Estradiol & Tamoxifen neuroprotective/neuroregenerative agents spinal cord injury

雌二醇

• 批准号: 8687680
• 负责人: JORGE David MIRANDA
• 金额: $ 24.33万
• 依托单位: UNIVERSITY OF PUERTO RICO MED SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8687680
• 关键词: 20 year old; Adolescence; Adolescent; Adult; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohols; Animal Model; Brain; Brain imaging; Clinical; Cognition; Communication; Complex; Dendritic Spines; Development; Diamond; Environment; Equilibrium; Estradiol; Ethanol; Ethanol dependence; Evaluation; Genetic; Glutamate Receptor; Glutamate Transporter; Glutamates; High Prevalence; Homeostasis; Human; Image; Injection of therapeutic agent; Knowledge; Lead; Measures; Mediating; Microdialysis; Microinjections; Modeling; Morphology; Mus; Neuronal Plasticity; Neurotransmitters; Nucleus Accumbens; Pathway interactions; Pharmacology; Pharmacotherapy; Play; Population; Prefrontal Cortex; Prevalence; Procedures; Process; Proteins; Puerto Rico; Relative (related person); Research; Rewards; Role; Series; Shapes; Site; Specificity; Spinal cord injury; Substance abuse problem; Synapses; Synaptic plasticity; Tamoxifen; Testing; United States; Universities; Vertebral column; Western Blotting; Work; adolescent alcohol; alcohol misuse; alcohol use disorder; alcohol use initiation; base; cognitive function; density; drinking; drinking behavior; drug seeking behavior; experience; extracellular; in vivo; insight; lifetime risk; mouse genome; mouse model; neurobiological mechanism; neurochemistry; neurotransmission; novel; postsynaptic; presynaptic; protein expression; social; tau Proteins; transmission process; underage drinking

Excessive alcohol drinking among human adolescents is a major social and biomedical problem in the United States and Puerto Rico. Moreover, early initiation of alcohol use or misuse leads to greater risk of lifetime alcohol use disorders. Recent human brain imaging studies clearly show that the prefrontal cortex (PFC), which underlies various executive cognitive functions, undergoes extensive structural and functional re-organization from adolescence to adulthood. This is consistent with the notion that heightened synaptic plasticity is a cardinal feature of adolescent brain development. Although usually adaptive and beneficial, heightened plasticity may lead to greater vulnerability to substance abuse. Indeed, the mechanism underlying synaptic plasticity are similar to the mechanisms mediating ethanol dependence. Research performed in animal models is needed because studies involving the administration of alcohol to human adolescents are illegal. We have recently developed an adolescent C57BL/6J (B6) mouse model that shows greater propensity for ethanol drinking behavior. The use of the B6 strain may be especially valuable given its wealth of available genetic information (i.e., Mouse Genome Project). Studies proposed in this application are to combine our 86 adolescent drinking model with in-vivo neurochemical and pharmacological approached that have never been employed during the adolescent period. Our primary objective is to determine the role of extracellular glutamate homeostasis in the PFC and its projections to the nucleus accumbens (NAC). Our working hypothesis is that elevated glutamatergic transmission in the PFC-NAC circuit leads to greater propensity for alcohol drinking during adolescence. We also propose to study the effects of adolescent drinking on dendritic spines in the PFC, which are the major postsynaptic components of glutamatergic synapses. It is anticipated that prefrontal spine plasticity will be severely altered following adolescent alcohol drinking experience. Collectively, these studies will generate new and novel information regarding the role of synaptic glutamate transmission in the PFC-NAC circuitry in mediating adolescent alcohol drinking. This will provide valuable insight into this crucial clinical and social issue, as well as facilitate development of new glutamate- and neuroplasticity-based pharmacotherapies that reduce harmful consequences of alcohol abuse.

青少年过度饮酒是一个重大的社会和生物医学问题。 美国和波多黎各。此外，及早开始饮酒或误用酒精会导致更大的风险 终生酒精使用障碍。最近的人脑成像研究清楚地表明，前额叶皮质 (PFC)是各种执行认知功能的基础，经历了广泛的结构性和 从青春期到成年期的功能性重组。这与以下观点是一致的 突触可塑性增强是青春期大脑发育的一个基本特征。尽管通常 适应性和有益的可塑性增强可能会导致更容易受到药物滥用的影响。 事实上，突触可塑性的机制与乙醇的调节机制相似。 依赖。在动物模型中进行研究是必要的，因为涉及 向青少年灌输酒精是非法的。我们最近培养出了一名青少年 C57BL/6J(B6)小鼠模型，表现出更大的饮酒行为倾向。的用法 B6菌株可能特别有价值，因为它有丰富的遗传信息(即小鼠基因组 项目)。这项申请中提出的研究是将我们的86名青少年饮酒模型与体内研究相结合 在青春期从未使用过的神经化学和药理学方法 句号。我们的主要目标是确定细胞外谷氨酸稳态在PFC中的作用。 及其向伏隔核(NAC)的投射。我们的工作假设是 PFC-NAC回路中的谷氨酸能传递导致更大的饮酒倾向 青春期。我们还建议研究青少年饮酒对前额叶树突棘的影响， 它们是谷氨酸能突触的主要突触后成分。预计前额叶 青少年饮酒后，脊柱的可塑性会发生严重变化。总而言之， 这些研究将产生关于突触谷氨酸作用的新的和新的信息 青少年饮酒在PFC-NAC回路中的传递。这将提供有价值的 洞察这一关键的临床和社会问题，以及促进新谷氨酸的开发-以及 以神经可塑性为基础的药物疗法，减少酒精滥用的有害后果。