Behavioral state development in infants

描述(申请人提供)：睡眠占据了我们成年人生活的三分之一，但它的功能仍不清楚。在婴儿中，睡眠甚至更突出，自发的肌阵挛抽动也是活跃(或快速眼动)睡眠的一个决定性特征。在过去的十年里，首席调查员实验室的研究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作用。此外，现在人们普遍认为，抽动产生的感觉反馈(即再传入)在神经轴的各个层面都受到密切监控。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(SBS)-在初级感觉皮质中响应于内源性和外源性产生的感觉刺激而产生。抽动及其相关的再传入和皮层SBS被认为共同参与了地形图组织的发展和维持。首席研究员的实验室一直致力于这一努力，通过监测未麻醉的新生大鼠的神经生理活动，这些大鼠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。这个应用程序解决了两个主要目标。首先，在大鼠出生后的第一周，发现了一个短暂的时期，此时切断了穹隆体部的自发皮质活动，并有可能在切断之后恢复功能。假设与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，包括在未麻醉的幼鼠身上应用新的安培测量，以测量与行为状态、肌阵挛抽动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是自发产生的(在活跃的睡眠中)还是由外周本体感受器刺激引起的，因此受到不同的调节。由于个体区分自身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副本的产生，因此在新生大鼠中识别将自发和诱发的感觉信息传输到躯体感觉皮质的神经电路是很重要的。这一目标将使用多种方法相结合来实现，包括表面脑电、安培测量和选择性单侧灭活中脑和前脑的脑区。首席调查员实验室的初步结果现在证明了在未麻醉的幼鼠身上使用安培测量的可行性。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。这个应用程序与蓝图兼容，像它一样关注正常条件下和神经损伤后婴儿早期的睡眠、神经功能和大脑可塑性。此外，为这项工作提供信息的方法正在有助于从根本上重新定义婴儿睡眠的概念，这将很快为更广泛地了解婴儿和成年人的睡眠功能奠定基础。

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.