High bioavailable testosterone levels increase the incidence of isolated REM sleep behavior disorder: Results from multivariable and network Mendelian randomization analysis.

OBJECTIVES: To explore the causal relationships between sex hormone levels and incidence of isolated REM sleep behavior disorder (iRBD). METHODS: In our study, we utilized Genome-Wide Association Studies (GWAS) data for iRBD, including 9447 samples with 1061 cases of iRBD provided by the International RBD Study Group. Initially, we conducted a two-sample univariate MR analysis to explore the impact of sex hormone-related indicators on iRBD. This was followed by the application of multivariable MR methods to adjust for other hormone levels and potential confounders. Finally, we undertook a network MR analysis, employing brain structure Magnetic Resonance Imaging (MRI) characteristics as potential mediators, to examine whether sex hormones could indirectly influence the incidence of iRBD by affecting brain structure. RESULTS: Bioavailable testosterone (BioT) is an independent risk factor for iRBD (Odds Ratio [95 % Confidence Interval] = 2.437 [1.308, 4.539], P = 0.005, corrected-P = 0.020), a finding that remained consistent even after adjusting for other sex hormone levels and potential confounders. Additionally, BioT appears to indirectly increase the risk of iRBD by reducing axial diffusivity and increasing the orientation dispersion index in the left cingulum and cingulate gyrus. CONCLUSIONS: Our research reveals that elevated levels of BioT contribute to the development of iRBD. However, the specific impact of BioT on different sexes remains unclear. Furthermore, high BioT may indirectly lead to iRBD by impairing normal pathways in the left cingulum and cingulate gyrus and fostering abnormal pathway formation.

Activating PV-positive neurons in ventral thalamic reticular nucleus reduces pain sensitivity in mice.

Previous studies have demonstrated that thalamic reticular nucleus (TRN) and the sub-nuclei play important roles in pain sensation. Our previous findings showed that activating parvalbumin-positive (PV+) neurons in dorsal sector of TRN (dTRN) could reduce the pain threshold and consequently increase the pain sensitivity of mice. Recent studies have shown that activation of GABAergic projection of TRN to ventrobasal thalamus (VB) alleviated pathological pain. GABAergic neurons in TRN are mainly PV+ neurons. However, the exact roles of ventral TRN (vTRN) PV+ neurons in pain sensation remain unclear. In this study, the designer receptors exclusively activated by designer drugs (DREADD) method was used to activate the PV+ neurons in vTRN of PV-Cre transgenic mice, and the mechanical threshold and thermal latency were measured to investigate the regulatory effects of vTRN on pain sensitivity in mice. Thereafter, PV-Cre transgenic mice, conditional anterograde axonal tract tracing, and immunohistochemistry were used to investigate the distribution of PV+ neurons fibers in vTRN. The results showed that the activation of PV+ neurons in vTRN increased the mechanical threshold and thermal latency, which indicated reduction of pain sensitivity. The fibers of these neurons mainly projected to ventral posterolateral thalamic nucleus (VPL), ventral posteromedial thalamic nucleus (VPM), ventrolateral thalamic nucleus (VL), centrolateral thalamic nucleus (CL) and various other brain regions. These findings indicated that activation of PV+ neurons in the vTRN decreased pain sensitivity in mice, which provided additional evidence on the mechanisms of PV+ neurons of TRN in regulating neuralgia.

Differential efferent projections of GABAergic neurons in the basolateral and central nucleus of amygdala in mice.

The Basolateral amygdala (BLA) and central nucleus of the amygdala (CEA) have been proved to play a key role in the control of anxiety, stress and fear-related behaviors. BLA is a cortex-like complex consisting of both γ-aminobutyric acidergic (GABAergic) interneurons and glutamatergic neurons. The CEA is a striatum-like output of the amygdala, consisting almost exclusively of GABAergic medium spiny neurons. In this study, we explored the morphology and axonal projections of the GABAergic neurons in BLA and CEA, using conditional anterograde axonal tracing, immunohistochemistry, and VGAT-Cre transgenic mice to further understand their functional roles. We found that the axonal projections of GABAergic neurons from the BLA mainly distributed to the forebrain, whilst GABAergic neurons from the CEA distributed to the forebrain, midbrain and brainstem. In the forebrain, the axonal projections of GABAergic neurons from the BLA projected to the anterior olfactory nucleus, the cerebral cortex, the septum, the striatum, the thalamus, the amygdala and the hippocampus. The axonal projections of GABAergic neurons from the CEA distributed to the nuclei of the prefrontal cortex, the bed nucleus of the stria terminalis, the hypothalamus and the thalamus. In the midbrain and brainstem, the axonal projections of GABAergic neurons from the CEA were found in the periaqueductal gray, the substantia nigra, and the locus coeruleus. These data reveal the neuroanatomical basis for exploring the function of GABAergic neurons in the BLA and CEA, particularly during the processing of fear-related behavior.

DJ-1 Inhibits α-Synuclein Aggregation by Regulating Chaperone-Mediated Autophagy.

α-Synuclein misfolding and aggregation play an important role in the pathogenesis of Parkinson's disease (PD). Loss of function and mutation of the PARK7/DJ-1 gene cause early-onset familial PD. DJ-1 can inhibit α-synuclein aggregation, and may function at an early step in the aggregation process. Soluble wild-type (WT) α-synuclein is mainly degraded by chaperone-mediated autophagy (CMA), and impairment of CMA is closely related to the pathogenesis of PD. Here, we investigated whether DJ-1 could reduce α-synuclein accumulation and aggregation by CMA. DJ-1 knockout mice and DJ-1 siRNA knockdown SH-SY5Y cells were used to investigate the potential mechanisms underlying the relationship between DJ-1 deficiency and α-synuclein aggregation. First, we confirmed that DJ-1 deficiency increased the accumulation and aggregation of α-synuclein in both SH-SY5Y cells and PD animal models, and overexpression of DJ-1 in vitro effectively decreased α-synuclein levels. α-Synuclein overexpression activated CMA by elevating the levels of lysosome-associated membrane protein type-2A (LAMP2A), but DJ-1 deficiency suppressed upregulation of LAMP2A. DJ-1 deficiency downregulated the level of lysosomal 70 kDa heat-shock cognate protein (HSC70) but not the levels of that in homogenates. Further studies showed that DJ-1 deficiency accelerated the degradation of LAMP2A in lysosomes, leading to the aggregation of α-synuclein. Our study suggests that DJ-1 deficiency aggravates α-synuclein aggregation by inhibiting the activation of CMA and provides further evidence of the molecular interaction between PD-related proteins via the CMA pathway.

Meta-analysis on the prevalence of REM sleep behavior disorder symptoms in Parkinson's disease.

BACKGROUND: Our study was aimed to evaluate the risk of a selected non-motor symptom, namely rapid eye movement behavior disorder (RBD) symptoms, among patients with newly diagnosed Parkinson disease compared with health controls. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for meta-analysis and Cochrane manual were followed. Studies on RBD symptoms and PD were searched using PubMed, Embase, Web of Science and Cochrane library databases. All studies were published before August 3rd, 2016. Eligible studies were those that reported a prevalence of RBD symptoms among newly diagnosed PD and health control. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated by random-effected models. Heterogeneity across studies was assessed using Cochran Q and I2 statistics. RESULTS: We identified eight studies including 2462 PD patients and 3818 health controls. The overall prevalence of RBD symptoms in PD was 582/2462 (23.6%) compared to 131/3818 (3.4%) in control. And the pooled OR was 5.69 (95% CI 3.60 to 9.00; p = 0.001) with a moderate heterogeneity I2 = 70.5%. After excluding the study of low weight, the overall polled OR was 3.54 (95% CI 2.77 to 4.52; p < 0.00001) and the heterogeneity was completely eliminated (I2 = 0%). CONCLUSIONS: RBD symptoms are common non-motor symptoms of PD, and people with PD are at a higher risk of developing RBD. Further studies are needed to understand the natural history of RBD symptoms in PD and its etiological and clinical implications.

[Overexpression of ß(1)-adrenoceptor can not protect rat cardiomyocytes from injury induced by isoprenaline].

The purpose of this study was to investigate the effect of the overexpression of ß(1)-adrenoceptor (ß(1)-AR) on the contractile function and cell survival of rat cardiomyocytes injured by isoprenaline (ISO). The rat cardiomyocytes were isolated using the collagenase perfusion method and then transfected with ß(1)-AR gene using adenoviruses vector. Four hours after the infection, the rat cardiomyocytes were treated with ISO for 24 h to imitate the high catecholamine levels of chronic heart failure. Western blot was performed to measure the protein expression of ß(1)-AR. The percentages of rod cells were measured to test cell survival. Video-based edge-detection system was used to measure the contractile function of the cardiomyocytes. The results indicated that the expression of ß(1)-AR in ß(1)-AR-transfected cardiomyocytes was significantly increased compared with that in control group (P<0.01). Meanwhile, ß(1)-AR transfection also increased ß(1)-AR protein levels in ISO-injured cardiomyocytes. The cardiomyocyte survival was significantly decreased in ISO group compared with that in control group. ß(1)-AR-transfection alone had no effect on cardiomyocyte survival in ß(1)-AR group, but it further decreased cardiomyocyte survival in ß(1)-AR+ISO group. Contractile amplitudes of ISO-injured cardiomyocytes were significantly decreased regardless of whether they were transfected with ß(1)-AR or not, although ß(1)-AR-transfected cardiomyocytes showed significantly increased contractile function compared with control group (P<0.05). These results suggest that the overexpression of ß(1)-AR has no significant protective effect on rat cardiomyocytes injured by ISO.