The ATP Level in the Medial Prefrontal Cortex Regulates Depressive-like Behavior via the Medial Prefrontal Cortex-Lateral Habenula Pathway.

BACKGROUND: Depression is the most common mental illness. Mounting evidence suggests that dysregulation of extracellular ATP (adenosine triphosphate) is involved in the pathophysiology of depression. However, the cellular and neural circuit mechanisms through which ATP modulates depressive-like behavior remain elusive. METHODS: By use of ex vivo slice electrophysiology, chemogenetic manipulations, RNA interference, gene knockout, behavioral testing, and two depression mouse models, one induced by chronic social defeat stress and one caused by a IP3R2-null mutation, we systematically investigated the cellular and neural circuit mechanisms underlying ATP deficiency-induced depressive-like behavior. RESULTS: Deficiency of extracellular ATP in both defeated susceptible mice and IP3R2-null mutation mice led to reduced GABAergic (gamma-aminobutyric acidergic) inhibition and elevated excitability in lateral habenula-projecting, but not dorsal raphe-projecting, medial prefrontal cortex (mPFC) neurons. Furthermore, the P2X2 receptor in GABAergic interneurons mediated ATP modulation of lateral habenula-projecting mPFC neurons and depressive-like behavior. Remarkably, chemogenetic activation of the mPFC-lateral habenula pathway induced depressive-like behavior in C57BL/6J mice, while inhibition of this pathway was sufficient to alleviate the behavioral impairment in both defeated susceptible and IP3R2-null mutant mice. CONCLUSIONS: Overall, our study provides compelling evidence that ATP level in the mPFC is critically involved in regulating depressive-like behavior in a pathway-specific manner. These results shed new light on the mechanisms underlying depression and the antidepressant effect of ATP.

Alerting effects of light in healthy individuals: a systematic review and meta-analysis.

Light plays an essential role in psychobiological and psychophysiological processes, such as alertness. The alerting effect is influenced by light characteristics and the timing of interventions. This meta-analysis is the first to systematically review the effect of light intervention on alertness and to discuss the optimal protocol for light intervention. In this meta-analysis, registered at PROSPERO (Registration ID: CRD42020181485), we conducted a systematic search of the Web of Science, PubMed, and PsycINFO databases for studies published in English prior to August 2021. The outcomes included both subjective and objective alertness. Subgroup analyses considered a variety of factors, such as wavelength, correlated color temperature (CCT), light illuminance, and timing of interventions (daytime, night-time, or all day). Twenty-seven crossover studies and two parallel-group studies were included in this meta-analysis, with a total of 1210 healthy participants (636 (52%) male, mean age 25.62 years). The results revealed that light intervention had a positive effect on both subjective alertness (standardized mean difference (SMD) = -0.28, 95% confidence interval (CI): -0.49 to -0.06, P = 0.01) and objective alertness in healthy subjects (SMD = -0.34, 95% CI: -0.68 to -0.01, P = 0.04). The subgroup analysis revealed that cold light was better than warm light in improving subjective alertness (SMD = -0.37, 95% CI: -0.65 to -0.10, P = 0.007, I2 = 26%) and objective alertness (SMD = -0.36, 95% CI: -0.66 to -0.07, P = 0.02, I2 = 0). Both daytime (SMD = -0.22, 95% CI: -0.37 to -0.07, P = 0.005, I2 = 74%) and night-time (SMD = -0.32, 95% CI: -0.61 to -0.02, P = 0.04, I2 = 0) light exposure improved subjective alertness. The results of this meta-analysis and systematic review indicate that light exposure is associated with significant improvement in subjective and objective alertness. In addition, light exposure with a higher CCT was more effective in improving alertness than light exposure with a lower CCT. Our results also suggest that both daytime and night-time light exposure can improve subjective alertness.

Lycium barbarum polysaccharide-glycoprotein preventative treatment ameliorates aversive.

Previous studies have shown that Lycium barbarum polysaccharide, the main active component of Lycium barbarum, exhibits anti-inflammatory and antioxidant effects in treating neurological diseases. However, the therapeutic action of Lycium barbarum polysaccharide on depression has not been studied. In this investigation, we established mouse models of depression using aversive stimuli including exposure to fox urine, air puff and foot shock and physical restraint. Concurrently, we administered 5 mg/kg per day Lycium barbarum polysaccharide-glycoprotein to each mouse intragastrically for the 28 days. Our results showed that long-term exposure to aversive stimuli significantly enhanced depressive-like behavior evaluated by the sucrose preference test and the forced swimming test and increased anxiety-like behaviors evaluated using the open field test. In addition, aversive stimuli-induced depressed mice exhibited aberrant neuronal activity in the lateral habenula. Importantly, concurrent Lycium barbarum polysaccharide-glycoprotein treatment significantly reduced these changes. These findings suggest that Lycium barbarum polysaccharide-glycoprotein is a potential preventative intervention for depression and may act by preventing aberrant neuronal activity and microglial activation in the lateral habenula. The study was approved by the Jinan University Institutional Animal Care and Use Committee (approval No. 20170301003) on March 1, 2017.

Zeaxanthin dipalmitate alleviates hepatic injury induced by superimposed chronic hepatitis B and non-alcoholic steatohepatitis in non-obese mice.

A hepatitis B virus (HBV) transgenic mice model was used to establish the fatty liver superimposed model by feeding the methionine choline-deficient (MCD) diet for 8 weeks, with or without the gavage of 2 mg/kg zeaxanthin dipalmitate (ZD) three times per week. Both wild-type and HBV transgenic mice, with MCD diet, gained typical non-obese non-alcoholic steatohepatitis (NASH) and HBV symptoms. Coadministration with ZD exhibited evident therapeutic effects through alleviating those pathological events. Moreover, long-term vehicle-ZD treatment was found to be safe. Thus, ZD is a promising and safe hepato-protective agent against hepatic injury induced by superimposed HBV and NASH in non-obese mice.

Mechanisms of secondary degeneration after partial optic nerve transection.

Secondary degeneration occurs commonly in the central nervous system after traumatic injuries and following acute and chronic diseases, including glaucoma. A constellation of mechanisms have been shown to be associated with secondary degeneration including apoptosis, necrosis, autophagy, oxidative stress, excitotoxicity, derangements in ionic homeostasis and calcium influx. Glial cells, such as microglia, astrocytes and oligodendrocytes, have also been demonstrated to take part in the process of secondary injury. Partial optic nerve transection is a useful model which was established about 13 years ago. The merit of this model compared with other optic nerve injury models used for glaucoma study, including complete optic nerve transection model and optic nerve crush model, is the possibility to separate primary degeneration from secondary degeneration in location. Therefore, it provides a good tool for the study of secondary degeneration. This review will focus on the research progress of the mechanisms of secondary degeneration using partial optic nerve transection model.