Role of waking activity in determining sleep-based modification of cortical circuits

 描述(由申请人提供)：我是一名医学博士，精神病学家，目前在威尔康奈尔精神病学系担任讲师，从事研究员工作。我的博士工作是使用双光子钙成像研究新皮质微电路活动。为了获得研究这种行为自然的动物的神经元活动的工具，我把我的奖学金献给了纽约大学的Gyorgy Buzsaki博士。在Buzsaki博士的指导下，我已经掌握了大鼠硅探针记录的许多方面，但在这里，我建议在一个研究睡眠基础神经科学的项目的背景下，与Buzsaki博士的团队一起进行进一步的光遗传学培训。睡眠对正常的大脑功能至关重要，也在许多神经精神疾病中发挥作用，包括抑郁症和癫痫发作障碍。也许这表明了睡眠的一个更精确的作用：几十年的研究表明，学习后的睡眠可以增强学习。相比之下，其他研究表明，睡眠会自动下调神经元和突触的活动。睡眠的自稳作用和记忆巩固作用如何相互作用还不清楚，特别是考虑到它们在突触水平上做出不同的预测：记忆巩固预测突触在睡眠中加强，自稳预测突触减弱。这项建议旨在综合记忆巩固作用对睡眠和体内平衡的作用。我的结果将使用硅探针进行测量，我的干预将涉及学习范式和光遗传学。我的前两个目标将评估睡眠前的一个新的目标学习范例如何影响随后的睡眠如何调节前扣带皮质的神经活动。AIM 1将使用硅 根据神经元是否接受睡前学习范式，评估单个神经元放电和神经元组装行为在睡眠期间的变化。Aim 2将使用光遗传学来专门研究睡眠期间突触的变化，这取决于睡眠前是否有学习。突触在理论上被认为在学习和动态平衡方面都特别关键。我将使用光遗传学来精确探测起源于远端神经元的突触，光遗传学提供了比传统电刺激更少污染、更精确和更具启发性的刺激范式的优势。在目标3中，我将直接对清醒过程中神经元小亚群的尖峰频率进行光遗传操作，而不是学习，以更准确地确定先前的活动如何影响随后的睡眠调节。这项最后的实验将利用Buzsaki实验室开发的新的光遗传-硅探测器工具。我将接受Buzsaki博士和Francis Lee博士的指导，并将参加生物统计学和神经科学理论课程，以增加我的培训。我乐观地认为，申请表中描述的项目和培训将为该领域提供新的知识，并为我的独立研究做好准备。标题：清醒活动在确定基于睡眠的大脑皮层回路改变中的作用。

 DESCRIPTION (provided by applicant): I am an M.D., Ph.D. psychiatrist currently doing research fellowship work as an Instructor in the Weill Cornell Department of Psychiatry. My doctoral work was in the study of neocortical microcircuit activity using two-photon calcium imaging. To gain tools to study neuronal activity in the naturally behaving animal I have devoted my fellowship to training with Dr. Gyorgy Buzsaki at New York University. With Dr. Buzsaki I have mastered many aspects of silicon probe recording in rats, but here I propose further training in optogenetics with Dr. Buzsaki's group in the context of a project studying the basic neuroscience of sleep. Sleep is crucial to normal brain function and also plays a role in many neuropsychiatric diseases including depression and seizure disorders. Perhaps indicative of a more precise role for sleep: decades of research show that learning is enhanced by post-learning sleep. By contrast, other work shows that sleep homeostatically downregulates neuronal and synaptic activity. How the homeostatic role for sleep and the memory consolidation role interact is not at all clear, especially given that they make differing predictins at the level of synapses: memory consolidation predicts synaptic strengthening over sleep, homeostasis predicts synaptic weakening. This proposal aims to synthesize the memory consolidation role for sleep and the homeostatic role. My outcomes will be measured using silicon probes and my interventions will involve learning paradigms and optogenetics. My first two Aims will assess how a novel object learning paradigm prior to sleep affects how the subsequent sleep modulates neural activity in the anterior cingulate cortex. Aim 1 will use silicon probes to assess the changes over sleep in single neuron firing and neuronal assembly behavior depending on whether neurons were subjected to a pre-sleep learning paradigm. Aim 2 will use optogenetics to specifically study synaptic changes over sleep depending on whether there was learning prior to sleep. Synapses have been theorized to be particularly crucial in both learning and homeostasis. I will use optogenetics to precisely probe synapses originating from distal neurons, with optogenetics giving the advantage of less contaminated and more precise and revelatory stimulation paradigms than traditional electrical stimuli. In Aim 3 I will ue direct optogenetic manipulation of spike rates in small subsets of neurons during waking, rather than learning, to determine more precisely how prior activity affects subsequent sleep modulation. This final experiment will take advantage of new combined optogenetic-silicon probe tools developed in the Buzsaki Lab. I will receive mentorship from Dr. Buzsaki and from Dr. Francis Lee and will take biostatistical and neuroscience theory courses to add to my training. I am optimistic that the projects, and training described in this application will provid the field with new knowledge and will prepare me well for independent research. Title: Role of waking activity in determining sleep-based modification of cortical circuits.