Estradiol & Tamoxifen neuroprotective/neuroregenerative agents spinal cord injury

雌二醇

• 批准号: 9302474
• 负责人: JORGE David MIRANDA
• 金额: $ 24.1万
• 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/9302474
• 关键词: 20 year old; Adolescence; Adolescent; Adult; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohols; Animal Model; Brain; Brain imaging; Clinical; Cognition; Communication impairment; Complex; Dendritic Spines; Development; Diamond; Disease; Environment; Equilibrium; Estradiol; Ethanol; Ethanol dependence; Evaluation; Glutamate Receptor; Glutamate Transporter; Glutamates; Grant; High Prevalence; Homeostasis; Human; Image; Injection of therapeutic agent; Knowledge; Lead; Measures; Mediating; Microdialysis; Microinjections; Modeling; Morphology; Mus; Nerve Regeneration; Neuronal Plasticity; Neurotransmitters; Nucleus Accumbens; Pathway interactions; Pharmacology; Pharmacotherapy; Play; Population; Prefrontal Cortex; Prevalence; Procedures; Process; Proteins; Puerto Rico; 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; adolescent alcohol; adolescent brain development; alcohol consequences; alcohol misuse; alcohol risk; alcohol use initiation; base; cognitive function; density; drinking; drinking behavior; drug seeking behavior; experience; extracellular; genetic information; imaging study; 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.

人类青少年中的过度饮酒是一个主要的社会和生物医学问题， 美国和波多黎各。此外，早期开始使用或滥用酒精会导致更大的风险， 终生酒精使用障碍最近的人类大脑成像研究清楚地表明， (PFC)作为各种执行认知功能的基础， 从青春期到成年期的功能重组。这与以下概念是一致的， 突触可塑性增强是青少年大脑发育的一个重要特征。虽然通常 适应性和有益的，提高可塑性可能导致更容易滥用药物。 事实上，突触可塑性的机制与乙醇的调节机制相似 依赖需要在动物模型中进行研究，因为研究涉及 给人类青少年注射酒精是违法的我们最近发现了一个青少年 C57 BL/6 J（B6）小鼠模型，显示出更大的乙醇饮用行为倾向。的使用 B6菌株可能是特别有价值的，因为它具有丰富的可用遗传信息（即，小鼠基因组 项目）。本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 神经化学和药理学的方法，从来没有在青少年时期使用过， 期我们的主要目的是确定细胞外谷氨酸稳态在PFC中的作用。 及其向延髓核的投射。我们的假设是 PFC-NAC回路中的代谢能传输导致在治疗期间饮酒的更大倾向 青春期我们还建议研究青少年饮酒对PFC中树突棘的影响， 其是突触能突触的主要突触后成分。据预测， 青少年饮酒后脊柱的可塑性将发生严重改变。总的来说， 这些研究将产生关于突触谷氨酸作用的新的和新颖的信息 PFC-NAC回路中的传输介导青少年饮酒。这将提供宝贵的 深入了解这一关键的临床和社会问题，以及促进新的谷氨酸盐的开发， 基于神经可塑性的药物疗法，减少酒精滥用的有害后果。