Activity dependent plasticity and neuronal spiking homeostasis in vivo

描述（由申请人提供）：为了正确传输和存储信息，神经网络必须能够补偿内部环境的短期和长期变化（例如睡眠/觉醒周期，发育，衰老和疾病）以及外部刺激驱动输入的快速变化。在体外实验中，已经描述了在这种扰动下稳定神经元活动的稳态可塑性机制（1），但对它们在稳定自由行为动物回路功能中的作用知之甚少。内稳态可塑性的失调被广泛假设为导致衰弱的病理学，包括阿尔茨海默病（2）、Rett综合征（3）和癫痫（4），因此理解其在体内的作用是至关重要的。目前尚不清楚神经元和神经网络是否表现出稳态调节的尖峰活动（放电率稳态）和/或复杂的网络特性在清醒和自由行为的动物，预测我的目的是测试在这项研究中，以下活动的个别新皮层神经元随着时间的推移在自由行为的大鼠。首先，将在自由行为和自由观看的幼年大鼠的视觉皮层中评估神经元活动和对活动剥夺的反应。通过使用遗传操作和活动剥夺，将研究体内稳态突触可塑性、突触缩放的充分研究形式在放电率稳态中的机制作用。最后，我将利用这个实验技术的一个独特的功能来研究可塑性机制和行为状态之间的相互作用。对行为正常的动物的长期记录使我能够询问稳态可塑性的表达是否受行为、唤醒状态、网络状态（通过局部场电位）和昼夜因素的控制（5）。在行为正常的动物中，放电率稳态的表征对于理解神经网络如何运作是至关重要的。研究稳态可塑性机制（如突触缩放）对正常脑功能的贡献对于理解其生理作用至关重要。此外，对活动和觉醒状态在稳态可塑性表达中的作用的研究将阐明睡眠在脑功能和可塑性中的作用。这些知识将促进我们对基本细胞、系统和计算神经科学的理解，并为未来研究破坏神经元稳态的疾病提供见解。 公共卫生相关性：人们普遍认为，稳态可塑性的失调在许多神经系统疾病的发病机制中是重要的，包括阿尔茨海默病、癫痫和Rett综合征。为了开始讨论稳态可塑性在疾病中的作用，首先必须了解神经元活动的稳态可塑性如何在完整的、自由行为的动物中起作用。这项工作将提供正常行为动物的稳态可塑性的第一个特征，将探索这种可塑性的分子机制，并将确定稳态可塑性的表达模式，因为它们与行为和活动状态有关。

DESCRIPTION (provided by applicant): In order to properly transmit and store information, neural networks must be able to compensate for short and long-term changes in internal environment (e.g. sleep/wake cycles, development, aging, and disease) as well rapid changes in external, stimulus-driven inputs. Homeostatic plasticity mechanisms that stabilize neuronal activity in the face of such perturbations have been described in vitro (1), but little is known about their role in stabilizing circuit function in the freely behaving animal. Dysregulation of homeostatic plasticity is widely hypothesized to contribute to debilitating pathologies including Alzheimer's disease (2), Rett syndrome (3), and epilepsy (4), thus an understanding of its role in vivo is critical. It is currently unknown whether neurons and neural networks exhibit homeostatic regulation of spike activity (firing rate homeostasis) and/or complex network properties in the awake and freely behaving animal, a prediction I aim to test in this study by following the activit of individual neocortical neurons over time in the freely behaving rat. First, neuronal activity an the response to activity deprivation will be assessed in the visual cortex of freely behaving and freely viewing juvenile rats. Through the use of genetic manipulations and activity deprivation, the mechanistic role of a well- studied form of homeostatic synaptic plasticity, synaptic scaling, in firing rate homeostasis in vivo will be investigated. Finally, I will exploit a unique feature o this experimental technique to examine the interaction between plasticity mechanisms and behavioral state. Chronic recordings in normally behaving animals enable me to ask whether the expression of homeostatic plasticity is governed by behavior, arousal state, network state (via local field potentials), and circadian factors (5). Characterization of firing rate homeostasi in the normally behaving animal is essential for understanding how neural networks operate. Investigating the contributions of homeostatic plasticity mechanisms such as synaptic scaling to normal brain function is critical for understanding their physiological role. Further, an examination of the role of activity and arousal-state in the expression of homeostatic plasticity will clarify the role of sleep in brain function and plasticity. This knowledge will advance our understanding of basic cellular, systems, and computational neuroscience, as well as provide insight for future investigations of diseases that disrupt neuronal homeostasis. PUBLIC HEALTH RELEVANCE: It is widely hypothesized that dysregulation of homeostatic plasticity is important in the pathogenesis of many neurological disorders, including Alzheimer's disease, epilepsy, and Rett syndrome. In order to begin addressing the role of homeostatic plasticity in disease, it is essential first to understand how homeostatic plasticity of neuronal activity operates in the intact, freely behaving animal. This work will provide the first characterization of homeostatic plasticity in the normally behaving animal, will explore molecular mechanisms of this plasticity, and will determine the expression patterns of homeostatic plasticity as they relate to behavior and activity state.