Supporting data for "Therapeutic effects of transcorneal electrical stimulation in animal models of depression and cognitive impairment"

Depression and dementia are among the leading causes of global disability, and yet current treatments are often limited by inadequate efficacies. This emphasizes the need to search for novel antidepressants and therapies for cognitive impairment. Transcorneal electrical stimulation (TES) is a non-invasive neuromodulation technique that has shown promising neuroprotective effects in various eye disorders. It has been reported to activate brain regions that are implicated in mood alteration and cognitive decline, which suggests the potential of TES in modulating emotion and cognitive function. To date, the non-visual effects of TES, especially its psychiatric and memory-enhancing effects, remain largely unknown. This study investigated the therapeutic effects of TES on depressive-like behaviors and memory deficits in rodent models of depression and cognitive decline, respectively. <br> In this thesis, I reviewed findings on the neuroprotective mechanisms underlying the effects of TES in an attempt to develop the hypothesis that TES possesses antidepressant-like properties. I then showed that long-term TES treatment induced antidepressant-like behaviors in the S334ter-line-3 rat model of retinal degeneration and a rat model of depression induced by chronic unpredictable stress. I found that the antidepressant-like effects of TES partially depended on neurogenesis and involved a normalization of plasma corticosterone level, as well as regulation of gene and protein expression related to neurogenesis, synaptic plasticity, and apoptosis in the hippocampus and amygdala. I further validated the antidepressant- like effects of TES in a chronic restraint stress model (CRS) of depression. I demonstrated that TES ameliorated depressive-like behaviors in the CRS model with efficacy similar to escitalopram treatment. Furthermore, I showed that TES reduced HPA axis hyperactivity, restored glucocorticoid receptor expression, enhanced hippocampal neurogenesis, regulated the oxytocin-GPCR-CREB signaling pathway, and further demonstrated the neurogenesis-dependent effects of TES in hedonic-like behavior and HPA axis response. To better understand the role of hippocampal neurogenesis in the antidepressant effects of neuromodulation treatments, I systematically reviewed studies on the neurogenic and antidepressant outcomes of neuromodulation in depression models. I showed that antidepressant- like effects of neuromodulation were generally accompanied by an increased hippocampal cell proliferation/neurogenesis. Yet, there was insufficient evidence to conclude whether the neuromodulation-induced neurogenesis and antidepressant-like responses were causally related. Finally, I showed that TES improved memory impairment in aged mice and the 5XFAD model of Alzheimer’s disease. I also reported the effects of TES in reducing the hippocampal amyloid burden and restoring postsynaptic protein expression in male 5xFAD mice. <br> Overall, this thesis presents preclinical findings that support TES as a potential therapeutic tool for depression and cognitive impairment.

抑郁症与痴呆是全球范围内导致残疾的主要诱因之一，然而当前的治疗手段往往受限于疗效不足。这凸显了开发针对情绪障碍与认知损害的新型抗抑郁药物及治疗方案的迫切需求。经角膜电刺激（Transcorneal Electrical Stimulation, TES）是一种非侵入性神经调控技术，已在多种眼部疾病中展现出具有前景的神经保护效应。已有研究表明，该技术可激活与情绪改变及认知衰退相关的脑区，提示其在调节情绪与认知功能方面的潜在价值。截至目前，TES的非视觉效应，尤其是其精神调控与记忆增强作用，仍鲜为人知。本研究分别针对抑郁症与认知衰退啮齿动物模型，探究了TES对抑郁样行为及记忆缺陷的治疗作用。<br>本学位论文首先梳理了TES发挥神经保护作用的潜在机制相关研究成果，尝试提出TES具备抗抑郁样特性的假说。随后研究证实，长期TES治疗可在S334ter-3系视网膜变性大鼠模型以及慢性不可预见性应激诱导的抑郁症大鼠模型中诱导出抗抑郁样行为。研究发现，TES的抗抑郁样效应部分依赖于神经发生，且可使血浆皮质酮水平恢复正常，同时调控海马体与杏仁核中与神经发生、突触可塑性及细胞凋亡相关的基因与蛋白表达。本研究进一步在慢性束缚应激（Chronic Restraint Stress, CRS）抑郁症模型中验证了TES的抗抑郁样效应，结果显示TES可改善该模型的抑郁样行为，其疗效与艾司西酞普兰（Escitalopram）治疗相当。此外，研究表明TES可减轻下丘脑-垂体-肾上腺轴（Hypothalamic-Pituitary-Adrenal Axis, HPA）的过度激活，恢复糖皮质激素受体表达，增强海马神经发生，并调控催产素-GPCR-CREB信号通路；同时证实了TES在快感样行为与HPA轴应答中依赖于神经发生的作用效应。为进一步明确海马神经发生在神经调控治疗抗抑郁效应中的作用，本研究系统性综述了抑郁症模型中神经调控的神经发生与抗抑郁结局相关研究，结果显示神经调控的抗抑郁样效应通常伴随海马细胞增殖/神经发生水平的提升，但现有证据仍不足以证明神经调控诱导的神经发生与抗抑郁样反应之间存在因果关联。最后，本研究证实TES可改善老年小鼠及阿尔茨海默病（Alzheimer’s Disease, AD）的5XFAD模型小鼠的记忆损伤，同时报道了TES可降低雄性5XFAD小鼠的海马淀粉样蛋白负荷，并恢复其突触后蛋白表达水平。<br>综上，本学位论文提供的临床前研究结果支持TES作为一种潜在的治疗工具，用于抑郁症与认知损害的干预。