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 紊乱前额叶皮层（PFC）支持成人的认知灵活性，并且前额叶皮层的改变 功能可能会导致这种认知过程的障碍。认知灵活性，像其他方面一样， 执行功能在出生后发育缓慢。前额叶的发育性细化 电路和功能理论上是认知能力长期获得的基础， 这种精细化可能会导致精神疾病背景下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受遗传程序的控制，但随后的 电路细化严重依赖于活动。出生后GABA能紧张性的成熟， 在出生后的第一周内提供了一种兴奋性来源， 此后的变化。重要的是，中间神经元的发育功能障碍，特别是那些 表达小清蛋白（PV）或生长抑素（SST）的脑内神经元与受损的定势转换行为和前额叶皮层有关。 成年后的电路功能。然而，PV和SST中间神经元的活动如何影响前额叶 回路的发展-包括中间神经元本身的发展-在不同的发展 时间窗口是我们知识中的一个根本空白。此外，一旦建立了成熟的连通性， 和PV中间神经元一起工作，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，前额叶SST活动是建立 增加丘脑皮层对光伏电池的驱动，反过来，维持和增强连接的强度 这些PV细胞在锥体细胞上形成，PV活动随后迭代地细化 来自皮层和皮层下来源的传入兴奋性驱动。这种活动中的发育成熟 在成年期建立PV和SST中间神经元的适当连接，其活性对于成熟至关重要。 支持认知灵活性的前额叶网络功能。为了验证这一假设，在目标1中，我们将研究如何 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力转移 成年老鼠在目标2中，我们将测试在不同的时间段内，如何抑制前额叶PV或SST中间神经元的活性。 使用DREADD受体hM 4DGi的发育窗口影响成人网络功能和行为， 目标1中评估的生理和行为结果。了解PV和SST中间神经元 支持认知，以及这些细胞的发育扰动如何影响成人PFC功能，将提供 深入了解精神疾病中认知缺陷的神经生物学起源，并更广泛地了解 细胞类型选择性GABA释放在塑造发展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.