A novel animal model to study the association between alcohol abuse during late adolescence with common conditions observed in combat Veterans

一种新的动物模型，用于研究青春期后期酗酒与退伍军人中观察到的常见状况之间的关联

• 批准号: 10644999
• 负责人: Alexandre Esteves Medina
• 金额: --
• 依托单位: BALTIMORE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10644999
• 关键词: Address; Adolescence; Adolescent; Adolescent Behavior; Adult; Affect; Age; Age Years; Alcohol abuse; Alcohol consumption; Alcohols; Animal Model; Animals; Behavior; Behavioral; Blood; Blood alcohol level measurement; Brain; Canis familiaris; Centers for Disease Control and Prevention (U.S.); Chronic; Complex; Consumption; Data; Dependence; Development; Dopamine; Drug Exposure; Electrophysiology (science); Emotional; Ethanol Metabolism; Event; Exploratory Behavior; Exposure to; Family suidae; Felis catus; Ferrets; Goals; Heavy Drinking; Housing; Human; Impulsivity; Intervention; Length; Light; Link; Literature; Long-Term Effects; Measures; Mental Depression; Mental Health; Mental disorders; Modeling; Molecular; Moods; Motivation; Neurologic; Neurons; Opiate Addiction; Opioid; Parvalbumins; Pharmaceutical Preparations; Phase; Positioning Attribute; Post-Traumatic Stress Disorders; Predisposition; Prefrontal Cortex; Process; RBL2 gene; Reporting; Research; Rewards; Risk Taking; Rodent; Role; Social Behavior; Soldier; Stress; Structure; Study models; Substance abuse problem; Suicide; Synapses; Synaptophysin; Testing; Tetrahydrocannabinol; Therapeutic Intervention; Time; Traumatic Brain Injury; Traumatic Brain Injury recovery; Veterans; addiction; adolescent brain development; age group; alcohol and other drug; alcohol exposure; alcohol measurement; alcohol testing; biological adaptation to stress; chronic alcohol ingestion; combat; combat veteran; cost; cost comparison; dopaminergic neuron; drinking; drug of abuse; experimental study; hippocampal pyramidal neuron; mature animal; neurotransmission; nonhuman primate; novel; postnatal; service member; transmission process; underage drinking

The maturation of the prefrontal cortex (PFC) is a hallmark of the transition between adolescence to adulthood. Because the PFC matures around 25 years of age, it is safe to say that most frontline soldiers are still during adolescence. The Center of Disease Control and Prevention reports that service members have the highest alcohol use of all queried professions. Moreover, alcohol use increases following combat deployment. Therefore, most service members are exposed to large amounts of alcohol during a period that the PFC is still immature. The PFC acts through top-down control to regulate the activity of many subcortical regions; and doing so regulates and integrates emotional and stress responses, as well as motivation and reward seeking. Taking the aforementioned facts together we hypothesize that “consumption of constant and high levels of alcohol by service members, affects PFC development and makes these subjects more prone to develop conditions that afflict our Veterans such as: altered stress response, addiction, depression, mood swings and Post-traumatic stress disorder (PTSD). Testing this hypothesis and its underlying mechanisms in an appropriate animal model would make a great contribution to the field. Unfortunately, current animal models have limitations in studying consequences of chronic alcohol use restricted to late adolescence. For instance, rodents have a very short-late adolescence, making it difficult to mimic a chronic and heavy alcohol consumption. In non-human primates, “late adolescence” is too long making experiments very time consuming and costly. In this 3-year BLRD application, we propose to develop a novel animal model that can mimic prolonged heavy alcohol consumption restricted to late adolescence. Developing this model would pave the way to test how alcohol exposure during late adolescence can alter dopaminergic neurotransmission and stress responses - making the prefrontal cortex vulnerable to “second hits” such as high stress and Traumatic Brain Injury (TBI). This information could help us understand why Veterans are much vulnerable to mental health disorders and potentially devise therapeutic interventions.

前额叶皮层（PFC）的成熟是青少年到成年之间过渡的标志。 由于PFC的成熟大约25岁，因此可以肯定地说，大多数一线士兵仍在 青少年。疾病控制与预防中心报告说，服务成员的最高 所有查询职业的饮酒。此外，战斗部署后，饮酒增加。 因此，大多数服务成员在PFC仍在 不成熟。 PFC通过自上而下的控制起作用，以调节许多皮层区域的活性。和 这样做可以调节并整合情感和压力的反应，以及动机和回报。 将理由的事实融合在一起，我们假设“消费恒定和高水平 服务成员的酒精会影响PFC的开发，并使这些主题更容易发展 困扰我们退伍军人的条件，例如：改变压力反应，成瘾，抑郁，情绪波动和 创伤后应激障碍（PTSD）。测试该假设及其基本机制 适当的动物模型将为该领域做出巨大贡献。 不幸的是，当前的动物模型在研究慢性酒精的后果方面存在局限性 仅限于青少年晚期。例如，啮齿动物具有非常短的青少年，因此很难 模仿长期繁重的饮酒。在非人类的隐私中，“青春期晚期”太长了 使实验非常耗时且昂贵。在这个为期三年的大集中申请中，我们建议开发 可以模仿大量饮酒的新型动物模型仅限于青少年晚期。 开发此模型将为测试青少年晚期的酒精暴露如何改变铺平道路 多巴胺能神经传递和压力反应 - 使前额叶皮层容易受到“第二 命中”，例如高压力和创伤性脑损伤（TBI）。此信息可以帮助我们理解为什么 退伍军人很容易受到心理健康障碍的影响，并可能设计出治疗性干预措施。