Developmental trajectories of brain rhythm dynamics in healthy adolescent rats: oscillatory network reconfigurations at the vulnerable age of schizophrenia prodrome

本研究的主要目的是研究振荡的发展轨迹， 青春期正常健康大鼠神经网络的同步，因为它在人类中的改变可能 有助于精神疾病的病理学，包括精神分裂症（SZ）。事实上，突然出现 SZ的出现有一个前驱期，但其潜在机制导致神经元的积累， 发育过程中的网络异常最终导致青春期后期的前驱症状， 然后到成年后完全表现出的障碍是不为人所知的。振荡 神经活动同步是网络功能和异常振荡的基本机制， 在SZ中建立，可能是SZ特有的下游表型缺陷的基础。神经振荡是 与表达小清蛋白的（PV+）GABA中间神经元直接相关。出现规则的神经元振荡 当GABA能突触从新生儿早期的兴奋性转换为后期的抑制性时， 接着是功能振荡器层级的开发，该功能振荡器层级通常跨多个空间 和时间尺度。控制PV+细胞活性的主要输入，特别针对NMDA受体 表达NR 2A（GluN 2A）亚单位，出生后数周，在GABA转换后很久， 传输我们假设振荡皮层网络的成熟是一个长期的过程， 在青春期和成年早期， 振荡的层次结构及其协调模式可能遵循不同的轨迹， 在成年人中发现的协调良好的局部和区域间耦合。因此，我们建议进行纵向调查 通过正常大鼠的围青春期，男性和女性，以确定如何振荡层次 发展，包括局部和区域间的节奏耦合，重点是海马（HC）和前额叶 皮质（PFC）网络及其节律协调（目标1）。我们有初步的数据表明全氟化学品- δ、HC-θ和γ振荡在青春期可能遵循不同的发展轨迹， 显著的性别差异。为了从机理上深入了解振荡电路的发展，我们还提出了 (Aim 2）研究PV+中间神经元在不同阶段的慢振荡和快振荡中的作用。 通过操纵他们的NMDAR输入神经发育。具体而言，我们将探讨 NMDA-NR 2开关，已知发生在出生后发育中，振荡网络的成熟。 我们推测，NR 2A：NR 2B比率的发育性增加，在相关性中相对延长， 大脑区域，强烈影响伽马振荡及其低频调制的发展。 确定青少年期振荡神经网络正常神经发育的原则， 在SZ前驱症状的易感年龄收集皮质微电路重构的重要信息， 为今后的翻译研究奠定基础。

The primary aim of the proposed research is to study the developmental trajectory of oscillatory synchronization in neural networks of normal healthy rats during adolescence, as its alterations in human may contribute to the pathology of psychiatric diseases, including schizophrenia (SZ). In fact, sudden manifestation of SZ is preceded by a prodromal period but the underlying mechanisms leading to accumulation of neuronal network abnormalities through development which eventually lead to prodromal signs in late-adolescence and then to the fully manifested disorder after crossing into adulthood are not well-known. Oscillatory synchronization of neural activity is an essential mechanism of network function and abnormal oscillations, well established in SZ, may underlie downstream phenotypic deficits characteristic for SZ. Neural oscillations are directly related to parvalbumin-expressing (PV+) GABA interneurons. Regular neuronal oscillations appear when GABAergic synapses switch from excitatory in early neonates to inhibitory at later stages which is then followed by development of a functional oscillator hierarchy which normally operates across multiple spatial and temporal scales. The major input controlling PV+ cell activity, specifically targeting NMDA receptors expressing the NR2A (GluN2A) subunit, develops weeks after birth, well after the switch in GABA transmission. We hypothesize that maturation of oscillatory cortical networks is a protracted process occurring over the length of adolescence and into early adulthood during which the different components of the oscillatory hierarchy and patterns of their coordination may follow different trajectories to arrive to the pattern of well-coordinated local and inter-regional coupling, found in adults. Thus, we propose longitudinal investigations through the peri-adolescent period of normal rats, males and females to define how the oscillatory hierarchy develops, including local and inter-regional rhythmic coupling, focusing on hippocampus (HC) and prefrontal cortex (PFC) networks and their rhythmic coordination (Aim 1). We have preliminary data indicating that PFC- delta, HC-theta, and gamma oscillations may follow distinct developmental trajectories during adolescence with notable sex differences. To gain a mechanistic insight into development of oscillatory circuits, we also propose (Aim 2) to examine the role of PV+ interneurons in slow and fast oscillations at different stages of neurodevelopment by manipulating their NMDAR input. Specifically, we will explore the potential effect of the NMDA-NR2 switch, known to take place in postnatal development, on the maturation of oscillatory networks. We hypothesize that the developmental increase of the NR2A:NR2B ratio, relatively protracted in associative brain regions, strongly affects the development of gamma oscillations and its low frequency modulation. Identifying the principles of normal neurodevelopment of oscillatory neural networks in peri-adolescence, and collecting vital information of reconfigurations in cortical microcircuitry at a vulnerable age of SZ prodrome, may help establishing a basis for future translational studies.