Cortico-hippocampal mechanisms of context memory

情境记忆的皮质海马机制

• 批准号: 10617764
• 负责人: Jelena Radulovic
• 金额: $ 67.33万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10617764
• 关键词: Affect; Anxiety; Area; Behavioral; Biochemical; Biological; Brain; Cells; DNA; Data; Decision Making; Dementia; Dependence; Development; Disease; Dorsal; Ensure; Episodic memory; Extracellular Matrix; Fright; Functional disorder; Gene Expression Profile; Genetic; Hippocampus; Hour; Impairment; Inflammation; Inflammation Mediators; Inflammatory; Knowledge; Label; Link; LoxP-flanked allele; Mediating; Memory; Memory Loss; Memory impairment; Mental Depression; Mental disorders; Modeling; Modification; Molecular; Monitor; Mood Disorders; Mus; Nature; Neocortex; Neurons; Pathway interactions; Pattern; Pilot Projects; Population; Post-Traumatic Stress Disorders; Process; Publishing; Qualifying; Receptor Signaling; Reporter; Research; Retrieval; Rodent; Role; Signal Pathway; Signal Transduction; Site; Stress; Synapses; System; TLR9 gene; Testing; Time; Toll-like receptors; Training; Transforming Growth Factor beta; Transforming Growth Factor beta Receptors; Variant; Viral; activity marker; candidate identification; cognitive function; conditional knockout; conditioned fear; design; episodic like memory; experience; genetic manipulation; in vivo; knock-down; memory consolidation; mouse model; neocortical; neurobiological mechanism; neuronal circuitry; neuropsychiatric disorder; novel; postsynaptic; postsynaptic neurons; preservation; presynaptic; presynaptic neurons; stress related disorder; targeted treatment

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.

摘要

项目成果

Primary cilia are required for the persistence of memory and stabilization of perineuronal nets.

• DOI: 10.1016/j.isci.2021.102617
• 发表时间: 2021-06-25
• 期刊: iScience
• 影响因子: 5.8
• 作者: Jovasevic V;Zhang H;Sananbenesi F;Guedea AL;Soman KV;Wiktorowicz JE;Fischer A;Radulovic J
• 通讯作者: Radulovic J

Protocol for assessing the role of hippocampal perineuronal nets in aversive memories.

• DOI: 10.1016/j.xpro.2021.100931
• 发表时间: 2021-12-17
• 期刊: STAR protocols
• 作者: Jovasevic V;Zhang H;Petrovic Z;Cicvaric A;Radulovic J
• 通讯作者: Radulovic J