Behavioral state development in infants

描述（由申请人提供）：睡眠占据了我们成人生活的三分之一，但我们仍然不知道它的功能。在婴儿中，睡眠更为突出，自发的肌阵挛性抽搐是活跃（或REM）睡眠的一个定义特征。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流行的观念，即大脑在控制婴儿睡眠方面没有任何作用。此外，现在被广泛接受的是，抽搐的感觉反馈（即参考）在神经轴的所有水平上都受到密切监测。对这一应用特别重要的是最近发现的振荡事件-称为纺锤波爆发(SBs)-在初级感觉皮层中产生，以响应内源性和外源性产生的感觉刺激。据认为，抽搐，其相关参考和皮质SBs共同参与地形组织的发展和维持。首席研究员的实验室一直致力于监测未麻醉的新生大鼠的神经生理活动，因为它们自发地在睡眠和清醒之间循环，并对特定的外周触觉和本体感觉刺激做出反应。这个应用程序有两个主要目的。首先，在大鼠出生后的第一周，发现胼胝体切开术解除了自发皮层活动的抑制，并且胼胝体切开术后功能恢复是可能的。据推测，与睡眠有关的抽搐有助于这种功能的恢复，就像它有助于正常的发育一样。为了验证这一假设，将使用神经生理学和神经药理学方法，包括对未麻醉的幼鼠进行新的应用，以测量与行为状态、肌挛性抽搐和外周刺激有关的皮层胆碱、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的调节差异取决于它们是自发产生的（在活跃睡眠期间）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和外部产生的感觉输入的能力依赖于产生一个参考副本，因此在新生大鼠中识别将自发和诱发的感觉信息传递到体感皮层的神经回路是很重要的。这一目标将通过多种方法的结合来实现，包括表面脑电图，安培测量，以及选择性地在中脑和前脑的大脑区域单侧失活。来自首席研究员实验室的初步结果现在证明了在未麻醉的幼鼠中使用安培术的可行性。美国国立卫生研究院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。这个应用程序是兼容的蓝图，因为它的重点是睡眠，神经功能和大脑可塑性在早期婴儿在正常条件下和神经损伤后。此外，这项工作的方法有助于对婴儿睡眠进行根本性的重新概念化，这将很快为更广泛地理解婴儿和成人的睡眠功能提供基础。

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.