Cortico-Hippocampal Mechanisms of Context Memory

总结 最高的认知功能，如推理、计划和决策，都是， 直接或间接地受到我们过去个人经历的影响，这些经历表现在 作为情节记忆的大脑皮层回路。这些回路的功能障碍 与我们这个时代最普遍和最具挑战性的精神疾病有关， 从痴呆到焦虑抑郁和创伤后应激障碍了解 因此，情景记忆形成和提取的神经生物学机制是必不可少的 用于开发针对此类疾病的有效分子和基于电路的疗法。我们 活动依赖性炎症信号在离散背海马中的关键作用 (DH)在稳定和稳定中， 与压力有关的记忆。目标1旨在确定以下方面的贡献 离散的DH-RSC投射到RSC的早期标记和持续的炎症信号传导， DH和RSC。目标2将重点关注海马Toll样受体（Tlr）的直接贡献 TGFb 1和Aim 3对记忆巩固和诱导的作用将研究 TGFb对大脑皮层记忆依赖性和炎症信号的失活的影响 DH-RSC电路。这些目标将在具有类似情节记忆的小鼠模型中进行测试， 应用DH-RSC回路的投射特异性操作，细胞特异性遗传修饰， Tlr 9和TGFb受体的操作，以及定量分子生物学和成像 方法来监测记忆回路中的炎症信号。我们希望电路特定 Tlr 9/ TGFb信号传导将成为神经精神疾病治疗的候选靶点 源于情景记忆缺失的疾病 在本增刊中，我们建议将肯德拉帕克作为我们项目的一员， TLR 9在记忆相关炎症信号中的作用。肯德拉帕克已经定义了她 明确的职业目标是成为未来的医生科学家。我们的目标是在她参加这个R 01 该项目的目的是提供研究方面的培训，从而确保她 为实现这一目标奠定了坚实的基础。我们欢迎有机会培训 非裔美国妇女作为未来的领导者在生物精神病学，并在该领域 尤其是记忆的神经生物学。

SUMMARY 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. We posit a key role of activity-dependent inflammatory signaling in discrete dorsohippocampal (DH) projections to the retrosplenial cortex (RSC) DH-RSC circuit in the stabilization and persistence of stress-related memories. 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 quantitative molecular biologic and imaging approaches to monitor inflammatory signaling in memory circuits. We hope that circuit specific Tlr9/ TGFb signaling will emerge as candidate target for therapies for neuropsychiatric disorders rooted in episodic memory deficits. In this supplement, we propose to add Kendra Parker as a member in our project to study the role of Tlr9 in memory-related inflammatory signaling. Kendra Parker has defined her career goal explicitly as a future physician scientist. Our goal during her participation in this R01 project is to provide the training in research resulting in publications, and thus ensure that she receives a strong foundation toward that outcome. We welcome the opportunity to train an African American woman as a future leader in biological psychiatry, and in the field of neurobiology of memory in particular.