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，博士精神病学家，目前在威尔康奈尔大学精神病学系担任讲师。我的博士研究工作是利用双光子钙成像研究新皮层微电路活动。为了获得研究自然行为动物神经元活动的工具，我将我的奖学金投入到纽约大学的Gyorgy Buzsaki博士的培训中。与Buzsaki博士一起，我已经掌握了大鼠硅探针记录的许多方面，但在这里，我建议在研究睡眠基础神经科学的项目背景下，与Buzsaki博士的团队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，在许多神经精神疾病中也起着重要作用，包括抑郁症和癫痫发作。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能力。相比之下，其他的研究表明，睡眠稳态下调神经元和突触的活动。睡眠的稳态作用和记忆巩固作用是如何相互作用的还不清楚，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，稳态预测突触减弱。 该建议旨在综合睡眠的记忆巩固作用和稳态作用。我的成果将使用硅探针进行测量，我的干预措施将涉及学习范式和光遗传学。我的前两个目标将评估一个新的对象学习范式之前的睡眠如何影响随后的睡眠如何调节前扣带皮层的神经活动。AIM 1将使用硅 探针，以评估单神经元放电和神经元组装行为的睡眠变化，这取决于神经元是否经历了睡眠前的学习范式。目标2将利用光遗传学专门研究睡眠中的突触变化，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体内平衡中特别重要。我将使用光遗传学来精确地探测源自远端神经元的突触，光遗传学的优势是比传统的电刺激更少污染，更精确和更有启示性的刺激模式。在目标3中，我将使用直接的光遗传学操纵清醒时而不是学习时神经元小子集的尖峰频率，以更精确地确定先前的活动如何影响随后的睡眠调节。最后的实验将利用Buzsaki实验室开发的新的组合光遗传学-硅探针工具。 我将接受Buzsaki博士和弗朗西斯李博士的指导，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，本申请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。清醒活动在确定基于睡眠的皮层回路修改中的作用。

 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.