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: 10455684
• 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/10455684
• 关键词: Acute; Address; Anatomy; Animal Model; Antidepressive Agents; Anxiety; Area; Behavior; Behavioral; 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; Persons; 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.

项目概要/摘要 重度抑郁症 (MDD) 是导致残疾和生产力下降的主要原因，但我们不知道其具体原因 根本原因，我们也没有足够的治疗方法。开发更有效的疗法需要 更好地了解抗抑郁药（AD）的细胞和分子机制。新生成的 齿状回 (DG) 内的（未成熟）神经元除了与 AD 相关外，还与 AD 作用有关 具有海马体依赖性认知、模式分离、社会记忆和压力引起的焦虑。 新生 DG 神经元数量的增加与海马功能的改善相关，而 数量减少与海马功能受损有关。此外，我最近发表的文章表明 抑制新生神经元的兴奋性而不改变神经元数量会导致MDD相关 表型并消除 AD 效应。相反，增强未成熟神经元的活性而不改变 神经发生足以减轻不可预测的慢性轻度应激（uCMS）的影响，这是一种经过充分验证的、广泛的 使用抑郁症模型。由于新生神经元更容易形成突触，更容易兴奋，并且具有 更大的突触可塑性，了解神经发生对行为的复杂影响需要知识 新生神经元的突触连接、DG 活动水平、DG 内的信息流， 以及这些属性如何因经验而改变。因此，我建议建立一个输入定义的电路图 成熟和未成熟的 DG 神经元，并识别该图谱中的变化以及活动依赖性 AD 治疗和 uCMS 背景下转录的变化。在目标 1 中，我将建立一个突触前输入 通过结合转基因技术绘制日常生活中明显背腹、成熟和未成熟 DG 神经元的图 使用单突触狂犬病病毒在完整大脑中逆行追踪的小鼠技术。那么我来测试一下效果 AD 治疗和慢性化学遗传学神经元沉默对这些解剖学上确定的回路的影响。在目标 2 中， 我将研究 uCMS 的影响，它会产生与 MDD 相关的行为表型，无论是否患有慢性病 AD 治疗和 DG 电路上的急性化学遗传学神经元激活。在这两个目标中，我还将研究 突触、分子和行为变化以及活动依赖性单细胞转录组学。通过结合 基因表达数据和 DG 与行为表型的连接，根据所产生的变化 uCMS、AD 治疗和化学遗传学操作，我将能够构建生物学相关的 DG 可用于测试功能假设的网络模型，包括背腹 DG 二分法。学习中 慢性 AD 治疗和急性/慢性化学遗传学操作对于识别 AD 作用的信号通路，尤其是速效 AD。该 DG 网络模型的开发将 有助于阐明 DG 和神经发生在 MDD 相关表型和 AD 作用中的关键作用。