Neuromodulation and Neurodegeneration: the Missing Link and Mechanisms of Action

描述(由申请人提供)：众所周知，神经退行性变很难研究，目前还没有经过验证或可接受的方法来预防或减缓人类的病程。治疗帕金森病(PD)的一种非常成功的干预方法是通过脑深部刺激(DBS)进行神经调节。DBS成功地恢复了运动功能，但人们对DBS在疾病过程中的作用知之甚少。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，电刺激的神经保护作用一直难以证明。因此，至关重要的是，我们不能错过神经科患者的关键机会，研究与神经调节相关的神经保护的因果联系、机制和时间表。我提出了一种跨学科的方法，这是我唯一接受过培训的方法，它使用光遗传学、电生理学、生物化学和协作设备工程来研究完整的行为啮齿动物神经元健康和大脑电路活动之间的相互作用。 具体地说，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，以及它们在动物行为中的作用。我们的发现可能使我们能够积极地干扰细胞，如黑质致密部(SNC)中的多巴胺能神经元，这些神经元在帕金森病中退化和死亡。下面我列出了三个具体的挑战，我将使用创新的、跨学科的方法来应对。1.所有黑质多巴胺能神经元对行为的影响是一样的吗？还是存在一些热点，在那里，细胞由于其异质性的电和神经化学特性以及连接性，在退化时可以最大限度地干扰行为？2.一旦多巴胺能神经元开始退化，是否可以通过改变已定义的大脑回路的活动来阻止或减缓神经退化？我将通过对SNC的输入进行慢性光遗传控制并测量退化率的变化来测试这一有趣的假设。3.生长因子信号是否直接参与多巴胺能神经保护？神经保护所需的时间线是什么？以前的实验以非特定的方式和/或时间分辨率较差的方式大量地应用生长因子。我将开发光遗传学方法来实现对生长因子信号的细胞类型的特异性控制，这样我就可以直接探索生长因子在特定细胞类型中的保护作用，特别是 容易退化的细胞。这些工具还可以应用于神经系统以外的研究，因为生长因子信号涉及关键的细胞现象，如影响细胞生存、分化和功能的基因转录。这些创新项目加在一起，将有助于我通过神经调节建立细胞弹性的长期目标，并对神经退化研究产生范式转换的影响。

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.