Impact of Cannabis on Prefrontal Maturation

摘要 聚合人类协会研究将青少年时期滥用大麻与增加的可能性联系起来， 在以后的生活中发展认知和情绪调节缺陷，其中许多是精炼和依赖于 前额叶皮层（PFC）在青春期成熟。然而，这个青少年的神经生物学基础 脆弱性仍然不清楚，因为我们对青少年大麻暴露如何影响 神经回路的成熟。我们的长期目标是确定敏感的神经发育过程， 易受反复大麻暴露的影响，重点是PFC神经元回路， 青春期的重塑我们最近的研究数据显示，PFC成熟的一个标志是 在青春期重新校准兴奋-抑制（E-I）平衡，这是维持适当的 成年期PFC介导的行为我们的数据还表明，正是GABA功能的成熟， 使PFC在青春期不稳定，这是一个与大脑活动密切相关的发育过程。 来自腹侧海马体的传入传递。同样，青少年，而不是成年人，接触THC 损害PFC GABA功能的成熟。这提出了一个令人兴奋的可能性，即PFC赤字导致的 青少年THC暴露的机制与驱动PFC的特定输入的中断有关 成熟基于我们的初步数据，我们将测试中心假设，即发展PFC GABA 青少年时期的回路对大麻通过腹侧海马的负面影响高度敏感 中介机制。因此，进行这项研究的基本原理是，如果PFC GABA成熟是 受到青少年THC暴露的影响，PFC抑制控制的正常促进将被阻止， 这反过来又可能导致PFC去抑制的持久状态，导致成年后的行为缺陷。我们 我们将通过追求三个具体目标来填补这一知识空白。我们将使用最近开发的 燃烧/吸烟室在3个不重叠的青少年窗口提供THC，以建立精确的 PFC GABA功能（目标1）和PFC敏感行为（目标2）变化敏感的时期 反复接触四氢大麻酚目前可用的特定输入DREADD操作将用于目标3， 确定THC引起的持久PFC GABA缺乏是否与腹侧海马神经元的破坏有因果关系， 从露营地到PFC的传输。

Abstract Converging human association studies link cannabis abuse during adolescence with an increased likelihood of developing cognitive and emotional regulation deficits later in life, many of which are refined and dependent on prefrontal cortex (PFC) maturation during adolescence. However, the neurobiology underlying this adolescent vulnerability remains unclear due to our limited knowledge on how adolescent cannabis exposure impacts the maturation of neural circuits. Our long-term goal is to identify sensitive neurodevelopmental processes that are vulnerable to repeated cannabis exposure, with emphasis on PFC neuronal circuits that undergo functional remodeling during adolescence. Data from our recent studies revealed that a hallmark of PFC maturation is the re-calibration of an excitatory-inhibitory (E-I) balance during adolescence that is required for sustaining proper PFC-mediated behaviors in adulthood. Our data also indicate that it is the maturation of GABA function that renders the PFC labile during adolescence, a developmental process that is intimately linked to the activity of afferent transmission from the ventral hippocampus. Similarly, adolescent, but not adult, exposure to THC impaired the maturation of PFC GABA function. This raises the exciting possibility that the PFC deficit resulting from adolescent THC exposure is mechanistically linked to the disruption of specific inputs driving PFC maturation. Based on our preliminary data, we will test the central hypothesis that the developing PFC GABA circuit during adolescence is highly sensitive to the negative impact of cannabis through a ventral hippocampal -mediated mechanism. Thus, the rationale for undertaking this research is that if PFC GABA maturation is compromised by adolescent THC exposure, the normal facilitation of PFC inhibitory control will be arrested, which in turn could lead to an enduring state of PFC disinhibition resulting in behavioral deficits in adulthood. We will fill this gap in knowledge through the pursuit of 3 Specific Aims. We will use a recently developed combustion/smoking chamber to deliver THC at 3 non-overlapping adolescent windows to establish the precise period during which changes in PFC GABA function (Aim 1) and PFC-sensitive behaviors (Aim 2) are susceptible to repeated THC exposure. Currently available input-specific DREADD manipulations will be used in Aim 3 to establish whether the enduring PFC GABA deficit elicited by THC is causally linked to disruption of ventral hippocampal-to-PFC transmission.