Rapid actions of ketamine in the prefrontal cortex

 描述(申请人提供)：NMDAR(NMDAR)拮抗剂氯胺酮目前正在试验中用于治疗严重的、顽固性抑郁症。新出现的临床数据表明，氯胺酮鼻腔给药能在几分钟内(5~40min)起到缓解作用，且认知副作用比全身注射氯胺酮少。这项拟议的研究将使用非人类灵长类动物范式来研究鼻腔给药氯胺酮与注射氯胺酮对前额叶皮质(PFC)回路直接与抑郁和认知相关的影响的细胞和回路机制。我们观察到决策任务中与厌恶事件有关的内侧前额叶持续神经元活动，这可能导致负面情绪状态，并在抑郁症中异常增强。我们将检验这一假设，即氯胺酮迅速侵蚀内侧前额叶神经元产生的持久的损失和惩罚表征，类似于氯胺酮侵蚀背外侧前额叶皮质(DlPFC)神经元对视觉空间的持久表征的能力。我们推测，代表丢失的神经回路的中断可能是患者鼻腔注射氯胺酮的超快效应(几分钟内)的基础，而更高阶PFC区域的棘突生成可能有助于更持久的抗抑郁作用(几小时到几天)。由于鼻内吸入通过筛板上的孔将药物直接输送到大脑，我们进一步假设，氯胺酮鼻腔直接轨迹中的内侧PFC区域可能比更远的dlPFC神经元受到更大的影响。这些数据将有助于解释为什么鼻腔给药起效更快，认知副作用比氯胺酮注射更少。目的1比较鼻内和肌肉注射亚麻醉剂量氯胺酮对决策任务和空间工作记忆任务的影响。我们预测氯胺酮将减弱先前惩罚对决策的影响，允许更有弹性的行为反应，鼻腔给药将优先影响这一行为，而IM注射将对这两个任务的表现产生更全面的影响。目的2将比较鼻腔给药氯胺酮和肌肉给药氯胺酮对持续神经元放电的影响。 与抑郁相关的内侧PFC区(BA24、BA25和dmPFC)与dlPFC相比。我们预测，氯胺酮将迅速侵蚀PFC内侧区域持续存在的丢失表现。我们进一步假设，鼻腔给药对内侧PFC神经元有更多的靶向作用，而肌注氯胺酮将改变内侧和外侧PFC区神经元的放电。最后，Aim 3将通过将氯胺酮和其他更具选择性的NMDAR NR2A与NR2B拮抗剂直接应用到PFC内侧神经元上，测试氯胺酮的作用是否由内侧PFC的局部作用介导，类似于之前在dlPFC中的实验。这些实验的结果将为研究氯胺酮快速抗抑郁作用的细胞和电路机制提供重要的见解。

 DESCRIPTION (provided by applicant): The NMDA receptor (NMDAR) antagonist, ketamine, is currently in experimental use for the treatment of severe, intractable depression. Emerging clinical data indicate that intranasal ketamine administration can produce relief within minutes (5~40min), with fewer cognitive side effects than systemic ketamine injections. The proposed research will use a non-human primate paradigm to study the cellular and circuit mechanisms underlying the effects of intranasal vs. injected ketamine administration in prefrontal cortical (PFC) circuits immediately relevant to depression and cognition. We have observed persistent neuronal activity in medial PFC related to aversive events in a decision-making task, which may contribute to negative affective states and be abnormally heightened in depression. We will test the hypothesis that ketamine rapidly erodes the persistent representations of loss and punishment generated by medial prefrontal neurons, similar to ketamine's ability to erode persistent representations of visual space by dorsolateral prefrontal cortical (dlPFC) neurons. We hypothesize that the disruption of neural circuits representing loss may underlie the ultra-rapid effects of intranasal ketamine in patients (within minutes), while spinogenesis in higher order PFC regions may contribute to the more sustained anti-depressant actions (hours to days). As intranasal inhalation delivers drug directly to the brain through the holes in the cribiform plate, we further hypothesize that the medial PFC regions in the direct trajectory of intranasal ketamine may be more affected than the dlPFC neurons that are more distant. Such data would help to explain why intranasal administration has a more rapid onset with fewer cognitive side effects than ketamine injections. Aim 1 will compare the effects of intranasal vs. intramuscular administration of sub-anesthetic doses of ketamine on performance of the decision-making vs. spatial working memory tasks. We predict that ketamine will attenuate the effects of previous punishment on decision-making, allowing a more resilient behavioral response, and that intranasal administration will preferentially influence this behavior, while IM injections will have more global effects on performance in both tasks. Aim 2 will compare the effects of intranasal vs. intramuscular administration of ketamine on persistent neuronal firing in medial PFC regions relevant to depression (BA24, BA25 and dmPFC) compared to the dlPFC. We predict that ketamine will rapidly erode persistent representations of loss in medial PFC areas. We further hypothesize that intranasal administration will have more targeted effect on medial PFC neurons, while IM ketamine will alter neuronal firing in both medial and lateral PFC areas. Finally, Aim 3 will test whether the effects of ketamine are mediated by local actions in the medial PFC using iontophoretic application of ketamine and other more selective NMDAR NR2A vs. NR2B antagonists directly onto medial PFC neurons, similar to previous experiments in the dlPFC. The results from these experiments will provide important insights into the cellular and circuit mechanisms underlying the rapid anti-depressant effects of ketamine.