Activity-Dependent Synapse Refinement in the Memory Circuit in vivo

描述（由申请人提供）：功能性神经回路的形成对于大脑的正常功能至关重要。有人提出，突触连接是在发育的特定时期通过神经活动来完善的，以建立适当的神经回路。海马回路由高度组织化的单向突触连接组成：从内嗅皮层（EC）到齿状回（DG），再到CA 3，再到CA 1，再到EC。然而，尽管海马体对记忆形成、情绪处理和社会行为的重要性众所周知，但我们对海马体回路是否以及如何通过活动进行优化以及这种重塑发生的发育时期知之甚少。许多形式的精神疾病，如自闭症和精神分裂症，都与海马回路的异常改变有关。因此，对海马回路的完善方式的理解应该会对这些破坏性疾病的病因学和治疗产生新的见解。在这里，我们已经建立了一个遗传系统，以研究活动在小鼠海马神经回路的建立和修改中的作用。在这个系统中，我们有条件地将特定的神经元群体的记忆回路在体内的有限的时间内，并检查失活对神经连接的影响。我们首先研究了EC到DG和DG到CA 3连接的改进。我们的初步研究结果表明，当从胚胎阶段失活，不活跃的EC和DG轴突仍然达到其适当的目标，但在很短的发展时期内消除活性依赖性的竞争与活跃的轴突。我们的数据还表明，EC和DG轴突细化在不同的发育阶段。使用这个系统，我们将确定（1）活动何时对突触细化起重要作用，（2）敏感期的活动抑制是否导致永久性突触变化，（3）神经发生是否对DG中的突触细化起作用，（4）突触细化涉及哪些特定的突触变化，以及（5）微型和动作电位触发的神经传递是否在突触精细化中发挥独特的作用。为此，我们建议：“目标1。识别活动依赖性突触细化的敏感期和关键期。“目标2。确定敏感期活动抑制的功能后果。“目标3。检查神经发生在DG轴突细化中的作用。“目标4。研究在突触细化过程中发生了哪些突触事件。“目标5。检查活动依赖性突触细化中微型和动作电位触发的神经传递的不同作用。通过这些研究，我们应该了解功能性记忆回路是如何通过神经活动在海马体中产生的。预计我们的研究将帮助我们设计策略来预防和治疗与海马体异常回路形成相关的精神疾病，如自闭症和精神分裂症。 公共卫生相关性：为了在大脑中建立适当的神经回路，突触连接在一定的发育时期内通过神经活动进行细化。在海马体中，功能回路的活动依赖性细化对于有效的学习和记忆形成至关重要。使用小鼠遗传系统中，海马电路中的神经元的限制群体可以有条件地失活，我们将确定敏感和关键时期的细化和分析的机制，在体内海马活动依赖性突触细化，以了解这一基本方面的功能记忆电路的形成。这项研究计划也应该产生新的见解的病理生理学和治疗与异常回路形成的海马体，如自闭症和精神分裂症的精神疾病。

DESCRIPTION (provided by applicant): Formation of functional neural circuits is critical for proper functioning of the brain. It has been proposed that synaptic connections are refined by neural activity during certain periods of development to establish appropriate neural circuits. Hippocampal circuits consist of highly organized unidirectional synaptic connections: from the entorhinal cortex (EC) to the dentate gyrus (DG) to CA3 to CA1 to the EC. However, despite the well known importance of the hippocampus to memory formation, emotional processing, and social behavior, we know very little about whether and how hippocampal circuits are refined by activity and the developmental periods over which such remodeling occurs. Many forms of mental illness such as autism and schizophrenia are associated with abnormal alterations in the hippocampal circuitry. Thus, the understanding of the manner by which hippocampal circuits are refined should yield novel insights into both the etiology and treatment of these devastating disorders. Here, we have established a genetic system to study the role of activity in the establishment and modification of neural circuits in the mouse hippocampus in vivo. In this system, we conditionally inactivate specific neuronal populations in the memory circuit for restricted periods of time in vivo and examine the effect of inactivation on neural connections. We first examined the refinement of EC-to-DG and DG-to-CA3 connections. Our preliminary results show that when inactivated from embryonic stages, inactive EC and DG axons still reach their appropriate target, but are eliminated during a short period of development by activity-dependent competition with active axons. Our data also suggest that EC and DG axons are refined at different developmental stages. Using this system, we will determine (1) when activity plays important roles for synapse refinement, (2) whether activity suppression during sensitive periods leads to permanent synaptic changes, (3) whether neurogenesis plays a role for synapse refinement in the DG, (4) what specific synaptic changes are involved in synapse refinement, and (5) whether miniature and action potential-triggered neurotransmission play unique roles in synapse refinement. For this, we propose to: " Aim 1. Identify the sensitive and critical periods for activity-dependent synapse refinement. " Aim 2. Determine the functional consequences of activity suppression during the sensitive periods. " Aim 3. Examine the role of neurogenesis in the refinement of DG axons. " Aim 4. Investigate what synaptic events take place during synapse refinement. " Aim 5. Examine the differential roles for miniature and action potential-triggered neurotransmission in activity- dependent synapse refinement. Through these studies we should understand how functional memory circuits are created in the hippocampus by neural activity. It is anticipated that our research will help us design strategies to prevent and treat mental illness associated with abnormal circuit formation in the hippocampus, such as autism and schizophrenia. PUBLIC HEALTH RELEVANCE: To establish appropriate neural circuits in the brain, synaptic connections are refined by neural activity during a certain period of development. In the hippocampus, activity-dependent refinement of functional circuits is critical for efficient learning and memory formation. Using a mouse genetic system in which restricted populations of neurons in the hippocampal circuit can be conditionally inactivated, we will identify sensitive and critical periods of refinement and analyze the mechanism of activity-dependent synapse refinement in the hippocampus in vivo to understand this fundamental aspect of functional memory circuit formation. This research program should also yield novel insights into the pathophysiology and treatment of mental illness associated with abnormal circuit formation in the hippocampus, such as autism and schizophrenia.