Targeting Circadian Protein Rev-erbα to Alleviate Inflammation, Oxidative Stress, and Enhance Functional Recovery Following Brain Trauma.

Traumatic brain injury (TBI) is a significant cause of morbidity and mortality worldwide, and its pathophysiology is characterized by oxidative stress and inflammation. Despite extensive research, effective treatments for TBI remain elusive. Recent studies highlighted the critical interplay between TBI and circadian rhythms, but the detailed regulation remains largely unknown. Motivated by the observed sustained decrease in Rev-erbα after TBI, we aimed to understand the critical role of Rev-erbα in the pathophysiology of TBI and determine its feasibility as a therapeutic target. Using a mouse model of TBI, we observed that TBI significantly downregulates Rev-erbα levels, exacerbating inflammatory and oxidative stress pathways. The regulation of Rev-erbα with either the pharmacological activator or inhibitor bidirectionally modulated inflammatory and oxidative events, which in turn influenced neurobehavioral outcomes, highlighting the protein's protective role. Mechanistically, Rev-erbα influences the expression of key oxidative stress and inflammatory regulatory genes. A reduction in Rev-erbα following TBI likely contributes to increased oxidative damage and inflammation, creating a detrimental environment for neuronal survival and recovery which could be reversed via the pharmacological activation of Rev-erbα. Our findings highlight the therapeutic potential of targeting Rev-erbα to mitigate TBI-induced damage and improve outcomes, especially in TBI-susceptible populations with disrupted circadian regulation.

A Critical Period for the Development of Schizophrenia-Like Pathology by Aberrant Postnatal Neurogenesis.

Schizophrenia is a complex and serious mental disorder, and patients with schizophrenia are characterized by psychological hallucinations, deregulated emotionality, and cognitive impairment. Evidence indicated that postnatal neurogenesis in the hippocampus is profoundly impaired in schizophrenic individuals but the role of such dysregulated neurodevelopmental processing in the pathophysiological progress of schizophrenia has not been well investigated. Here in this study, by using the rodent model of schizophrenia through maternal immune activation of poly (I:C) injection, we aimed to examine whether the postnatal neurogenesis might be involved in the development of schizophrenia-like pathology. Through the comprehensive behavioral analyses of multiple core symptoms of schizophrenia at different developmental stages (6-, 9-, and 12-weeks after birth) of the affected offspring, we found a delayed onset of schizophrenia-like behaviors in poly (I:C) animals through the development. Meanwhile, there is an age-dependent alteration of postnatal neurogenesis in the poly (I:C) animals along different development stages by which the aberrant dendritic elaboration functionally correlated with the schizophrenia-like symptoms in 9-week-old of age for the animals. Interestingly, increase in the neurogenesis during a critical period of neurodevelopment exacerbates the schizophrenia-like pathology. Conversely, temporal suppression of aberrant postnatal neurogenesis during the same period of neurodevelopment ameliorates the occurrence of schizophrenia-like symptoms. Together, these findings strongly suggested the aberrant dendritic growth of postnatal neurogenesis during the critical time window of development is essential for controlling the pathophysiological progression of schizophrenia-like symptoms. And pharmacological treatments that adjust these abnormalities may provide potential therapeutic benefits toward patients with schizophrenia in clinic.

HDAC6 dysfunction contributes to impaired maturation of adult neurogenesis in vivo: vital role on functional recovery after ischemic stroke.

BACKGROUND: Promoting post-stroke neurogenesis has long been proposed to be a therapeutic strategy for the enhancement of functional recovery after cerebral ischemic stroke. Despite numerous approaches have been widely reported the proliferation or differentiation of the neurogenic population therapeutic strategies by targeting adult neurogenesis not yet to be successfully clarified in clinical settings. Here, we hypothesized that alterations in microenvironment of the ischemic brain might impede the functional maturation of adult newly generated neurons that limits functional recovery after stroke. METHODS: The in vivo retroviral based labeling model was applied to directly birth-date and trace the maturation process of adult newly generating neurons after hypoxic challenge. A rehabilitation therapy procedure was adopted through the combination of task-specific motor rehabilitating training with environmental enrichment to promote functional recovery after stroke. In addition, a pharmacological or genetic suppression of HDAC6 was performed to evaluate the functional significance of HDAC6 in the pathology of ischemic stroke induced deficits. RESULTS: Serial morphological analyses at multiple stages along the maturation process showed significant retardation of the dendritic maturation on the newly generated neurons after stroke. Subsequent biochemical analyses revealed an aberrant nuclear translocation of HDAC6 that leads to the hyper-acetylation of α-tubulin (an indication of over-stabilized microtubules) after hypoxic challenge was observed at different time points after stroke. Furthermore, the mimicry experiments with either pharmacological or genetic suppression of HDAC6, phenocopied the stroke induced retardation in dendritic maturation of newly generating neurons in vivo. More importantly, we provide direct evidence showing the proper function of HDAC6 is required for rehabilitation therapy induced therapeutic benefits after stroke. CONCLUSION: Together, our current study unravels that dysfunction of HDAC6 contributes to stroke induced deficits in neurogenesis and provides an innovative therapeutic strategy that targets HDAC6 for promoting functional recovery toward the patients with stroke in clinic.