An adolescent sensitive period for thalamo-prefrontal circuit maturation

项目摘要：敏感期是指可塑性的发育时间窗口，在此期间， 神经系统的功能也变得固定。通常，这些窗口代表的时期， 大脑回路和功能的完善特别容易受到正在进行的活动的影响。一个经典 例如视觉系统，短暂的发展性单眼剥夺会永久损害 视力下降的眼睛。这种功能损害即使在剥夺的眼睛视力恢复后仍然存在， 在竞争性活动中，代表闭眼和睁眼的丘脑皮质输入的平衡发生了变化， 依赖的方式。虽然敏感期调节感觉皮层的回路完善，但尚不清楚是否 它们还控制着前额叶皮层（PFC）回路的成熟，这是一个支持大脑活动的关联皮层区域。 更高的认知功能 在这里，我们建议通过短暂抑制丘脑-mPFC来干扰内侧PFC回路的成熟 小鼠在青春期的投射。我们假设这将导致认知功能的持续缺陷， 行为。我们的初步数据给予强有力的支持，这一假设作为抑制中背丘脑 在广泛的出生后发育时间窗口导致持续缺陷的收购mPFC 依赖性工作记忆任务在此R21应用程序中，我们将首先缩小敏感时间窗口 在三个不同的时间窗口，从早期到晚期， 从青春期到成年早期我们假设，在一个或两个青少年时间窗内的抑制将 影响成年人的认知能力，而成年早期的抑制对成年人的认知能力没有持久的影响。 任务绩效其次，使用体内生理学，我们将同时记录来自mPFC的几个节点 回路，包括mPFC，MD和腹侧海马在成年人的任务性能。我们将进一步包括 眶额皮层（OFC）在这项分析中，因为它的输入在青春期没有受到抑制。我们 假设青少年对丘脑-mPFC投射的抑制将导致mPFC的持续变化 这可能解释了行为表现的缺陷。 目标1。为了确定青春期丘脑-mPFC投射的短暂抑制是否导致 持续的认知缺陷 目的2：确定青春期丘脑-mPFC投射的短暂抑制是否导致 mPFC电路功能持续异常 研究青少年时期PFC回路的成熟对于理解精神疾病非常重要 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， 受试者表现出丘脑-前额叶连通性下降，这与认知缺陷有关 疾病的转化。

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.