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：敏感期表示可塑性的发育时间窗口，在此期间解剖学 神经系统的功能变得硬连线。通常，这些窗口代表了以下时期： 大脑回路和功能的精细化特别容易受到正在进行的活动的变化的影响。经典之作 例如，短暂的单眼发育剥夺可能会永久损害视觉系统 被剥夺的眼睛的敏锐度。即使在视力丧失后，这种功能障碍仍然存在，因为 代表闭眼和睁眼的丘脑皮质输入的平衡在竞争性活动中发生了变化- 依赖方式。虽然敏感期调节感觉皮层的电路细化，但尚不清楚是否 它们还控制前额叶皮层 (PFC) 中电路的成熟，前额叶皮层是一个关联皮层区域，支持 更高的认知功能。 在这里，我们建议通过暂时抑制丘脑-mPFC 来扰乱内侧 PFC 电路的成熟 青春期小鼠的投射。我们假设这将导致认知能力持续缺陷 行为。我们的初步数据有力地支持了这一假设，因为丘脑内侧背侧受到抑制 在广泛的出生后发育时间窗口内导致 mPFC 获得的持续缺陷 依赖工作记忆任务。在这个 R21 应用程序中，我们将首先缩小敏感时间窗口 通过在三个不同的时间窗口（从早起）抑制丘脑-mPFC 投射来参与 青春期至成年早期。我们假设在一个或两个青春期时间窗口内的抑制会 影响成年认知表现，而成年早期的抑制对成年认知表现没有持久影响 任务表现。其次，利用体内生理学，我们将同时记录 mPFC 的多个节点 成人任务执行期间的电路包括 mPFC、MD 和腹侧海马。我们将进一步包括 该分析中的眶额皮质（OFC），因为它的输入在青春期期间没有受到抑制。我们 假设青少年对丘脑-mPFC 预测的抑制将导致 mPFC 的持续变化 可以解释行为表现缺陷的电路功能。 目标 1. 确定青春期期间丘脑-mPFC 投射的短暂抑制是否会导致 持续的认知缺陷 目标 2：确定青春期期间丘脑-mPFC 投射的短暂抑制是否会导致 mPFC 电路功能持续异常 研究青少年时期 PFC 回路成熟对于理解精神疾病非常重要 具有神经发育起源和 PFC 功能改变。值得注意的是，在精神分裂症中，高危青少年 受试者表现出丘脑-前额叶连接减少，这与认知缺陷有关 和疾病转化。