An adolescent sensitive period for thalamo-prefrontal circuit maturation

青少年丘脑-前额叶回路成熟的敏感期

• 批准号: 10064112
• 负责人: Christoph Kellendonk
• 金额: $ 24.3万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2022-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10064112
• 关键词: Adolescence; Adolescent; Adult; Affect; Anatomy; Animals; Area; Behavior; Behavioral; Chronic; Cognition; Cognitive; Cognitive deficits; Data; Development; Equilibrium; Eye; Hippocampus (Brain); Impairment; Left; Lesion; Medial; Medial Dorsal Nucleus; Mental disorders; Mus; Nervous System Physiology; Organ; Performance; Physiology; Prefrontal Cortex; Schizophrenia; Sensory; Short-Term Memory; Source; Structure; System; Task Performances; Thalamic structure; Time; Training; Virus; Vision; Visual system structure; brain circuitry; cognitive function; cognitive performance; designer receptors exclusively activated by designer drugs; early adolescence; emerging adult; frontal lobe; high-risk adolescents; in vivo; mature animal; monocular deprivation; postnatal; sensory cortex; sensory system

Project summary: Sensitive periods denote developmental time windows of plasticity during which the anatomy and function of the nervous system becomes hard-wired. Frequently, these windows represent periods in which the refinement of brain circuitry and function is particularly susceptible to changes in ongoing activity. A classic example is the visual system where transient developmental monocular deprivation can permanently impair acuity in the deprived eye. This impairment in function persists even after deprived eye vision is restored as the balance of thalamocortical inputs representing the closed and open eyes is shifted in a competitive activity- dependent manner. While sensitive periods regulate circuit refinement in sensory cortices, it is unclear whether they also govern maturation of circuitry in the prefrontal cortex (PFC), an associative cortical area that supports higher cognitive functioning. Here, we propose to perturb the maturation of medial PFC circuitry by transiently inhibiting thalamo-mPFC projections in the mouse during adolescence. We hypothesize that this will lead to persistent deficits in cognitive behaviors. Our preliminary data give strong support for this hypothesis as inhibition of the medio-dorsal thalamus during a broad postnatal developmental time window leads to persistent deficits in the acquisition of a mPFC dependent working memory task. In this R21 application we will first narrow down the sensitive time window involved by inhibiting thalamo-mPFC projections during three different time windows ranging from early adolescence to early adulthood. We hypothesize that inhibition during one or both adolescent time windows will affect adult cognitive performance, whereas inhibition during early adulthood has no lasting consequences for task performance. Second, using in vivo physiology we will simultaneously record from several nodes of mPFC circuitry including mPFC, MD, and ventral hippocampus during adult task performance. We will further include the orbito-frontal cortex (OFC) in this analysis, as its inputs were not inhibited during adolescence. We hypothesize that adolescent inhibition of thalamo-mPFC projections will lead to persistent changes in mPFC circuit function that may explain deficits in the behavioral performance. Aim 1. To determine whether transient inhibition of thalamo-mPFC projections during adolescence leads to persistent deficits in cognition Aim 2: To determine whether transient inhibition of thalamo-mPFC projections during adolescence leads to persistent abnormalities in mPFC circuit function Studying adolescent periods of PFC circuit maturation will be important for understanding psychiatric disorders with a neurodevelopmental origin and altered PFC function. Notably, in schizophrenia, high-risk adolescent subjects display decreased thalamo-prefrontal connectivity, which has been associated with cognitive deficits and illness conversion.

项目摘要：敏感时期表示解剖结构的可塑性窗口 神经系统的功能变得坚硬。这些窗口通常代表其中的时期 脑电路和功能的完善特别容易受到正在进行活动的变化的影响。经典 示例是视觉系统，瞬态发育单眼剥夺会永久损害 剥夺眼睛的敏锐度。即使剥夺了眼视力恢复，这种功能障碍仍然存在 代表闭合眼和睁开眼的丘脑皮质输入的平衡在竞争活动中移动 - 依赖方式。敏感时期调节感觉皮层中的电路精炼，但尚不清楚是否清楚 它们还控制着前额叶皮层（PFC）中电路的成熟，这是一个支持的关联皮质区域 更高的认知功能。 在这里，我们建议通过瞬时抑制丘脑-MPFC来扰动内侧PFC电路的成熟 青春期小鼠的投影。我们假设这将导致认知的持续缺陷 行为。我们的初步数据为这一假设提供了强烈的支持，因为抑制了中质丘脑 在产后的广泛发育时间窗口中，导致获得MPFC的持续缺陷 依赖的工作记忆任务。在此R21应用程序中，我们将首先缩小敏感时间窗口 涉及在三个不同时间内抑制thalamo-MPFC预测的窗口，从早期开始 青春期至成年早期。我们假设在一个或两个青少年期间的抑制作用Windows将会 影响成人认知表现，而成年初期的抑制对 任务性能。其次，使用体内生理学，我们将同时记录MPFC的几个节点 成人任务性能期间，包括MPFC，MD和腹海马在内的电路。我们将进一步包括 在此分析中，Orbito-Frontal皮层（OFC），因为其输入在青春期没有抑制。我们 假设青少年抑制丘脑-MPFC预测将导致MPFC的持续变化 电路功能可能解释行为性能的缺陷。 目的1。确定青春期潜在客户期间丘脑-MPFC投影的短暂抑制是否 认知持续缺陷 目标2：确定在青春期潜在客户期间对丘脑-MPFC投影的短暂抑制 MPFC电路函数的持续异常 研究PFC电路成熟的青少年时期对于理解精神疾病很重要 具有神经发育起源和PFC功能的改变。值得注意的是，在精神分裂症中，高风险青少年 受试者显示出降低的丘脑前额外连接性，这与认知缺陷有关 和疾病转化。