Cortico-hippocampal mechanisms of context memory

摘要 最高的认知功能，如推理、计划和决策，都是直接或 间接地，受我们过去的个人经历的影响，这些经历表现在海马区-皮质回路中 作为插曲记忆。这些回路的功能障碍与最普遍和最具挑战性的 我们这个时代的精神障碍，从痴呆症到焦虑、抑郁和创伤后应激障碍。 因此，理解情景记忆形成和提取的神经生物学机制 对于开发有效的基于分子和电路的治疗此类疾病的方法至关重要。海流 该项目的重点是系统整合，这是一个过程，通过 海马区和大脑皮层回路，导致持续的大脑皮层代表情节记忆。基于 现有的证据，包括我们自己公布的和试点的数据，我们假设活动依赖的关键作用 大鼠背海马区向脾后皮质的离散投射中的炎症信号 系统整合，包括对DH-RSC电路进行标记、激活和停用。AIM 1的设计 确定离散的DH-RSC投影对RSC和持续的早期标记的贡献 肝动脉和肾小管上皮细胞中的炎症信号。目标2将重点放在海马Toll样蛋白的直接贡献上 受体(TLR)对记忆巩固和TGFb1的诱导，目标3将检查 TGFb对大鼠记忆皮层依赖性和炎症信号失活的影响 巡回赛。这些目标将在小鼠的情景式记忆模型中通过应用特定的投影进行测试 Dh-RSC电路的操作，TLR9和TGFb受体的细胞特异性遗传操作，以及 在体内通过病毒表达的信号报告来监测电路的活动。我们还计划申请 定量的分子生物学和生化方法将使我们能够确定浓度- 依赖的TGFb对水解酶激活和失活相关基因表达模式的影响 RSC电路。我们认为，提高我们对组织中神经元炎症的理解 记忆电路将提高我们对系统整合的基础知识。同时，我们希望， 电路特异性TLR9/TGFb信号将成为神经精神疾病治疗的候选靶点 病症根源于间歇性记忆缺陷。

ABSTRACT The highest cognitive functions such as reasoning, planning, and decision-making, are all, directly or indirectly, influenced by our past personal experiences, which are represented in hippocampal-cortical circuits as episodic memories. Dysfunction of these circuits has been linked to the most prevalent and challenging mental disorders of our time, ranging from dementia to anxiety, depression, and post-traumatic stress disorder. Understanding the neurobiological mechanisms of episodic memory formation and retrieval are therefore essential for the development of effective molecular and circuit-based therapies for such disorders. The current project focuses on systems consolidation, a process which, through sustained interactions between hippocampal and cortical circuits, leads to a lasting cortical representation of episodic memories. Based on existing evidence, including our own published and pilot data, we posit a key role of activity-dependent inflammatory signaling in discrete dorsohippocampal (DH) projections to the retrosplenial cortex (RSC) in systems consolidation, including tagging, activation, and deactivation of the DH-RSC circuit. Aim 1 is designed to determine the contributions of discrete DH-RSC projections to early tagging of RSC and sustained inflammatory signaling in DH and RSC. Aim 2 will focus on the direct contribution of hippocampal Toll-like receptors (Tlr) to memory consolidation and induction of TGFb1, and Aim 3 will examine the contribution of TGFb to the cortical dependence of memories and deactivation of inflammatory signaling in the DH-RSC circuit. These aims will be tested in mouse models of episodic-like memories by applying projection-specific manipulations of the DH-RSC circuit, cell-specific genetic manipulations of Tlr9 and TGFb receptors, and by monitoring circuit activity through virally expressed signaling reporters in vivo. We also plan to apply quantitative molecular biologic and biochemical approaches that will enable us to determine the concentration- dependent TGFb effects on gene expression patterns associated with activation and deactivation of the DH- RSC circuit. We believe that advancing our understanding of neuronal inflammation in the organization of memory circuits will advance our fundamental knowledge of systems consolidation. At the same time, we hope that circuit-specific Tlr9/TGFb signaling will emerge as candidate target for therapies for neuropsychiatric disorders rooted in episodic memory deficits.