Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by severe developmental delay, motor impairment, language and cognition deficits, and often with increased seizure activity. AS is caused by deficiency of UBE3A, which is both an E3 ligase and a cofactor for transcriptional regulation. We previously showed that the small conductance potassium channel protein SK2 is a UBE3A substrate, and that increased synaptic SK2 levels contribute to impairments in synaptic plasticity and fear-conditioning memory, as inhibition of SK2 channels significantly improved both synaptic plasticity and fear memory in male AS mice. In the present study, we investigated UBE3a-mediated regulation of synaptic plasticity and fear-conditioning in female AS mice. Results from both western blot and immunofluorescence analyses showed that synaptic SK2 levels were significantly increased in hippocampus of female AS mice, as compared to wild-type (WT) littermates. Like in male AS mice, long-term potentiation (LTP) was significantly reduced while long-term depression (LTD) was enhanced at hippocampal CA3-CA1 synapses of female AS mice, as compared to female WT mice. Both alterations were significantly reduced by treatment with the SK2 inhibitor, apamin. The shunting effect of SK2 channels on NMDA receptor was significantly larger in female AS mice as compared to female WT mice. Female AS mice also showed impairment in both contextual and tone memory recall, and this impairment was significantly reduced by apamin treatment. Our results indicate that like male AS mice, female AS mice showed significant impairment in both synaptic plasticity and fear-conditioning memory due to increased levels of synaptic SK2 channels. Any therapeutic strategy to reduce SK2-mediated inhibition of NMDAR should be beneficial to both male and female patients.

Background Hemiplegic shoulder pain (HSP) is a common symptom for post-stroke patients, which has a severely adverse impact on their rehabilitation outcomes. However, the cause of HSP has not been clearly identified due to its complicated multifactorial etiologies. As possible causes of HSP, the abnormality of both muscular electrical activity and blood perfusion remains lack of investigations. Objective This study aimed to analyze the alteration of muscular electrical activity and blood perfusion of upper extremity in patients with HSP by using surface electromyography (sEMG) and laser speckle contrast imaging (LSCI) measurement techniques, which may provide some insight into the etiology of HSP. Methods In this observational and cross-sectional study, three groups of participants were recruited. They were hemiplegic patients with shoulder pain (HSP group), hemiplegic patients without shoulder pain (HNSP group), and healthy participants (Healthy group). The sEMG data and blood perfusion data were collected from all the subjects and used to compute three different physiological measures, the root-mean-square (RMS) and median-frequency (MDF) parameters of sEMG recordings, and the perfusion unit (PU) parameter of blood perfusion imaging. Results The RMS parameter of sEMG showed significant difference (p < 0.05) in the affected side between HSP, HNSP, and Healthy groups. The MDF parameter of sEMG and PU parameter of blood perfusion showed no significant difference in both sides among the three groups (p > 0.05). The RMS parameter of sEMG showed a statistically significant correlation with the pain intensity (r = -0.691, p =0.012). Conclusion This study indicated that the muscular electrical activity of upper extremity had a correlation with the presence of HSP, and the blood perfusion seemed to be no such correlation. The findings of the study suggested an alternative way to explore the mechanism and treatment of HSP.

Neuronal apoptosis is an important factor in the etiology of Alzheimer's disease (AD). Aerobic exercise (AE) enhances learning and memory, improves cognitive impairment, increases telomere binding protein expression, and decreases apoptosis regulators, but it remains unclear whether it can improve cognitive impairment caused by neuronal apoptosis in AD. Therefore, this study investigated whether an 8-week running table exercise intervention could reduce apoptosis and improve cognitive function in the hippocampal neurons of AD model mice. After the exercise intervention, we evaluated the learning memory ability (positioning, navigation, and spatial search) of mice using a Morris water labyrinth, Nissl staining, immunohistochemistry, and protein application to detect hippocampal PI3K/Akt/GSK-3β signaling pathway protein and hippocampal neuronal cell apoptosis protein B cell lymphoma 2 (Bcl-2) and apoptosis-promoting protein bcl-2-related X (Bax) protein expression. The results showed that aerobic exercise improved the location and spatial exploration ability of mice, increased the number of PI3K- and p-Akt-positive cells, increased the expression of PI3K, p-Akt, and bcl-2 proteins, decreased the expression of GSK-3β and Bax proteins, and increased the bcl-2/Bax ratio of mice. The results suggest that aerobic exercise can reduce apoptosis and improve cognitive function in AD mice. The molecular mechanism may involve activation of the PI3K/Akt/GSK-3β signaling pathway.

Objective To explore the efficacy of high-frequency repetitive transcranial magnetic stimulation (rTMS) of the swallowing motor area of the cerebellum in patients with dysphagia after brainstem stroke. Methods A total of 36 patients with dysphagia after brainstem stroke were recruited and divided into 3 groups. Before stimulation, single-pulse transcranial magnetic stimulation (TMS) was used to determine the swallowing dominant cerebellar hemisphere and the representation of the mylohyoid muscle. The three groups of patients received bilateral cerebellar sham stimulation, dominant cerebellar rTMS + contralateral sham stimulation, or bilateral cerebellar rTMS. The stimulus plan for each side was 10 Hz, 80% resting movement threshold (rMT), 250 pulses, 1 s per stimulus, and 9 s intervals. Sham rTMS was performed with the coil held at 90° to the scalp. The changes in the motor evoked potential (MEP) amplitude and the clinical swallowing function scales of the patients after stimulation were compared among the three groups. Results 34 patients were finally included for statistical analysis. The scores of penetration aspiration scale (PAS) and functional dysphagia scale (FDS) of the patients after 2 weeks of rTMS in the unilateral stimulation group and bilateral stimulation group were better than that in the sham stimulation group, and there was no significant difference between the two groups. The increase in the MEP amplitude of the cerebral hemisphere in the bilateral stimulation group was higher than that in the other two groups, and the increase in the MEP amplitude in the unilateral stimulation group was higher than that in sham stimulation group. There was no correlation between the improvement in patients' clinical swallowing function (PAS scores and FDS scores) and the increase in MEP amplitude in either the unilateral stimulation group or the bilateral stimulation group. Conclusion High-frequency rTMS in the cerebellum can improve swallowing function in PSD patients and increase the excitability of the representation of swallowing in the bilateral cerebral hemispheres. Compared with unilateral cerebellar rTMS, bilateral stimulation increased the excitability of the cerebral swallowing cortex more significantly, but there was no significant difference in clinical swallowing function.

Low-intensity focused ultrasound (LIFU) is a potential noninvasive method to alleviate allodynia by modulating the central nervous system. However, the underlying analgesic mechanisms remain unexplored. Here, we assessed how LIFU at the anterior cingulate cortex (ACC) affects behavior response and central plasticity resulting from chronic constrictive injury (CCI). The safety of LIFU stimulation was assessed by hematoxylin and eosin (H&E) and Fluoro-Jade C (FJC) staining. A 21-day ultrasound exposure therapy was conducted from day 91 after CCI surgery in mice. We assessed the 50% mechanical withdrawal threshold (MWT50) using Von Frey filaments (VFFs). The expression levels of microtubule-associated protein 2 (MAP2), growth-associated protein 43 (GAP43), and tau were determined via western blotting (WB) and immunofluorescence (IF) staining to evaluate the central plasticity in ACC. The regions of ACC were activated effectively and safely by LIFU stimulation, which significantly increased the number of c-fos-positive cells (P < 0.05) with no bleeding, coagulative necrosis, and neuronal loss. Under chronic neuropathic pain- (CNP-) induced allodynia, MWT50 decreased significantly (P < 0.05), and overexpression of MAP2, GAP43, and tau was also observed. After 3 weeks of treatment, significant increases in MWT50 were found in the CCI+LIFU group compared with the CCI group (P < 0.05). WB and IF staining both demonstrated a significant reduction in the expression levels of MAP2, GAP43, and tau (P < 0.05). LIFU treatment on ACC can effectively attenuate CNP-evoked mechanical sensitivity to pain and reverse aberrant central plasticity.

Cerebral ischemia/reperfusion (I/R) injury is a complex pathophysiological process that can lead to neurological function damage and the formation of cerebral infarction. The p38 MAPK pathway has attracted considerable attention in cerebral I/R injury (IRI), but little research has been carried out on its direct role in vivo. In this study, to observe the effects of p38 MAPK endogenous inhibition on cerebral IRI, p38 heterozygous knockdown (p38KI/+) mice were used. We hypothesized that p38 signaling might be involved in I/R injury and neurological damage reduction and that neurological behavioral deficits improve when p38 MAPK is inhibited. First, we examined the neurological damage and neurological behavioral deficit effects of I/R injury in WT mice. Cerebral I/R injury was induced by the bilateral common carotid artery occlusion (BCCAO) method. The cerebral infarction area and volume were assessed and analyzed by 2,3,5-triphenyltetrazolium chloride (TTC) staining. p38 MAPK and caspase-3 were detected by western blotting. Neuronal apoptosis was measured using TUNEL staining. Neurological deficits were detected by behavioral testing. Furthermore, to assess whether these neuroprotective effects occurred when p38 MAPK was inhibited, p38 heterozygous knockdown (p38KI/+) mice were used. We found that p38 MAPK endogenous inhibition rescued hippocampal cell apoptosis, reduced ischemic penumbra, and improved neurological behavioral deficits. These findings showed that p38 MAPK endogenous inhibition had a neuroprotective effect on IRI and that p38 MAPK may be a potential therapeutic target for cerebral IRI.

Lumbar disc herniation (LDH) induced nerve compression syndromes have been a prevalent problem with complex neural mechanisms. Changes in distributed brain areas are involved in the occurrence and persistence of syndromes. The present study aimed to investigate the changes of brain functional network in LDH patients with chronic sciatica using graph theory analysis. A total of thirty LDH adults presenting L4 and/or L5 root (s) compression syndromes (LDH group) and thirty age-, sex-, BMI- and education-matched healthy control (HC group) were recruited for functional MRI scan. Whole-brain functional network was constructed for each participant using Pearson's correlation. Global and nodal properties were calculated and compared between two groups, including small-worldness index, clustering coefficient, characteristic path length, degree centrality (DC), betweenness centrality (BC) and nodal efficiency. Both LDH and HC groups showed small-world architecture in the functional network of brain. However, LDH group showed that nodal centralities (DC, BC and nodal efficiency) increased in opercular part of inferior frontal gyrus; and decreased in orbital part of inferior frontal gyrus, lingual cortex and inferior occipital gyrus. The DC and efficiency in the right inferior occipital gyrus were negatively related with the Oswestry Disability Index in LDH group. In conclusion, the LDH-related chronic sciatica syndromes may induce regional brain alterations involving self-referential, emotional responses and pain regulation functions. But the whole-brain small-world architecture was not significantly disturbed. It may provide new insights into LDH patients with radicular symptoms from new perspectives.

Background Postherpetic neuralgia (PHN) is the most common and severe complication after varicella-zoster infection, especially in elderly patients. PHN is always refractory to treatment. Both pulsed radiofrequency (PRF) and short-term spinal cord stimulation (stSCS) have been used as effective analgesia methods in clinic. However, which technique could provide better pain relief remains unknown. Objectives This study is aimed at evaluating the efficacy and safety of PRF and stSCS in elderly patients with PHN. Study Design. A prospective, randomized-controlled study. Setting. Department of Pain Management, the Second Affiliated Hospital of Guangzhou Medical University. Methods A total of 70 elderly patients with PHN were equally randomized to the PRF group or stSCS group. Patients in the PRF group received PRF treatment, while patients in the stSCS group received stSCS treatment. The primary outcome was the effective rate. The secondary outcomes included the Visual Analogue Scale (VAS), the 36-Item Short Form Health Survey Questionnaire (SF-36), and the pregabalin dosage. All outcomes were evaluated at baseline and at different postoperative time points. Results At 12 months after surgery, the effective rate reached 79.3% in stSCS group, while 42.1% in PRF group. The effective rate was significantly higher in the stSCS group than in the PRF group at 3, 6, and 12 months after surgery. VAS scores decreased significantly at each postoperative time point in both groups (P < 0.001). The VAS scores were significantly lower in the stSCS group than in the PRF group at 3, 6, and 12 months after surgery. SF-36 scores (bodily pain and the physical role) were significantly improved at each postoperative time point in both groups (P < 0.001). The SF-36 scores were significantly higher in the stSCS group than in the PRF group at some postoperative time points. The pregabalin dosage was significantly lower in the stSCS group than in the PRF group at 3, 6, and 12 months after surgery. Limitations. A single-center study with a relatively small sample size. Conclusions Both PRF and stSCS are effective and safe neuromodulation techniques for elderly patients with PHN. However, stSCS could provide better and longer-lasting analgesic effect compared to PRF.

Objective The aim of our study is to examine the effects of neonatal tactile stimulations on the brain structures that previously defined as the focus of epilepsy in the Wistar-Albino-Glaxo from Rijswijk (WAG/Rij) rat brain with genetic absence epilepsy. Methods In the present research, morphology and density of dendritic spines were analyzed in layer V pyramidal neurons of the somatosensory cortex (SoCx) of WAG/Rij rats (nonstimulated control, tactile-stimulated, and maternal separated rats) and healthy Wistar (nonepileptic) rats. To achieve this, a Golgi-Cox method was used. Results Dendritic spine number in layer V of the SoCx has been detected significantly higher in adult WAG/Rij rats at postnatal day 150 in comparison to nonepileptic adult control Wistar rats (p < 0.001). Moreover, quantitative analyses of dendrite structure in adult WAG/Rij rats showed a decrease in dendrite spine density of pyramidal neurons of SoCx which occurred in early neonatal exposure to maternal separation (MS) and tactile stimulation (TS) (p < 0.001). Conclusions Our findings provide the first evidence that tactile stimulations during the early postnatal period have a long-term impact on dendrite structure in WAG/Rij rat's brain and demonstrate that neonatal tactile stimulation can regulate dendritic spines in layer V in pyramidal neurons of SoCx in epileptic brains.

Recently, we showed that DNA double-strand breaks (DSBs) are increased by the Aβ42-amyloid peptide and decreased by all-trans retinoic acid (RA) in SH-SY5Y cells and C57BL/6J mice. The present work was aimed at investigating DSBs in cells and murine models of Alzheimer's disease carrying the preseniline-1 (PS1) P117L mutation. We observed that DSBs could hardly decrease following RA treatment in the mutated cells compared to the wild-type cells. The activation of the amyloidogenic pathway is proposed in the former case as Aβ42- and RA-dependent DSBs changes were reproduced by an α-secretase and a γ-secretase inhibitions, respectively. Unexpectedly, the PS1 P117L cells showed lower DSB levels than the controls. As the DSB repair proteins Tip60 and Fe65 were less expressed in the mutated cell nuclei, they do not appear to contribute to this difference. On the contrary, full-length BRCA1 and BARD1 proteins were significantly increased in the chromatin compartment of the mutated cells, suggesting that they decrease DSBs in the pathological situation. These Western blot data were corroborated by in situ proximity ligation assays: the numbers of BRCA1-BARD1, not of Fe65-Tip60 heterodimers, were increased only in the mutated cell nuclei. RA also enhanced the expression of BARD1 and of the 90 kDa BRCA1 isoform. The increased BRCA1 expression in the mutated cells can be related to the enhanced difficulty to inhibit this pathway by BRCA1 siRNA in these cells. Overall, our study suggests that at earlier stages of the disease, similarly to PS1 P117L cells, a compensatory mechanism exists that decreases DSB levels via an activation of the BRCA1/BARD1 pathway. This supports the importance of this pathway in neuroprotection against Alzheimer's disease.