Depression is a common chronic psychiatric illness, which is resistant to medical treatments. While melatonin may alleviate certain depression symptoms, evidence for its efficacy against core symptoms is lacking. Here, we tested a mechanism whereby melatonin rescues the behavioral outcomes of the chronic unpredictable mild stress (CUMS) mouse model of depression. CUMS mice showed depressive behaviors to tail suspension, open field behavior, and sucrose preference test, and cognitive dysfunction in the Morris water maze. Impairments in these measures were relieved by melatonin treatment. Moreover, CUMS mice had impaired glymphatic function across the sleep-wake cycle due to the astrocytic loss and disturbance of circadian regulation of the polarized expression of aquaporin-4 (AQP4) water channels in perivascular astrocytes. EEG results in CUMS mice showed a reduced total sleep time and non-rapid eye movement (NREM) sleep, due to sleep fragmentation in the light phase. CUMS mice lost the normal rhythmic expressions of circadian proteins Per2, Cry2, Bmal1, Clock, and Per1. However, the melatonin treatment restored glymphatic system function and the polarization of AQP4, while improving sleep structure, and rectifying the abnormal expression of Per2, Bmal1, Clock, and Per1 in CUMS mice. Interestingly, Per2 expression correlated negatively with the polarization of AQP4. Further studies demonstrated that Per2 directed the location of AQP4 expression via interactions with the α-dystrobrevin (Dtna) subunit of AQP4 in primary cultured astrocytes. In conclusion, we report a new mechanism whereby melatonin improves depression outcomes by regulating the expression of the circadian protein Per2, maintaining the circadian rhythm of astrocytic AQP4 polarization, and restoring glymphatic function.

Aims: The involvement of pyroptosis in ischemic stroke remains to be established. Therefore, we used the specific pyroptosis inhibitor Vx765 as an experimental intervention target in a murine model of stroke.Methods: A total of 564 C57BL/6 mice were subjected to photothrombotic procedures and treated via gavage with Vx765 at 1‐hour post‐ischemia. We subsequently assessed the expression of Gasdermin D (GSDMD), inflammasomes, caspase‐1, and interleukin‐1β (IL‐1β) using immunofluorescence (IF) and Western blot (WB) analyses. We also examined ultrastructural changes of cortical neurons with transmission electron microscopy (TEM) and measured infarct volumes dynamically by magnetic resonance imaging (MRI). Moreover, we evaluated the neurologic deficits by modified neurological severity scores, the rotarod test, and Treadscan.Results: Elevated expression of GSDMD and GSDMD p30, the pore‐forming subunit, was evident in the peri‐ischemic region on days one and three post‐ischemia. The neuronal plasma, nuclear, and mitochondrial membranes showed ultrastructural damage at day three post‐stroke. Elevated expression of inflammasomes, caspase‐1, and IL‐1β was also present on days one and three post‐injury. There were significant differences between Vx765‐treated and vehicle groups in mean infarct volumes (14.36 vs 21.52 mm³; 12.34 vs 18.56 mm³; 4.13 vs 10.06 mm³; P < .05 at day one, three, and seven post‐surgery, respectively). Mice treated with Vx765 showed better motor recovery as assessed by serial behavior tests and had better neuronal survival, which was attributable to pyroptosis inhibition, as illustrated by downregulated expression of the effector protein GSDMD, inflammasomes, caspase‐1, and IL‐1β. Besides, treatment with Vx765 preserved neuronal membrane structures after the ischemic injury.Conclusions: Pyroptosis emerges as an important pathway for neuronal death in an acute ischemic stroke. Vx765, a low molecular weight drug that has proven safe in clinical epilepsy trials, has potential therapeutic value for cerebral ischemia by targeting the canonical inflammasome pathway of pyroptosis.

Background: Results of several longitudinal cohort studies suggested an association between cerebral small‐vessel disease and depression. Therefore, we performed a meta‐analysis to explore whether cerebral small‐vessel disease imparts increased risk for incident depression. Methods and Results: We searched prospective cohort studies relevant to the relationship between cerebral small‐vessel disease and incident depression published through September 6, 2019, which yielded 16 cohort studies for meta‐analysis based on the relative odds ratio (OR) calculated with fixed‐ and random‐effect models. Baseline white matter hyperintensities (WMHs) (pooled OR, 1.37; 95% CI, 1.14–1.65), enlarged perivascular spaces (pooled OR, 1.33; 95% CI, 1.03–1.71), and cerebral atrophy (pooled OR, 2.83; 95% CI, 1.54–5.23) were significant risk factors for incident depression. Presence of deep WMHs (pooled OR, 1.47; 95% CI, 1.05–2.06) was a stronger predictor of depression than were periventricular WMHs (pooled OR, 1.31; 95% CI, 0.93–1.86). What's more, the pooled OR increased from 1.20 for the second quartile to 1.96 for the fourth quartile, indicating that higher the WMH severity brings greater risk of incident depression (25th–50th: pooled OR, 1.20; 95% CI, 0.68–2.12; 50th–75th; pooled OR, 1.42; 95% CI, 0.81–2.46; 75th–100th: OR, 1.96; 95% CI, 1.06–3.64). These results were stable to subgroup analysis for age, source of participants, follow‐up time, and methods for assessing WMHs and depression. Conclusions: Cerebral small‐vessel disease features such as WMHs, enlarged perivascular spaces, and cerebral atrophy, especially the severity of WMHs and deep WMHs, are risk factors for incident depression.

We applied an MRI technique diffusion tensor imaging along the perivascular space (DTI-ALPS) for assessing glymphatic system (GS) in a genome-wide association study (GWAS) and phenome-wide association study (PheWAS) of 40,486 European individuals. Exploratory analysis revealed 17 genetic loci significantly associating with the regional DTI-ALPS index. We found 58 genes, including SPPL2C and EFCAB5 , which prioritized in the DTI-ALPS index subtypes and associated with neurodegenerative diseases. PheWAS of 241 traits suggested that body mass index and blood pressure phenotypes closely related to GS function. Moreover, we detected disrupted GS function in 44 of 625 predefined disease conditions. Notably, Mendelian randomization and mediation analysis indicated that lower DTI-ALPS index was a risk factor for ischemic stroke (odds ratio = 1.56, P = 0.028) by partly mediating the risk factor of obesity. Results provide insights into the genetic architecture and mechanism for the DIT-ALPS index and highlight its great clinical value, especially in cerebral stroke.