- 作者列表："Cola ML","Plate S","Yankowitz L","Petrulla V","Bateman L","Zampella CJ","de Marchena A","Pandey J","Schultz RT","Parish-Morris J
BACKGROUND:Individuals with autism spectrum disorder (ASD) are characterized by social communication challenges and repetitive behaviors that may be quickly detected by experts (Autism Res 10:653-62, 2017; American Psychiatric Association, Diagnostic and statistical manual of mental disorders, 2013). Recent research suggests that even naïve non-experts judge a variety of human dimensions using narrow windows of experience called "first impressions." Growing recognition of sex differences in a variety of observable behaviors in ASD, combined with research showing that some autistic girls and women may "camouflage" outward symptoms, suggests it may be more difficult for naïve conversation partners to detect ASD symptoms in girls. Here, we explore the first impressions made by boys and girls with ASD and typically developing (TD) peers. METHODS:Ninety-three school-aged children with ASD or TD were matched on IQ; autistic girls and boys were additionally matched on autism symptom severity using the ADOS-2. Participants completed a 5-minute "get-to-know-you" conversation with a new young adult acquaintance. Immediately after the conversation, confederates rated participants on a variety of dimensions. Our primary analysis compared conversation ratings between groups (ASD boys, ASD girls, TD boys, TD girls). RESULTS:Autistic girls were rated more positively than autistic boys by novel conversation partners (better perceived social communication ability), despite comparable autism symptom severity as rated by expert clinicians (equivalent true social communication ability). Boys with ASD were rated more negatively than typical boys and typical girls by novel conversation partners as well as expert clinicians. There was no significant difference in the first impressions made by autistic girls compared to typical girls during conversations with a novel conversation partner, but autistic girls were rated lower than typical girls by expert clinicians. LIMITATIONS:This study cannot speak to the ways in which first impressions may differ for younger children, adults, or individuals who are not verbally fluent; in addition, there were more autistic boys than girls in our sample, making it difficult to detect small effects. CONCLUSIONS:First impressions made during naturalistic conversations with non-expert conversation partners could-in combination with clinical ratings and parent report-shed light on the nature and effects of behavioral differences between girls and boys on the autism spectrum.
背景: 自闭症谱系障碍 (ASD) 个体的特征是社会交往挑战和专家可能快速发现的重复行为 (autism Res 10:653-2017; 美国精神病学协会，《精神障碍诊断与统计手册》，2013)。最近的研究表明，即使是天真的非专家也会使用被称为 “第一印象” 的狭窄经验窗口来判断各种人类维度。越来越多的人认识到 ASD 中各种可观察到的行为的性别差异，结合研究显示一些自闭症女孩和女性可能会 “伪装” 外在症状,表明天真的谈话伙伴可能更难发现女孩的 ASD 症状。在这里，我们探讨 ASD 男孩和女孩以及典型发育中的 (TD) 同龄人的第一印象。 方法: 93 名患有 ASD 或 TD 的学龄儿童在智商上匹配; 自闭症女孩和男孩在自闭症症状严重程度上使用 ADOS-2 进行额外匹配。参与者与一位新的年轻成人熟人完成了 5 分钟的 “结识你” 对话。谈话结束后，邦联立即对参与者进行了各种维度的评分。我们的主要分析比较了组间的对话评分 (ASD 男孩、 ASD 女孩、 TD 男孩、 TD 女孩)。 结果: 孤独症女孩被新颖的谈话伙伴 (更好的感知社会交往能力) 评定比孤独症男孩更积极,尽管专家临床医生评定的自闭症症状严重程度相当 (相当于真正的社会沟通能力)。新的谈话伙伴以及专家临床医生对 ASD 男孩的评价比典型男孩和典型女孩的评价更消极。与典型女孩相比，自闭症女孩在与新型谈话伙伴交谈时的第一印象没有显著差异，但自闭症女孩被专家临床医生评为低于典型女孩。 局限性: 这项研究不能说明对于年幼的儿童、成人或语言不流利的个人，第一印象可能会有所不同; 此外,在我们的样本中，自闭症男孩比女孩多，使得很难检测到小的影响。 结论: 与非专家谈话伙伴进行自然对话时的第一印象可以 -- 结合临床评级和家长报告 -- 揭示女孩和男孩之间行为差异对自闭症的性质和影响频谱。
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.