Modulation of forebrain circuits by local neurosteroid production

通过局部神经类固醇产生调节前脑回路

• 批准号: 7714385
• 负责人: LUKE R REMAGE-HEALEY
• 金额: $ 9万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-05 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7714385
• 关键词: Acute; Address; Adolescent; Alzheimer' s Disease; Award; Birds; Brain; Clinical Treatment; Clinical Trials; Complex; Development; Discrimination; Disease; Disease Progression; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Epilepsy; Estrogens; Event; Future; Goals; Human; K-Series Research Career Programs; Laboratories; Light; Memory; Mentors; Mentorship; Microdialysis; Modems; Monitor; Neurons; Neurosciences; Neurotransmitters; Outcome; Output; Pathology; Pattern; Phase; Positioning Attribute; Principal Investigator; Production; Prosencephalon; Qualifying; Regulation; Research; Research Training; Role; Shapes; Steroids; Stimulus; Stroke; Synaptic plasticity; System; Techniques; Testing; Therapeutic; Therapeutic Agents; Training; Work; critical period; extracellular; functional outcomes; improved; in vivo; innovation; nervous system disorder; neural circuit; neurochemistry; neurosteroids; novel therapeutic intervention; public health relevance; relating to nervous system; skills; tool

Modem neuroscience is only beginning to understand how the activity of forebrain circuits is modulated by neurochemicals, including steroids such as estrogen. Appreciation of the neuroprotective effects of steroids has led to ongoing clinical trials for steroid treatment of human neurocircuit pathologies. Current clinical treatments deliver steroids peripherally, and therapeutic steroids consequently reach the brain slowly in a uniform, global manner. However, only a subset of steroid treatments appears to be effective at reducing neurological disease progression. The most recent, emergent research on the actions of steroids within the brain emphasizes both local and acute effects on neurons and neurocircuits. In order to optimize our use of steroids as neuro-therapeutic agents, we must therefore consider the fine temporal and spatial scale of steroid regulation within neurocircuits. With the advancement of in vivo neurosteroid microdialysis, I have established that forebrain steroid levels can be experimentally monitored and manipulated in discrete neurocircuits. In this K99/R00 career development award, I will determine how local steroid actions contribute to forebrain circuit activity and function. During the Mentorship Phase, I will acquire skills in electrophysiological, functional, and developmental approaches to forebrain circuits, and combine them with recently- optimized in vivo neurosteroid microdialysis techniques. I have assembled a highly-qualified team of mentors and collaborators with a comprehensive set of skills to facilitate my training and maturation into an independent neuroscientist. During the Independent Phase, I will direct my laboratory to apply these innovative tools to a broad- scale, integrative study of how forebrain circuits are modulated by local, brain-derived steroids. Results of the training and research outlined in this K99/R00 Award will provide an integrated understanding of neural circuit regulation, and could have wide-ranging implications for the future development of novel therapeutic approaches to neurological diseases. PUBLIC HEALTH RELEVANCE: The research outlined in this K99/R00 PI Award will shed light on how brain-derived steroids contribute to the acute regulation of forebrain circuit function. The ultimate goal of this work is to improve our understanding of steroid actions within neural circuits, in order to optimize the future development of steroids as neuro- therapeutic agents for disorders such as epilepsy, stroke, and Alzheimer's disease.

现代神经科学才刚刚开始了解神经化学物质（包括雌激素等类固醇）如何调节前脑回路的活动。对类固醇神经保护作用的认识导致正在进行类固醇治疗人类神经回路病理的临床试验。目前的临床治疗是在外周输送类固醇，因此治疗性类固醇以均匀、全面的方式缓慢到达大脑。然而，只有一部分类固醇治疗似乎能有效减少神经系统疾病的进展。关于类固醇在大脑中作用的最新研究强调了对神经元和神经回路的局部和急性影响。因此，为了优化类固醇作为神经治疗剂的使用，我们必须考虑神经回路内类固醇调节的精细时间和空间尺度。随着体内神经类固醇微透析的进步，我已经确定可以在离散的神经回路中通过实验监测和操纵前脑类固醇水平。在这个 K99/R00 职业发展奖中，我将确定局部类固醇作用如何促进前脑回路活动和功能。在指导阶段，我将获得前脑回路的电生理学、功能和发育方法方面的技能，并将它们与最近优化的体内神经类固醇微透析技术相结合。我组建了一支由导师和合作者组成的高素质团队，他们拥有一套全面的技能，以促进我的培训和成熟，成为一名独立的神经科学家。在独立阶段，我将指导我的实验室将这些创新工具应用于广泛的综合研究，研究前脑回路如何受到局部脑源性类固醇的调节。 K99/R00 奖中概述的培训和研究结果将提供对神经回路调节的综合理解，并可能对神经系统疾病新型治疗方法的未来发展产生广泛的影响。公共健康相关性：K99/R00 PI 奖中概述的研究将揭示脑源性类固醇如何促进前脑回路功能的急性调节。这项工作的最终目标是提高我们对类固醇在神经回路中作用的理解，以优化类固醇作为癫痫、中风和阿尔茨海默氏病等疾病的神经治疗剂的未来发展。