Sensitive periods for interneuron development supporting cognitive flexibility

认知灵活性是执行功能的核心组成部分，在一系列神经精神疾病中受损 精神错乱。前额叶皮质(PFC)支持成人的认知灵活性，以及前额叶的改变 在这个认知过程中，功能可能会造成损害。认知灵活性，就像 执行功能在出生后的发育过程中发展缓慢。前额叶的发育精细化 电路和功能被认为是认知能力长期获得的基础，而大脑中的异常 在精神障碍的背景下，这种改进可能会导致前额叶回路和功能的缺陷。 虽然前额叶回路发育的早期阶段主要由遗传程序控制，但随后 电路的精细化在很大程度上依赖于活动。GABA能神经递质的出生后成熟 强有力地调节皮质活动--在出生后第一周迅速提供兴奋性来源 此后改变为抑制。重要的是，中间神经元的发育障碍，特别是那些 表达小白蛋白(PV)或生长抑素(SST)与定势转移行为和前额叶受损有关 成年后的回路功能。然而，PV和SST中间神经元的活动如何影响前额叶 电路发育--包括中间神经元本身的发育--在不同发育阶段 时间窗口是我们知识中的一个根本鸿沟。此外，一旦建立了成熟的连接，SST如何 和PV中间神经元共同参与皮质活动，以支持成年后的认知灵活性 未知。 我们假设，在出生后早期发育过程中，需要前额叶SST活动来建立 增加丘脑皮质对光伏细胞的驱动，进而维持和增强连接的强度 这些光伏细胞形成锥体细胞，光伏活动随后迭代地提炼出 来自皮质和皮质下来源的兴奋性驱动。这种在活动中的发育成熟 在成年期建立PV和SST中间神经元的适当连接，其活动是成熟所必需的 前额叶网络功能支持认知灵活性。为了验证这一假设，在目标1中，我们将检查 PV和SST中间神经元组织PFC网络活动以支持额外维度的注意定势转移 成年小鼠。在目标2中，我们将测试前额叶PV或SST中间神经元在不同时间的抑制活性 使用DREADD受体hM4DGi的发育窗影响成人网络功能和使用 AIM中评估的生理和行为结果1.了解PV和SST中间神经元如何 支持认知，以及这些细胞的发育障碍如何影响成人的PFC功能，将提供 对精神障碍中认知缺陷的神经生物学起源的洞察，以及更广泛地了解 细胞类型选择性释放GABA塑造发育中的PFC。

Cognitive flexibility is a core component of executive functioning that is impaired in a range of neuropsychiatric disorders. The prefrontal cortex (PFC) supports cognitive flexibility in the adult, and alterations in prefrontal function likely contribute to impairments in this cognitive process. Cognitive flexibility, like other aspects of executive functioning, develops slowly across postnatal development. Developmental refinement of prefrontal circuitry and function is theorized to underlie the protracted acquisition of cognitive abilities, and abnormalities in this refinement may contribute to deficits in prefrontal circuitry and function in the context of psychiatric disorders. While the early stages of prefrontal circuit development are largely governed by genetic programs, subsequent circuit refinement is heavily dependent on activity. Postnatal maturation of GABAergic tone is poised to powerfully regulate cortical activity—providing a source of excitability during the first postnatal week that rapidly changes to inhibition thereafter. Importantly, developmental dysfunction of interneurons, especially those expressing parvalbumin (PV) or somatostatin (SST), is linked with impaired set-shifting behavior and prefrontal circuit function in adulthood. Yet, how activity in PV and SST interneurons influences prefrontal circuit development—including the development of the interneurons themselves—during different developmental time windows is a fundamental gap in our knowledge. Further, once mature connectivity is established, how SST and PV interneurons work together to engage cortical activity to support cognitive flexibility in adulthood, remains unknown. We hypothesize that during early postnatal development, prefrontal SST activity is required for establishing increasing thalamocortical drive onto PV cells that, in turn, sustains and augments the strength of the connections these PV cells make onto pyramidal cells, and that PV activity subsequently iteratively refines the strength of incoming excitatory drive from cortical and subcortical sources. This developmental maturation in activity establishes proper connectivity of PV and SST interneurons in adulthood, whose activity is essential for mature prefrontal network function supporting cognitive flexibility. To test this hypothesis, in Aim 1 we will examine how PV and SST interneurons organize PFC network activity to support extra dimensional attentional set shifting in adult mice. In Aim 2, we will test how inhibiting activity of prefrontal PV or SST interneurons during different developmental windows using the DREADD receptor, hM4DGi, affects adult network function and behavior using the physiological and behavioral outcomes assessed in Aim 1. Understanding how PV and SST interneurons support cognition, and how developmental perturbations of these cells affect adult PFC function, will provide insight into neurobiological origins of cognitive deficits in psychiatric disorders and more broadly into the role of cell-type selective GABA release in sculpting the developing PFC.