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: 10903002
• 负责人: Elif Tunc-Ozcan
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10903002
• 关键词: Acute; Address; Anatomy; Animal Model; Antidepressive Agents; Anxiety; Area; Behavior; Behavioral; Brain; Cells; Chronic; Chronic stress; Clinical; Cognition; Complex; Data; Development; Disease; Dorsal; Faculty; Functional disorder; Gene Combinations; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Grant; Hippocampus; Impairment; Knowledge; Life; Link; Major Depressive Disorder; Maps; Mediating; Memory; Mentors; Molecular; Neurobiology; Neurons; New Mexico; Newborn Infant; Patients; Pattern; Persons; Pharmaceutical Preparations; Phase; Phenotype; Positioning Attribute; Pre-Clinical Model; Production; Productivity; Property; Publications; Rabies virus; Role; Secure; Signal Pathway; Source; Stream; Stress; Synapses; Synaptic plasticity; Technology; Testing; Therapeutic; Transgenic Mice; Universities; Work; antidepressant effect; behavioral phenotyping; biological adaptation to stress; cell type; dentate gyrus; depressed patient; depression model; depressive symptoms; disability; effective therapy; excitatory neuron; experience; genetic manipulation; granule cell; improved; molecular phenotype; network models; neural; neurogenesis; new therapeutic target; newborn neuron; presynaptic; prevent; promote resilience; rabies viral tracing; receptor; response; side effect; social; therapeutic target; transcriptomics

Project Summary: Since completing my K99, I have secured a faculty position at the University of New Mexico, where the work described on the R00 portion of the grant will be conducted.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. The development of more effective therapies will require a 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 the excitability of newborn neurons without altering neuronal numbers leads to MDD-related phenotypes and abolishes AD effects. Conversely, enhancing the activity of immature neurons without altering neurogenesis is sufficient to alleviate the effects of unpredictable chronic mild stress (uCMS), a well-validated, widely used model of depression. Since immature 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 these neurons, the level of DG activity, the information streams within the DG, and how the experience changes these properties. 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 activitydependent 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 MDDrelated phenotypes and AD action.

项目摘要： 自从完成K99以来，我已经在新墨西哥大学获得了教职员工的职位，在这里将进行赠款部分所述的工作。Major抑郁症（MDD）是残疾和生产力失去的主要原因，但我们不知道其潜在的原因，也不知道我们也有适当的治疗。更有效的疗法的发展将需要更好地了解抗抑郁药的细胞和分子机制（AD）。除了它们与海马依赖性认知，模式分离，社交记忆和压力引起的焦虑的相关性外，齿状回（DG）中新产生的（未成熟）神经元与AD作用有关。新生儿DG神经元的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相关。此外，我最近的出版物表明，抑制新生儿神经元而不改变神经元数的兴奋性会导致与MDD相关的表型并消除AD效应。相反，在不改变神经发生的情况下增强未成熟神经元的活性足以减轻不可预测的慢性轻度应激（UCMS）的影响，慢性轻度应激（UCMS）是一种验证良好的，广泛使用的抑郁模型。由于未成熟的神经元形式更容易突触，更令人兴奋，并且具有更大的突触可塑性，因此了解神经发生对行为的复杂作用需要了解这些神经元的突触连通性，DG活性水平，DG中的信息流以及体验如何改变这些特性。因此，我建议在AD处理和UCMS的背景下，建立一个成熟和未成熟DG神经元的输入定义的电路图，并确定该图中的变化以及转录的活动依赖性变化。在AIM 1中，我将通过将转基因小鼠技术与单突触狂犬病病毒在完整大脑中的单突性小鼠技术相结合，在日常生活中建立一个明显的背腹，成熟和未成熟的DG神经元的突触前输入图。然后，我将测试AD处理和慢性化学发生神经元沉默对这些解剖学上鉴定的电路的影响。在AIM 2中，我将检查产生与MDD相关的行为表型的UCMS的影响，并进行慢性AD处理以及急性化学发生神经元激活对DG电路的影响。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。通过将基因表达数据和DG连通性与行为表型相结合，鉴于UCMS，AD处理和化学遗传操作产生的变化，我将能够构建一个可用于测试包括背侧DG二进型在内的具有生物学相关的DG网络模型。研究慢性广告处理和急性/慢性化学发生操作对于识别AD动作的信号通路，尤其是快速作用AD的信号通路也很有价值。该DG网络模型的开发将有助于阐明DG和神经发生在MDDRECH的表型和AD作用中的关键作用。