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

项目总结 在过去的十年里，麻醉剂氯胺酮已经成为一种很有前途的抗抑郁药物，它既有快速的抗抑郁作用，也有 起效和长效。然而，氯胺酮在抑郁症治疗中的广泛使用是有限的 具有镇静、致幻、健忘和上瘾的特性。负责的全脑网络 对于氯胺酮的每一种生理作用，目前尚不清楚。为了因果性地评估哪个神经 亚回路和大脑区域有助于氯胺酮的抗抑郁作用而不是其他特性，因此需要一种 方法无创地将氯胺酮局部输送到大脑内的皮质和深层靶点。这样的一种方法 有可能在临床上被转化为提供一种非侵入性的治疗方法来调节所需的神经回路 同时将偏离目标的影响降至最低。 为此，我们开发了一种生物相容的纳米颗粒平台，将药物有效载荷浸泡在 超声波的应用。这些纳米粒子可以静脉注射并随后被激活。 通过临床可用的聚焦超声系统在大脑的血管系统内。然后释放的药物将会 被动地扩散穿过血脑屏障，在原本不受干扰的情况下达到预期的效果 大脑。使用麻醉剂异丙酚，我们已经证明了我们可以进行非侵入性的时空定位 秒和毫米量级的神经调节，不需要基因等不可逆转的方法 心理治疗。我们进一步发现，我们的纳米颗粒可以用来将全脑反应映射到焦点 药理扰动，突出了它们作为神经科学研究工具的潜力。 在这项建议中，我们将利用氯胺酮纳米颗粒将氯胺酮局部输送到下缘皮质。 (Il)，已知当地给予氯胺酮具有抗抑郁药样疗效的地区。到时候我们会的 使用脑电地形图(ECOG)来定量氯胺酮在IL中的作用如何携带皮质伽马和高密度脂蛋白 频率振荡被认为是氯胺酮抗抑郁作用背后的塑料变化。 然后，我们将把这些知识与行为研究结合起来，以评估这些生理变化是如何 在行为上表现为大鼠对负价态的敏感性，已知IL可调节负价态。我们还将 异丙酚选择性静止氯胺酮全身给药时IL的变化 和行为终结点。总而言之，这将为IL的作用提供统一的生理和行为洞察 使用可以转化为人体研究的行为范式来研究氯胺酮的抗抑郁效果。 我们设想，这个模型可以用来确定氯胺酮的大脑靶点，以诱导所需的精神障碍 在减少意外副作用的同时还能产生良好的效果。与此同时，我们的工作将验证潜在的临床 非侵入性地将氯胺酮特异性地输送到所述靶点的治疗，提供了精确的药理学 在抑郁症治疗中辅助谈话疗法或其他非侵入性神经调节方法。

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.