Neural Control of Choroidal Function

项目总结 在包括人类在内的灵长类动物中，黄斑，尤其是中心凹，对高视力至关重要。这个 黄斑中心凹和黄斑的代谢需要主要由脉络膜毛细血管网来满足。 脉络膜位于Bruch膜后面。有相当多的证据表明 脉络膜血流灌注导致许多眼部疾病，如老年性黄斑变性和糖尿病 视网膜病变，影响这些视网膜区域。重要的是，脉络膜血流基本上是由 来自副交感神经系统的输入。然而，副交感神经回路控制着 灵长类动物的脉络膜血管系统知之甚少。Pre和Pre的准确位置 供应脉络膜的节后副交感运动神经元及其运动前输入没有 这些神经元的功能作用也没有得到充分的定义。因此，总的目标是 这一建议的目的是确定控制脑电活动的副交感神经回路的位置和功能。 非人灵长类的脉络膜血管构筑。我们建议进行神经解剖学，电生理学， 和药理实验来解决这些问题。具体来说，在目标1中，我们将使用逆行 示踪剂，包括常规的和跨突触的，用来识别控制运动的马达和前马达电路 脉络膜的副交感神经支配。在研究的功能部分，我们将使用红外(IR)激光 多普勒流量计、红外激光散斑流量图(LSFG)和光学相干层析成像(OCT)/OCT 血管造影术(OCTA)测量脉络膜血管。具体地说，在目标2中，我们将研究 电微刺激调节节前运动神经元活动的脉络膜血管构筑 用光来调节视网膜的活动。在目标3A中，我们假设药物失活 节前运动神经元减少黑暗中的整体脉络膜血流量和厚度，减少脉络膜 血流补偿血压的变化，并消除亮度引起的 脉络膜血管系统。在目标3B中，我们假设神经节前的电解性或化学性损害 运动神经元将导致脉络膜血流量减少。从长远来看，我们假设视网膜会 显示外段丢失和炎性标志物的证据。我们将非侵入性地评估视网膜，视网膜 OCT/OCTA、LSFG和视网膜电信号(ERG)/多焦显示的色素上皮与生活中的脉络膜健康 艾格。我们将通过视网膜组织学进一步评估死后视网膜的健康状况。拟议中的实验将 构成了对副交感神经回路和作用的第一次广泛而系统的研究， 灵长类脉络膜血管中控制血流的节前神经元。这些结果将设置 为未来研究的阶段，在该研究中，该电路被调制以提高中央视觉的存活率 人类黄斑变性。

PROJECT SUMMARY In primates, including humans, the macula and especially the fovea, is critical for high-acuity vision. The metabolic needs of the fovea and macula are primarily met by the choriocapillaris, the capillary network of the choroid located immediately behind Bruch’s membrane. There is considerable evidence that compromised choroidal perfusion contributes to many eye diseases, such as age-related macular degeneration and diabetic retinopathy, that affect these retinal regions. Importantly, choroidal blood flow is substantially controlled by inputs from the parasympathetic nervous system. However, the parasympathetic circuitry controlling the choroidal vasculature in primates is very poorly understood. The precise locations of the pre- and postganglionic parasympathetic motoneurons supplying the choroid, as well as their premotor inputs have not been established, nor have the functional roles of these neurons been fully defined. Therefore, the overall goal of this proposal is to determine the location and function of the parasympathetic circuits controlling the choroidal vasculature in non-human primates. We propose to perform neuroanatomical, electrophysiological, and pharmacological experiments to address these questions. Specifically, in Aim 1, we will use retrograde tracers, both conventional and trans-synaptic, to identify the motor and premotor circuitry controlling the parasympathetic innervation of the choroid. In the functional part of the study, we will use infrared (IR) laser doppler flowmetry, IR laser speckle flowgraphy (LSFG), and optical coherence tomography (OCT)/OCT angiography (OCTA) to measure the choroidal vasculature. Specifically, in Aim 2, we will study the effects on the choroidal vasculature of modulating preganglionic motoneuron activity by electrical microstimulation and of modulating retinal activity by light. In Aim 3A, we hypothesize that pharmacological inactivation of preganglionic motoneurons reduces overall choroidal blood flow and thickness in darkness, reduces choroidal blood flow compensation for changes in blood pressure, and eliminates luminance induced changes in the choroidal vasculature. In Aim 3B, we hypothesize that electrolytic or chemical lesions of preganglionic motoneurons will result in reduced choroidal blood flow. In the long term, we hypothesize that the retina will show evidence of outer segment loss and inflammatory markers. We will non-invasively assess retina, retinal pigment epithelium, and choroid health in life by OCT/OCTA, LSFG, and electroretinogram (ERG)/multifocal ERG. We will further assess retinal health postmortem by retinal histology. The proposed experiments will constitute the first extensive and systematic investigation of the circuitry and role of the parasympathetic, preganglionic neurons controlling blood flow in the choroidal vasculature of a primate. These results will set the stage for future studies in which this circuitry is modulated in order to improve the survival of central vision in human macular degeneration.