Biological psychiatry global open science最新文献

{"title":"Childhood Maltreatment and Amygdala-Mediated Anxiety and Posttraumatic Stress Following Adult Trauma","authors":"Farah Harb ,&nbsp;Michael T. Liuzzi ,&nbsp;Ashley A. Huggins ,&nbsp;E. Kate Webb ,&nbsp;Jacklynn M. Fitzgerald ,&nbsp;Jessica L. Krukowski ,&nbsp;Terri A. deRoon-Cassini ,&nbsp;Christine L. Larson","doi":"10.1016/j.bpsgos.2024.100312","DOIUrl":"https://doi.org/10.1016/j.bpsgos.2024.100312","url":null,"abstract":"<div><h3>Background</h3><p>Childhood abuse (physical, emotional, and sexual) is associated with aberrant connectivity of the amygdala, a key threat-processing region. Heightened amygdala activity also predicts adult anxiety and posttraumatic stress disorder (PTSD) symptoms, as do experiences of childhood abuse. The current study explored whether amygdala resting-state functional connectivity may explain the relationship between childhood abuse and anxiety and PTSD symptoms following trauma exposure in adults.</p></div><div><h3>Methods</h3><p>Two weeks posttrauma, adult trauma survivors (<em>n</em> = 152, mean age [SD] = 32.61 [10.35] years; women = 57.2%) completed the Childhood Trauma Questionnaire and underwent resting-state functional magnetic resonance imaging. PTSD and anxiety symptoms were assessed 6 months posttrauma. Seed-to-voxel analyses evaluated the association between childhood abuse and amygdala resting-state functional connectivity. A mediation model evaluated the potential mediating role of amygdala connectivity in the relationship between childhood abuse and posttrauma anxiety and PTSD.</p></div><div><h3>Results</h3><p>Childhood abuse was associated with increased amygdala connectivity with the precuneus while covarying for age, gender, childhood neglect, and baseline PTSD symptoms. Amygdala-precuneus resting-state functional connectivity was a significant mediator of the effect of childhood abuse on anxiety symptoms 6 months posttrauma (<em>B</em> = 0.065; 95% CI, 0.013–0.130; SE = 0.030), but not PTSD. A secondary mediation analysis investigating depression as an outcome was not significant.</p></div><div><h3>Conclusions</h3><p>Amygdala-precuneus connectivity may be an underlying neural mechanism by which childhood abuse increases risk for anxiety following adult trauma. Specifically, this heightened connectivity may reflect attentional vigilance for threat or a tendency toward negative self-referential thoughts. Findings suggest that childhood abuse may contribute to longstanding upregulation of attentional vigilance circuits, which makes one vulnerable to anxiety-related symptoms in adulthood.</p></div>","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"4 4","pages":"Article 100312"},"PeriodicalIF":0.0,"publicationDate":"2024-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2667174324000259/pdfft?md5=4955da1ff7dfd0f2b9407a74bb2203aa&pid=1-s2.0-S2667174324000259-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140816417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Astrocytes Regulate Neuronal Network Burst Frequency Through NMDA Receptors in a Species- and Donor-Specific Manner","authors":"Noora Räsänen ,&nbsp;Jari Tiihonen ,&nbsp;Marja Koskuvi ,&nbsp;Šárka Lehtonen ,&nbsp;Nelli Jalkanen ,&nbsp;Nelli Karmila ,&nbsp;Isabelle Weert ,&nbsp;Olli Vaurio ,&nbsp;Ilkka Ojansuu ,&nbsp;Markku Lähteenvuo ,&nbsp;Olli Pietiläinen ,&nbsp;Jari Koistinaho","doi":"10.1016/j.bpsgos.2024.100313","DOIUrl":"https://doi.org/10.1016/j.bpsgos.2024.100313","url":null,"abstract":"<div><h3>Background</h3><p>Development of synaptic activity is a key neuronal characteristic that relies largely on interactions between neurons and astrocytes. Although astrocytes have known roles in regulating synaptic function and malfunction, the use of human- or donor-specific astrocytes in disease models is still rare. Rodent astrocytes are routinely used to enhance neuronal activity in cell cultures, but less is known about how human astrocytes influence neuronal activity.</p></div><div><h3>Methods</h3><p>We established human induced pluripotent stem cell–derived neuron-astrocyte cocultures and studied their functional development on microelectrode array. We used cell lines from 5 neurotypical control individuals and 3 pairs of monozygotic twins discordant for schizophrenia. A method combining NGN2 overexpression and dual SMAD inhibition was used for neuronal differentiation. The neurons were cocultured with human induced pluripotent stem cell–derived astrocytes differentiated from 6-month-old astrospheres or rat astrocytes.</p></div><div><h3>Results</h3><p>We found that the human induced pluripotent stem cell–derived cocultures developed complex network bursting activity similar to neuronal cocultures with rat astrocytes. However, the effect of NMDA receptors on neuronal network burst frequency (NBF) differed between cocultures containing human or rat astrocytes. By using cocultures derived from patients with schizophrenia and unaffected individuals, we found lowered NBF in the affected cells. We continued by demonstrating how astrocytes from an unaffected individual rescued the lowered NBF in the affected neurons by increasing NMDA receptor activity.</p></div><div><h3>Conclusions</h3><p>Our results indicate that astrocytes participate in the regulation of neuronal NBF through a mechanism that involves NMDA receptors. These findings shed light on the importance of using human and donor-specific astrocytes in disease modeling.</p></div>","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"4 4","pages":"Article 100313"},"PeriodicalIF":0.0,"publicationDate":"2024-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2667174324000260/pdfft?md5=3a2c7a8849f9c169e3a42a600e02e9df&pid=1-s2.0-S2667174324000260-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140650022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Parietal-Frontal Pathway Controls Relapse of Fear Memory in a Novel Context","authors":"Bitna Joo ,&nbsp;Shijie Xu ,&nbsp;Hyungju Park ,&nbsp;Kipom Kim ,&nbsp;Jong-Cheol Rah ,&nbsp;Ja Wook Koo","doi":"10.1016/j.bpsgos.2024.100315","DOIUrl":"10.1016/j.bpsgos.2024.100315","url":null,"abstract":"<div><h3>Background</h3><p>Fear responses significantly affect daily life and shape our approach to uncertainty. However, the potential resurgence of fear in unfamiliar situations poses a significant challenge to exposure-based therapies for maladaptive fear responses. Nonetheless, how novel contextual stimuli are associated with the relapse of extinguished fear remains unknown.</p></div><div><h3>Methods</h3><p>Using a context-dependent fear renewal model, the functional circuits and underlying mechanisms of the posterior parietal cortex (PPC) and anterior cingulate cortex (ACC) were investigated using optogenetic, histological, in vivo, and ex vivo electrophysiological and pharmacological techniques.</p></div><div><h3>Results</h3><p>We demonstrated that the PPC-to-ACC pathway governs fear relapse in a novel context. We observed enhanced populational calcium activity in the ACC neurons that received projections from the PPC and increased synaptic activity in the basolateral amygdala–projecting PPC-to-ACC neurons upon renewal in a novel context, where excitatory postsynaptic currents amplitudes increased but inhibitory postsynaptic current amplitudes decreased. In addition, we found that parvalbumin–expressing interneurons controlled novel context-dependent fear renewal, which was blocked by the chronic administration of fluoxetine.</p></div><div><h3>Conclusions</h3><p>Our findings highlight the PPC-to-ACC pathway in mediating the relapse of extinguished fear in novel contexts, thereby contributing significant insights into the intricate neural mechanisms that govern fear renewal.</p></div>","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"4 4","pages":"Article 100315"},"PeriodicalIF":0.0,"publicationDate":"2024-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2667174324000284/pdfft?md5=ae24fe8944c102ccfc38f3089aa41842&pid=1-s2.0-S2667174324000284-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140774870","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Segmentation and Volume Estimation of the Habenula Using Deep Learning in Patients With Depression","authors":"Yusuke Kyuragi ,&nbsp;Naoya Oishi ,&nbsp;Momoko Hatakoshi ,&nbsp;Jinichi Hirano ,&nbsp;Takamasa Noda ,&nbsp;Yujiro Yoshihara ,&nbsp;Yuri Ito ,&nbsp;Hiroyuki Igarashi ,&nbsp;Jun Miyata ,&nbsp;Kento Takahashi ,&nbsp;Kei Kamiya ,&nbsp;Junya Matsumoto ,&nbsp;Tomohisa Okada ,&nbsp;Yasutaka Fushimi ,&nbsp;Kazuyuki Nakagome ,&nbsp;Masaru Mimura ,&nbsp;Toshiya Murai ,&nbsp;Taro Suwa","doi":"10.1016/j.bpsgos.2024.100314","DOIUrl":"https://doi.org/10.1016/j.bpsgos.2024.100314","url":null,"abstract":"<div><h3>Background</h3><p>The habenula is involved in the pathophysiology of depression. However, its small structure limits the accuracy of segmentation methods, and the findings regarding its volume have been inconsistent. This study aimed to create a highly accurate habenula segmentation model using deep learning, test its generalizability to clinical magnetic resonance imaging, and examine differences between healthy participants and patients with depression.</p></div><div><h3>Methods</h3><p>This multicenter study included 382 participants (patients with depression: <em>N</em> = 234, women 47.0%; healthy participants: <em>N</em> = 148, women 37.8%). A 3-dimensional residual U-Net was used to create a habenula segmentation model on 3T magnetic resonance images. The reproducibility and generalizability of the predictive model were tested on various validation cohorts. Thereafter, differences between the habenula volume of healthy participants and that of patients with depression were examined.</p></div><div><h3>Results</h3><p>A Dice coefficient of 86.6% was achieved in the derivation cohort. The test-retest dataset showed a mean absolute percentage error of 6.66, indicating sufficiently high reproducibility. A Dice coefficient of &gt;80% was achieved for datasets with different imaging conditions, such as magnetic field strengths, spatial resolutions, and imaging sequences, by adjusting the threshold. A significant negative correlation with age was observed in the general population, and this correlation was more pronounced in patients with depression (<em>p</em> &lt; 10⁻⁷, <em>r</em> = −0.59). Habenula volume decreased with depression severity in women even when the effects of age and scanner were excluded (<em>p</em> = .019, η² = 0.099).</p></div><div><h3>Conclusions</h3><p>Habenula volume could be a pathophysiologically relevant factor and diagnostic and therapeutic marker for depression, particularly in women.</p></div>","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"4 4","pages":"Article 100314"},"PeriodicalIF":0.0,"publicationDate":"2024-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2667174324000272/pdfft?md5=cd0346c4a7672f3d362fb35a88c9489c&pid=1-s2.0-S2667174324000272-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140825195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Causally Probing the Role of the Hippocampus in Fear Discrimination: A Precision Functional Mapping–Guided, Transcranial Magnetic Stimulation Study in Participants With Posttraumatic Stress Symptoms","authors":"Ryan D. Webler ,&nbsp;Cristian Morales Carrasco ,&nbsp;Samuel E. Cooper ,&nbsp;Mo Chen ,&nbsp;Christopher O. Hunt ,&nbsp;Sierra Hennessy ,&nbsp;Lancy Cao ,&nbsp;Carol Lam ,&nbsp;Allen Chiu ,&nbsp;Cash Differding ,&nbsp;Erin Todd ,&nbsp;Timothy J. Hendrickson ,&nbsp;Desmond J. Oathes ,&nbsp;Alik S. Widge ,&nbsp;Robert J.M. Hermosillo ,&nbsp;Steven M. Nelson ,&nbsp;Damien A. Fair ,&nbsp;Shmuel M. Lissek ,&nbsp;Ziad Nahas","doi":"10.1016/j.bpsgos.2024.100309","DOIUrl":"10.1016/j.bpsgos.2024.100309","url":null,"abstract":"<div><h3>Background</h3><p>Fear overgeneralization is a promising pathogenic mechanism of clinical anxiety. A dominant model posits that hippocampal pattern separation failures drive overgeneralization. Hippocampal network–targeted transcranial magnetic stimulation (HNT-TMS) has been shown to strengthen hippocampal-dependent learning/memory processes. However, no study has examined whether HNT-TMS can alter fear learning/memory.</p></div><div><h3>Methods</h3><p>Continuous theta burst stimulation was delivered to individualized left posterior parietal stimulation sites derived via seed-based connectivity, precision functional mapping, and electric field modeling methods. A vertex control site was also stimulated in a within-participant, randomized controlled design. Continuous theta burst stimulation was delivered prior to 2 visual discrimination tasks (1 fear based, 1 neutral). Multilevel models were used to model and test data. Participants were undergraduates with posttraumatic stress symptoms (final <em>n</em> = 25).</p></div><div><h3>Results</h3><p>Main analyses did not indicate that HNT-TMS strengthened discrimination. However, multilevel interaction analyses revealed that HNT-TMS strengthened fear discrimination in participants with lower fear sensitization (indexed by responses to a control stimulus with no similarity to the conditioned fear cue) across multiple indices (anxiety ratings: β = 0.10, 95% CI, 0.04 to 0.17, <em>p</em> = .001; risk ratings: β = 0.07, 95% CI, 0.00 to 0.13, <em>p</em> = .037).</p></div><div><h3>Conclusions</h3><p>Overgeneralization is an associative process that reflects deficient discrimination of the fear cue from similar cues. In contrast, sensitization reflects nonassociative responding unrelated to fear cue similarity. Our results suggest that HNT-TMS may selectively sharpen fear discrimination when associative response patterns, which putatively implicate the hippocampus, are more strongly engaged.</p></div>","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"4 3","pages":"Article 100309"},"PeriodicalIF":0.0,"publicationDate":"2024-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2667174324000223/pdfft?md5=7a9516295d2cdd0fa8af53013eee1ed2&pid=1-s2.0-S2667174324000223-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140274399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Carbon Dioxide Reactivity Differentially Predicts Fear Expression After Extinction and Retrieval-Extinction in Rats","authors":"Marissa Raskin ,&nbsp;Nicole E. Keller ,&nbsp;Laura A. Agee ,&nbsp;Jason Shumake ,&nbsp;Jasper A.J. Smits ,&nbsp;Michael J. Telch ,&nbsp;Michael W. Otto ,&nbsp;Hongjoo J. Lee ,&nbsp;Marie-H. Monfils","doi":"10.1016/j.bpsgos.2024.100310","DOIUrl":"10.1016/j.bpsgos.2024.100310","url":null,"abstract":"<div><h3>Background</h3><p>Cues present during a traumatic event may result in persistent fear responses. These responses can be attenuated through extinction learning, a core component of exposure therapy. Exposure/extinction is effective for some people, but not all. We recently demonstrated that carbon dioxide (CO₂) reactivity predicts fear extinction memory and orexin activation and that orexin activation predicts fear extinction memory, which suggests that a CO₂ challenge may enable identification of whether an individual is a good candidate for an extinction-based approach. Another method to attenuate conditioned responses, retrieval-extinction, renders the original associative memory labile via distinct neural mechanisms. The purpose of the current study was to examine whether we could replicate previous findings that retrieval-extinction is more effective than extinction at preventing the return of fear and that CO₂ reactivity predicts fear memory after extinction. We also examined whether CO₂ reactivity predicts fear memory after retrieval-extinction.</p></div><div><h3>Methods</h3><p>Male rats first underwent a CO₂ challenge and fear conditioning and were assigned to receive either standard extinction (<em>n</em> = 28) or retrieval-extinction (<em>n</em> = 28). Then, they underwent a long-term memory (LTM) test and a reinstatement test.</p></div><div><h3>Results</h3><p>We found that retrieval-extinction resulted in lower freezing during extinction, LTM, and reinstatement than standard extinction. Using the best subset approach to linear regression, we found that CO₂ reactivity predicted LTM after extinction and also predicted LTM after retrieval-extinction, although to a lesser degree.</p></div><div><h3>Conclusions</h3><p>CO₂ reactivity could be used as a screening tool to determine whether an individual may be a good candidate for an extinction-based therapeutic approach.</p></div>","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"4 3","pages":"Article 100310"},"PeriodicalIF":0.0,"publicationDate":"2024-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2667174324000235/pdfft?md5=c817ee5a2326365cdef19c645837a09c&pid=1-s2.0-S2667174324000235-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140278665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Role of Subgenual Resting-State Connectivity Networks in Predicting Prognosis in Major Depressive Disorder","authors":"Diede Fennema ,&nbsp;Gareth J. Barker ,&nbsp;Owen O’Daly ,&nbsp;Suqian Duan ,&nbsp;Ewan Carr ,&nbsp;Kimberley Goldsmith ,&nbsp;Allan H. Young ,&nbsp;Jorge Moll ,&nbsp;Roland Zahn","doi":"10.1016/j.bpsgos.2024.100308","DOIUrl":"10.1016/j.bpsgos.2024.100308","url":null,"abstract":"<div><h3>Background</h3><p>A seminal study found higher subgenual frontal cortex resting-state connectivity with 2 left ventral frontal regions and the dorsal midbrain to predict better response to psychotherapy versus medication in individuals with treatment-naïve major depressive disorder (MDD). Here, we examined whether these subgenual networks also play a role in the pathophysiology of clinical outcomes in MDD with early treatment resistance in primary care.</p></div><div><h3>Methods</h3><p>Forty-five people with current MDD who had not responded to ≥2 serotonergic antidepressants (<em>n</em> = 43, meeting predefined functional magnetic resonance imaging minimum quality thresholds) were enrolled and followed over 4 months of standard care. Functional magnetic resonance imaging resting-state connectivity between the preregistered subgenual frontal cortex seed and 3 previously identified left ventromedial, ventrolateral prefrontal/insula, and dorsal midbrain regions was extracted. The clinical outcome was the percentage change on the self-reported 16-item Quick Inventory of Depressive Symptomatology.</p></div><div><h3>Results</h3><p>We observed a reversal of our preregistered hypothesis in that higher resting-state connectivity between the subgenual cortex and the a priori ventrolateral prefrontal/insula region predicted favorable rather than unfavorable clinical outcomes (<em>r</em>_<em>s</em>₃₉ = −0.43, <em>p</em> = .006). This generalized to the sample including participants with suboptimal functional magnetic resonance imaging quality (<em>r</em>_<em>s</em>₄₃ = −0.35, <em>p</em> = .02). In contrast, no effects (<em>r</em>_<em>s</em>₃₉ = 0.12, <em>r</em>_<em>s</em>₃₉ = −0.01) were found for connectivity with the other 2 preregistered regions or in a whole-brain analysis (voxel-based familywise error–corrected <em>p</em> &lt; .05).</p></div><div><h3>Conclusions</h3><p>Subgenual connectivity with the ventrolateral prefrontal cortex/insula is relevant for subsequent clinical outcomes in current MDD with early treatment resistance. Its positive association with favorable outcomes could be explained primarily by psychosocial rather than the expected pharmacological changes during the follow-up period.</p></div>","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"4 3","pages":"Article 100308"},"PeriodicalIF":0.0,"publicationDate":"2024-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2667174324000211/pdfft?md5=cb47f1f2aef4f224ee0b415359e1d315&pid=1-s2.0-S2667174324000211-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140277614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Examining Differences in the Genetic and Functional Architecture of Attention-Deficit/Hyperactivity Disorder Diagnosed in Childhood and Adulthood","authors":"Sophie Breunig ,&nbsp;Jeremy M. Lawrence ,&nbsp;Isabelle F. Foote ,&nbsp;Hannah J. Gebhardt ,&nbsp;Erik G. Willcutt ,&nbsp;Andrew D. Grotzinger","doi":"10.1016/j.bpsgos.2024.100307","DOIUrl":"https://doi.org/10.1016/j.bpsgos.2024.100307","url":null,"abstract":"<div><h3>Background</h3><p>Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder with diagnostic criteria requiring symptoms to begin in childhood. We investigated whether individuals diagnosed as children differ from those diagnosed in adulthood with respect to shared and unique architecture at the genome-wide and gene expression level of analysis.</p></div><div><h3>Methods</h3><p>We used genomic structural equation modeling (SEM) to investigate differences in genetic correlations (<em>r</em>_<em>g</em>) of childhood-diagnosed (<em>n</em>_{<em>cases</em>} = 14,878) and adulthood-diagnosed (<em>n</em>_{<em>cases</em>} = 6961) ADHD with 98 behavioral, psychiatric, cognitive, and health outcomes. We went on to apply transcriptome-wide SEM to identify functional annotations and patterns of gene expression associated with genetic risk sharing or divergence across the ADHD subgroups.</p></div><div><h3>Results</h3><p>Compared with the childhood subgroup, adulthood-diagnosed ADHD exhibited a significantly larger negative <em>r</em>_<em>g</em> with educational attainment, the noncognitive skills of educational attainment, and age at first sexual intercourse. We observed a larger positive <em>r</em>_<em>g</em> for adulthood-diagnosed ADHD with major depression, suicidal ideation, and a latent internalizing factor. At the gene expression level, transcriptome-wide SEM analyses revealed 22 genes that were significantly associated with shared genetic risk across the subtypes that reflected a mixture of coding and noncoding genes and included 15 novel genes relative to the ADHD subgroups.</p></div><div><h3>Conclusions</h3><p>This study demonstrated that ADHD diagnosed later in life shows much stronger genetic overlap with internalizing disorders and related traits. This may indicate the potential clinical relevance of distinguishing these subgroups or increased misdiagnosis for those diagnosed later in life. Top transcriptome-wide SEM results implicated genes related to neuronal function and clinical characteristics (e.g., sleep).</p></div>","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"4 3","pages":"Article 100307"},"PeriodicalIF":0.0,"publicationDate":"2024-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S266717432400020X/pdfft?md5=3ca5ec9970a8199978e570c835878074&pid=1-s2.0-S266717432400020X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140546332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Complement C5a Receptor Signaling Alters Stress Responsiveness and Modulates Microglia Following Chronic Stress Exposure","authors":"Hsiao-Jou Cortina Chen ,&nbsp;Jereme G. Spiers ,&nbsp;Titaya Lerskiatiphanich ,&nbsp;Sandra E. Parker ,&nbsp;Nickolas A. Lavidis ,&nbsp;Jenny N. Fung ,&nbsp;Trent M. Woodruff ,&nbsp;John D. Lee","doi":"10.1016/j.bpsgos.2024.100306","DOIUrl":"10.1016/j.bpsgos.2024.100306","url":null,"abstract":"<div><h3>Background</h3><p>Accumulating evidence underscores the pivotal role of heightened inflammation in the pathophysiology of stress-related diseases, but the underlying mechanisms remain elusive. The complement system, a key effector of the innate immune system, produces the C5–cleaved activation product C5a upon activation, initiating inflammatory responses through the canonical C5a receptor 1 (C5aR1). While C5aR1 is expressed in stress-responsive brain regions, its role in stress responsiveness remains unknown.</p></div><div><h3>Methods</h3><p>To investigate C5a-C5aR1 signaling in stress responses, mice underwent acute and chronic stress paradigms. Circulating C5a levels and messenger RNA expression of C5aR1 in the hippocampus and adrenal gland were measured. C5aR1-deficient mice were used to elucidate the effects of disrupted C5a-C5aR1 signaling across behavioral, hormonal, metabolic, and inflammation parameters.</p></div><div><h3>Results</h3><p>Chronic restraint stress elevated circulating C5a levels while reducing C5aR1 messenger RNA expression in the hippocampus and adrenal gland. Notably, the absence of C5aR1 signaling enhanced adrenal sensitivity to adrenocorticotropic hormone, concurrently reducing pituitary adrenocorticotropic hormone production and enhancing the response to acute stress. C5aR1-deficient mice exhibited attenuated reductions in locomotor activity and body weight under chronic stress. Additionally, these mice displayed increased glucocorticoid receptor sensitivity and disrupted glucose and insulin homeostasis. Chronic stress induced an increase in C5aR1-expressing microglia in the hippocampus, a response mitigated in C5aR1-deficient mice.</p></div><div><h3>Conclusions</h3><p>C5a-C5aR1 signaling emerges as a key metabolic regulator during stress, suggesting that complement activation and dysfunctional C5aR1 signaling may contribute to neuroinflammatory phenotypes in stress-related disorders. The results advocate for further exploration of complement C5aR1 as a potential therapeutic target for stress-related conditions.</p></div>","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"4 3","pages":"Article 100306"},"PeriodicalIF":0.0,"publicationDate":"2024-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2667174324000193/pdfft?md5=89f35819977dcab92fc7ad91573cc714&pid=1-s2.0-S2667174324000193-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140282257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Guide for Authors","authors":"","doi":"10.1016/S2667-1743(24)00016-8","DOIUrl":"https://doi.org/10.1016/S2667-1743(24)00016-8","url":null,"abstract":"","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"4 2","pages":"Article 100303"},"PeriodicalIF":0.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2667174324000168/pdfft?md5=7ecdec12c83f82a66840b3044549899e&pid=1-s2.0-S2667174324000168-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140133997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}