Leveraging Rapid-Acting Antidepressants for Personalized Response

项目摘要 至少十分之一的人在生活中经历过使人衰弱的抑郁症，这代表了主要的个人、社会、 经济负担。有鉴于此，令人不安的是，目前对抑郁症的治疗是不够的。 例如，一种标准的一线抗抑郁药通常是有益的，但可能需要数周才能达到有效的效果。 剂量，但仍有超过一半的患者会失败。一个关键的挑战是，虽然抑郁症的临床表现 在患者中是异质的-可能是由于不同的脑回路和系统水平的中断， 目前的药物治疗并不针对个人的具体需求。最近，化合物与快速- 有效的抗抑郁特性已经成为潜在的革命性疗法。一种这样的化合物是 氯胺酮，主要是一种NMDA受体拮抗剂，低剂量可缓解一系列抑郁症状 起效迅速，反应持续。氯胺酮的治疗前景导致最近的临床批准 治疗难治性抑郁症和急性自杀意念但是，与传统的治疗方法类似，快速- 抗抑郁药并非对所有病人都有效，也不是针对某个人的特定症状。因此， 扩大和加强氯胺酮的有益作用的机会将在这里得到解决。 现在有几项研究将氯胺酮的行为作用与额叶皮层新突触的生长联系起来 锥体神经元，但它是未知的输入途径受益于这种连接的增加。输入 氯胺酮可塑性作用的特异性至关重要，因为额叶皮层的不同传入被认为 在离散行为障碍的基础上，例如通常伴随慢性疾病的奖励处理缺陷， 应力目的1将揭示氯胺酮的典型的可塑性行动的各种输入到额叶皮层使用在体内 老鼠的光学成像接下来，氯胺酮诱导的突触可塑性将通过刺激一个 给药期间的特定途径。目标2将利用这种方法来修改皮质皮质通路 与奖励导向行为的假设相关性。具体来说，一个工具性蔗糖偏好任务 最近开发的内部使用强化学习的原则，以揭示奖励处理的缺陷 在长期的社会失败之后。在这种模式下，输入特异性刺激压后皮质输入， 内侧额叶皮质将被添加到氯胺酮治疗，并改善救援的压力诱导的缺陷， 奖励敏感性总之，这项工作将揭示快速抗抑郁药的神经和行为作用是否 可以个性化，推动关键的见解需要调整这些新兴的疗法，以最好地为患者服务。

PROJECT SUMMARY At least 1 in 10 people experience debilitating depression in their life, representing major personal, social, and economic burden. In light of this it is troubling that current treatments for depression have been inadequate. A standard first-line antidepressant, for example, is often beneficial but can take weeks to reach an effective dose and will still fail in over half of patients. A key challenge is that while the clinical presentation of depression is heterogeneous across patients—likely due to distinct brain circuit and system-level disruptions underlying their symptoms—current medications are not personalized to one’s specific needs. Recently, compounds with fast- acting antidepressant properties have emerged as potential revolutionizing therapies. One such compound is ketamine, primarily an NMDA receptor antagonist, which at low dose relieves an array of depressive symptoms with rapid onset and sustained response. The therapeutic promise of ketamine led to recent clinical approvals for treatment-resistant depression and acute suicidal ideation. Still, similar to conventional treatments, rapid- acting antidepressants are not effective for all patients nor targeted to one’s specific symptoms. Thus, a critical opportunity to extend and enhance the beneficial actions of ketamine will be addressed here. Several studies now link the behavioral actions of ketamine to the growth of new synapses on frontal cortical pyramidal neurons, but it is unknown which input pathways benefit from this increase in connectivity. The input specificity of ketamine’s plasticity actions is crucial because distinct afferents to frontal cortex are thought to underlie discrete behavioral impairments, such as deficits in reward processing that commonly follow chronic stress. Aim 1 will uncover ketamine’s typical plasticity actions on various inputs to frontal cortex using in vivo optical imaging in the mouse. Next, ketamine-induced synaptic plasticity will be augmented by stimulating one specific pathway during drug administration. Aim 2 will harness this approach to modify a corticocortical pathway with hypothesized relevance to reward-guided behavior. Specifically, an instrumental sucrose preference task recently developed in-house uses principles of reinforcement learning to reveal deficits in reward processing following chronic social defeat. With this paradigm, input-specific stimulation of retrosplenial cortex inputs to medial frontal cortex will be added to ketamine treatment and to improve the rescue of stress-induced deficits in reward sensitivity. Together, this work will reveal if the neural and behavioral actions of rapid antidepressants can be individualized, fueling the critical insights needed to adapt these emerging therapies to best serve patients.