State dependent dynamics of sensory responses in auditory cortex

描述（由申请人提供）：我们的感知是由我们的行为状态塑造的。当我们疲惫时，我们无法注意到通常突出的刺激，当我们专注于一件事时，我们忽略了其他人，通过练习，我们甚至可以提高我们的感知能力。虽然这些都是经验的基本方面，但这种“状态依赖”的大脑机制却知之甚少，特别是在神经元和突触的水平上。知觉和行为状态的融合可能并不比初级感觉皮层更相关，初级感觉皮层是感觉知觉和皮层处理第一次相遇的地方。因此，这是本建议的目标，以了解初级感觉皮层的大脑活动的状态依赖的机制。该项目使用小鼠的听觉系统作为模型，因为听觉对于小鼠和人类来说都是一种重要的、发育良好的感觉，并且因为与耳聋、其他交流障碍以及精神或神经障碍的理解和潜在治疗相关。 为了“放大”到感知和行为动物的细胞和突触水平，本研究使用了一套强大的尖端技术：双光子靶向和盲膜片钳记录沿着定制开发的行为和感觉刺激传递方法。这种整合的方法将有望使我们能够回答一个关于感知的状态依赖性的基本重要问题。与被动地坐着不动相比，当动物处于警觉或移动的状态时，听觉皮层的回路动力学是如何变化的？特别是，我们将确定如何通过抑制性和兴奋性突触活动调节主神经元放电，以及哪些类型的抑制性神经元似乎负责抑制成分。为此，我们将在定制设计的跑步机设备上监测动物的运动，并通过记录多个前脑区域的局部场电位（LFP）和多单位放电来测量警觉性。 这些实验将为皮层感觉反应的动力学提供新的见解，因为它们与动物的状态有关。这项工作也将为将来研究耳聋和脑部疾病中行为状态对知觉的调节是如何受到干扰提供方法和结果的基础。 公共卫生相关性：流行的短语“心灵高于物质”表达了这样一个事实，即我们的感知是由我们的内在状态塑造的，例如：困倦或警觉，或幻觉或抑郁等病理状态。这种“状态依赖”是我们经历的一个复杂但非常重要的方面，因此阐明其大脑表现对理解健康的大脑和精神疾病具有广泛的意义。本研究旨在探讨小鼠在不同的清醒和运动状态下，听觉皮层中的基本细胞和突触生理学是如何改变的。

DESCRIPTION (provided by applicant): Our perception is shaped by our behavioral state. When we are tired we fail to notice normally salient stimuli, when focused on one thing we ignore others, and with practice we can even improve our ability to perceive. While these are basic aspects of experience, the mechanisms in the brain of such 'state dependence' are poorly understood, particularly at the level of neurons and synapses. The convergence of perception and behavioral state is perhaps no more relevant than in primary sensory cortex, where sensory perception and cortical processing first meet. Therefore, it is the goal of this proposal to understand the mechanisms of the state dependence of brain activity in primary sensory cortex. This project uses the auditory system of mice as a model, because hearing is an important, well developed sense for both mice and humans, and because of the relevance for the understanding and potential treatment of deafness, other communication disorders, and psychiatric or neurologic disorders. To 'zoom in' to the cellular and synaptic level in a perceiving and behaving animal this study uses a powerful set of cutting edge techniques: two-photon targeted and blind patch- clamp recording along with custom-developed behavioral and sensory stimulus delivery methods. This integrative approach will hopefully allow us to answer a basic important question about the state dependence of perception. How do the circuit dynamics in auditory cortex change when an animal is alert or mobile when compared to passively sitting still? In particular, we will determine how principal neuron firing is regulated by inhibitory and excitatory synaptic activity, and what types of inhibitory neurons appears to be responsible for the inhibitory component. To do so, we will monitor the movements of the animal on a custom designed treadmill apparatus, and measure alertness by recording the local field potential (LFP) and multiunit firing in multiple forebrain areas. These experiments will provide new insights into the dynamics of cortical sensory responses as they relate to the state of the animal. This work will also provide a foundation of methods and results for future study of how the modulation of perception by behavioral state is perturbed in deafness and brain diseases. PUBLIC HEALTH RELEVANCE: The popular phrase 'mind over matter' expresses the fact that our perception is shaped by our internal state of being, such as: sleepy or alert, or pathological states like hallucinating or depressed. Such 'state dependence' is a complex yet very important facet of our experience and therefore elucidating its brain manifestations has broad implications for understanding the healthy brain and psychiatric illness. This research proposes to explore how the basic cellular and synaptic physiology in auditory cortex, measured in responses to sounds, is altered in mice between different states of wakefulness and locomotion.