Neural activity and circuitry-mediated hippocampal stress responses

神经活动和电路介导的海马应激反应

• 批准号: 10301288
• 负责人: Elif Tunc-Ozcan
• 金额: $ 9.87万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-22 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10301288
• 关键词: Acute; Address; Anatomy; Animal Model; Antidepressive Agents; Anxiety; Area; Behavior; Behavioral; Biological; Brain; Cells; Chronic; Chronic stress; Clinical; Cognition; Complex; Cytoplasmic Granules; Data; Development; Disease; Dorsal; Functional disorder; Gene Expression; Genes; Genetic Transcription; Goals; Hippocampus (Brain); Impairment; Knowledge; Life; Link; Major Depressive Disorder; Maps; Mediating; Memory; Mentors; Molecular; Neurobiology; Neurons; Newborn Infant; Pattern; Phase; Phenotype; Pre-Clinical Model; Production; Productivity; Property; Publications; Rabies virus; Role; Signal Pathway; Source; Stream; Stress; Synapses; Synaptic plasticity; Technology; Testing; Therapeutic; Transgenic Mice; antidepressant effect; behavioral phenotyping; biological adaptation to stress; cell type; dentate gyrus; depressed patient; depression model; depressive symptoms; disability; effective therapy; excitatory neuron; experience; improved; molecular phenotype; network models; neurogenesis; new therapeutic target; newborn neuron; presynaptic; prevent; rabies viral tracing; receptor; relating to nervous system; resilience; response; side effect; social; therapeutic target; transcriptomics

Project Summary/Abstract Major depressive disorder (MDD) is a leading cause of disability and lost productivity, but we do not know its underlying causes, nor do we have adequate treatments. Development of more effective therapies will require better understanding of the cellular and molecular mechanisms of antidepressants (AD). Newly generated (immature) neurons within the dentate gyrus (DG) have been linked to AD action in addition to their association with hippocampus-dependent cognition, pattern separation, social memory, and stress-induced anxiety. Increased numbers of newborn DG neurons are associated with improved hippocampal function, while decreased numbers are associated with impaired hippocampal function. Moreover, my recent publication showed that suppressing excitability of newborn neurons without altering neuronal number leads to MDD-related phenotypes and abolishes AD effects. Conversely, enhancing activity of immature neurons without altering neurogenesis is sufficient to alleviate effects of unpredictable chronic mild stress (uCMS), a well-validated, widely used model of depression. Since newborn neurons form synapses more readily, are more excitable, and have greater synaptic plasticity, understanding the complex effects of neurogenesis on behavior requires knowledge of the synaptic connectivity of newborn neurons, the level of DG activity, the information streams within the DG, and how these properties are changed by experience. Thus, I propose to establish an input-defined circuit map of mature and immature DG neurons, and to identify the changes in this map, together with activity-dependent changes in transcription, in the context of AD treatment and uCMS. In Aim 1, I will establish a presynaptic input map of distinctly dorsal-ventral, mature and immature DG neurons in everyday life by combining transgenic mouse technology with monosynaptic rabies virus retrograde tracing in the intact brain. Then, I will test the impact of AD treatment and chronic chemogenetic neuronal silencing on these anatomically identified circuits. In Aim 2, I will examine the effects of uCMS, which produces MDD-related behavioral phenotypes, with and without chronic AD treatment and with acute chemogenetic neuronal activation on DG circuitry. In both Aims, I also will examine synaptic, molecular and behavioral changes, and activity-dependent single-cell transcriptomics. By combining gene expression data and DG connectivity with behavioral phenotypes in the light of changes produced by uCMS, AD treatment and chemogenetic manipulations, I will be able to construct a biologically relevant DG network model that can be used to test functional hypotheses, including dorsal-ventral DG dichotomy. Studying chronic AD treatment and acute/chronic chemogenetic manipulations also will be valuable for identifying signaling pathways underlying AD action, especially fast-acting ADs. Development of this DG network model will help to clarify the critical role of the DG and of neurogenesis in MDD-related phenotypes and AD action.

项目摘要/摘要 重度抑郁症（MDD）是残疾和生产力失去的主要原因，但我们不知道 基本原因，我们也没有足够的治疗方法。开发更有效的疗法将需要 更好地了解抗抑郁药的细胞和分子机制（AD）。新生成 （未成熟的）齿状回（DG）中的神经元除了其关联外，还与AD作用联系起来 依赖海马依赖性认知，模式分离，社交记忆和压力引起的焦虑。 新生DG神经元数量增加与海马功能的改善有关，而 数量减少与海马功能受损有关。而且，我最近的出版物表明 抑制新生神经元的兴奋性而不改变神经元数会导致MDD相关 表型和废除AD效应。相反，增强未成熟神经元的活性而不会改变 神经发生足以减轻不可预测的慢性轻度应激（UCMS）的影响，这是一种验证的，广泛的 使用的抑郁模型。由于新生儿神经元形式更容易突触，因此更加兴奋，并且有 更大的突触可塑性，了解神经发生对行为的复杂作用需要知识 新生神经元的突触连通性，DG活性的水平，DG中的信息流， 以及如何通过经验改变这些属性。因此，我建议建立输入定义的电路图 成熟和未成熟的DG神经元，并确定该图中的变化以及活动依赖性 在AD处理和UCM的背景下，转录变化。在AIM 1中，我将建立突触前输入 通过结合转基因，日常生活中明显的背腹，成熟和未成熟的DG神经元的地图 小鼠技术具有单突触狂犬病病毒在完整的大脑中逆行追踪。然后，我将测试影响 在这些解剖学上鉴定的电路上的AD处理和慢性化学发生神经元沉默。在AIM 2中， 我将检查产生与MDD相关的行为表型的UCMS的效果，有或没有慢性 AD处理和DG回路上的急性化学发生神经元激活。在这两个目标中，我还将检查 突触，分子和行为变化以及活动依赖性单细胞转录组学。通过组合 基因表达数据和DG连接与行为表型的连通性鉴于由 UCMS，AD治疗和化学发生操作，我将能够构建与生物学相关的DG 可用于测试功能假设的网络模型，包括背腹DG二分法。研究 慢性广告治疗和急性/慢性化学作用操纵对于识别也很有价值 信号通路AD动作，尤其是快速作用广告。此DG网络模型的开发将 有助于阐明DG和神经发生在与MDD相关的表型和AD作用中的关键作用。