Developing cytoskeletal-based interventions for adolescent-onset depression

开发基于细胞骨架的干预措施来治疗青少年抑郁症

• 批准号: 9305770
• 负责人: Lauren Paige Shapiro
• 金额: $ 4.4万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-20 至 2019-06-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9305770
• 关键词: Actins; Adolescence; Adolescent; Adolescent Development; Age; American; Animal Model; Antidepressive Agents; Behavioral; Behavioral Assay; Brain; Chronic; Confocal Microscopy; Cytoskeleton; Data; Dendritic Spines; Development; Dose; Event; Excitatory Synapse; Feeling suicidal; Fluorescence; Fluorescence Microscopy; Fluoxetine; Gene Silencing; Immunoblotting; Individual; Integrin Signaling Pathway; Integrins; Intervention; Ketamine; Knockout Mice; Longevity; LoxP-flanked allele; Measures; Mediating; Mental Depression; Molecular; Morphology; Mus; Neurobiology; Neurons; Outcome; Pattern; Performance; Phenotype; Phosphotransferases; Play; Prefrontal Cortex; Process; Property; Prosencephalon; Proteins; Public Health; Recurrence; Research; Resistance; Rho-associated kinase; Role; Signal Transduction; Site; Structure; Swimming; Synapses; System; Testing; Therapeutic; Time; Viral; Virulent; adolescent-onset depression; base; child depression; critical period; density; depressive symptoms; experimental study; fasudil; feeding; frontal lobe; high risk; improved; inhibitor/antagonist; knock-down; mood regulation; neurodevelopment; neuropsychiatric disorder; new therapeutic target; novel; personalized approach; receptor; reconstruction; relating to nervous system; resilience; selective expression; suicidal risk; therapeutic target; young adult

PROJECT SUMMARY Adolescent-onset depression is a particularly virulent form of depression due to increased resistance to antidepressant treatment. Furthermore, the manifestation of depression in adolescence and young adulthood is associated with higher risk for depression recurrence across the lifespan. As a result, there is a dire need for the development of novel antidepressants that are suitable for the adolescent brain. Adolescence represents a critical period of neurodevelopment. It is defined by structural and synaptic maturation and reorganization within the prefrontal cortex (PFC). During this time, dendritic spines, the primary site of excitatory synapses, are pruned, refined, and stabilized. Research in animal models suggests that structural stability confers resilience to neuropsychiatric diseases, such as depression. Research using conditional knockout mice indicates that one critical regulator of the neural maturation and stabilization in adolescence is the β1-integrin receptor. The β1-integrin signaling pathway inhibits Rho Kinase-II (ROCKII) activity to promote stabilization of the actin cytoskeleton. I have shown that the ROCKII inhibitor, fasudil, has antidepressant-like efficacy in adolescent, but not adult, mice. Fasudil also prunes dendritic spines while increasing synaptic marker expression in the adolescent PFC, suggesting that it enhances typical dendritic spine pruning and strengthens synapses. I hypothesize that fasudil converges with endogenous β1-integrin- mediated signaling events during adolescence to exert its structural and therapeutic-like benefits. Aim 1 will measure the expression and activity levels of proteins downstream of the β1-integrin receptor in the healthy developing PFC, a critical step in determining the feasibility of therapeutically targeting the β1-integrin signaling cascade in adolescents. Next, Aim 2 will use viral-mediated gene silencing, confocal fluorescence microscopy, and 3D dendritic spine reconstruction to test the hypothesis that fasudil’s beneficial impact on the maturation and pruning of dendritic spines in the PFC during adolescence is due to convergence with endogenous β1-integrin-mediated signaling and synergistic inhibition of ROCKII. Aim 3 will evaluate the antidepressant-like efficacy of enhancing signaling of the β1-integrin cascade and will test the hypothesis that the behavioral efficacy of fasudil is also attributable to convergence with endogenous β1-integrin-mediated signaling to inhibit ROCKII. I will also assess the antidepressant-like efficacy of DPH, a novel activator of Arg kinase, a primary β1-integrin substrate in the PFC. Lastly, I will test whether site-selective β1-integrin knockdown in the adolescent PFC induces a depressive-like phenotype. Positive outcomes from these experiments will indicate that β1-integrin signaling events may be a viable target in the development of novel intervention strategies for adolescent-emergent depression and will identify β1-integrin-mediated signaling as a resiliency factor in mood regulation in adolescence.

项目摘要 青少年抑郁症是一种特别致命的抑郁症， 抗抑郁治疗此外，抑郁症在青春期和青年期的表现是 与终生抑郁复发的高风险相关。因此，迫切需要 开发适合青少年大脑的新型抗抑郁药。 青春期是神经发育的关键时期。它是由结构和突触 前额叶皮层（PFC）的成熟和重组。在此期间，树突棘， 兴奋性突触的位点，被修剪、精炼和稳定。动物模型研究表明， 结构稳定性赋予了对神经精神疾病如抑郁症的复原力。 使用条件性基因敲除小鼠的研究表明，神经成熟的一个关键调节因子， 在青春期稳定的是β1-整联蛋白受体。β1-整合素信号通路抑制Rho激酶-II （ROCKII）活性以促进肌动蛋白细胞骨架的稳定。我已经证明了ROCKII抑制剂， 法舒地尔在青春期而非成年小鼠中具有抗抑郁样功效。法舒地尔还能修剪树突棘 同时增加青少年PFC中突触标记物的表达，这表明它增强了典型的树突状细胞， 脊椎修剪和加强突触。我假设法舒地尔与内源性β1整合素- 介导的信号事件在青春期发挥其结构和治疗样的好处。 目的1将测量β1-整联蛋白受体下游蛋白的表达和活性水平， 健康发育的PFC，确定治疗靶向β1整合素的可行性的关键步骤 青少年的信号级联。下一步，Aim 2将使用病毒介导的基因沉默，共聚焦荧光 显微镜和3D树突棘重建，以检验法舒地尔的有益影响的假设， 在青春期，PFC中树突棘的成熟和修剪是由于与 内源性β1-整联蛋白介导的信号传导和ROCKII的协同抑制。 目的3将评估增强β1整合素级联信号传导的抗抑郁样功效， 将检验法舒地尔的行为疗效也归因于内源性聚合的假设。 β1-整联蛋白介导的信号传导抑制ROCKII。我还将评估DPH的抗抑郁样疗效， 新的精氨酸激酶激活剂，PFC中的主要β1-整合素底物。最后，我将测试是否位点选择性 青少年PFC中β1-整合素敲低诱导抑郁样表型 这些实验的阳性结果表明β1-整联蛋白信号转导事件可能是一种可行的免疫调节剂。 目标在开发新的干预策略，为突发性抑郁症，并将确定 β1-整合素介导的信号传导作为青春期情绪调节的弹性因素