Therapeutic effects of transcorneal electrical stimulation in animal models of depression and cognitive impairment

Abstract

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. 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.

Overall, this thesis presents preclinical findings that support TES as a potential therapeutic tool for depression and cognitive impairment.