Whole-Brain Oscillatory and Behavioral Responses to Noninvasive Local Ketamine Uncaging in the Medial Prefrontal Cortex

项目摘要 在过去的十年中，麻醉剂氯胺酮已成为一种有前途的抗抑郁药，具有快速- 起效快、疗效持久。然而，氯胺酮用于抑郁症治疗的广泛使用是有限的， 它的镇静、致幻、遗忘和成瘾特性。全脑网络负责 氯胺酮的每一种生理作用仍是未知的。为了从因果关系上评估 子电路和大脑区域有助于氯胺酮的抗抑郁药与其他属性，需要一个 一种非侵入性地将氯胺酮局部递送到大脑内的皮质和深部靶点的方法。这种方法 可以潜在地在临床上转化为提供用于调节所需神经回路的非侵入性疗法 同时最小化脱靶效应。 为此，我们开发了一种生物相容性纳米颗粒平台， 超声波应用这些纳米颗粒可以静脉注射， 用临床上可用的聚焦超声波系统在大脑的脉管系统中进行检查。然后释放的药物将 被动地扩散穿过血脑屏障，以在原本未受干扰的脑内实现其期望的效果。 个脑袋使用麻醉剂异丙酚，我们已经证明我们可以进行非侵入性的时空定位， 神经调节的数量级秒和毫米，而不需要不可逆的方法，如基因 疗法我们进一步发现，我们的纳米颗粒可用于绘制全脑对局灶性脑损伤的反应。 药理学扰动，突出其作为神经科学研究工具的潜力。 在这个建议中，我们将利用氯胺酮负载纳米粒子局部传递氯胺酮到边缘下皮层 (IL)在该地区，已知局部氯胺酮给药具有抗抑郁药样功效。然后我们将 使用皮质电描记术（ECOG）定量氯胺酮在IL中的作用如何引起皮质γ和高 频率振荡，这被认为是驱动可塑性变化的基础氯胺酮的抗抑郁作用。 然后，我们将把这些知识与行为研究相结合，以评估这些生理变化 在行为上表现为大鼠对负效价的敏感性，已知IL调节负效价。我们还将 在全身氯胺酮给药期间，释放丙泊酚以选择性地沉默IL， 和行为终点。总之，这将为IL的作用提供统一的生理和行为见解。 氯胺酮的抗抑郁疗效，使用行为范例，可以转化为人类研究。 我们设想，这种模型可以用来确定氯胺酮的大脑靶点，以诱导所需的精神疾病。 同时减少意外的副作用。与此同时，我们的工作将验证一个潜在的临床 用于将氯胺酮特异性地非侵入性递送至所述靶点的治疗， 作为谈话治疗或其他非侵入性方法的辅助手段，用于抑郁症治疗中的神经调节。

PROJECT SUMMARY Over the past decade, the anesthetic agent ketamine has emerged as a promising antidepressant with both fast- onset and long-acting efficacy. However, the widespread use of ketamine for depression therapy is limited due to its sedative, hallucinogenic, amnestic, and addictive properties. The whole-brain networks that are responsible for each of ketamine’s physiologic effects remain unknown. In order to causatively assess which neural subcircuits and brain regions contribute to ketamine’s antidepressant vs other properties, there is a need for a method to noninvasively deliver ketamine locally to both cortical and deep targets within the brain. Such a method could potentially be clinically translated to provide a noninvasive therapy for modulating desired neural circuits while minimizing off-target effects. To this end, we have developed a platform of biocompatible nanoparticles that uncage a drug payload upon ultrasound application. These nanoparticles can be administered intravenously and subsequently activated within the brain’s vasculature with clinically available focused ultrasound systems. The released drug would then passively diffuse across the blood brain barrier to achieve their desired effect within the otherwise unperturbed brain. With the anesthetic propofol, we have shown that we can perform noninvasive spatiotemporally localized neuromodulation on the order of seconds and millimeters without the need for irreversible methods such as gene therapy. We further found that our nanoparticles can be used to map whole-brain responses to focal pharmacologic perturbation, highlighting their potential as a tool for neuroscientific inquiry. In this proposal, we will utilize ketamine-loaded nanoparticles to locally deliver ketamine to the infralimbic cortex (IL), a region in which local ketamine administration is known to have antidepressant-like efficacy. We will then use electrocorticography (ECOG) to quantify how ketamine action in IL entrains cortical gamma and high frequency oscillations, which are believed to drive plastic changes underlying ketamine’s antidepressant action. We will then incorporate this knowledge with behavioral studies to assess how these physiologic changes manifest behaviorally in the rat’s sensitivity to negative valence, which IL is known to modulate. We will also uncage propofol to selectively silence the IL during systemic ketamine administration with the same physiologic and behavioral endpoints. Together, this will provide unified physiologic and behavioral insight into the role of IL for ketamine’s antidepressant efficacy using behavioral paradigms that can be translated into human studies. We envision that this model could be used to identify brain targets for ketamine to induce the desired psychiatric effects while reducing unintended side effects. At the same time, our work would validate a potential clinical therapy for noninvasively delivering ketamine specifically to said targets, providing a precise pharmacologic adjunct to talk therapy or other noninvasive methods for neuromodulation in depression therapy.