Impact of Cannabis on Prefrontal Maturation

大麻对前额叶成熟的影响

• 批准号: 10654964
• 负责人: Kuei-Yuan Tseng
• 金额: $ 35.98万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10654964
• 关键词: Adolescence; Adolescent; Adult; Affective; Age; Attenuated; Automobile Driving; Behavior; Behavior Control; Behavioral; CNR1 gene; Calibration; Cannabis; Cannabis Abuse; Cognitive; Cognitive deficits; Data; Development; Developmental Process; Disinhibition; Electrophysiology (science); Equilibrium; Exposure to; Glutamates; Goals; Hippocampus; Human; Impairment; Infusion procedures; Intervention; Knowledge; Life; Link; Mediating; Mission; National Institute of Drug Abuse; Neurobiology; Predisposition; Prefrontal Cortex; Process; Public Health; Rattus; Research; Risk; Signal Transduction; Smoking; Substance Use Disorder; Sucrose; Synapses; THC exposure; Testing; Tetrahydrocannabinol; United States National Institutes of Health; age related; behavioral response; cognitive reappraisal; critical period; designer receptors exclusively activated by designer drugs; emotion dysregulation; emotion regulation; epidemiology study; fear memory; gamma-Aminobutyric Acid; in vivo; interest; neural circuit; neuronal circuitry; postnatal; preference; prevent; substance use; transmission process; vulnerable adolescent

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.

抽象的 融合人类协会研究将青春期大麻滥用与增加的可能性联系在一起 在以后的生活中发展认知和情感调节赤字，其中许多是完善的，并取决于 青春期期间的前额叶皮层（PFC）成熟。但是，这个青少年的神经生物学 由于我们对青少年大麻暴露如何影响的知识有限，因此脆弱性尚不清楚 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 容易反复暴露大麻，重点是经历功能性的PFC神经元电路 青春期重塑。我们最近研究的数据表明，PFC成熟的标志是 在青春期中重新校准兴奋性抑制（E-I）平衡，这是维持适当的必需品 PFC介导的成年行为。我们的数据还表明，GABA函数的成熟是 在青春期使PFC不稳定呈现，这是一个与 从腹侧海马传播传播。同样，青少年但不是成年人，暴露于THC PFC GABA功能的成熟受损。这提出了令人兴奋的可能性，即PFC赤字导致 从青春期的THC暴露在机械上与驱动PFC的特定输入的破坏有关 成熟。根据我们的初步数据，我们将测试开发PFC GABA的中心假设 青春期电路对大麻通过腹侧海马的负面影响高度敏感 - 介导的机制。因此，进行这项研究的理由是，如果PFC GABA成熟是 青少年THC暴露损害，PFC抑制控制的正常促进将被捕， 反过来，这可能导致PFC抑制的持久状态，导致成年后的行为缺陷。我们 通过追求3个特定目标，将填补知识的差距。我们将使用最近开发的 燃烧/吸烟室以在3个非重叠的青春期窗户上运送THC以建立精确的 PFC GABA功能变化（AIM 1）和PFC敏感行为（AIM 2）的时期 重复THC暴露。目前可用的特定于投入的无与伦比的操纵将用于AIM 3 确定THC引起的持久PFC GABA赤字是否与腹部的破坏有因果关系 海马到PFC传输。