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.

项目总结/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 根本原因，我们也没有足够的治疗方法。开发更有效的治疗方法将需要 更好地了解抗抑郁药（AD）的细胞和分子机制。新生成 齿状回（DG）内的（未成熟）神经元除了与AD相关外， 与校园依赖性认知，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有关， 数目减少与海马功能受损有关。此外，我最近的出版物显示， 在不改变神经元数量的情况下抑制新生神经元的兴奋性， 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，广泛应用的方法。 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， 更大的突触可塑性，理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， 以及这些属性是如何被经验改变的。因此，我建议建立一个输入定义的电路图 的成熟和未成熟的DG神经元，并确定在这个地图的变化，连同活动依赖性 在AD治疗和uCMS的背景下，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了日常生活中明显的背腹侧、成熟和未成熟DG神经元的图谱。 小鼠技术与单突触狂犬病病毒逆行追踪在完整的大脑。然后，我将测试影响 AD治疗和慢性化学遗传神经元沉默在这些解剖学上确定的电路。在目标2中， 我将检查uCMS的影响，它产生了MDD相关的行为表型，有和没有慢性 AD治疗和DG回路上的急性化学发生性神经元激活。在这两个目标中，我也将研究 突触、分子和行为变化以及活性依赖性单细胞转录组学。通过组合 基因表达数据和DG连接与行为表型的变化， uCMS，AD治疗和化学遗传学操作，我将能够构建一个生物学相关的DG 网络模型，可用于测试功能假设，包括背腹DG二分法。研究 慢性AD治疗和急性/慢性化学遗传学操作也将是有价值的， AD作用的信号通路，尤其是快速作用的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。