A New Model of Gestational Cannabis Exposure

妊娠期大麻暴露的新模式

• 批准号: 10202140
• 负责人: Alexandre Esteves Medina
• 金额: $ 23.18万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10202140
• 关键词: Age; Animal Model; Animals; Applications Grants; Brain; Breast Feeding; CNR1 gene; Cannabis; Cells; Characteristics; Consumption; Control Groups; Development; Electrophysiology (science); Endocannabinoids; Event; Exposure to; Ferrets; Fetal Alcohol Spectrum Disorder; Goals; Growth; Human; Impairment; Individual; Intervention; Maps; Marijuana; Mental Health; Modeling; Molecular; Mothers; National Institute of Drug Abuse; Neuronal Plasticity; Neurons; Ocular Dominance; Pharmaceutical Preparations; Pharmacology; Pregnancy; Probability; Process; Protocols documentation; Signal Transduction; Synapses; THC exposure; Testing; Third Pregnancy Trimester; Time; Visual Cortex; alcohol exposure; base; experimental group; experimental study; fetal marijuana exposure; gamma-Aminobutyric Acid; human model; in vivo; interest; marijuana use; marijuana use in pregnancy; neurobehavioral; neuronal circuitry; neurotransmission; novel; offspring; optical imaging; orientation selectivity; patch clamp; postnatal; prevent; public health research; sensory cortex; synaptogenesis; tool; transmission process

Summary The use of cannabis during pregnancy have dramatically increased during the last ten years. While the effects of cannabis and its components on brain development are poorly known, recent studies have observed frequent mental health problems in the offspring of mothers that used marijuana during gestation. During the third trimester of human gestation the brain undergoes a “growth spurt” that is characterized by an intensive process of synaptogenesis. This stage is followed by a period of refinement by activity-dependent neuronal plasticity where synapses reaching “correct targets” are strengthened whereas synapses reaching “incorrect targets” are pruned. The exposure to drugs and certain medications during this period have the potential to alter these processes, resulting in multiple neurobehavioral problems. It has been demonstrated in humans and animal models that developmental THC exposure reduces the expression of CB1r. In layer 2/3 of the visual cortex endocannabinoid neurotransmission is essential for the expression of iLTD and for the developmental transition between high to low GABA release probability characteristic of mature inhibitory cells in this region. Proper levels of inhibition are essential for the ocular dominance plasticity and the establishment of neuronal circuits responsible for neuronal orientation tuning and formation of orientation selectivity columns. Based on this scientific premise we hypothesize that THC exposure during the third trimester equivalent of human gestation leads to persistent reduction in endocannabinoid transmission, resulting in an impairment in iLTD and preventing maturation of inhibition. As a consequence, both ocular dominance plasticity and orientation selectivity would be impaired. Here we will use a combination of in vivo and ex vivo electrophysiology and optical imaging of intrinsic signals to test this hypothesis. The accomplishment of these experiments would result in the development of a novel model of prenatal exposure to cannabis that could be used to investigate mechanisms of action of gestational marijuana and potential interventions.

概括 在过去十年中，怀孕期间吸食大麻的情况急剧增加。 虽然大麻及其成分对大脑发育的影响鲜为人知， 最近的研究发现，母亲的后代经常出现心理健康问题 在怀孕期间吸食大麻。在人类妊娠晚期，大脑 经历一个“生长突增”，其特征是突触发生的密集过程。 此阶段之后是一段由活动依赖性神经元可塑性细化的时期，其中 达到“正确目标”的突触得到加强，而达到“不正确目标”的突触得到加强 “目标”被修剪。在此期间接触药物和某些药物有 改变这些过程的潜力，导致多种神经行为问题。它一直 在人类和动物模型中证明，发育时期的 THC 暴露会降低 CB1r 的表达。在视觉皮层 2/3 层，内源性大麻素神经传递是 对于 iLTD 的表达以及从高到低的发育过渡至关重要 该区域成熟抑制细胞的 GABA 释放概率特征。适当的水平 抑制对于眼部优势可塑性和神经元的建立至关重要 负责神经元方向调整和方向选择性形成的电路 列。基于这个科学前提，我们假设第三次接触 THC 相当于人类妊娠的三个月导致内源性大麻素持续减少 传输，导致 iLTD 受损并阻止抑制成熟。作为一个 结果，眼部优势可塑性和方向选择性都会受到损害。 在这里，我们将结合体内和离体电生理学和光学成像 检验这一假设的内在信号。这些实验的完成将导致 开发一种产前接触大麻的新模型，可用于 研究妊娠大麻的作用机制和潜在的干预措施。