激发了我们的中心假设，即细胞- 前馈和反馈突触的特定类型整合驱动输入/输出转换 在购买力平价中。为了验证这一假说，我们提出了光和化学发生回路的互补使用。 手法、脑片电生理学和计算建模。首先，我们将确定时间 不同层5投射神经元中反馈和前馈传入相互作用的规则(AIM 1)。然后，我们将结合双色光遗传学和电路特异性化学发生沉默(DREADD)来 确定细胞类型的特定突触整合如何驱动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是什么离子电导 前馈-反馈整合的细胞类型特异性(目标3)。这项研究的完成将提供新的 对支持感觉和反馈信息相互作用的细胞机制的洞察 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 并为今后的基础研究和翻译研究奠定了基础。

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.