Glial dependent modulation of depressive like behaviors

抑郁样行为的神经胶质依赖性调节

• 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
• 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

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并存，尽管睡眠障碍是抑郁症的原因还是后果尚不清楚。在临床人群中，一整晚的睡眠剥夺具有立即的抗抑郁作用，尽管信号通路尚不清楚。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）睡眠剥夺提高腺苷，iii）腺苷转运体和代谢酶的单核苷酸多态性已在睡眠障碍的抑郁症患者中发现。 我们证明了星形胶质细胞有助于急性睡眠剥夺的行为反应。我们在星形胶质细胞中有条件地表达囊泡蛋白的SNARE结构域，以损害胞吐作用，从而导致细胞外腺苷减少，如通过神经元A1受体（A1 R）的基础激活减少、非快速眼动（NREM）睡眠期间慢波活动（SWA）减少和睡眠剥夺后恢复睡眠受损所评估的。我们推测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。 目的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的假设。我们将确定一整晚（12小时）的睡眠剥夺是否会导致抗抑郁样效应，然后使用dnSNARE小鼠询问星形胶质细胞睡眠稳态是否需要介导抑郁样反应。 目的2：我们将测试的假设，A1受体介导的抗抑郁样睡眠剥夺的影响。我们将确定12小时的睡眠剥夺是否会导致A1 R的激活增强，并使用A1 R拮抗剂和A1 R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A1 R。 目的3：我们将测试的假设，持续（12小时）的药理学激活中央A1 R将产生抗抑郁样作用。我们将通过脑室内（i. c. v.）并将询问这种受体途径的激活是否产生抗抑郁样作用。 目的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免疫反应性研究和使用新的泰特标签转基因小鼠，使GFP标记的c-fos活性神经元，以确定睡眠剥夺激活的额叶皮层神经元。最后，我们将用dnSNARE病毒感染额叶corex星形胶质细胞，并询问区域特异性转导是否抑制睡眠剥夺的抗抑郁作用。 识别睡眠剥夺抗抑郁样作用的信号通路有可能为未来的发展提供帮助。 以神经胶质为基础的治疗方法，用于立即缓解抑郁症。 公共卫生关系：我们将测试这一假设，即睡眠剥夺的抗抑郁作用介导的神经胶质细胞信号腺苷A1受体。识别睡眠剥夺的抗抑郁样作用的信号通路有可能识别出一个新的治疗领域，以立即缓解抑郁症。