Depletion of microglia with PLX3397 attenuates MK-801-induced hyperactivity associated with regulating inflammation-related genes in the brain.

Acute administration of MK-801 (dizocilpine), an N-methyl-D-aspartate receptor (NMDAR) antagonist, can establish animal models of psychiatric disorders. However, the roles of microglia and inflammation-related genes in these animal models of psychiatric disorders remain unknown. Here, we found rapid elimination of microglia in the prefrontal cortex (PFC) and hippocampus (HPC) of mice following administration of the dual colony-stimulating factor 1 receptor (CSF1R)/c-Kit kinase inhibitor PLX3397 (pexidartinib) in drinking water. Single administration of MK-801 induced hyperactivity in the open-field test (OFT). Importantly, PLX3397-induced depletion of microglia prevented the hyperactivity and schizophrenia-like behaviors induced by MK-801. However, neither repopulation of microglia nor inhibition of microglial activation by minocycline affected MK-801-induced hyperactivity. Importantly, microglial density in the PFC and HPC was significantly correlated with behavioral changes. In addition, common and distinct glutamate-, GABA-, and inflammation-related gene (116 genes) expression patterns were observed in the brains of PLX3397- and/or MK-801-treated mice. Moreover, 10 common inflammation-related genes ( CD68, CD163, CD206, TMEM119, CSF3R, CX3CR1, TREM2, CD11b, CSF1R, and F4/80) with very strong correlations were identified in the brain using hierarchical clustering analysis. Further correlation analysis demonstrated that the behavioral changes in the OFT were most significantly associated with the expression of inflammation-related genes ( NLRP3, CD163, CD206, F4/80, TMEM119, and TMEM176a), but not glutamate- or GABA-related genes in PLX3397- and MK-801-treated mice. Thus, our results suggest that microglial depletion via a CSF1R/c-Kit kinase inhibitor can ameliorate the hyperactivity induced by an NMDAR antagonist, which is associated with modulation of immune-related genes in the brain.

Chronic lithium treatment ameliorates ketamine-induced mania-like behavior via the PI3K-AKT signaling pathway.

Ketamine, a rapid-acting antidepressant drug, has been used to treat major depressive disorder and bipolar disorder (BD). Recent studies have shown that ketamine may increase the potential risk of treatment-induced mania in patients. Ketamine has also been applied to establish animal models of mania. At present, however, the underlying mechanism is still unclear. In the current study, we found that chronic lithium exposure attenuated ketamine-induced mania-like behavior and c-Fos expression in the medial prefrontal cortex (mPFC) of adult male mice. Transcriptome sequencing was performed to determine the effect of lithium administration on the transcriptome of the PFC in ketamine-treated mice, showing inactivation of the phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT) signaling pathway. Pharmacological inhibition of AKT signaling by MK2206 (40 mg/kg), a selective AKT inhibitor, reversed ketamine-induced mania. Furthermore, selective knockdown of AKT via AAV-AKT-shRNA-EGFP in the mPFC also reversed ketamine-induced mania-like behavior. Importantly, pharmacological activation of AKT signaling by SC79 (40 mg/kg), an AKT activator, contributed to mania in low-dose ketamine-treated mice. Inhibition of PI3K signaling by LY294002 (25 mg/kg), a specific PI3K inhibitor, reversed the mania-like behavior in ketamine-treated mice. However, pharmacological inhibition of mammalian target of rapamycin (mTOR) signaling with rapamycin (10 mg/kg), a specific mTOR inhibitor, had no effect on ketamine-induced mania-like behavior. These results suggest that chronic lithium treatment ameliorates ketamine-induced mania-like behavior via the PI3K-AKT signaling pathway, which may be a novel target for the development of BD treatment.

Motor Imagery-Based Brain-Computer Interface Combined with Multimodal Feedback to Promote Upper Limb Motor Function after Stroke: A Preliminary Study.

BACKGROUND: Recently, the brain-computer interface (BCI) has seen rapid development, which may promote the recovery of motor function in chronic stroke patients. METHODS: Twelve stroke patients with severe upper limb and hand motor impairment were enrolled and randomly assigned into two groups: motor imagery (MI)-based BCI training with multimodal feedback (BCI group, n = 7) and classical motor imagery training (control group, n = 5). Motor function and electrophysiology were evaluated before and after the intervention. The Fugl-Meyer assessment-upper extremity (FMA-UE) is the primary outcome measure. Secondary outcome measures include an increase in wrist active extension or surface electromyography (the amplitude and cocontraction of extensor carpi radialis during movement), the action research arm test (ARAT), the motor status scale (MSS), and Barthel index (BI). Time-frequency analysis and power spectral analysis were used to reflect the electroencephalogram (EEG) change before and after the intervention. RESULTS: Compared with the baseline, the FMA-UE score increased significantly in the BCI group (p = 0.006). MSS scores improved significantly in both groups, while ARAT did not improve significantly. In addition, before the intervention, all patients could not actively extend their wrists or just had muscle contractions. After the intervention, four patients regained the ability to extend their paretic wrists (two in each group). The amplitude and area under the curve of extensor carpi radialis improved to some extent, but there was no statistical significance between the groups. CONCLUSION: MI-based BCI combined with sensory and visual feedback might improve severe upper limb and hand impairment in chronic stroke patients, showing the potential for application in rehabilitation medicine.

Chronic lithium exposure attenuates ketamine-induced mania-like behavior and c-Fos expression in the forebrain of mice.

Ketamine, a dissociative anaesthetic, has been used in the treatment of major depressive disorder (MDD) as a rapid acting antidepressant drug. Recent studies have shown that ketamine may increase the potential risk of treatment-induced mania in MDD patients. Lithium is a well-known mood stabilizer and has been widely used for the treatment of mania. It is not fully understood which forebrain regions are involved in ketamine- and lithium-induced expression of c-Fos. Therefore, our aim was to investigate the effect of chronic lithium treatment on mania-like behavior and c-Fos expression in the mouse forebrain activated by a single administration of ketamine. In the open field test, our results showed that ketamine significantly increased the total distance and total cumulative duration of movement in mice, while chronic lithium could attenuate these effects of ketamine. In addition, acute ketamine induced higher c-Fos expression in the lateral septal nucleus, hypothalamus, amygdala, and hippocampus of mice in the treatment group compared to those in the control group. However, chronic lithium inhibited the significant increase in c-Fos-immunoreactive neurons following acute ketamine administration in the dentate gyrus of the hippocampus, field CA1 of the hippocampus, dorsal subiculum, ventral subiculum, ventral subiculum, central amygdaloid nucleus and basolateral amygdaloid nucleus. In summary, our research shows that pretreatment with lithium moderates the effects of acute ketamine administration on mania-like behavior and c-Fos expression in the forebrain. These findings could be helpful in better understanding the episodes of mania related to ketamine treatment for MDD and bipolar disorder.

Motor imagery based brain-computer interface control of continuous passive motion for wrist extension recovery in chronic stroke patients.

Motor recovery of wrist and fingers is still a great challenge for chronic stroke survivors. The present study aimed to verify the efficiency of motor imagery based brain-computer interface (BCI) control of continuous passive motion (CPM) in the recovery of wrist extension due to stroke. An observational study was conducted in 26 chronic stroke patients, aged 49.0 ± 15.4 years, with upper extremity motor impairment. All patients showed no wrist extension recovery. A 24-channel highresolution electroencephalogram (EEG) system was used to acquire cortical signal while they were imagining extension of the affected wrist. Then, 20 sessions of BCI-driven CPM training were carried out for 6 weeks. Primary outcome was the increase of active range of motion (ROM) of the affected wrist from the baseline to final evaluation. Improvement of modified Barthel Index, EEG classification and motor imagery pattern of wrist extension were recorded as secondary outcomes. Twenty-one patients finally passed the EEG screening and completed all the BCI-driven CPM trainings. From baseline to the final evaluation, the increase of active ROM of the affected wrists was (24.05 ± 14.46)˚. The increase of modified Barthel Index was 3.10 ± 4.02 points. But no statistical difference was detected between the baseline and final evaluations (P > 0.05). Both EEG classification and motor imagery pattern improved. The present study demonstrated beneficial outcomes of MI-based BCI control of CPM training in motor recovery of wrist extension using motor imagery signal of brain in chronic stroke patients.