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

健康青少年大鼠脑节律动态的发育轨迹：精神分裂症前驱症状脆弱年龄的振荡网络重构

• 批准号: 10373688
• 负责人: BERNAT KOCSIS
• 金额: $ 27.56万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10373688
• 关键词: Adolescence; Adolescent; Adult; Affect; Age; Agreement; Animal Experimentation; Autopsy; Behavioral; Biological Markers; Biological Psychiatry; Birth; Brain; Brain region; Cells; Characteristics; Clinical Research; Coupling; Data; Development; Disease; Distant; Dopamine; Equilibrium; Female; Frequencies; Fruit; Future; Glutamates; High Frequency Oscillation; Hippocampus (Brain); Human; Impaired cognition; Impairment; Interneurons; Investigation; Knowledge; Lead; Length; Longitudinal Studies; Measures; Mental disorders; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NMDA receptor antagonist; Neurons; Neurotransmitters; Parvalbumins; Pathologic; Pathologic Processes; Pathology; Pattern; Periodicity; Phase; Phenotype; Physiological; Play; Populations at Risk; Prefrontal Cortex; Process; Prodromal Schizophrenia; Psychiatry; Psychoses; Rattus; Research; Risk; Rodent; Rodent Model; Role; Schizophrenia; Sex Differences; Specificity; Structural defect; Structure; Symptoms; Synapses; System; Testing; Theta Rhythm; Time; antagonist; cognitive function; early detection biomarkers; emerging adult; endophenotype; gamma-Aminobutyric Acid; insight; male; neonate; neural circuit; neural network; neurochemistry; neurodevelopment; neuroimaging; periadolescent; postnatal development; psychotic symptoms; receptor; relating to nervous system; translational study; transmission process

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.

本研究的主要目的是研究振荡的发展轨迹 正常健康大鼠青春期神经网络的同步性，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，突然的表现 SZ 之前有一个前驱期，但导致神经元积累的潜在机制 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疾病尚不为人所知。振荡型 神经活动的同步是网络功能和异常振荡的重要机制 在 SZ 建立的，可能是 SZ 下游表型缺陷特征的基础。神经振荡是 与表达小清蛋白（PV+）GABA 中间神经元直接相关。出现规律的神经元振荡 当 GABA 能突触从新生儿早期的兴奋性转变为后期的抑制性时， 随后开发了一个功能振荡器层次结构，该层次结构通常跨多个空间运行 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 NR2A (GluN2A) 亚基，在出生后几周、GABA 转换后很久才发育 传播。我们假设振荡皮层网络的成熟是一个漫长的过程 在整个青春期和成年早期，在此期间， 振荡层次结构及其协调模式可能遵循不同的轨迹来达到以下模式： 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（雄性和雌性）的青春期前后来定义振荡等级如何 发展，包括局部和区域间的节律耦合，重点关注海马体（HC）和前额叶 皮层 (PFC) 网络及其节律协调（目标 1）。我们有初步数据表明 PFC- delta、HC-theta 和 gamma 振荡在青春期可能遵循不同的发育轨迹 显着的性别差异。为了深入了解振荡电路的发展，我们还建议 （目标 2）检查 PV+ 中间神经元在不同阶段的慢速和快速振荡中的作用 通过操纵 NMDAR 输入来促进神经发育。具体来说，我们将探讨其潜在影响 NMDA-NR2 转换已知发生在出生后发育中，即振荡网络的成熟过程中。 我们假设 NR2A:NR2B 比率的发育增加在联想性中相对延长 大脑区域，强烈影响伽马振荡的发展及其低频调制。 确定青春期振荡神经网络正常神经发育的原理，以及 在 SZ 前驱症状的脆弱年龄收集皮质微电路重新配置的重要信息，可能 帮助为未来的转化研究奠定基础。