- 作者列表："Ziskind D","Bennett A","Jawad A","Blum N
BACKGROUND AND OBJECTIVES:Guidelines suggest young children with autism spectrum disorder (ASD) receive intensive nonpharmacologic interventions. Additionally, associated symptoms may be treated with psychotropic medications. Actual intervention use by young children has not been well characterized. Our aim in this study was to describe interventions received by young children (3-6 years old) with ASD. The association with sociodemographic factors was also explored. METHODS:Data were analyzed from the Autism Speaks Autism Treatment Network (AS-ATN), a research registry of children with ASD from 17 sites in the United States and Canada. AS-ATN participants receive a diagnostic evaluation and treatment recommendations. Parents report intervention use at follow-up visits. At follow-up, 805 participants had data available about therapies received, and 613 had data available about medications received. RESULTS:The median total hours per week of therapy was 5.5 hours (interquartile range 2.0-15.0), and only 33.4% of participants were reported to be getting behaviorally based therapies. A univariate analysis and a multiple regression model predicting total therapy time showed that a diagnosis of ASD before enrollment in the AS-ATN was a significant predictor. Additionally, 16.3% of participants were on ≥1 psychotropic medication. A univariate analysis and a multiple logistic model predicting psychotropic medication use showed site region as a significant predictor. CONCLUSIONS:Relatively few young children with ASD are receiving behavioral therapies or total therapy hours at the recommended intensity. There is regional variability in psychotropic medication use. Further research is needed to improve access to evidence-based treatments for young children with ASD.
背景和目的: 指南建议患有自闭症谱系障碍 (ASD) 的幼儿接受强化的非药物干预。此外，相关症状可以用精神药物治疗。幼儿的实际干预使用尚未得到很好的表征。我们在本研究中的目的是描述患有 ASD 的幼儿 (3-6 岁) 接受的干预措施。还探讨了与社会人口学因素的相关性。 方法: 数据来自自闭症说话自闭症治疗网络 (AS-ATN)，这是一个来自美国和加拿大 17 个研究中心的 ASD 儿童研究登记处。AS-ATN 参与者接受诊断评估和治疗建议。家长在随访访视时报告干预使用情况。随访时，805 名参与者有接受治疗的数据，613 的参与者有接受药物治疗的数据。 结果: 每周治疗的总小时数中位数为 5.5 小时 (四分位距 2.0-15.0)，据报道只有 33.4% 的参与者接受了基于行为的治疗。单变量分析和预测总治疗时间的多元回归模型表明，在 AS-ATN 入组前诊断 ASD 是一个显著的预测因子。此外，16.3% 的参与者服用 ≥ 1 种精神药物。单变量分析和预测精神药物使用的多变量 logistic 模型显示站点区域是一个显著的预测因子。 结论: 在推荐强度下，接受行为治疗或总治疗时间相对较少的 ASD 幼儿。精神药物使用存在区域变异性。需要进一步的研究来改善 ASD 幼儿获得循证治疗的机会。
METHODS::The adipocyte-derived hormone adiponectin has a broad spectrum of functions beyond metabolic control. We previously reported that adiponectin acts in the brain to regulate depression-related behaviors. However, its underlying neural substrates have not been identified. Here we show that adiponectin receptor 1 (AdipoR1) is expressed in the dorsal raphe nucleus (DRN) and colocalized with tryptophan hydroxylase 2 (TPH2), a marker of serotonin (5-HT) neurons. Selective deletion of AdipoR1 in 5-HT neurons induced anhedonia in male mice, as indicated by reduced female urine sniffing time and saccharin preference, and behavioral despair in female mice and enhanced stress-induced decrease in sucrose preference in both sexes. The expression levels of TPH2 were downregulated with a concurrent reduction of 5-HT-immunoreactivity in the DRN and its two major projection regions, the hippocampus and medial prefrontal cortex (mPFC), in male but not female mice lacking AdipoR1 in 5-HT neurons. In addition, serotonin transporter (SERT) expression was upregulated in both DRN projection fields of male mice but only in the mPFC of female mice. These changes presumably lead to decreased 5-HT synthesis and/or increased 5-HT reuptake, thereby reducing 5-HT transmission. The augmented behavioral responses to the selective serotonin reuptake inhibitor fluoxetine but not desipramine, a selective norepinephrine reuptake inhibitor, observed in conditional knockout male mice supports deficient 5-HT transmission underlying depression-related phenotypes. Our results indicate that adiponectin acts on 5-HT neurons through AdipoR1 receptors to regulate depression-related behaviors in a sex-dependent manner.
METHODS::Multiple schizophrenia (SCZ) risk loci may be involved in gene co-regulation mechanisms, and analysis of coexpressed gene networks may help to clarify SCZ molecular basis. We have previously identified a dopamine D2 receptor (DRD2) coexpression module enriched for SCZ risk genes and associated with cognitive and neuroimaging phenotypes of SCZ, as well as with response to treatment with antipsychotics. Here we aimed to identify regulatory factors modulating this coexpression module and their relevance to SCZ. We performed motif enrichment analysis to identify transcription factor (TF) binding sites in human promoters of genes coexpressed with DRD2. Then, we measured transcript levels of a group of these genes in primary mouse cortical neurons in basal conditions and upon overexpression and knockdown of predicted TFs. Finally, we analyzed expression levels of these TFs in dorsolateral prefrontal cortex (DLPFC) of SCZ patients. Our in silico analysis revealed enrichment for NURR1 and ERR1 binding sites. In neuronal cultures, the expression of genes either relevant to SCZ risk (Drd2, Gatad2a, Slc28a1, Cnr1) or indexing coexpression in our module (Btg4, Chit1, Osr1, Gpld1) was significantly modified by gain and loss of Nurr1 and Err1. Postmortem DLPFC expression data analysis showed decreased expression levels of NURR1 and ERR1 in patients with SCZ. For NURR1 such decreased expression is associated with treatment with antipsychotics. Our results show that NURR1 and ERR1 modulate the transcription of DRD2 coexpression partners and support the hypothesis that NURR1 is involved in the response to SCZ treatment.SIGNIFICANCE STATEMENT In the present study, we provide in silico and experimental evidence for a role of the TFs NURR1 and ERR1 in modulating the expression pattern of genes coexpressed with DRD2 in human DLPFC. Notably, genetic variations in these genes is associated with SCZ risk and behavioral and neuroimaging phenotypes of the disease, as well as with response to treatment. Furthermore, this study presents novel findings on a possible interplay between D2 receptor-mediated dopamine signaling involved in treatment with antipsychotics and the transcriptional regulation mechanisms exerted by NURR1. Our results suggest that coexpression and co-regulation mechanisms may help to explain some of the complex biology of genetic associations with SCZ.
METHODS::Abnormal neurotransmission is central to schizophrenia (SZ). Alterations across multiple neurotransmitter systems in SZ suggest that this illness may be associated with dysregulation of core intracellular processes such as signaling pathways that underlie the regulation and integration of these systems. The AKT-mTOR signaling cascade has been implicated in SZ by gene association, postmortem brain and animal studies. AKT and mTOR are serine/threonine kinases which play important roles in cell growth, proliferation, survival, and differentiation. Both AKT and mTOR require phosphorylation at specific sites for their complete activation. mTOR forms two functionally distinct multiprotein complexes, mTOR Complex 1 (mTORC1) and Complex 2 (mTORC2). mTORC1 mediates ribosome biogenesis, protein translation, and autophagy, whereas mTORC2 contributes to actin dynamics. Altered protein synthesis and actin dynamics can lead to an abnormal neuronal morphology resulting in deficits in learning and memory. Currently, there is a lack of direct evidence to support the hypothesis of disrupted mTOR signaling in SZ, and we have addressed this by characterizing this signaling pathway in SZ brain. We found a reduction in AKT and mTOR protein expression and/or phosphorylation state in dorsolateral prefrontal cortex (DLPFC) from 22 pairs of SZ and matched comparison subjects. We also found reduced protein expression of GβL, a subunit protein common to both mTOR complexes. We further investigated mTOR complex-specific subunit composition and phosphorylation state, and found abnormal mTOR expression in both complexes in SZ DLPFC. These findings provide evidence that proteins associated with the AKT-mTOR signaling cascade are downregulated in SZ DLPFC.