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Exploring mitochondrial blood-based and genetic markers in older adults with mild cognitive impairment and remitted major depressive disorder. 探索轻度认知障碍和重度抑郁症缓解期老年人的线粒体血液和遗传标记。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-10-29 DOI: 10.1038/s41398-024-03155-9
Jaehyoung Choi, Erika L Beroncal, Timofei Chernega, Heather J Brooks, James L Kennedy, Corinne E Fisher, Alastair J Flint, Nathan Herrmann, Krista L Lanctôt, Linda Mah, Benoit H Mulsant, Bruce G Pollock, Tarek K Rajji, Ana C Andreazza

Mild cognitive impairment (MCI) is a prodromal stage in aging to possible progression to Alzheimer's disease and related dementia (ADRD), where co-occurrence of major depressive disorder (MDD) accelerates the progression. Metabolic and mitochondrial abnormalities in ADRD and other neurodegenerative disorders have been widely suggested, while possible mitochondrial dysfunction has been associated with etiopathology of both MCI and MDD. Hence, investigation of mitochondrial markers in MCI, MDD, and presence of both conditions is warranted. In total, 332 older adult participants were included: 168 with MCI, 108 with MCI plus remitted MDD (rMDD), and 56 with rMDD but without MCI. We measured plasma circulating mitochondrial DNA (ccf-mtDNA), lactate, and extracted nuclear mitochondrial encoded (NMt) single-nucleotide variants (SNVs) (n = 312). Non-parametric statistical tests on ccf-mtDNA and lactate levels were performed on the diagnosis, clinical and cardiometabolic variables. Binary sequence kernel association test (SKAT-O) and burden test were performed on NMt-SNV, adjusted for age, race, gender, type II diabetes, and APOE genotype. Lower level of lactate was observed in MCI (KW χ2 = 14.8, P = 0.0024), more specifically, significant differences of lower plasma lactate between MCI only and rMDD, but not between MCI+rMDD and MCI were found, suggesting potential roles in MCI driving lactate lower levels. While higher levels of ccf-mtDNA were observed in APOE-ε4 carrier (χ2 = 5.04, P = 0.05). This relationship was present only in MCI (P = 0.043) and MCI+rMDD groups (P = 0.023). No significant nuclear-encoded mitochondrial gene associations were observed with MCI or MDD. The results suggest decreased level of plasma lactate in individuals with MCI and MCI+rMDD, with inverse correlation with ccf-mtDNA, in addition to effect of APOE-ε4 in further increasing ccf-mtDNA specifically in participants with cognitive impairment. These findings contribute to a deeper understanding of the mitochondrial markers in MCI and MDD, warranting further research to explore the precise roles of mitochondrial abnormalities in the development and progression of MCI.

轻度认知功能障碍(MCI)是衰老的一个前驱阶段,有可能发展为阿尔茨海默病和相关痴呆症(ADRD),同时出现重度抑郁障碍(MDD)会加速病情发展。人们普遍认为 ADRD 和其他神经退行性疾病中存在代谢和线粒体异常,而线粒体功能障碍可能与 MCI 和 MDD 的病因病理有关。因此,有必要对 MCI、MDD 以及同时患有这两种疾病的患者的线粒体标记物进行调查。研究共纳入了 332 名老年参与者:其中 168 人患有 MCI,108 人患有 MCI 加缓解型 MDD(rMDD),56 人患有 rMDD 但未患有 MCI。我们测量了血浆循环线粒体 DNA(ccf-mtDNA)、乳酸盐和提取的核线粒体编码(NMt)单核苷酸变异(SNVs)(n = 312)。对诊断、临床和心脏代谢变量的ccf-mtDNA和乳酸盐水平进行了非参数统计检验。对 NMt-SNV 进行了二元序列核关联检验(SKAT-O)和负荷检验,并对年龄、种族、性别、II 型糖尿病和 APOE 基因型进行了调整。在 MCI 中观察到较低的乳酸水平(KW χ2 = 14.8,P = 0.0024),更具体地说,在 MCI 和 rMDD 之间发现了较低的血浆乳酸,而在 MCI+rMDD 和 MCI 之间没有发现显著差异,这表明 MCI 有可能是乳酸水平较低的原因。在 APOE-ε4 携带者中观察到较高水平的 ccf-mtDNA (χ2 = 5.04,P = 0.05)。只有 MCI 组(P = 0.043)和 MCI+rMDD 组(P = 0.023)存在这种关系。没有观察到核编码线粒体基因与 MCI 或 MDD 有明显关系。研究结果表明,MCI 和 MCI+rMDD 患者血浆乳酸水平下降,与 ccf-mtDNA 呈反相关,此外,APOE-ε4 还能进一步增加认知障碍患者的 ccf-mtDNA。这些发现有助于加深对MCI和MDD中线粒体标记物的理解,值得进一步研究,以探索线粒体异常在MCI发生和发展中的确切作用。
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引用次数: 0
Understanding novel neuromodulation pathways in tDCS: brain stem recordings in rats during trigeminal nerve direct current stimulation. 了解 tDCS 的新型神经调节途径:三叉神经直流电刺激期间大鼠脑干记录。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-10-28 DOI: 10.1038/s41398-024-03158-6
Alireza Majdi, Boateng Asamoah, Myles Mc Laughlin

tDCS is widely assumed to cause neuromodulation via the electric field in the cortex acting directly on cortical neurons. However, recent evidence suggests that tDCS may indirectly influence brain activity through cranial nerve pathways, notably the trigeminal nerve, but these neuromodulatory pathways remain unexplored. To investigate the first stages in this potential pathway we developed an animal model to study the effect of trigeminal nerve direct current stimulation (TN-DCS) on neuronal activity in the principal sensory nucleus (NVsnpr) and the mesencephalic nucleus of the trigeminal nerve (MeV). We conducted experiments on twenty-four male Sprague Dawley rats (n = 10 NVsnpr, n = 10 MeV during anodic stimulation, and n = 4 MeV during cathodic stimulation). DC stimulation, ranging from 0.5 to 3 mA, targeted the trigeminal nerve's marginal branch. Concurrently, single-unit electrophysiological recordings were obtained using a 32-channel silicon probe, encompassing three 1-min intervals: pre, during, and post-stimulation. Xylocaine trigeminal nerve blockage served as a control. TN-DCS increased neuronal spiking activity in both NVsnpr and MeV, returning to baseline during the post-stimulation phase. The 3 mA DC stimulation of the blocked trigeminal nerve failed to induce increased spiking activity in the trigeminal nuclei. These findings provide empirical support for trigeminal nuclei modulation via TN-DCS, suggesting the cranial nerve pathways could play a role in mediating the tDCS effects in humans.

人们普遍认为,tDCS 通过皮层中的电场直接作用于皮层神经元,从而引起神经调节。然而,最近的证据表明,tDCS 可能会通过颅神经通路(尤其是三叉神经)间接影响大脑活动,但这些神经调节通路仍有待探索。为了研究这一潜在通路的第一阶段,我们建立了一个动物模型,研究三叉神经直流电刺激(TN-DCS)对三叉神经主感觉核(NVsnpr)和间脑核(MeV)神经元活动的影响。我们对 24 只雄性 Sprague Dawley 大鼠进行了实验(正极刺激时,n = 10 NVsnpr;负极刺激时,n = 10 MeV;阴极刺激时,n = 4 MeV)。直流电刺激的范围为 0.5 至 3 mA,目标是三叉神经的边缘分支。同时,使用 32 个通道的硅探针进行单机电生理记录,包括三个 1 分钟的时间间隔:刺激前、刺激中和刺激后。对照组为三叉神经阻滞的二甲卡因。TN-DCS 增加了 NVsnpr 和 MeV 的神经元尖峰活动,并在刺激后阶段恢复到基线。对阻断的三叉神经进行 3 毫安直流电刺激未能引起三叉神经核的尖峰活动增加。这些发现为通过 TN-DCS 调节三叉神经核提供了经验支持,表明颅神经通路可能在介导人类的 tDCS 效应中发挥作用。
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引用次数: 0
Memory complaints after COVID-19: a potential indicator of primary cognitive impairment or a correlate of psychiatric symptoms? COVID-19 后的记忆抱怨:是原发性认知障碍的潜在指标,还是精神症状的相关因素?
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-10-26 DOI: 10.1038/s41398-024-03154-w
Yiling Dong, Ana Paula Ritto, Rodolfo Furlan Damiano, Amanda Goulart Coli, Rodrigo Hadade, Cristiana Castanho de Almeida Rocca, Antonio de Pádua Serafim, Bruno Fukelmann Guedes, Ricardo Nitrini, Marta Imamura, Orestes Vicente Forlenza, Geraldo Busatto Filho

Cognitive impairment and symptoms of psychiatric disorders have been reported frequently as features of post-acute sequelae of SARS-CoV-2 infection. This study aims to investigate subjective memory complaints in COVID-19 survivors and determine if these are more strongly associated with objective cognitive impairment related to sequelae of SARS-CoV-2 infection or with symptoms of psychiatric conditions. A total of 608 COVID-19 survivors were evaluated in-person 6-11 months after hospitalization, with 377 patients assigned to a "no subjective memory complaint (SMC)" group and 231 patients assigned to an SMC group based on their Memory Complaint Scale scores. Follow-up evaluations included an objective cognitive battery and scale-based assessments of anxiety, depression, and post-traumatic stress symptoms. We found the perception of memory impairment in COVID-19 survivors to be more strongly associated to core symptoms of psychiatric conditions rather than to primary objective cognitive impairment. Univariate analysis indicated significant differences between the "no SMC" and SMC groups, both for the psychiatric symptom evaluations and for the cognitive evaluations (p < 0.05); however, the psychiatric symptoms all had large partial eta-squared values (ranging from 0.181 to 0.213), whereas the cognitive variables had small/medium partial eta-squared values (ranging from 0.002 to 0.024). Additionally, multiple regression analysis indicated that only female sex and depressive and post-traumatic stress symptoms were predictors of subjective memory complaints. These findings may help guide clinical evaluations for COVID-19 survivors presenting with memory complaints while also serving to expand our growing understanding of the relationship between COVID-19, subjective memory complaints, and the risk of cognitive decline.

据报道,认知障碍和精神障碍症状是 SARS-CoV-2 感染急性期后遗症的常见特征。本研究旨在调查 COVID-19 幸存者的主观记忆抱怨,并确定这些抱怨是否与 SARS-CoV-2 感染后遗症相关的客观认知障碍或精神症状有更密切的联系。共对 608 名 COVID-19 幸存者进行了住院后 6-11 个月的亲自评估,其中 377 名患者被分配到 "无主观记忆主诉 (SMC) 组",231 名患者根据其记忆主诉量表评分被分配到主观记忆主诉组。随访评估包括客观认知测试和基于量表的焦虑、抑郁和创伤后应激症状评估。我们发现,COVID-19幸存者的记忆障碍感知与精神疾病的核心症状而非主要的客观认知障碍有更密切的关系。单变量分析表明,"无 SMC "组和 SMC 组在精神症状评估和认知评估方面均存在显著差异(P<0.05)。
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引用次数: 0
The effect of polygenic risk score and childhood adversity on transdiagnostic symptom dimensions at first-episode psychosis: evidence for an affective pathway to psychosis. 多基因风险评分和童年逆境对首次精神病发作时跨诊断症状维度的影响:精神病情感途径的证据。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-10-26 DOI: 10.1038/s41398-024-03149-7
Luis Alameda, Victoria Rodriguez, Marta Di Forti, Edoardo Spinazzola, Giulia Trotta, Celso Arango, Manuel Arrojo, Miguel Bernardo, Julio Bobes, Lieuwe de Haan, Cristina Marta Del-Ben, Charlotte Gayer-Anderson, Lucia Sideli, Peter B Jones, James B Kirkbride, Caterina La Cascia, Giada Tripoli, Laura Ferraro, Daniele La Barbera, Antonio Lasalvia, Sarah Tosato, Pierre-Michel Llorca, Paulo Rossi Menezes, Jim van Os, Bart P Rutten, Jose Luis Santos, Julio Sanjuán, Jean-Paul Selten, Andrei Szöke, Ilaria Tarricone, Andrea Tortelli, Eva Velthorst, Hannah E Jongsma, Evangelos Vassos, Diego Quattrone, Robin M Murray, Monica Aas

Childhood adversity is associated with various clinical dimensions in psychosis; however, how genetic vulnerability shapes the adversity-associated psychopathological signature is yet to be studied. We studied data of 583 First Episode Psychosis (FEP) cases from the EU-GEI FEP case-control study, including Polygenic risk scores for major depressive disorder (MDD-PRS), bipolar disorder (BD-PRS) and schizophrenia (SZ-PRS); childhood adversity measured with the total score of the Childhood Trauma Questionnaire (CTQ); and positive, negative, depressive and manic psychopathological domains from a factor model of transdiagnostic dimensions. Genes and environment interactions were explored as a departure from a multiplicative effect of PRSs and total CTQ on each dimension. Analyses were adjusted for age, sex, 10 PCA, site of recruitment and for medication. A childhood adversity and PRS multiplicative interaction was observed between A) the CTQ and MDD-PRS on the predominance of positive (β = 0.42, 95% CI = [0.155, 0.682], p = 0.004); and depressive (β = 0.33, 95% CI = [0.071, 0.591], p = 0.013) dimensions; B) between the CTQ and BD-PRS on the positive dimension (β = 0.45, 95% CI = [0.106, 0.798], p = 0.010), and C) with the CTQ and SZ-PRS on the positive dimension (β = -0.34, 95% CI = [-0.660, -0.015], p = 0.040). Bonferroni corrected p-value of significance was set at 0.0125. In conclusion, despite being underpowered, this study suggests that genetic liability for MDD and BD may have a moderating effect on the sensibility of childhood adversity on depressive and positive psychotic dimensions. This supports the hypothesis of an affective pathway to psychosis in those exposed to childhood adversity.

童年时期的逆境与精神病的各种临床症状有关;然而,遗传易感性如何形成与逆境有关的精神病理学特征尚有待研究。我们研究了来自 EU-GEI FEP 病例对照研究的 583 个首发精神病(FEP)病例的数据,包括重度抑郁障碍(MDD-PRS)、双相情感障碍(BD-PRS)和精神分裂症(SZ-PRS)的多基因风险评分;以童年创伤问卷(CTQ)总分衡量的童年逆境;以及跨诊断维度因子模型中的阳性、阴性、抑郁和躁狂精神病理学领域。基因与环境之间的相互作用被视为 PRSs 和 CTQ 总量对每个维度的乘法效应。分析对年龄、性别、10 PCA、招募地点和药物进行了调整。在 A) CTQ 和 MDD-PRS 之间观察到童年逆境和 PRS 在积极(β = 0.42,95% CI = [0.155,0.682],p = 0.004)和抑郁(β = 0.33,95% CI = [0.071,0.591],p = 0.013);B)CTQ 与 BD-PRS 在积极维度上的差异(β = 0.45,95% CI = [0.106,0.798],p = 0.010),以及 C)CTQ 与 SZ-PRS 在积极维度上的差异(β = -0.34,95% CI = [-0.660,-0.015],p = 0.040)。Bonferroni 校正后的显著性 P 值定为 0.0125。总之,尽管这项研究的力量不足,但它表明,MDD 和 BD 的遗传责任可能对童年逆境对抑郁和积极精神病维度的敏感性有调节作用。这支持了关于童年逆境是导致精神病的情感途径的假设。
{"title":"The effect of polygenic risk score and childhood adversity on transdiagnostic symptom dimensions at first-episode psychosis: evidence for an affective pathway to psychosis.","authors":"Luis Alameda, Victoria Rodriguez, Marta Di Forti, Edoardo Spinazzola, Giulia Trotta, Celso Arango, Manuel Arrojo, Miguel Bernardo, Julio Bobes, Lieuwe de Haan, Cristina Marta Del-Ben, Charlotte Gayer-Anderson, Lucia Sideli, Peter B Jones, James B Kirkbride, Caterina La Cascia, Giada Tripoli, Laura Ferraro, Daniele La Barbera, Antonio Lasalvia, Sarah Tosato, Pierre-Michel Llorca, Paulo Rossi Menezes, Jim van Os, Bart P Rutten, Jose Luis Santos, Julio Sanjuán, Jean-Paul Selten, Andrei Szöke, Ilaria Tarricone, Andrea Tortelli, Eva Velthorst, Hannah E Jongsma, Evangelos Vassos, Diego Quattrone, Robin M Murray, Monica Aas","doi":"10.1038/s41398-024-03149-7","DOIUrl":"10.1038/s41398-024-03149-7","url":null,"abstract":"<p><p>Childhood adversity is associated with various clinical dimensions in psychosis; however, how genetic vulnerability shapes the adversity-associated psychopathological signature is yet to be studied. We studied data of 583 First Episode Psychosis (FEP) cases from the EU-GEI FEP case-control study, including Polygenic risk scores for major depressive disorder (MDD-PRS), bipolar disorder (BD-PRS) and schizophrenia (SZ-PRS); childhood adversity measured with the total score of the Childhood Trauma Questionnaire (CTQ); and positive, negative, depressive and manic psychopathological domains from a factor model of transdiagnostic dimensions. Genes and environment interactions were explored as a departure from a multiplicative effect of PRSs and total CTQ on each dimension. Analyses were adjusted for age, sex, 10 PCA, site of recruitment and for medication. A childhood adversity and PRS multiplicative interaction was observed between A) the CTQ and MDD-PRS on the predominance of positive (β = 0.42, 95% CI = [0.155, 0.682], p = 0.004); and depressive (β = 0.33, 95% CI = [0.071, 0.591], p = 0.013) dimensions; B) between the CTQ and BD-PRS on the positive dimension (β = 0.45, 95% CI = [0.106, 0.798], p = 0.010), and C) with the CTQ and SZ-PRS on the positive dimension (β = -0.34, 95% CI = [-0.660, -0.015], p = 0.040). Bonferroni corrected p-value of significance was set at 0.0125. In conclusion, despite being underpowered, this study suggests that genetic liability for MDD and BD may have a moderating effect on the sensibility of childhood adversity on depressive and positive psychotic dimensions. This supports the hypothesis of an affective pathway to psychosis in those exposed to childhood adversity.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"454"},"PeriodicalIF":5.8,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11513137/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142508717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Effects of separate and combined estradiol and progesterone administration on fear extinction in healthy pre-menopausal women. 单独和联合服用雌二醇和黄体酮对绝经前健康妇女恐惧消退的影响。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-10-24 DOI: 10.1038/s41398-024-03079-4
Michael Kaczmarczyk, Christian Eric Deuter, Hanna Deus, Anna Kallidou, Christian J Merz, Julian Hellmann-Regen, Christian Otte, Katja Wingenfeld

Altered fear conditioning and extinction learning are discussed as key etiological features in anxiety disorders. Women have an increased risk for anxiety disorders and fear conditioning has been shown to be influenced by the menstrual cycle phase and circulating gonadal hormones. The objective of our study was to investigate the effects of separate and combined estradiol and progesterone administration on fear extinction in healthy women. We conducted a placebo-controlled, randomized study in healthy women, who completed a fear conditioning paradigm on three consecutive days: fear acquisition training on day 1, fear extinction training on day 2, and return of fear test on day 3. Skin conductance responses (SCRs) served as main outcome variable. Two hours before testing on day 2, participants received pills containing either placebo, estradiol (2 mg), progesterone (400 mg) or the combination of both. We examined 116 women (mean age 25.7 ± 6.0 years), who showed significantly stronger conditioned SCRs to the CS+ than CS- during fear acquisition training indicating successful fear learning. At the beginning of the fear extinction training, estradiol administration reduced the differentiation between the conditioned stimuli. In the return of fear test, the estradiol groups showed heightened SCR responses to the previously extinguished stimulus, i.e., impaired extinction recall. Administration of progesterone did not have any significant influence on SCRs. There were also no effects on fear potentiated startle response. In our interpretation, exogenous estradiol administration affected the extinction of the conditioned fear response which led subsequently to a stronger return of fear. From a clinical perspective our findings suggest that estradiol levels may have an influence on the success of exposure therapy and could be taken into consideration when planning exposure sessions.

恐惧条件反射和消退学习的改变是焦虑症的主要病因。女性罹患焦虑症的风险更高,而恐惧条件反射已被证明会受到月经周期阶段和循环中的性腺激素的影响。我们的研究旨在调查单独或联合服用雌二醇和孕酮对健康女性恐惧消退的影响。我们对健康女性进行了一项安慰剂对照随机研究,她们在连续三天内完成了恐惧条件反射范式:第1天进行恐惧获得训练,第2天进行恐惧消退训练,第3天进行恐惧恢复测试。皮肤传导反应(SCR)是主要的结果变量。在第 2 天测试前两小时,参与者服用含有安慰剂、雌二醇(2 毫克)、黄体酮(400 毫克)或两者结合的药片。我们对 116 名女性(平均年龄为 25.7 ± 6.0 岁)进行了研究,在恐惧获得训练期间,她们对 CS+ 的条件 SCR 明显强于 CS-,这表明恐惧学习取得了成功。在恐惧消退训练开始时,雌二醇会降低条件刺激之间的差异。在恐惧回归测试中,雌二醇组对先前熄灭的刺激表现出更高的SCR反应,即熄灭回忆受损。黄体酮对SCR没有显著影响。对恐惧强直性惊吓反应也没有影响。根据我们的解释,外源性雌二醇会影响条件性恐惧反应的消退,从而导致更强的恐惧恢复。从临床角度来看,我们的研究结果表明,雌二醇水平可能会影响暴露疗法的成功与否,因此在计划暴露疗程时应加以考虑。
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引用次数: 0
Long-term effects of a double hit murine model for schizophrenia on parvalbumin expressing cells and plasticity-related molecules in the thalamic reticular nucleus and the habenula. 精神分裂症双击小鼠模型对丘脑网状核和脑叶中副发光体表达细胞和可塑性相关分子的长期影响。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-10-24 DOI: 10.1038/s41398-024-03166-6
Patrycja Klimczak, Julia Alcaide, Yaiza Gramuntell, Esther Castillo-Gómez, Emilio Varea, Marta Perez-Rando, Juan Nacher

The exposure to aversive experiences during early-life affects brain maturation and induces changes in behavior. Additionally, when these experiences coincide with subtle neurodevelopmental alterations, they may contribute to the emergence of psychiatric disorders, such as schizophrenia. Studies in patients and animal models have identified changes in parvalbumin (PV) expressing inhibitory neurons, highlighting their significance in the etiology of this disorder. Most studies have been focused on the cortex, but PV+ neurons also provide inhibitory input to diencephalic regions, particularly to the thalamus (through cells in the thalamic reticular nucleus, TRN) and the habenula. Remarkably, alterations in both nuclei have been described in schizophrenia. Some of these changes in PV+ cells may be mediated by perineuronal nets (PNN), specialized regions of the extracellular matrix that often surround them and regulate their synaptic input and activity. Interestingly, the physiological maturation and integration of PV+ neurons, which involves the assembly of PNN, occurs during early postnatal life. Plasticity molecules associated to inhibitory neurons, such as PSA-NCAM, or NMDA receptors (NMDAR) can also influence the structure and function of these cells. Growing evidence also indicates that glial cells regulate the physiology of PV+ neurons by influencing their maturation and modulating their synaptic connectivity. To explore the impact of early-life aversive experiences and concomitant subtle neurodevelopmental alterations on diencephalic PV+ cells, we analyzed adult male mice subjected to a double-hit model (DHM) of schizophrenia, combining a single injection of an NMDAR antagonist at P7 and post-weaning social isolation. We observed that exploratory behavior, PV+ neurons and their associated PNN, as well as PSA-NCAM and NMDAR expression and glial cells, in the TRN and the habenula were affected by the DHM or one of its factors. To our knowledge, this is the first report on such alterations in these diencephalic structures in an animal model combining neurodevelopmental alterations and early-life stress during adolescence. Our findings complement previous work on PV+ neurons in cortical regions and underscore the importance of studying diencephalic inhibitory networks and their intricate interactions with aversive experiences and neurodevelopmental alterations during early life in the context of schizophrenia.

幼年时期的厌恶经历会影响大脑的成熟,并诱发行为的改变。此外,当这些经历与微妙的神经发育改变同时发生时,可能会导致精神分裂症等精神疾病的出现。对患者和动物模型的研究发现,表达抑制性神经元的副发光素(PV)发生了变化,这凸显了它们在精神分裂症病因学中的重要性。大多数研究都集中在大脑皮层,但 PV+ 神经元也向间脑区域提供抑制性输入,尤其是丘脑(通过丘脑网状核中的细胞)和哈贝脑。值得注意的是,精神分裂症患者的这两个核团都发生了改变。PV+细胞的部分变化可能是由神经元周围网(PNN)介导的,PNN是细胞外基质的专门区域,通常围绕着PV+细胞,并调节其突触输入和活动。有趣的是,PV+神经元的生理性成熟和整合涉及 PNN 的组装,发生在出生后早期。与抑制性神经元相关的可塑性分子,如 PSA-NCAM 或 NMDA 受体(NMDAR),也会影响这些细胞的结构和功能。越来越多的证据还表明,神经胶质细胞通过影响PV+神经元的成熟和调节其突触连接来调节PV+神经元的生理学。为了探索早年的厌恶经历和伴随而来的细微神经发育改变对间脑 PV+ 细胞的影响,我们分析了接受精神分裂症双重打击模型(DHM)的成年雄性小鼠,该模型结合了在小鼠 7 岁时注射一次 NMDAR 拮抗剂和断奶后的社会隔离。我们观察到,探索行为、PV+神经元及其相关的PNN、PSA-NCAM和NMDAR的表达以及神经胶质细胞、TRN和哈氏神经节均受到DHM或其中一个因素的影响。据我们所知,这是首次报道在一个结合了神经发育改变和青春期早期生活压力的动物模型中这些间脑结构的这种改变。我们的研究结果补充了之前关于皮质区域 PV+ 神经元的研究,并强调了在精神分裂症的背景下研究双脑抑制网络及其与厌恶体验和生命早期神经发育改变之间错综复杂的相互作用的重要性。
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引用次数: 0
The mediation role of gray matter volume in the relationship between childhood maltreatment and psychological resilience in adolescents with first-episode major depressive disorder. 灰质体积在初发重度抑郁障碍青少年的童年虐待与心理复原力之间的中介作用。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-10-24 DOI: 10.1038/s41398-024-03169-3
Hui Chen, Peiqu Liu, Xianliang Chen, Jiali Liu, Huajia Tang, Yusheng Tian, Xiaoping Wang, Fengmei Lu, Jiansong Zhou

Previous studies have revealed morphologic alterations in patients with major depressive disorder (MDD) with experiences of childhood trauma. However, the underlying neural mechanisms remain largely unknown. This study aims to explore the brain structural changes and their possible mediation role in the relationship between childhood maltreatment and psychological resilience in drug-naïve adolescents with first-episode MDD. A total of 57 adolescents with first-episode MDD and 36 healthy controls (HCs) completed the T1-weighted magnetic resonance imaging scan. The adverse childhood experiences and current psychological resilience were assessed using the Childhood Trauma Questionnaire-Short Form and the Connor Davidson Resilience Scale, respectively. The voxel-based morphometry approach was applied to examine changes in the gray matter volume (GMV). Compared with the HCs, adolescents with MDD had significantly reduced GMV volumes in the left fusiform gyrus, right orbitofrontal gyrus, right superior temporal gyrus, right calcarine cortex, right middle frontal gyrus, left angular gyrus, right precuneus, right posterior cingulate gyrus, and right posterior central gyrus, as well as significantly increased GMV volumes in the left lenticular putamen and right lenticular pallidum. The GMV of the right calcarine cortex was found to be negatively correlated with the severity of emotional abuse and positively correlated with the level of psychological resilience. Moreover, the GMV of the right calcarine cortex might partially mediate the relationship between childhood maltreatment and psychological resilience. The present study provided further evidence for structural impairments in adolescents with MDD. Our findings also confirmed the important role of depression-related GMV changes in childhood growth experiences and psychological resilience characteristics during adolescent brain maturation.

以往的研究显示,有童年创伤经历的重度抑郁症(MDD)患者会出现形态学改变。然而,其背后的神经机制在很大程度上仍不为人知。本研究旨在探讨初次发病的MDD患者的大脑结构变化及其在童年虐待与心理复原力之间可能的中介作用。共有57名初发MDD青少年和36名健康对照组(HCs)完成了T1加权磁共振成像扫描。童年不良经历和目前的心理复原力分别通过童年创伤问卷简表和康纳-戴维森复原力量表进行评估。研究人员采用基于体素的形态计量学方法来检测灰质体积(GMV)的变化。与正常人相比,患有 MDD 的青少年左侧纺锤形回、右侧眶额回、右侧颞上回、右侧钙皮质、右侧额中回、左侧角回、右侧楔前回、右侧扣带回后部和右侧中央后回的灰质体积明显减少,而左侧皮质透镜和右侧苍白球透镜的灰质体积则明显增加。研究发现,右侧钙皮质的 GMV 与情感虐待的严重程度呈负相关,而与心理复原力水平呈正相关。此外,右心盏皮层的GMV可能部分介导了童年虐待与心理复原力之间的关系。本研究进一步证明了患有 MDD 的青少年存在结构性损伤。我们的研究结果还证实,在青少年大脑成熟过程中,与抑郁症相关的GMV变化在童年成长经历和心理复原力特征中起着重要作用。
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引用次数: 0
Intravenous chaperone treatment of late-stage Alzheimer´s disease (AD) mouse model affects amyloid plaque load, reactive gliosis and AD-related genes. 对晚期阿尔茨海默病(AD)小鼠模型进行静脉注射伴侣素治疗,可影响淀粉样斑块负荷、反应性胶质细胞增生和AD相关基因。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-10-24 DOI: 10.1038/s41398-024-03161-x
Ruixin Zhang, Makiko Ohshima, David Brodin, Yu Wang, Antonin Morancé, Marianne Schultzberg, Gefei Chen, Jan Johansson

Treatment strategies that are efficient against established Alzheimer's disease (AD) are needed. BRICHOS is a molecular chaperone domain that prevents amyloid fibril formation and associated cellular toxicity. In this study, we treated an AD mouse model seven months after pathology onset, using intravenous administration of recombinant human (rh) Bri2 BRICHOS R221E. Two injections of rh Bri2 BRICHOS R221E per week for three months in AD mice reduced amyloid β (Aβ) burden, and mitigated astro- and microgliosis, as determined by glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule 1 (Iba1) immunohistochemistry. Sequencing of RNA from cortical microglia cells showed that BRICHOS treatment normalized the expression of identified plaque-induced genes in mice and humans, including clusterin and GFAP. Rh Bri2 BRICHOS R221E passed the blood-brain barrier (BBB) in age-matched wild-type mice as efficiently as in the AD mice, but then had no effect on measures of AD-like pathology, and mainly affected the expression of genes that affect cellular shape and movement. These results indicate a potential of rh Bri2 BRICHOS against advanced AD and underscore the ability of BRICHOS to target amyloid-induced pathology.

我们需要有效防治阿尔茨海默病(AD)的治疗策略。BRICHOS是一种分子伴侣结构域,可防止淀粉样蛋白纤维的形成和相关的细胞毒性。在这项研究中,我们利用静脉注射重组人(rh)Bri2 BRICHOS R221E来治疗发病七个月后的AD小鼠模型。通过神经胶质纤维酸性蛋白(GFAP)和电离钙结合适配分子 1(Iba1)免疫组化测定,AD 小鼠每周注射两次 rh Bri2 BRICHOS R221E,连续注射三个月,可减少淀粉样蛋白 β(Aβ)负担,减轻星形胶质细胞和小胶质细胞病变。对大脑皮层小胶质细胞的 RNA 测序显示,BRICHOS 治疗可使小鼠和人类中已确定的斑块诱导基因(包括集束蛋白和 GFAP)的表达正常化。Rh Bri2 BRICHOS R221E 在年龄匹配的野生型小鼠体内通过血脑屏障(BBB)的效率与在 AD 小鼠体内通过血脑屏障(BBB)的效率相同,但对类似于 AD 的病理学指标没有影响,主要影响的是影响细胞形状和运动的基因的表达。这些结果表明,rh Bri2 BRICHOS具有抗晚期AD的潜力,并强调了BRICHOS针对淀粉样蛋白诱导的病理学的能力。
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引用次数: 0
Genomic structural equation modeling reveals latent phenotypes in the human cortex with distinct genetic architecture. 基因组结构方程建模揭示了人类大脑皮层中具有独特遗传结构的潜在表型。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-10-24 DOI: 10.1038/s41398-024-03152-y
Rajendra A Morey, Yuanchao Zheng, Henry Bayly, Delin Sun, Melanie E Garrett, Marianna Gasperi, Adam X Maihofer, C Lexi Baird, Katrina L Grasby, Ashley A Huggins, Courtney C Haswell, Paul M Thompson, Sarah Medland, Daniel E Gustavson, Matthew S Panizzon, William S Kremen, Caroline M Nievergelt, Allison E Ashley-Koch, Mark W Logue

Genetic contributions to human cortical structure manifest pervasive pleiotropy. This pleiotropy may be harnessed to identify unique genetically-informed parcellations of the cortex that are neurobiologically distinct from functional, cytoarchitectural, or other cortical parcellation schemes. We investigated genetic pleiotropy by applying genomic structural equation modeling (SEM) to map the genetic architecture of cortical surface area (SA) and cortical thickness (CT) for 34 brain regions recently reported in the ENIGMA cortical GWAS. Genomic SEM uses the empirical genetic covariance estimated from GWAS summary statistics with LD score regression (LDSC) to discover factors underlying genetic covariance, which we are denoting genetically informed brain networks (GIBNs). Genomic SEM can fit a multivariate GWAS from summary statistics for each of the GIBNs, which can subsequently be used for LD score regression (LDSC). We found the best-fitting model of cortical SA identified 6 GIBNs and CT identified 4 GIBNs, although sensitivity analyses indicated that other structures were plausible. The multivariate GWASs of the GIBNs identified 74 genome-wide significant (GWS) loci (p < 5 × 10-8), including many previously implicated in neuroimaging phenotypes, behavioral traits, and psychiatric conditions. LDSC of GIBN GWASs found that SA-derived GIBNs had a positive genetic correlation with bipolar disorder (BPD), and cannabis use disorder, indicating genetic predisposition to a larger SA in the specific GIBN is associated with greater genetic risk of these disorders. A negative genetic correlation was observed between attention deficit hyperactivity disorder (ADHD) and major depressive disorder (MDD). CT GIBNs displayed a negative genetic correlation with alcohol dependence. Even though we observed model instability in our application of genomic SEM to high-dimensional data, jointly modeling the genetic architecture of complex traits and investigating multivariate genetic links across neuroimaging phenotypes offers new insights into the genetics of cortical structure and relationships to psychopathology.

人类大脑皮层结构的遗传贡献表现出普遍的多义性。这种多效性可能被用来识别大脑皮层中独特的遗传学划分,这些划分在神经生物学上有别于功能、细胞结构或其他大脑皮层划分方案。我们通过应用基因组结构方程建模(SEM)来绘制最近在 ENIGMA 皮质 GWAS 中报告的 34 个脑区的皮质表面积(SA)和皮质厚度(CT)的遗传结构图,从而研究遗传多效性。基因组 SEM 利用通过 LD 评分回归(LDSC)从 GWAS 概要统计中估算出的经验遗传协方差来发现潜在的遗传协方差因素,我们将其称为遗传信息脑网络(GIBNs)。基因组 SEM 可以根据每个 GIBNs 的汇总统计数据拟合多变量 GWAS,然后将其用于 LD 分数回归(LDSC)。我们发现,皮层 SA 的最佳拟合模型确定了 6 个 GIBN,CT 确定了 4 个 GIBN,尽管敏感性分析表明其他结构也是可行的。GIBN 的多变量 GWAS 发现了 74 个全基因组显著(GWS)位点(p -8),其中包括许多以前与神经影像表型、行为特征和精神状况有关的位点。GIBN GWAS 的 LDSC 发现,SA 衍生的 GIBN 与双相情感障碍(BPD)和大麻使用障碍有正的遗传相关性,这表明特定 GIBN 中较大 SA 的遗传易感性与这些障碍的更大遗传风险相关。注意缺陷多动障碍(ADHD)和重度抑郁障碍(MDD)之间存在负遗传相关性。CT GIBN 与酒精依赖呈遗传负相关。尽管我们在将基因组 SEM 应用于高维数据时观察到了模型的不稳定性,但对复杂性状的遗传结构进行联合建模以及对神经影像表型的多变量遗传联系进行研究,为了解大脑皮层结构的遗传学及其与精神病理学的关系提供了新的视角。
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引用次数: 0
Soluble form of Lingo2, an autism spectrum disorder-associated molecule, functions as an excitatory synapse organizer in neurons. 自闭症谱系障碍相关分子 Lingo2 的可溶形式在神经元中发挥兴奋性突触组织者的功能。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-10-23 DOI: 10.1038/s41398-024-03167-5
Fumiaki Yoshida, Ryota Nagatomo, Shun Utsunomiya, Misaki Kimura, Shiyori Shun, Rena Kono, Yuma Kato, Yosuke Nao, Kazuma Maeda, Ryuta Koyama, Yuji Ikegaya, Stefan F Lichtenthaler, Sho Takatori, Hiroshi Takemoto, Koichi Ogawa, Genta Ito, Taisuke Tomita

Autism Spectrum Disorder (ASD) is a developmental disorder characterized by impaired social communication and repetitive behaviors. In recent years, a pharmacological mouse model of ASD involving maternal administration of valproic acid (VPA) has become widely used. Newborn pups in this model show an abnormal balance between excitatory and inhibitory (E/I) signaling in neurons and exhibit ASD-like behavior. However, the molecular basis of this model and its implications for the pathogenesis of ASD in humans remain unknown. Using quantitative secretome analysis, we found that the level of leucine-rich repeat and immunoglobulin domain-containing protein 2 (Lingo2) was upregulated in the conditioned medium of VPA model neurons. This upregulation was associated with excitatory synaptic organizer activity. The secreted form of the extracellular domain of Lingo2 (sLingo2) is produced by the transmembrane metalloprotease ADAM10 through proteolytic processing. sLingo2 was found to induce the formation of excitatory synapses in both mouse and human neurons, and treatment with sLingo2 resulted in an increased frequency of miniature excitatory postsynaptic currents in human neurons. These findings suggest that sLingo2 is an excitatory synapse organizer involved in ASD, and further understanding of the mechanisms by which sLingo2 induces excitatory synaptogenesis is expected to advance our understanding of the pathogenesis of ASD.

自闭症谱系障碍(ASD)是一种以社会交流障碍和重复行为为特征的发育障碍。近年来,母体服用丙戊酸(VPA)的自闭症药理学小鼠模型得到广泛应用。该模型中的新生幼鼠表现出神经元中兴奋和抑制(E/I)信号的异常平衡,并表现出类似 ASD 的行为。然而,这种模型的分子基础及其对人类 ASD 发病机制的影响仍然未知。通过定量分泌组分析,我们发现富亮氨酸重复和含免疫球蛋白结构域蛋白2(Lingo2)的水平在VPA模型神经元的条件培养基中上调。这种上调与兴奋性突触组织者的活动有关。研究发现,sLingo2 可诱导小鼠和人类神经元兴奋性突触的形成,用 sLingo2 处理可增加人类神经元微型兴奋性突触后电流的频率。这些发现表明,sLingo2 是一种参与 ASD 的兴奋性突触组织者,进一步了解 sLingo2 诱导兴奋性突触形成的机制有望促进我们对 ASD 发病机制的了解。
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引用次数: 0
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Translational Psychiatry
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