Behavioral state development in infants

睡眠占据了我们成年生活的三分之一，但它的功能仍然未知。在婴儿中，睡眠甚至更加突出，自发性肌阵挛抽搐是主动（或REM）睡眠的定义特征。在过去的十年里，首席研究员实验室的研究已经帮助消除了直到最近才占主导地位的观念，即大脑在控制婴儿睡眠方面没有任何作用。而且，现在广泛接受的是感觉反馈（即，在神经轴的所有水平处密切监测抽搐的神经传导）。对这一应用特别重要的是最近发现的振荡事件-所谓的纺锤波爆发（SB）-这是在初级感觉皮层中产生的内源性和外源性产生的感觉刺激。据认为，抽搐，其相关的refference，和皮层SBs共同参与的发展和维护的地形组织。主要研究者的实验室一直致力于通过监测未麻醉的新生大鼠的神经生理活动，因为它们在睡眠和觉醒之间自发循环，并对特定的外周触觉和本体感受刺激做出反应。本申请涉及两个广泛的目标。首先，在大鼠出生后第一周内，当胼胝体切开术抑制自发性皮质活动时，以及胼胝体切开术后功能恢复时，发现了一个短暂的时期。据推测，睡眠相关的抽搐有助于这种功能的恢复，就像它有助于正常发育一样。为了验证这一假设，将使用神经生理学和神经药理学方法，包括电流分析法在未麻醉幼鼠中的新应用，用于测量与行为状态、肌阵挛性抽搐和外周刺激相关的皮质胆碱、谷氨酸和GABA水平的实时细胞外变化。其次，最近的研究表明，SBs的差异调节取决于它们是自发产生的（在主动睡眠期间）还是由外周本体感受器刺激引起的。由于个体区分自我产生的感觉输入和外部产生的感觉输入的能力依赖于传出复制的产生，因此在新生大鼠中识别将自发和诱发的感觉信息传递到躯体感觉皮层的神经回路是很重要的。这一目标将使用多种方法的组合来实现，包括表面EEG、电流分析法和选择性单侧中脑和前脑脑区失活。主要研究者实验室的初步结果证明了在未麻醉的幼鼠中使用电流分析法的可行性。NIH神经科学蓝图强调需要更多的基础研究来了解神经发育，神经变性和神经可塑性。该应用程序与蓝图兼容，专注于在正常条件下和神经损伤后的婴儿早期的睡眠，神经功能和大脑可塑性。此外，为这项工作提供信息的方法有助于从根本上重新认识婴儿睡眠，这将很快为更广泛地理解婴儿和成人的睡眠功能奠定基础。 公共卫生相关性：NIH神经科学蓝图和NIMH变革蓝图强调了对大脑发育及其对损伤的反应的基础跨学科研究对于促进我们对儿童和青少年精神疾病高发病率原因的理解至关重要。本申请集中于来自睡眠相关的“抽搐”运动的感觉反馈在神经系统的构建中所起的作用，所述感觉反馈在产前和产后早期尤其突出，特别是关于大脑皮层及其互连。通过了解大脑如何解释这些运动，以及早期损伤和感觉中断如何改变大脑的反应，我们将开始阐明睡眠和清醒期间的早期感觉体验如何帮助塑造正常和病理结果。

DESCRIPTION (provided by applicant): Sleep occupies one-third of our adult lives and yet its function is still not known. In infants, sleep is even more prominent, as are the spontaneous myoclonic twitches that are a defining feature of active (or REM) sleep. Over the past decade, research in the Principal Investigator's laboratory has helped dispel the notion - which held sway until recently - that the brain plays no role in the control of infant sleep. Moreover, it is now widely accepted that sensory feedback (i.e., reafference) from twitching is closely monitored at all levels of the neuraxis. Of particular importance for this application is the recent discovery of oscillatory events-called spindle-bursts (SBs)-that are produced in primary sensory cortices in response to endogenously and exogenously generated sensory stimulation. It is thought that twitching, its associated reafference, and cortical SBs participate together in the development and maintenance of topographic organization. The Principal Investigator's laboratory has been engaged in this effort by monitoring neurophysiological activity in unanesthetized newborn rats as they cycle spontaneously between sleep and wakefulness and respond to specific peripheral tactile and proprioceptive stimulation. This application addresses two broad aims. First, a transient period during the first postnatal week in rats has been discovered when corpus callosotomy disinhibits spontaneous cortical activity and when recovery of function after callosotomy is possible. It is hypothesized that sleep-related twitching contributes to this recovery of function, just as it contributes to normal development. To test this hypothesis, neurophysiological and neuropharmacological approaches will be used, including the novel application of amperometry to unanesthetized infant rats for the measurement of real-time extracellular changes in cortical choline, glutamate, and GABA levels in relation to behavioral state, myoclonic twitching, and peripheral stimulation. Second, recent work suggests that SBs are differentially regulated depending on whether they are produced spontaneously (during active sleep) or evoked by peripheral proprioceptor stimulation. Because the ability of individuals to differentiate self-produced from externally produced sensory input relies upon the production of an efference copy, it is important to identify in newborn rats the neural circuitry that transmits spontaneous and evoked sensory information to somatosensory cortex. This aim will be accomplished using a combination of methods, including surface EEG, amperometry, and selective unilateral inactivation of brain regions in the midbrain and forebrain. Preliminary results from the Principal Investigator's laboratory now demonstrate the feasibility of using amperometry in unanesthetized infant rats. The NIH Blueprint for Neuroscience emphasizes the need for more basic research to understand neurodevelopment, neurodegeneration, and neuroplasticity. This application is compatible with the Blueprint, focusing as it does on sleep, neural function, and brain plasticity across early infancy under normal conditions and after neural insult. Moreover, the approach that informs this work is contributing to a fundamental reconceptualization of infant sleep that will soon provide the foundation for a broader understanding of the function of sleep in both infants and adults. PUBLIC HEALTH RELEVANCE: The NIH Blueprint for Neuroscience and the NIMH Blueprint for Change emphasize how basic, interdisciplinary research into the development of the brain and its response to injury is critical for advancing our understanding of the causes of the high rates of mental illness among children and adolescents. The current application focuses on the role that sensory feedback from sleep- related "twitch" movements, which are especially prominent during the prenatal and early postnatal period, plays in the construction of the nervous system, especially as concerns the cerebral cortex and its interconnections. By understanding how the brain interprets these movements and how early injury and sensory disruption alter the brain's responses, we will begin to shed light on how early sensory experiences during sleep and wakefulness help to shape both normal and pathological outcomes.