Imaging in vivo neurotransmitter modulation of brain network activity in realtime

 描述（由申请人提供）：神经元去极化和神经递质释放是正常生理学和脑病理生理学病因学的一些最基本组成部分的基础。有一个巨大的需求，高时间分辨率的测量神经递质的释放和大脑神经元网络的调制。虽然在小动物体内测量神经元去极化方面取得了进展，但目前部署、激发和测量电压敏感染料（VSD）信号的总体方法通常需要开颅术和其他侵入性措施，因此目前仅在啮齿动物研究中实用。我们的目标是开发一种变革性的脑成像技术，该技术将允许最终在活体人脑中对神经元去极化和相关神经递质释放进行微创/非侵入性成像。虽然在方法上具有挑战性，但我们相信，我们的多学科专家团队，包括神经科学家，神经药理学家，电气和生物工程师，以及脑成像物理学家和化学家，将能够在三年内规划出一条实用而清晰的道路，以发展这种潜在的范式转变成像技术。为此，我们提出三个目标。 目的一是研制电压敏感探针，用于在亚毫秒级测量人和其他灵长类动物皮层神经元的膜电位和动作电位。目标2将是量化高度时间分辨的神经递质的行动与措施的乳酸，pH值，和氧化还原电位的变化在体内。最后，目标3将进行一项试验性研究，通过向完整的皮肤和颅骨提供纳秒脉冲，响应电压或pH敏感染料的吸收光谱变化，对神经递质作用进行光声检测。我们假设，我们也可以从这些电压去极化，区域活性神经递质释放，并通过药理学操作，帮助推导出去极化已被神经递质调制。这将有助于理解到目前为止尚未与神经药理学直接联系的去极化波。 我们的方法将在啮齿动物的大脑中进行测试，然后转化为非人类灵长类动物的大脑。到三年结束时，我们预计将提供证据，证明进行神经活动的神经递质调节是可行的，包括神经元去极化，并制定了一项计划，用于构建大脑成像仪器来捕获这些事件，从而实现微创程序对健康和疾病中的人类大脑进行变革性成像。

 DESCRIPTION (provided by applicant): Neuronal depolarization and neurotransmitter release underlie some of the most fundamental components of normal physiology and the etiology of brain pathophysiology. There is a tremendous need for high temporal resolution measurements of neurotransmitter release and its modulation of brain neuronal networks. While there has been progress in measuring neuronal depolarization in vivo in small animals, the current overall methodology of deployment, excitation and measurement of signal from voltage sensitive dyes (VSDs) commonly entails craniotomy and other invasive measures, and thus is currently only practical in rodent studies. We aim to develop a transformative brain imaging technique which will allow minimally invasive/non-invasive imaging of neuronal depolarization and related neurotransmitter release ultimately in the living human brain. While challenging methodologically, we believe that our team of multidisciplinary experts consisting of neuroscientists, neuropharmacologists, electrical and bioengineers, and brain imaging physicists and chemists, will be able to plan over a period of three years a practical and clear path to the development of such a potentially paradigm-shifting imaging technique. To do so, we propose three Aims. Aim 1 is to develop voltage sensitive probes for sub-millisecond measurements of membrane potentials and action potentials of cortical neurons in humans and other primates in vivo. Aim 2 will be to quantify highly temporally resolved neurotransmitter action with measures of lactate, pH, and redox potential changes in vivo. Finally, Aim 3 will pursue a pilot study of photoacoustic detection of neurotransmitter action by delivery of nanosecond pulses to intact skin and skull in response to changed absorption spectra of voltage or pH sensitive dyes. We hypothesize that we can also derive from these voltage depolarizations, regionally active neurotransmitter release, and through pharmacologic manipulation, help derive where the depolarizations have been modulated by neurotransmitters. This will allow understanding of depolarization waves that up to now have not been linked with neuropharmacology directly. Our approaches will be tested in the rodent brain and then translated into non-human primate brain. By the end of three years, we anticipate providing the evidence that it is feasible to carry out neurotransmitter modulation of neuroactivity, including neuronal depolarization, and to have developed a plan for building a brain imaging instrument to capture these events, enabling minimally-invasive procedures for transformative imaging of the human brain in health and disease.