Regulation of Dendritic Compartmentalization Features

大脑由数十亿个称为神经元的微观细胞组成，这些细胞在密集，复杂的网络中相互连接。神经元有称为树突的大分支，类似于树上的树枝，上面布满了称为突触的特殊连接，神经元在这里相互交流。神经元实时汇总突触输入，当足够多的突触被激活时，发射“尖峰”将信号传递给下游的伙伴。由于每个神经元可能携带超过一万个突触，因此神经元可能执行的计算数量是惊人的。近几十年来，人们对这些操作取得了显着的见解，共同概述了单个神经元信息处理的基本机制。一个关键的发现是，神经元树突树的单个分支可以有力地增强突触输入并驱动神经元尖峰，这使神经元能够更有效地处理信息。通过这种方式，神经元被认为被分为多个功能“亚基”或“区室”，由树突树的各个分支表示。近年来，我们的实验室应用尖端的激光扫描显微镜和电生理学来研究活体神经元在大脑发育过程中沿着这些树枝状亚基的突触的成熟。我们发现了一种新的钙信号模式，发生在发育中的树突状细胞中，揭示了神经回路是如何形成的。在这项研究计划中，我们的目标是扩展这些发现，以更好地了解信息处理是如何控制在个别树突隔室。在我们的第一个目标中，我们将描述发育中的树突如何对突触输入的不同模式做出反应。这些实验是我们迄今为止所完成的工作的自然延伸，将为理解神经回路形成过程中突触活动是如何处理的提供坚实的基础。在第二个和第三个目标中，我们将直接研究大脑中特定的神经调质，特别是内源性大麻素和血清素，如何影响单个树突的功能。内源性大麻素是体内的天然化学物质，类似于大麻中的活性药物，血清素通常参与情绪，食欲和性行为的调节。虽然这些神经化学物质众所周知会改变神经元功能，但目前对这些过程的理解是初步的，并且明显落后于现代神经计算模型。我们提出的实验将扩展最近关于树突状亚基功能的发现，因此适合于推动我们对大脑神经调节的理解。这项研究计划将利用先进的技术和分析来揭示大脑功能背后的复杂细胞机制。

The brain is made of billions of microscopic cells called neurons, which are interconnected in dense, complex networks. Neurons have large branches called dendrites that resemble the branches on a tree, which are studded with specialized connections called synapses, where neurons communicate with one another. Neurons sum-up synaptic inputs in real-time and, when enough synapses are activated, fire ‘spikes’ to transmit signals to their partners downstream. Since every single neuron may carry more than ten thousand synapses, the number of computations that a neuron potentially performs is staggering. Remarkable insights into these operations have been made in recent decades, together outlining fundamental mechanisms for information processing at single neurons. One key finding is that individual branches of a neuron’s dendritic tree can powerfully boost synaptic inputs and drive neuronal spiking, which enable neurons to be more efficient at information processing. In this way, neurons are thought to be divided into multiple functional ‘subunits’ or ‘compartments’, represented by individual branches of the dendritic tree. In recent years, our laboratory has applied cutting-edge laser scanning microscopy and electrophysiology to study in live neurons the maturation of synapses along these dendritic subunits during brain development. We have discovered a novel mode of calcium signaling that takes place at developing dendritic compartments, shedding light on how neural circuits are formed. In this research proposal, we aim to extend these findings to better understand how information processing is controlled at individual dendritic compartments. In our first Objective, we will characterize how developing dendrites respond to different patterns of synaptic input. These experiments are a natural extension of the work we have accomplished to date, and will provide a firm foundation for understanding how synaptic activity is processed during neural circuit formation. In the second and third Objectives, we will directly investigate how specific neuromodulators in the brain, specifically endocannabinoids and serotonin, affect the function of individual dendrites. Endocannabinoids are natural chemicals in the body that resemble the active drug in cannabis, and serotonin is classically involved in the regulation of mood, appetite and sexual behavior. Although these neurochemicals are well-known to alter neuron function, current understanding of these processes is rudimentary, and significantly lags behind modern models of neural computation. The experiments we propose will expand on recent discoveries about dendritic subunit function, and are therefore suited to push forward our understanding of neuromodulation in the brain. This research program will make use of sophisticated technologies and analyses to uncover the complex cellular mechanisms that underlie brain function.