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The high comorbidity between obesity and mental disorders, such as depression and anxiety, often exacerbates metabolic and neurological symptoms significantly. However, neural mechanisms that underlie reciprocal control of feeding and mental states are largely elusive. Here we report that melanocortin 4 receptor (MC4R) neurons located in the dorsal bed nucleus of the stria terminus (dBNST) engage in the regulation of mentally associated weight gain by receiving GABAergic projections from hypothalamic AgRP neurons onto α5-containing GABAAreceptors and serotonergic afferents onto 5-HT3receptors. Chronic treatment with a high-fat diet (HFD) significantly blunts the hyperexcitability of AgRP neurons in response to not only hunger but also anxiety and depression-like stimuli. Such HFD-mediated desensitization reduces GABAergic outputs from AgRP neurons to downstream MC4RdBNSTneurons, resulting in severe mental dysregulation. Genetic enhancement of the GABAAR-α5 or suppression of the 5-HT3R within the MC4RdBNSTneurons not only abolishes HFD-induced anxiety and depression but also robustly reduces body weight by suppression of food intake. To gain further translational insights, we revealed that combined treatment of zonisamide (enhancing the GABAAR-α5 signaling) and granisetron (a selective 5-HT3R antagonist) alleviates mental dysfunction and yields a robust reversal of diet-induced obesity by reducing total calorie intake and altering food preference towards a healthy low-fat diet. Our results unveil a neural mechanism for reciprocal control of appetite and mental states, which culminates in a novel zonisamide-granisetron cocktail therapy for potential tackling the psychosis-obesity comorbidity.

Cerebellar abnormalities, particularly in Right Crus I (RCrusI), are consistently reported in autism spectrum disorders (ASD). Although RCrusI is functionally connected with ASD-implicated circuits, the contribution of RCrusI dysfunction to ASD remains unclear. Here, neuromodulation of RCrusI in neurotypical humans resulted in altered functional connectivity with the inferior parietal lobule, and children with ASD showed atypical functional connectivity in this circuit. Atypical RCrusI–inferior parietal lobule structural connectivity was also evident in the Purkinje neuron (PN) TscI ASD mouse model. Additionally, chemogenetically mediated inhibition of RCrusI PN activity in mice was sufficient to generate ASD-related social, repetitive, and restricted behaviors, while stimulation of RCrusI PNs rescued social impairment in the PN TscI ASD mouse model. Together, these studies reveal important roles for RCrusI in ASD-related behaviors. Further, the rescue of social behaviors in an ASD mouse model suggests that investigation of the therapeutic potential of cerebellar neuromodulation in ASD may be warranted.

Anxiety symptoms occur in a large portion of Alzheimer's disease (AD) patients. ApolipoproteinE-4 (ApoE ε4 allele), a risk factor for AD, has been recognized as an important contributor to psychiatric disorders. In the present study, we aimed to investigate the corticosterone level in relation to anxiety-like behavior changes in transgenic male mice with different glial fibrillary acidic protein (GFAP)-ApoE isoforms. GFAP-ApoE4 transgenic mice aged 3 months showed higher anxiety-like behavior in open field, light-dark box and elevated plus maze tasks compared with that of age-matched GFAP-ApoE3 mice. However, corticotropin releasing factor levels in the hypothalamus and plasma corticosterone secretion were similar in GFAP-ApoE3 and GFAP-ApoE4 transgenic male mice. Additionally, increased expression of the mineralocorticoid receptor (MR) and unchanged expression of the glucocorticoid receptor were observed in the hypothalamus of GFAP-ApoE4 mice. However, no significant differences were found in the expression levels of the MR in GFAP-ApoE3 and GFAP-ApoE4 mice at postnatal day 2. In conclusion, we found that MR upregulation rather than corticosterone level changes in the early stage of adulthood was associated with the higher anxiety-like level measured in GFAP-ApoE4 mice.

Adjacent segment degeneration (ASD) is known to occur after anterior cervical arthrodesis. However, it is not known whether cervical canal stenosis enhances the risk of ASD. The purpose of this study was to explore whether congenital stenosis could be used as a predictor of ASD after anterior cervical decompression and fusion (ACDF). We enrolled 141 patients who had undergone ACDF for cervical myelopathy and/or radiculopathy, and had at least 6 years of follow-up. In standard radiographs of cervical spine in lateral view, bony congenital stenosis was evaluated and all patients were divided into two groups: stenosis (n = 63) and non-stenosis (n = 78). Radiographic ASD was assessed according to the criteria of Kellgren and Lawrence and correlated with symptomatic ASD. Clinical and radiological parameters were compared between the groups. The primary outcome was the rate of radiographic ASD after initial ACDF. The incidence of symptomatic ASD was assessed by Kaplan–Meier method. Radiographic ASD and symptomatic ASD developed in 46.8 % and 18.4 % of all patients, respectively. There was a significant association between congenital stenosis and radiographic ASD. The area under the receiver operating characteristic curve of preoperative anteroposterior (AP) diameter of cervical canal for predicting radiographic ASD was 0.756. 13.0 mm was the cutoff value of preoperative AP diameter of cervical canal predicting radiographic ASD. Kaplan–Meier analysis predicted a disease-free survival rate of symptomatic ASD in 97.2 % of patients at 5 years and 78.0 % at 10 years after ACDF. There was no significant difference in survival rates of the adjacent segment between the two groups via log-rank analysis (P = 0.102). Congenital stenosis can increase the rate of radiographic ASD after initial ACDF. The cutoff value of 13.0 mm for preoperative AP diameter of cervical canal had the highest validity for predicting radiographic ASD.

Summary Objective To investigate the association between smoking and the risk for knee osteoarthritis (OA). Design Cohort, case–control, and cross-sectional studies were obtained from the Medline, Embase, and Web of Science databases. Estimates were calculated using a random-effects model. Subgroup analyses and meta-regression models were performed to investigate potential sources of heterogeneity. We further analyzed the dose–response relationship between cigarette consumption and risk of knee OA. Results Thirty-eight independent observational studies that included 481,744 participants were analyzed. Those who had ever smoked had a significantly decreased risk of developing knee OA relative to those who had never smoked (RR = 0.80; 95% CI 0.73–0.88). This was unaffected by study design, and the pooled relative risks (RRs) were 0.79 (95% CI, 0.65–0.96), 0.71 (95% CI, 0.61–0.84) and 0.83 (95% CI, 0.73–0.94) for cohort, case–control, and cross-sectional studies, respectively. Analysis of subgroups stratified by gender reduced the heterogeneity from moderate to low in both males and females. The lower risk for developing knee OA was more apparent in male smokers (RR = 0.69; 95% CI 0.58–0.80) than female smokers (RR = 0.89; 95% CI 0.77–1.02) and dose–response analysis showed a linear decrease in knee OA with increased cigarette consumption. Conclusions We found an inverse association between cigarette smoking and risk of knee OA, irrespective of study design. This association was more apparent in males. However, we have not demonstrated a causal relationship between smoking and OA, and further investigations are needed.

A central challenge to the development of protein-based therapeutics is the inefficiency of delivery of protein cargo across the mammalian cell membrane, including escape from endosomes. Here we report that combining bioreducible lipid nanoparticles with negatively supercharged Cre recombinase or anionic Cas9:single-guide (sg)RNA complexes drives the electrostatic assembly of nanoparticles that mediate potent protein delivery and genome editing. These bioreducible lipids efficiently deliver protein cargo into cells, facilitate the escape of protein from endosomes in response to the reductive intracellular environment, and direct protein to its intracellular target sites. The delivery of supercharged Cre protein and Cas9:sgRNA complexed with bioreducible lipids into cultured human cells enables gene recombination and genome editing with efficiencies greater than 70%. In addition, we demonstrate that these lipids are effective for functional protein delivery into mouse brain for gene recombination in vivo. Therefore, the integration of this bioreducible lipid platform with protein engineering has the potential to advance the therapeutic relevance of protein-based genome editing.

OBJECTIVE Letrozole, a next-generation aromatase inhibitor, has become a favored drug for the treatment of breast cancer in postmenopausal women. Although letrozole is generally well tolerated, its adverse effects on the central nervous system have been reported. The present study aimed to assess the behavioural outcomes of letrozole administration in mice to determine its side effects. METHODS C57BL/6J female ovariectomized mice received administration of letrozole (2.5 mg/kg per day) or vehicle by gavage for 3 weeks. Behavioural tasks were used to assess anxiety, depression, as well as learning and memory in mice. RESULTS Letrozole-treated mice showed an increased latency to enter the inner area of the chamber on the third day of the open field test, and traveled a shorter distance in the open arms of the elevated plus maze. No significant difference was found in the light-dark box or forced swimming task between letrozole-treated and vehicle-treated mice. Besides, letrozole did not change the spontaneous alternation behaviour of mice in the Y-maze. In the Morris water maze, mice administered with letrozole exhibited an improvement in spatial learning and memory compared with the vehicle-treated mice. CONCLUSION Our results indicate that the inhibition of oestrogen biosynthesis results in mild anxious behaviour, which may be a consideration in the treatment of breast cancer in postmenopausal women using aromatase inhibitors.

The association between intramedullary increased signal intensity (ISI) on T2-weighted magnetic resonance imaging and surgical outcome in cervical spondylotic myelopathy (CSM) remains controversial. The purpose of this study is to assess the impact of quantitative signal change ratio (SCR) on the surgical outcome for CSM. The prospective study included 108 consecutive patients who underwent surgical treatment for CSM. The Japanese Orthopaedic Association (JOA) score and recovery rate were used to evaluate clinical outcomes. JOA recovery rate less than 50 % was defined as a poor clinical result. The SCR was defined as the signal intensity at the level of ISI or severely compressed cord (in cases with no ISI) divided by the signal intensity at the C7–T1 disc level. Age, sex, body mass index, duration of symptoms, surgical technique, preoperative JOA score, levels of compression, preoperative SCR, preoperative C2–7 angle, preoperative C2–7 range of motion were assessed. Forty patients (37.0 %) had a recovery rate of less than 50 %. Multivariate logistic regression analysis revealed that a higher preoperative SCR and a longer duration of symptoms were significant risk factors for a poor clinical outcome. Receiver operating characteristic (ROC) curve analysis showed that the optimal preoperative SCR cutoff value as a predictor of poor clinical result was 1.46. The area under the ROC curve of preoperative SCR for predicting a poor surgical outcome was 0.844. Preoperative SCR significantly reflected the surgical outcome in patients with CSM. Patients with SCR greater than or equal to 1.46 can experience poor recovery after surgery.

The apolipoprotein E (ApoE) ɛ4 allele (ApoE4) is an important genetic risk factor for the pathogenesis of Alzheimer's disease (AD). In addition to genetic factors, environmental factors such as stress may play a critical role in AD pathogenesis. This study was designed to investigate the anxiety-like behavioral and cognitive changes in different human glial fibrillary acidic protein (GFAP)-ApoE transgenic adult male mice under chronic stress conditions. On the open field test, anxiety-like behavior was increased in the non-stressed GFAP-ApoE4 transgenic mice relative to the corresponding GFAP-ApoE3 (ApoE ɛ3 allele) mice. Anxiety-like behavior was increased in the stressed GFAP-ApoE3 mice relative to non-stressed GFAP-ApoE3 mice, but was unexpectedly decreased in the stressed GFAP-ApoE4 mice relative to non-stressed GFAP-ApoE4 mice. On the novel object recognition task, both GFAP-ApoE4 and GFAP-ApoE3 mice exhibited long-term non-spatial memory impairment after chronic stress. Interestingly, short-term non-spatial memory impairment (based on the novel object recognition task) was observed only in the stressed GFAP-ApoE4 male mice relative to non-stressed GFAP-ApoE4 transgenic mice. In addition, short-term spatial memory impairment was observed in the stressed GFAP-ApoE3 transgenic male mice relative to non-stressed GFAP-ApoE3 transgenic male mice; however, short-term spatial memory performance of GFAP-ApoE4 transgenic male mice was not reduced compared to non-stressed control mice based on the Y-maze task. In conclusion, our findings suggested that chronic stress affects anxiety-like behavior and spatial and non-spatial memory in GFAP-ApoE transgenic mice in an ApoE isoform-dependent manner.

Elderly females, particularly those carrying the apolipoprotein E (ApoE)-e4 allele, have a higher risk of developing Alzheimer's disease (AD). However, the underlying mechanism for this increased susceptibility remains unclear. In this study, we investigated the effects of the ApoE genotype and gender on the proteome of synaptosomes. We isolated synaptosomes and used label-free quantitative proteomics, to report, for the first time, that the synaptosomal proteomic profiles in the cortex of female human-ApoE4 mice exhibited significantly reduced expression of proteins related to energy metabolism, which was accompanied by increased levels of oxidative stress. In addition, we also first demonstrated that the proteomic response in synaptic termini was more susceptible than that in the soma to the adverse effects induced by genders and genotypes. This suggests that synaptic mitochondria might be 'older' than mitochondria in the soma of neurons; therefore, they might contain increased cumulative damage from oxidative stress. Furthermore, female human-ApoE4 mice had much lower oestrogen levels in the cortex and treatment with oestrogen protected ApoE3 stable transfected C6 neurons from oxidative stress. Overall, this study reveals complex ApoE- and gender-dependent effects on synaptic function and also provides a basis for future studies of candidates based on specific pathways involved in the pathogenesis of AD. The lack of oestrogen-mediated protection regulated by the ApoE genotype led to synaptic mitochondrial dysfunction and increased oxidative stress, which might make older females more susceptible to AD.

Previous studies have demonstrated that apolipoprotein E (ApoE) genotype and melatonin are closely associated with Alzheimer's disease (AD). However, the relationship between ApoE genotype and melatonin remains unclear. Recently, we reported that cultured rat cortical astrocytes and glioma C6 cells synthesize melatonin. In the current study, we investigated the effect of ApoE genotype on melatonin biosynthesis. C6 cells with stable expression of ApoE isoforms (ApoE 2, 3 and 4) were established. A higher level of melatonin was demonstrated in cultured ApoE4-C6 cells than that in ApoE3-C6 cells. In addition, we found that N-acetyltransferase (NAT) protein level was up-regulated in ApoE4-C6 cells compared with ApoE3-C6 cells. Further study suggested that mRNA expression of monoamine oxidase A (MAOA) and monoamine oxidase B (MAOB) decreased in ApoE4-C6 cells. In conclusion, the increased melatonin level in ApoE4-C6 cells results from up-regulation of NAT expression, a key enzyme for melatonin synthesis, and down-regulation of MAOA and MAOB expression, the metabolic enzyme for its precursor serotonin.

Ages at natural menarche and menopause are influenced by several genetic factors. This study aimed to investigate the possible relationship between the apolipoprotein E (ApoE) genotype and the age at menarche and natural menopause in Chinese females. In the current study, 398 (elderly group, aged 47–80 years) and 825 (young group, aged 15–25 years) Chinese females were enrolled under informed content. Ages at natural menarche and menopause were obtained by questionnaires. ApoE genotypes were identified by restriction fragment length polymorphism analysis. In the elderly group, the number of pregnancies and live births and breastfeeding were associated with the age at menopause (P = 0.008, P = 0.002, and P = 0.023, respectively). One-way ANOVA analysis revealed that the ApoE genotype was significantly associated with age at natural menopause (ANM; P = 0.010). Compared with ApoE e3/3 carriers, ApoE e3/4 females showed a 1.8-year delay in ANM (P = 0.002). Single ApoE allele-positive/allele-negative analysis also showed that the age at menopause of ApoE e4 carriers was delayed compared with those who were not carriers (P = 0.023). In the young group, no statistical difference was found in the age of menarche between the carriers of ApoE e3/3 and e3/4. Single ApoE allele-positive/allele-negative analysis showed that the age at menarche in ApoE e4 carriers was slightly earlier than in those who were not carriers (P = 0.048). Meanwhile, univariate association analysis revealed that the ApoE genotypes were not significantly associated with the age at menarche using age as a covariate in the pooled group (young + elderly) (P = 0.143). We demonstrated that the ApoE genotype is significantly linked to the age at natural menopause.

The effect of SUMO on the promoter activity and mRNA expression of BACE gene was investigated to find the connection between sumoylation and APP processing.The BACE promoter activity was measured by reporter gene analysis and BACE mRNA level was investigated using real-time RT-PCR method.BACE gene promoter activity was inhibited by the over-expression of SUMO proteins and was blocked by disrupting the SP1 site. Endogenous BACE mRNA level was also negatively regulated by the induction of SUMO proteins. Using a specific inhitor of SP1, BACE promoter activity was coordinately inhibited.SUMO negatively regulates the BACE expression and SP1 is involved in the process.

Tau phosphorylation and hypoxia are both linked to the pathology of Alzheimer's disease. To find out the possible connection between hypoxia and tau phosphorylation, we performed this study to evaluate the level of phosphorylated tau under hypoxic or normal condition. We found in our study that hypoxia promoted the phosphorylation of tau protein via ERK pathway, which suggest hypoxia might be involved in the process of tau pathology.