Stressor exposure induces neuronal remodeling in specific brain regions. Given the persistence of stress-related illnesses, key next steps in determining the contributions of neural structure to mental health are to identify cell types that fail to recover from stressor exposure and to identify “trigger points” and molecular underpinnings of stress-related neural degeneration. We evaluated dendrite arbor structure on hippocampal CA1 pyramidal neurons before, during, and following prolonged exposure to one key mediator of the stress response – corticosterone (cortisol in humans). Basal dendrite arbors progressively simplified during a 3-week exposure period, and failed to recover when corticosterone was withdrawn. Corticosterone exposure decreased levels of the dendrite stabilization factor Abl2/Arg nonreceptor tyrosine kinase and phosphorylation of its substrates p190RhoGAP and cortactin within 11 days, suggesting that disruption of Arg-mediated signaling may trigger dendrite arbor atrophy and, potentially, behavioral abnormalities resulting from corticosterone exposure. To test this, we administered the novel, bioactive Arg kinase activator, 5-(1,3-diaryl-1H-pyrazol-4-yl)hydantoin, 5-[3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl]-2,4-imidazolidinedione (DPH), in conjunction with corticosterone. We found that repeated treatment corrected CA1 arbor structure, otherwise simplified by corticosterone. DPH also corrected corticosterone-induced errors in a hippocampal-dependent reversal learning task and anhedonic-like behavior. Thus, pharmacological compounds that target cytoskeletal regulators, rather than classical neurotransmitter systems, may interfere with stress-associated cognitive decline and mental health concerns.

应激源暴露引起特定大脑区域的神经元重塑。考虑到与压力有关的疾病的持续存在，确定神经结构对精神健康的贡献的关键下一步是确定无法从压力暴露中恢复的细胞类型，并确定与压力有关的神经变性的“触发点”和分子基础。我们在长期暴露于应激反应的一种关键介质皮质酮（人类皮质醇）之前，之中和之后，评估了海马CA1锥体神经元上的树突状乔木结构。在3周的暴露时间内，基部树突状乔木逐渐简化，而撤出皮质酮后未能恢复。皮质酮暴露会在11天之内降低枝晶稳定因子Abl2 / Arg非受体酪氨酸激酶水平及其底物p190RhoGAP和皮质激素的磷酸化水平，这表明Arg介导的信号传导中断可能会触发枝状乔木萎缩，并可能导致皮质激素暴露引起的行为异常。为了测试这一点，我们使用了新型的具有生物活性的Arg激酶激活剂5-（1,3-二芳基-1H-吡唑-4-基）乙内酰脲，5- [3-（4-氟苯基）-1-苯基-1H-吡唑-4-基] -2,4-咪唑烷二酮（DPH）与皮质酮联用。我们发现，重复治疗可纠正CA1乔木结构，否则可通过皮质酮简化。DPH还纠正了在依赖海马的逆向学习任务和类似快狂的行为中皮质酮引起的错误。因此，