Glial dependent modulation of depressive like behaviors

抑郁样行为的神经胶质依赖性调节

基本信息

批准号：
8319749
负责人：
PHILIP G HAYDON
金额：
$ 41.8万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-04 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8319749
关键词：
Acute Adenosine Adenosine A1 Receptor Adverse effects Agonist Anhedonia Area Astrocytes Behavior Behavioral Behavioral Model Biological Assay Clinical Consumption Coupled Detection Electroencephalography Enzymes Exocytosis FOS gene Functional Magnetic Resonance Imaging Future G-Protein-Coupled Receptors High Pressure Liquid Chromatography Homeostasis Human Image In Situ Justice Knock-out Label Literature Major Depressive Disorder Mediating Mental Depression Metabolic Metabolism Microdialysis Modeling Molecular Genetics Mus Neuroglia Neurons Outcome Study Pathway interactions Patients Peripheral Pharmacology Polysomnography Population Proteins Receptor Activation Recovery Rewards Role SNAP receptor Signal Pathway Signal Transduction Single Nucleotide Polymorphism Sleep Sleep Deprivation Sleep Disorders Slow-Wave Sleep Sucrose Swimming Tail Suspension Testing Tetanus Helper Peptide Therapeutic Therapeutic Intervention Transgenic Mice Vesicle adenosine transporter base behavior test depressive symptoms extracellular frontal lobe glial cell development immunoreactivity in vivo non rapid eye movement novel novel therapeutics prevent receptor response sleep abnormalities

项目摘要

DESCRIPTION (provided by applicant): Sleep abnormalities are co-morbid with many psychiatric conditions though whether sleep disorders are a cause or consequence of depression is unclear. A total night of sleep deprivation has immediate antidepressive actions in the clinical population, although the signaling pathway is unknown. We propose that adenosine underlies the antidepressive effects of sleep deprivation because i) adenosine regulates sleep, ii) sleep deprivation elevates adenosine, and iii) single nucleotide polymorphisms in adenosine transporters and a metabolic enzyme have been identified in patients with depression with disturbed sleep. We demonstrated that astrocytes contribute to the behavioral responses to acute sleep deprivation. We conditionally expressed the SNARE domain of a vesicle protein in astrocytes to impair exocytosis resulting in reduced extracellular adenosine, as assessed by reduced basal activation of neuronal A1 receptors (A1R), reduced slow wave activity (SWA) during non-rapid eye movement (NREM) sleep and impaired recovery sleep following sleep deprivation. We hypothesize that the antidepressive effects of acute sleep deprivation are mediated by astrocyte-derived adenosine acting on neuronal A1 receptors. Aim 1: We will test the hypothesis that astrocytic modulation of sleep homeostasis contributes to antidepressive effects of sleep deprivation. We will determine whether a total night (12h) of sleep deprivation leads to antidepressive like effects, then using dnSNARE mice will ask whether the astrocytic sleep homeostat is required to mediate depressive-like responses. Aim 2: We will test the hypothesis that A1 receptors are required to mediate the antidepressive-like effects of sleep deprivation. We will determine whether 12h of sleep deprivation leads to enhanced activation of A1R and using central delivery of A1R antagonists and A1R knockout (A{1}R[-/-]) mice we will determine whether antidepressive-like effects of sleep deprivation require A1R. Aim 3: We will test the hypothesis that sustained (12h) pharmacological activation of central A1R will produce antidepressive like effects. We will deliver A1R agonists intracerebroventricularly (i.c.v.) and wil ask whether the activation of this receptor pathway yields antidepressive like effects. Aim 4: We will determine the role of frontal cortex in contributing to antidepressive effects of sleep deprivation. We will expand preliminary c-fos immunoreactivity studies and the use of novel Tet Tag transgenic mouse that enables GFP-labeling of c-fos active neurons to identify sleep deprivation activated neurons of the frontal cortex. Finally, we will virally transduce frontal corex astrocytes with dnSNARE and ask whether region specific transduction inhibits antidepressive effects of sleep deprivation. The identification of a signaling pathway underlying antidepressive like effects of sleep deprivation has the potential to for the future development of glial-based therapeutics for the immediate relief of depression. PUBLIC HEALTH RELEVANCE: We will test the hypothesis that the antidepressive effects of sleep deprivation are mediated by glial cells signaling to adenosine A1 receptors. The identification of a signaling pathway underlying antidepressive like effects of sleep deprivation has the potential to identify a new therapeutic area for immediate relief of depression.

描述（由申请人提供）：睡眠异常与许多精神疾病同时存在，但睡眠障碍是否是抑郁症的原因或后果尚不清楚。尽管信号通路尚不清楚，但整夜睡眠不足对临床人群具有立竿见影的抗抑郁作用。我们认为，腺苷是睡眠剥夺抗抑郁作用的基础，因为i）腺苷调节睡眠，ii）睡眠剥夺会升高腺苷，以及iii）在睡眠障碍的抑郁症患者中已发现腺苷转运蛋白和代谢酶的单核苷酸多态性。我们证明星形胶质细胞有助于对急性睡眠剥夺的行为反应。我们有条件地表达星形胶质细胞中囊泡蛋白的 SNARE 结构域，以损害胞吐作用，从而导致细胞外腺苷减少，通过神经元 A1 受体 (A1R) 基础激活减少、非快速眼球运动 (NREM) 期间慢波活动 (SWA) 减少来评估）睡眠和睡眠剥夺后恢复睡眠受损。我们假设急性睡眠剥夺的抗抑郁作用是由星形胶质细胞衍生的腺苷作用于神经元 A1 受体介导的。目标 1：我们将检验星形胶质细胞对睡眠稳态的调节有助于睡眠剥夺的抗抑郁作用这一假设。我们将确定一整夜（12小时）的睡眠剥夺是否会导致抗抑郁样作用，然后使用 dnSNARE 小鼠将询问是否需要星形细胞睡眠稳态来介导抑郁样反应。目标 2：我们将检验以下假设：A1 受体需要介导睡眠剥夺的抗抑郁样作用。我们将确定 12 小时的睡眠剥夺是否会导致 A1R 的激活增强，并使用 A1R 拮抗剂和 A1R 敲除 (A{1}R[-/-]) 小鼠的中枢递送，我们将确定睡眠剥夺的抗抑郁样作用是否需要 A1R 。目标 3：我们将检验以下假设：中枢 A1R 的持续（12 小时）药理激活会产生抗抑郁样作用。我们将通过脑室内 (i.c.v.) 递送 A1R 激动剂，并询问该受体途径的激活是否会产生抗抑郁样作用。目标 4：我们将确定额叶皮层在睡眠剥夺的抗抑郁作用中的作用。我们将扩大初步的 c-fos 免疫反应性研究，并使用新型 Tet Tag 转基因小鼠，该小鼠能够对 c-fos 活性神经元进行 GFP 标记，以识别睡眠剥夺激活的额叶皮层神经元。最后，我们将用 dnSNARE 病毒转导额叶核心星形胶质细胞，并询问区域特异性转导是否会抑制睡眠剥夺的抗抑郁作用。睡眠剥夺的抗抑郁效应背后的信号通路的识别有可能促进未来的发展基于神经胶质的疗法可立即缓解抑郁症。公共健康相关性：我们将检验以下假设：睡眠剥夺的抗抑郁作用是由神经胶质细胞向腺苷 A1 受体发出信号介导的。识别睡眠剥夺的抗抑郁样作用背后的信号通路有可能确定立即缓解抑郁症的新治疗领域。