Neuromodulation and Neurodegeneration: the Missing Link and Mechanisms of Action

描述（由申请人提供）：众所周知，神经变性很难研究，目前还没有经过证实或可接受的方法来预防或减缓人类的疾病进程。帕金森病（PD）的一种非常成功的干预是通过脑深部电刺激（DBS）进行神经调节。DBS成功地恢复了运动功能，但DBS对疾病过程的影响却知之甚少。有趣的是，一些啮齿动物模型研究和临床观察表明，DBS可能具有神经保护作用，但由于目前的做法是在疾病进展的后期植入电极，因此记录电刺激的神经保护作用具有挑战性。因此，至关重要的是，我们不能错过神经系统患者的关键机会，并研究通过神经调节与神经保护相关的因果关系，机制和时间表。我提出了一个跨学科的方法，我独特的训练，使用光遗传学，电生理学，生物化学和协作设备工程研究神经元健康和大脑回路活动之间的相互作用在完整的行为啮齿动物。 具体来说，我建议研究影响大脑中多巴胺能神经元功能和健康的因素及其在动物行为中的作用。我们的研究结果可以使我们积极干预细胞，如黑质中的多巴胺能神经元（SNc），这些神经元在PD中退化并死亡。下面我列出了3个具体的挑战，我将使用创新的，跨学科的方法来解决。 1.是否所有SNc多巴胺能神经元对行为都有同样的影响，或者是否存在细胞的热点，由于其异质性的电和神经化学特征和连接性，在退化时可以最大限度地干扰行为？ 2.一旦多巴胺能变性开始，神经变性可以通过改变大脑回路的活动来停止或减缓吗？我将通过对SNc的输入进行慢性光遗传学控制并测量退化率的变化来测试这个有趣的假设。 3.生长因子信号传导是否直接促进多巴胺能神经保护作用？神经保护作用所需的时间表是什么？先前的实验以非特异性方式和/或以较差的时间分辨率自由地应用生长因子。我将开发光遗传学方法来实现生长因子信号传导的细胞类型特异性控制，因此我可以直接探测生长因子在特定细胞类型中的保护作用，特别是 细胞容易退化。这些工具也可以应用于神经系统以外的研究，因为生长因子信号传导参与了关键的细胞现象，如基因转录，可以影响细胞的存活，分化和功能。 这些创新项目将有助于我通过神经调节建立细胞恢复力的长期目标，并在神经变性研究中产生范式转变的影响。

DESCRIPTION (provided by applicant): Neurodegeneration has proven notoriously difficult to study and there is currently no proven or acceptable method to prevent or slow down the course of disease in humans. A very successful intervention for Parkinson's disorder (PD) is neuromodulation via deep brain stimulation (DBS). DBS successfully restores motor function but what DBS does to the course of the disease is very poorly understood. Intriguingly, a few rodent model studies and clinical observations suggest that DBS could be neuroprotective, but because current practice is to implant the electrodes late in the progression of the disease, neuroprotective effects of electrical stimulation have been challenging to document. It is therefore vital that we are not missing on a crucial opportunity for neurological patients and research the causal links, mechanisms, and timelines associated with neuroprotection via neuromodulation. I propose an interdisciplinary approach for which I am uniquely trained that uses optogenetics, electrophysiology, biochemistry, and collaborative device engineering to study the interplay between neuronal health and brain circuit activity in intact behaving rodents. Specifically, I propose to study the factors influencing the function and health of dopaminergic neurons in the brain and their role in animal behavior. Our findings could allow us to positively interfere with cells such as the dopaminergic neurons in the substantia nigra pars compacta (SNc) that degenerate and die in PD. Below I list 3 specific challenges that I will tackle using innovative, interdisciplinary, approaches. 1. Are all SNc dopaminergic neurons equally impactful on behavior or are there hotspots where cells, due to their heterogeneous electrical and neurochemical characteristics and connectivity, can maximally interfere with behavior when degenerated? 2. Once dopaminergic degeneration starts, can neurodegeneration be halted or slowed down by altering the activity of defined brain circuits? I will test this intriguing hypotheis by performing chronic optogenetic control of inputs to the SNc and measure changes in the degeneration rate. 3. Is growth factor signaling directly contributing to dopaminergic neuroprotection and what are the timelines needed for neuroprotection? Previous experiments applied growth factors liberally in a non-specific fashion and/or with poor temporal resolution. I will develop optogenetic methods to achieve cell-type specific control of growth factor signaling so I can directly probe the protective role of growth factors in defined cell types, and especially cells prone to degeneration. These tools could also be applied to research beyond the nervous system since growth factor signaling is involved in key cellular phenomena such gene transcription that can impact the cell survival, differentiation, and function. Together these innovative projects will contribute to my long-term goals of building cellular resilience via neuromodulation and have a paradigm-shifting impact in neurodegeneration research.