Background and Aims: Sleep is predicted as a key modulator of cognition, but the underlying mechanisms are poorly understood. In this study, we investigated the effects of melatonin on chronic rapid eye movement sleep deprivation (CRSD)‐induced cognitive impairment and circadian dysfunction in rat models.Methods: Thirty‐six Sprague‐Dawley male rats were divided into three groups: CRSD with saline treatment, CRSD with chronic melatonin injection (20 mg/kg/day), and non‐sleep‐deprived control. The cognitive behavioral tests as well as the expression of clocks and HDAC3 were evaluated in all groups.Results: CRSD significantly reduced recognition index in novel object location, increased escape latency and distance traveling in Morris water maze while melatonin treatment attenuated CRSD‐induced hippocampal‐dependent spatial learning and memory deficits. Furthermore, the mRNAs of brain and muscle aryl hydrocarbon receptor nuclear translocator‐like 1(Bmal1) and circadian locomotor output cycles kaput (Clock) were globally down‐regulated by CRSD with constant intrinsic oscillation in both hippocampus and peripheral blood. The protein levels of hippocampal Bmal1, Clock, and HDAC3 were also remarkably down‐regulated following CRSD. Melatonin treatment reversed CRSD‐induced alterations of Bmal1/Clock and HDAC3 on both mRNA levels and protein levels.Conclusions: Our data indicate that melatonin treatment attenuates CRSD‐induced cognitive impairment via regulating HDAC3‐Bmal1/Clock interaction. These findings explore a broader understanding of the relationship between sleep and cognition and provide a potential new therapeutic target for cognitive impairment.

It is generally acknowledged that drug dependence is connected with abnormal functional organization in the individual’s brain. The present study aimed to identify the anterior cingulate cortex (ACC) abnormality with the cerebral networks involved in betel quid dependence (BQD) by resting-state functional connectivity (rsFC) using functional magnetic resonance imaging (fMRI). With fMRI data measured from 33 resting-state BQD individuals and 32 non-addicted and age-, sex-, education-matched healthy controls, we inquired into the BQD-related changes in FC between the regions of ACC with the whole brain involved in BQD individuals using a region of interest vised method, and to identify the relation of the alteration with the severity of BQD and duration. Compared to controls, the BQD group showed increased connectivity from ACC to the regions of the reward network (brainstem including midbrain regions such as the ventral tegmental area and pons, caudate, thalamus) and cerebellum. Decreased connectivity was observed in the BQD group in regions from ACC to the default mode network (medial prefrontal cortex and precuneus) and para Hippocampal/hypothalamus. Specifically, the BQD scale was positively correlated with increased FC of right ACC to left thalamus and left ACC to pons; the durations were negatively correlated with FC of right ACC to left precuneus. These disturbances in rsFC from ACC to the reward network and DMN revealed by fMRI may have a key function in providing insights into the neurological pathophysiology underlying BQD-associated executive dysfunction and disinhibition. These findings may contribute to our better understanding of the mechanisms underlying BQD.

Purpose: To investigate the mechanism underlying the regulatory effect of melatonin on chronic sleep deprivation‐related cognitive impairment.Methods: Chronic sleep deprivation (CSD) model was established using the MMPM method. After the model was established, melatonin receptor agonist and inhibitor were given, respectively. Water maze was conducted to record the escape latency and the duration of crossing the platform of space exploration. The concentration of TNF‐α, IL‐6, MDA, and SOD was measured by ELISA. Immunofluorescence was used to determine the expression level of CD86 and CD206, while the mRNA expression of Bax, Bcl‐2, P65, IκB, and BMAL1 was detected by qPCR. Western blotting assay was utilized to determine the protein expression of Bax, Bcl‐2, P65, p‐P65, IκB, p‐I κB, and BMAL1.Results: Compared with the control, the escape latency was greatly increased on the second and third day, accompanied by the increased expression of TNF‐α, IL‐6, MDA, and SOD in serum. Furthermore, dramatically upregulated Bax, Bcl‐2, P65, IκB, and CD86 were observed in the model group, accompanied by the declined expression level of BMAL1 and CD206. Compared with the model group, the escape latency was declined, the concentration of TNF‐α, IL‐6, MDA, and SOD was decreased, the expression level of Bax, Bcl‐2, P65, IκB, and CD86 was declined, and the level of BMAL1 and CD206 was promoted by the treatment of the melatonin agonist, while the opposite results were observed under the treatment of the melatonin inhibitor.Conclusion: Melatonin upregulates BMAL1 to attenuate chronic sleep deprivation‐related cognitive impairment by alleviating oxidative stress.

Small extracellular vesicles (sEVs) secreted by mesenchymal stem cells (MSCs) have shown great therapeutic potential in cerebral ischemia-reperfusion injury (CIRI). In this study, we firstly performed a systematic review to evaluate the efficacy of MSCs-derived sEV for experimental cerebral ischemia/reperfusion injury. 24 studies were identified by searching 8 databases from January 2012 to August 2022. The methodological quality was assessed by using the SYRCLE ‘s risk of bias tool for animal studies. All the data were analyzed using RevMan 5.3 software. As a result, the score of study quality ranged from 3 to 9 in a total of ten points. Meta-analyses showed that MSCs-derived sEVs could effectively alleviate neurological impairment scores, reduced the volume of cerebral infarction and brain water content, and attenuated neuronal apoptosis. Additionally, the possible mechanisms of MSCs-derived sEVs for attenuating neuronal apoptosis were inhibiting microglia-mediated neuroinflammation. Thus, MSCs-derived sEVs might be regarded as a novel insight for cerebral ischemic stroke. However, further mechanistic studies, therapeutic safety, and clinical trials are required. Systematic review registration. PROSPERO CRD42022312227.