Inhibition of RhoA/ROCK Pathway in the Early Stage of Hypoxia Ameliorates Depression in Mice via Protecting Myelin Sheath.

Neuroplasticity and connectivity in the central nervous system (CNS) are easily damaged after hypoxia. Long-term exposure to an anoxic environment can lead to neuropsychiatric symptoms and increases the likelihood of depression. Demyelination is an important lesion of CNS injury that may occur in depression. Previous studies have found that the RhoA/ROCK pathway is upregulated in neuropsychiatric disorders such as multiple sclerosis, stroke, and neurodegenerative diseases. Therefore, the chief aim of this study is to explore the regulatory role of the RhoA/ROCK pathway in the development of depression after hypoxia by behavioral tests, Western blotting, immunostaining as well as electron microscopy. Results showed that HIF-1α, S100ß, RhoA/ROCK, and immobility time in FST were increased, sucrose water preference ratio in SPT was decreased, and the aberrant activity of neurocyte and demyelination occurred after hypoxia. After the administration of Y-27632 and fluoxetine in hypoxia, these alterations were improved. Lingo1, a negative regulatory factor, was also overexpressed after hypoxia and its expression was decreased when the pathway blocked. However, fluoxetine had no effect on the expression of Lingo1. Then, we demonstrated that demyelination was associated with failures of oligodendrocyte precursor cell proliferation and differentiation and increased apoptosis of oligodendrocytes. Collectively, our data indicate that the RhoA/ROCK pathway plays a vital role in the initial depression during hypoxia. Blocking this pathway in the early stage of hypoxia can enhance the effectiveness of antidepressants, rescue myelin damage, and reduce the expression of the negative regulatory protein of myelination. The findings provide new insight into the prophylaxis and treatment of depression.

Demyelination contributes to depression comorbidity in a rat model of chronic epilepsy via dysregulation of Olig2/LINGO-1 and disturbance of calcium homeostasis.

Depression is the most common comorbidity among patients with epilepsy. Despite prior assumptions that antiepileptic drugs are to blame, more and more pathological studies have shown that latent neurological alterations associated with white matter injury and demyelination may underlie this link. However, whether disturbances in cerebral myelination contribute to the initiation of depression in epilepsy remains unclear. In the present study, we investigated the connection between demyelination disorders and the development of depression comorbidity in epilepsy. We first induced spontaneous recurrent epilepticus seizure (SRS) in young rats with pilocarpine. We then established depressive behaviors by recurrent forced swimming test and evaluate the depression state by sucrose preference test. The ratio of depression comorbidity in SRS rats was then calculated. Next, myelination in SRS-Depressed (SRS-D) rats was explored via PCR, western blotting, and immunohistochemistry for the key myelin promotion factor, Olig2 and inhibition factor, LINGO-1. Finally, in situ RNA hybridization of NCX3, one of the dominant Ca2+ extrusion proteins in oligodendrocytes (OLs) was performed to explore whether Ca2+ homeostasis of OLs was disturbed in epilepsy-induced hypoxic conditions and involved in the epilepsy-depression comorbidity. Our results revealed that one-quarter of the SRS rats displayed typical depressive behaviors, which were defined as SRS-D rats. In SRS-D rats, severe demyelination was also observed, accompanied with reduced expression of MBP, Olig2, and NCX3 and increased expression of LINGO-1 in the cingulate gyrus. In SRS-Non depressed rats, no significant changes were found from the control animals. This work provides new insights into the demyelination in epilepsy-depression comorbidity, which involves dysregulation of Olig2/LINGO-1 and disturbance of Ca2+ homeostasis.