Structural and Lipidomic Alterations of Striatal Myelin in 16p11.2 Deletion Mouse Model of Autism Spectrum Disorder

Myelin abnormalities have been observed in autism spectrum disorder (ASD). In this study, we seek to discover myelin-related changes in the striatum, a key brain region responsible for core ASD features, using the 16p11.2 deletion (16p11.2±) mouse model of ASD. We found downregulated expression of multiple myelin genes and decreased myelin thickness in the striatum of 16p11.2± mice versus wild type controls. Moreover, given that myelin is the main reservoir of brain lipids and that increasing evidence has linked dysregulation of lipid metabolism to ASD, we performed lipidomic analysis and discovered decreased levels of certain species of sphingomyelin, hexosyl ceramide and their common precursor, ceramide, in 16p11.2± striatum, all of which are major myelin components. We further identified lack of ceramide synthase 2 as the possible reason behind the decrease in these lipid species. Taken together, our data suggest a role for myelin and myelin lipids in ASD development

Salmon Calcitonin Exerts an Antidepressant Effect by Activating Amylin Receptors

Depressive disorder is defined as a psychiatric disease characterized by the core symptoms of anhedonia and learned helplessness. Currently, the treatment of depression still calls for medications with high effectiveness, rapid action, and few side effects, although many drugs, including fluoxetine and ketamine, have been approved for clinical usage by the Food and Drug Administration (FDA). In this study, we focused on calcitonin as an amylin receptor polypeptide, of which the antidepressant effect has not been reported, even if calcitonin gene-related peptides have been previously demonstrated to improve depressive-like behaviors in rodents. Here, the antidepressant potential of salmon calcitonin (sCT) was first evaluated in a chronic restraint stress (CRS) mouse model of depression. We observed that the immobility duration in CRS mice was significantly increased during the tail suspension test and forced swimming test. Furthermore, a single administration of sCT was found to successfully rescue depressive-like behaviors in CRS mice. Lastly, AC187 as a potent amylin receptor antagonist was applied to investigate the roles of amylin receptors in depression. We found that AC187 significantly eliminated the antidepressant effects of sCT. Taken together, our data revealed that sCT could ameliorate a depressive-like phenotype probably via the amylin signaling pathway. sCT should be considered as a potential therapeutic candidate for depressive disorder in the future

G protein-coupled receptor 158 modulates sensitivity to the sedative-hypnotic effect of ethanol in male mice

BACKGROUND: Sensitivity to ethanol is used to assess a predisposition to recover from unconsciousness induced by excessive ethanol. The role of G protein-coupled receptor 158 (GPR158) in modulating sensitivity to the sedative-hypnotic effect of ethanol has not been investigated. METHODS: Loss of righting reflex (LORR) is a behavioral feature to indicate a state of hypnosis in rodents. In this study, Gpr158-/- mice and wild-type (WT) littermates (n = 8/genotype) were tested with the paradigms of LORR induced by a dose of 3.5 g/kg ethanol, open-field test (OFT) and blood ethanol concentration measurement. The OFT was used to examine the role of GPR158 in the ethanol effect on motor activity in Gpr158-/- mice (n = 6/genotype). Furthermore, CamK2A-Cre;Gpr158fl/fl (n = 9) and Vgat-Cre;Gpr158fl/fl mice (n = 10) went through LORR test and OFT compared to the controls (n= 9 and 8, respectively). RESULTS: Gpr158 deficiency led to a prolonged LORR duration by 110.6% (t14 = -5.241, p = 0.0001), without altering spontaneous activity (t14 = -0.718, p = 0.485) or ethanol metabolism (F1, 8 = 0.259, p = 0.625). Gpr158 knockout did not affect the ethanol effect on locomotion (F1, 10 = 0.262, p = 0.62). Furthermore, LORR duration became longer in the conditional knockouts of Gpr158 within calcium/calmodulin dependent protein kinase II alpha-positive (CamK2A+ ) neurons by 69% (t16 = -2.914, p = 0.01) and vesicular GABA transporter-positive (Vgat+ ) neurons by 92% (t9.802 = -2.519, p = 0.023), respectively, while locomotion was not altered in Camk2A-Cre;Gpr158fl/fl (t16 = 0.49, p = 0.631) or Vgat-Cre;Gpr158fl/fl mice (t16 = 0.035, p = 0.972). CONCLUSIONS: This study reveals a critical role of neuronal GPR158 in shaping sensitivity to the sedative-hypnotic effect of ethanol, suggesting that GPR158 may be a potential target for treating alcohol use disorder

Association of earlier age at menopause with risk of incident dementia, brain structural indices and the potential mediators: a prospective community-based cohort studyResearch in context

Summary: Background: To date, there is no homogeneous evidence of whether earlier age at menopause is associated with incident dementia. In addition, the underlying mechanism and driven mediators are largely unknown. We aimed to fill these knowledge gaps. Methods: This community-based cohort study included 154,549 postmenopausal women without dementia at enrolment (between 2006 and 2010) from the UK Biobank who were followed up until June 2021. We followed up until June 2021. Age at menopause was entered as a categorical variable (<40, 40–49, and ≥50 years) with ≥50 years taken as a reference. The primary outcome was all-cause dementia in a time-to-event analysis and the secondary outcomes included Alzheimer's disease, vascular dementia, and other types of dementia. In addition, we investigated the association between magnetic resonance (MR) brain structure indices with earlier menopause, and explored the potential underlying driven mediators on the relationship between earlier menopause and dementia. Findings: 2266 (1.47%) dementia cases were observed over a median follow-up period of 12.3 years. After adjusting for confounders, women with earlier menopause showed a higher risk of all-cause dementia compared with those ≥50 years (adjusted-HRs [95% CIs]: 1.21 [1.09–1.34] and 1.71 [1.38–2.11] in the 40–49 years and <40 years groups, respectively; P for trend <0.001). No significant interactions between earlier menopause and polygenic risk score, cardiometabolic factors, type of menopause, or hormone-replacement therapy strata were found. Earlier menopause was negatively associated with brain MR global and regional grey matter indices, and positively associated with white matter hyperintensity. The relationship between earlier menopause and dementia was partially mediated by menopause-related comorbidities including sleep disturbance, mental health disorder, frailty, chronic pain, and metabolic syndrome, with the proportion (95% CI) of mediation effect being 3.35% (2.18–5.40), 1.38% (1.05–3.20), 5.23% (3.12–7.83), 3.64% (2.88–5.62) and 3.01% (2.29–4.40), respectively. Multiple mediator analysis showed a combined effect being 13.21% (11.11–18.20). Interpretation: Earlier age at menopause was associated with risk of incident dementia and deteriorating brain health. Further studies are warranted to clarify the underlying mechanisms by which earlier age at menopause is linked to an increased risk of dementia, and to determine public health strategies to attenuate this association. Funding: National Natural Science Foundation of China, the Science and Technology Program of Guangzhou, the Key Area Research and Development Program of Guangdong Province, the China Postdoctoral Science Foundation, and the Guangdong Basic and Applied Basic Research Foundation