Modulation of forebrain circuits by local neurosteroid production

现代神经科学才刚刚开始了解前脑回路的活动是如何被神经化学物质调节的，包括雌激素等类固醇。对类固醇的神经保护作用的认识已经导致正在进行的用于类固醇治疗人类神经回路病理的临床试验。目前的临床治疗在外周递送类固醇，并且治疗性类固醇因此以均匀的全局方式缓慢到达大脑。然而，只有一个子集的类固醇治疗似乎是有效的，在减少神经系统疾病的进展。最近，对类固醇在大脑中作用的紧急研究强调了对神经元和神经回路的局部和急性影响。为了优化我们使用类固醇作为神经治疗剂，因此，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。随着体内神经甾体微透析技术的发展，我已经建立了前脑甾体水平可以在离散神经回路中进行实验监测和操纵。在这个K99/R 00职业发展奖，我将确定如何本地类固醇行动有助于前脑回路活动和功能.在导师阶段，我将获得技能，在电生理，功能和发展的方法前脑电路，并联合收割机他们与最近优化的体内神经类固醇微透析技术。我组建了一个高素质的导师和合作者团队，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的工具应用到一个广泛的，综合的研究前脑回路是如何调制的本地，脑源性类固醇。K99/R 00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，并可能对未来开发神经系统疾病的新型治疗方法产生广泛的影响。

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.