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.

项目总结/文摘