Developmental Neuroscience最新文献

{"title":"Obsessive-Compulsive Disorder Associated with Autoimmunity in Youth: Clinical Course before and after Rituximab +/- Adjunctive Immunomodulation.","authors":"Jennifer Frankovich, Denise Calaprice, Meiqian Ma, Olivia Knight, Kate Miles, Cindy Manko, Joseph D Hernandez, Jesse Sandberg, Bahare Farhadian, Yuhuan Xie, Melissa Silverman, Juliette Madan, Vibeke Strand, Kiki Chang, Margo Thienemann, Jennifer Frankovich","doi":"10.1159/000544993","DOIUrl":"10.1159/000544993","url":null,"abstract":"<p><strong>Introduction: </strong>Multiple lines of evidence suggest that some cases of obsessive-compulsive disorder (OCD) are underlain by autoimmune and/or inflammatory processes that act on the brain to create neuropsychiatric symptomatology. However, studies of immunomodulatory treatments for such cases are sparse. Here we present consecutive cases of presumed-neuroimmune OCD in youth that have been treated with rituximab +/- adjunctive immunomodulatory treatments.</p><p><strong>Methods: </strong>Of the 458 cases evaluated by our clinic between September 15, 2012, and January 6, 2023, 23 patients were treated with rituximab +/- adjunctive immunomodulation orchestrated by our team (based on evidence of autoimmunity) and were followed routinely by the outpatient clinic team. Patients who presented for a second opinion and were not diagnosed, treated, and/or followed by our outpatient clinic (n = 5) or did not have OCD (n = 1) are not included. We present the immunological and psychiatric profiles (prior to treatment), selection criteria for the use of rituximab, rituximab treatment protocol, recovery status, and reasons for discontinuation (if applicable). Data were obtained from chart review of clinical records. Determination of recovery status was confirmed by the clinical team caring for the patients; patients were classified as did not recover, partial recovery (PR), or full recovery (FR). Since multiple treatments (psychotherapy, psychiatric medication, and immunomodulation) together contributed to recovery, the team additionally assessed the attribution of response to rituximab and details are documented.</p><p><strong>Results: </strong>Patients were between the ages of 4 and 20 at initiation of rituximab treatment. All suffered from severe, debilitating neuropsychiatric symptoms prior to rituximab initiation in the context of evidence for systemic autoimmunity. Approximately 70% had an unequivocal recovery following treatment with rituximab (+/- induction and adjunctive immunomodulation) which in most cases allowed the patients to achieve normal levels of function and cease psychotropic medications. Interpretation of attribution in many cases is complicated by the use of induction and adjunct immunomodulation. Most patients experienced transient increases in symptoms before improving; 11 experienced mild self-limited infusion-related reactions, and 14 experienced hypogammaglobulinemia. No patient had an organ or life-threatening reaction or infection following rituximab. One patient developed recurrent sinusitis following rituximab, and thus, rituximab was stopped despite neuropsychiatric improvements, then rituximab was restarted later due to recrudescence of psychiatric symptoms; the approval to use rituximab with intravenous immune globulin (IVIG) permitted its use. Patients who received adjunctive immunomodulation (IVIG, methotrexate, leflunomide, etc.) had a higher likelihood of achieving recovery (FR or PR) after rituximab (Fisher","PeriodicalId":50585,"journal":{"name":"Developmental Neuroscience","volume":" ","pages":"251-269"},"PeriodicalIF":2.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143598345","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Defining Clinical Course of Patients Evaluated for Pediatric Acute-Onset Neuropsychiatric Syndrome: Phenotypic Classification Based on 10 Years of Clinical Data.","authors":"Erin E Masterson, Kate Miles, Noelle Schlenk, Cindy Manko, Meiqian Ma, Bahare Farhadian, Kiki Chang, Melissa Silverman, Margo Thienemann, Jennifer Frankovich, Jennifer Frankovich","doi":"10.1159/000545598","DOIUrl":"10.1159/000545598","url":null,"abstract":"<p><strong>Introduction: </strong>Establishing clear and standardized terminology regarding disease state and course is crucial for enhancing communication, research, and treatment decisions, particularly when there are no clearly identified biological markers, as in the case of pediatric acute-onset neuropsychiatric syndrome (PANS). We aim to propose terminology for assessing disease state and classifying long-term clinical courses in individuals evaluated for PANS, advancing standardization in clinical care and research.</p><p><strong>Methods: </strong>We drew upon clinical expertise, insights from similar conditions, and a decade of longitudinal clinical data from the Stanford University Immune Behavioral Health (IBH) Clinic to devise terminology for characterizing patient status and clinical progression among patients evaluated for PANS. Utilizing parent- and clinician-reported data spanning from 2012 to 2023, we constructed a comprehensive dataset documenting patients' disease trajectory from initial flare to latest clinical encounter, encompassing intervening recovery periods. This allowed us to apply the proposed terminology to the IBH Clinic patient cohort, offering a detailed phenotypic analysis of PANS flares and clinical courses.</p><p><strong>Results: </strong>We analyzed 264 patients evaluated for PANS at the IBH Clinic and stratified them based on whether they met PANS criteria at initial flare (51%), after initial flare (24%), or had not met criteria at the time of analysis (25%). The average age at the initial flare ranged from 6.1 to 8.3 years across these patient subgroups. Among patients with PANS, the average isolated flare lasted 3.7-4.1 months and 95% of flares resolved within 1 year. Five years after initial flare, most (77%) patients with PANS had had multiple flares, and nearly half (43%) had experienced a flare that lasted >12 months, approximately half of which occurred at the initial flare.</p><p><strong>Conclusions: </strong>Patients evaluated for PANS at the IBH Clinic showed diverse clinical presentations and illness courses over the long term, with most experiencing a relapsing-remitting clinical course but some exhibiting persistent symptoms. Many experienced neuropsychiatric flares before meeting PANS classification criteria. This underscores the importance of clinicians being vigilant for new neuropsychiatric symptoms in pediatric patients, even if they do not immediately meet PANS criteria. Based on these data, we propose terms and definitions for characterizing patient status, flares, and clinical course, which we hope the clinical and research communities will build on and refine.</p>","PeriodicalId":50585,"journal":{"name":"Developmental Neuroscience","volume":" ","pages":"270-286"},"PeriodicalIF":2.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143796897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Eight Cases of Pediatric Acute-Onset Neuropsychiatric Syndrome with Inflammatory Bowel Disease: Immunologic Intersections.","authors":"Angela W Tang, Paula M Prieto Jimenez, Ian K T Miller, Juliette C Madan, Jaden Nguyen, Meiqian Ma, Melissa Silverman, Bahare Farhadian, Jenny Wilson, Alka Goyal, Cindy Manko, Yinka Davies, Shervin Rabizadeh, Jennifer Frankovich, Angela Tang","doi":"10.1159/000543969","DOIUrl":"10.1159/000543969","url":null,"abstract":"<p><p><p>Introduction: Pediatric acute-onset neuropsychiatric syndrome (PANS) is an immune-mediated disease characterized by abrupt onset neurobehavioral changes. Inflammatory bowel disease (IBD) includes ulcerative colitis (UC) and Crohn's disease (CD), chronic conditions characterized by gastrointestinal inflammation. We describe eight individuals with both PANS and IBD.</p><p><strong>Methods: </strong>All individuals with both IBD and PANS were identified from Stanford Immune Behavioral Health Clinic, Cedars-Sinai Medical Center Pediatric Inflammatory Bowel Disease Program, and Dartmouth Neuroimmune Psychiatric Disorders (NIPD) Clinic. Data were collected by chart review.</p><p><strong>Results: </strong>Eight cases of PANS with IBD were identified. Five were male. The mean age of onset was 9.3 years for PANS and 15.6 years for IBD. PANS preceded development of IBD in 7 of 8 cases by a mean of 8.4 years. Seven patients (88%) had a first-degree relative with an immune-mediated disease, including 5 with psoriasis or psoriatic arthritis. Five patients themselves had arthralgias or arthritis (63%). All 5 cases where PANS preceded IBD treatment sufficiently for analysis were free of major behavioral relapses after IBD was managed.</p><p><strong>Conclusion: </strong>The triad of PANS, joint complaints, and family history of autoimmunity, including psoriasis, may represent a subset of PANS at heightened risk for IBD and additional immune-mediated disorders. For children with this triad, clinicians should have a low threshold to evaluate for gastrointestinal inflammation with biomarkers like hemoglobin, CRP, fecal calprotectin, and diagnostic endoscopy when indicated. PANS symptoms may improve with effective treatment of IBD. The high prevalence of joint complaints in our cohort and psoriasis in first-degree family members suggests this subset of PANS may share immune mechanisms with psoriasis and arthritis. Treatment strategies used in IBD and arthritis should be studied for potential application in PANS. </p>.</p>","PeriodicalId":50585,"journal":{"name":"Developmental Neuroscience","volume":" ","pages":"287-302"},"PeriodicalIF":2.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077855/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143392458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Erratum.","authors":"Marta Raposo","doi":"10.1159/000545629","DOIUrl":"10.1159/000545629","url":null,"abstract":"","PeriodicalId":50585,"journal":{"name":"Developmental Neuroscience","volume":" ","pages":"418"},"PeriodicalIF":2.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144004325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Relationship between Early Exposure to General Anesthesia and Neurobehavioral Deficits.","authors":"Jia Yan, Jinnan Xu, Fan Wang, Yi Gao, Chuanyu Qi, Tiannan Chen, Jia Yan","doi":"10.1159/000542005","DOIUrl":"10.1159/000542005","url":null,"abstract":"<p><strong>Background: </strong>In contemporary medical practice, general anesthesia plays an essential role in pediatric surgical procedures. While modern anesthetic protocols have demonstrated safety and efficacy across various pathological conditions, concerns persist regarding the potential neurotoxic effects associated with early exposure to general anesthesia.</p><p><strong>Summary: </strong>Current research primarily examines the neurocognitive developmental impacts, with limited focus on neurobehavioral developmental disorders. This review presents a comprehensive analysis of clinical trial results related to five critical neurobehavioral developmental disorders: fine motor disability, attention-deficit hyperactivity disorder, impulse control disorders, autism spectrum disorder, and developmental coordination disorder. Furthermore, this review synthesizes insights from basic research on the potential toxicological mechanisms of general anesthetic agents that could influence clinical neurobehavioral changes. These findings provide valuable guidance for the prudent and safe utilization of anesthetic agents in pediatric patients.</p><p><strong>Key messages: </strong>This review explores the potential connections between general anesthesia and five neurobehavioral disorders, highlighting the importance of cautious anesthetic use in children in light of current research findings.</p>","PeriodicalId":50585,"journal":{"name":"Developmental Neuroscience","volume":" ","pages":"383-399"},"PeriodicalIF":2.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12500287/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142479781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Peripuberty Is a Sensitive Period for Prefrontal Parvalbumin Interneuron Activity to Impact Adult Cognitive Flexibility.","authors":"Gabriella M Sahyoun, Trang Dao Do, Amanda Anqueira-Gonzàlez, Ava Hornblass, Sarah E Canetta","doi":"10.1159/000539584","DOIUrl":"10.1159/000539584","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Introduction: &lt;/strong&gt;Developmental windows in which experiences can elicit long-lasting effects on brain circuitry and behavior are called \"sensitive periods\" and reflect a state of heightened plasticity. The classic example of a sensitive period comes from studies of sensory systems, like the visual system, where early visual experience is required for normal wiring of primary visual cortex and proper visual functioning. At a mechanistic level, loss of incoming visual input results in a decrease in activity in thalamocortical neurons representing the affected eye, resulting in an activity-dependent reduction in the representation of those inputs in the visual cortex and loss of visual perception in that eye. While associative cortical regions like the medial prefrontal cortex (mPFC) do not receive direct sensory input, recent findings demonstrate that changes in activity levels experienced by this region during defined windows in early development may also result in long-lasting changes in prefrontal cortical circuitry, network function, and behavior. For example, we recently demonstrated that decreasing the activity of mPFC parvalbumin-expressing (PV) interneurons during a period of time encompassing peripuberty (postnatal day P14) to adolescence (P50) led to a long-lasting decrease in their functional inhibition of pyramidal cells, as well as impairments in cognitive flexibility. While the effects of manipulating mPFC PV interneuron activity were selective to development, and not adulthood, the exact timing of the sensitive period for this manipulation remains unknown.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;To refine the sensitive period in which inhibiting mPFC PV cell activity can lead to persistent effects on prefrontal functioning, we used a chemogenetic approach to restrict our inhibition of mPFC PV activity to two distinct windows: (1) peripuberty (P14-P32) and (2) early adolescence (P33-P50). We then investigated adult behavior after P90. In parallel, we performed histological analysis of molecular markers associated with sensitive period onset and offset in visual cortex, to define the onset and offset of peak-sensitive period plasticity in the mPFC.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;We found that inhibition of mPFC PV interneurons in peripuberty (P14-P32), but not adolescence (P33-P50), led to an impairment in set-shifting behavior in adulthood manifest as an increase in trials to reach criterion performance and errors. Consistent with a pubertal onset of sensitive period plasticity in the PFC, we found that histological markers of sensitive period onset and offset also demarcated P14 and P35, respectively. The time course of expression of these markers was similar in visual cortex.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;Both lines of research converge on the peripubertal period (P14-P32) as one of heightened sensitive period plasticity in the mPFC. Further, our direct comparison of markers of sensitive period plasticity across the pr","PeriodicalId":50585,"journal":{"name":"Developmental Neuroscience","volume":" ","pages":"127-138"},"PeriodicalIF":2.3,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11612032/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141238768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dexmedetomidine Alleviates the Long-Term Neurodevelopmental Toxicity Induced by Sevoflurane in the Developing Brain.","authors":"Ting-Ting Yang, Ran Wei, Fei-Fei Jin, Wei Yu, Fang Zhang, Yu Peng, Shu-Jun Zhang, Si-Hua Qi, Jia-Ren Liu","doi":"10.1159/000542114","DOIUrl":"10.1159/000542114","url":null,"abstract":"<p><strong>Introduction: </strong>Sevoflurane is an extensively used anesthetic for pediatric patients; however, numerous studies showed that sevoflurane (SEVO) may cause long-term neurodevelopmental toxicity. Dexmedetomidine (DEX) has been shown to be protective against SEVO-induced neurotoxicity, but the mechanism remains unclear. The effects and mechanisms of different DEX administration routes on SEVO-induced neurotoxicity and long-term cognitive defects were determined and further investigated the role of sex in these processes.</p><p><strong>Methods: </strong>Male and female Sprague Dawley rats at postnatal day 7 (PND7) received an intraperitoneal injection of DEX (10 μg/kg) before or after exposure to 2.5% SEVO for 6 h, or before and after SEVO exposure. The respiratory and mortality rates of the pups were recorded during anesthesia. Neuroapoptosis was evaluated by TdT-mediated dUTP nick-end labeling staining. Immunohistochemistry and immunofluorescence were employed to detect the expression of caspase-3 in neuronal cells and neurons. The expression of GSK-3β and DISC1 was determined by Western blotting or RT-qPCR. Morris water maze (MWM) test was used to evaluate the learning and memory ability of rats until they were 3 weeks and 5 weeks old.</p><p><strong>Results: </strong>Compared with the control group, exposure to 2.5% SEVO resulted in increased neuroapoptosis and decreased the expression of DISC1 at levels of mRNA and protein and phosphorylated GSK-3β in the developing brain. SEVO exposure during critical neurodevelopmental periods could cause persistent cognitive defects in adolescent male and female rats and inhibited DISC1 and phosphorylated GSK-3β protein expression. The neurotoxic impacts of SEVO were lessened by the administration of DEX (10 μg/kg) before or after exposure.</p><p><strong>Conclusion: </strong>Our findings suggest that DEX (10 μg/kg) mitigates the neurotoxic effects of SEVO on the developing rat brain as well as postnatal cognitive defects by regulating the DISC1/GSK-3β signaling.</p>","PeriodicalId":50585,"journal":{"name":"Developmental Neuroscience","volume":" ","pages":"193-205"},"PeriodicalIF":2.3,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12140586/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142479780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preclinical Milestones in MECP2 Gene Transfer for Treating Rett Syndrome.","authors":"Indumathy Jagadeeswaran, Jiyoung Oh, Sarah E Sinnett","doi":"10.1159/000539267","DOIUrl":"10.1159/000539267","url":null,"abstract":"<p><strong>Background: </strong>Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2). After gene transfer in mice, exogenous MeCP2 expression must be regulated to avoid dose-dependent toxicity.</p><p><strong>Summary: </strong>The preclinical gene therapy literature for treating RTT illustrates a duly diligent progression that begins with proof-of-concept studies and advances toward the development of safer, regulated MECP2 viral genome designs. This design progression was partly achieved through international collaborative studies. In 2023, clinicians administered investigational gene therapies for RTT to patients a decade after the first preclinical gene therapy publications for RTT (clinical trial numbers NCT05606614 and NCT05898620). As clinicians take on a more prominent role in MECP2 gene therapy research, preclinical researchers may continue to test more nuanced hypotheses regarding the safety, efficacy, and mechanism of MECP2 gene transfer.</p><p><strong>Key message: </strong>This review summarizes the history of preclinical MECP2 gene transfer for treating RTT and acknowledges major contributions among colleagues in the field. The first clinical injections are a shared milestone.</p><p><strong>Background: </strong>Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2). After gene transfer in mice, exogenous MeCP2 expression must be regulated to avoid dose-dependent toxicity.</p><p><strong>Summary: </strong>The preclinical gene therapy literature for treating RTT illustrates a duly diligent progression that begins with proof-of-concept studies and advances toward the development of safer, regulated MECP2 viral genome designs. This design progression was partly achieved through international collaborative studies. In 2023, clinicians administered investigational gene therapies for RTT to patients a decade after the first preclinical gene therapy publications for RTT (clinical trial numbers NCT05606614 and NCT05898620). As clinicians take on a more prominent role in MECP2 gene therapy research, preclinical researchers may continue to test more nuanced hypotheses regarding the safety, efficacy, and mechanism of MECP2 gene transfer.</p><p><strong>Key message: </strong>This review summarizes the history of preclinical MECP2 gene transfer for treating RTT and acknowledges major contributions among colleagues in the field. The first clinical injections are a shared milestone.</p>","PeriodicalId":50585,"journal":{"name":"Developmental Neuroscience","volume":" ","pages":"147-156"},"PeriodicalIF":2.3,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11965835/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140899633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dysregulation of Brain Cholesterol Biosynthetic Pathway following Hypoxia Ischemia in Neonatal Mice.","authors":"Fuxin Lu, Celeste Yen, Chase D Corley, Jeffrey G McDonald, Tiina Manninen, Nicholas R Stewart, Christina M Zhu, Donna M Ferriero, Xiangning Jiang","doi":"10.1159/000543254","DOIUrl":"10.1159/000543254","url":null,"abstract":"<p><strong>Introduction: </strong>Brain cholesterol relies on de novo biosynthesis and is crucial for brain development. Cholesterol synthesis is a complex series of reactions that involves more than twenty enzymes to reach the final product and generates a large number of intermediate sterols along two alternate pathways. This is a highly regulated and oxygen-dependent process and thus sensitive to hypoxia.</p><p><strong>Methods: </strong>Using the modified Vannucci procedure, a clinically relevant animal model of neonatal hypoxia ischemia (HI), we characterized the profile of cholesterol and its sterol intermediates, along with the key enzymes on the cholesterol synthetic pathway over a time course of 5 days after HI in the postnatal day 10 mouse brain.</p><p><strong>Results: </strong>Although the total cholesterol levels in the injured cortices appeared to be minimally attenuated at 5 days following HI, there was an overall repression of brain cholesterol biosynthesis. Lanosterol and the downstream sterols in both the Bloch and Kandutsch-Russell (K-R) pathways were consistently reduced for up to 3 days except for desmosterol, which was elevated. Correspondingly, protein expression of the controlling transcription factors sterol regulatory element-binding protein 2 (SREBP-2) and SREBP-1 was decreased at early time points (within 6 h), in parallel with the downregulation of several substrate enzymes for up to 5 days post-HI. HMG-CoA reductase (HMGCR), the first rate-limiting enzyme, was upregulated in the first 24 h after HI. The expression of 24-dehydrocholesterol reductase (DHCR24) that catalyzes the last step to produce cholesterol on the Bloch pathway and bridges the Bloch to K-R pathway was also augmented.</p><p><strong>Conclusions: </strong>Our data suggest perturbed brain cholesterol biosynthesis following neonatal HI. As some sterol intermediates and enzymes have diverse functions in brain development and stress responses other than producing cholesterol, assessment of their dynamic changes after HI is important to understand the lipid responses in rodent HI models and to identify lipid-based targeted therapies in future studies.</p>","PeriodicalId":50585,"journal":{"name":"Developmental Neuroscience","volume":" ","pages":"1-17"},"PeriodicalIF":2.0,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12179323/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142878360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Scutellariae radix Ameliorates Prenatal Stress-Induced Anxiety-Like and Depression-Like Behavior in the Offspring via Reversing HPA Axis Hyperfunction and Ameliorating Neurodevelopmental Dysfunction.","authors":"Lixia Li, Wenying Zhang, Congying Sun, Zhiqiang Chai, Kaiyue Wang, Qian Zhou, Xiaoying Wang","doi":"10.1159/000543152","DOIUrl":"10.1159/000543152","url":null,"abstract":"<p><strong>Introduction: </strong>This study aimed to explore the impact and mechanism of Scutellariae radix (SR), dried root of Scutellaria baicalensis Georgi of Labiatae, on prenatal stress (PS)-induced anxiety-like and depression-like behavior in the offspring in a mouse prenatal stress model.</p><p><strong>Methods: </strong>The open field test (OFT), tail suspension test (TST), and forced swimming test (FST) were utilized to assess the behavior of the offspring. Histological changes were evaluated using HE staining and Nissl staining. ELISA was employed to detect the levels of related factors in the serum and fetal brains of offspring mice. Immunohistochemistry was used to determine the expressions of doublecortin and neurotrophic factors in the hippocampus, and RT-PCR reflected the expression of factors in the hippocampus and placenta of offspring mice. These various techniques collectively provided insight into the neurodevelopmental status by detecting indicators related to neurodevelopmental status. LC-MS/MS and molecular docking were used to clarify the chemical constituents and the pharmacodynamic components in S. radix.</p><p><strong>Results: </strong>S. radix ameliorated prenatal stress-induced anxiety-like and depression-like behavior in the offspring. It also alleviated hippocampal neurogenesis impairment caused by prenatal stress and restored abnormal expression of hippocampal glutamate (Glu) and brain-derived neurotrophic factor in the offspring. Additionally, S. radix maintained normal 11β-HSD1 expression in the placenta of prenatal stress mice, ensuring a normal level of glucocorticoids (GCs) and glucocorticoid receptors (GRs) in the fetus. Furthermore, S. radix increased the mRNA expression of GR and 11β-HSD2 while decreasing the mRNA expression of 11β-HSD1, thereby normalizing levels of serum CRH, ACTH, and GC in the offspring. Finally, docking results indicated that baicalein, wogonin, wogonoside, and baicalin exhibited stronger binding ability with the target.</p><p><strong>Conclusion: </strong>The results of our study indicate that S. radix may have the potential to alleviate prenatal stress-induced anxiety-like and depression-like behaviors in offspring, at least partially through protecting placental barrier function, reversing HPA axis hyperfunction, and ameliorating neurodevelopmental dysfunction.</p>","PeriodicalId":50585,"journal":{"name":"Developmental Neuroscience","volume":" ","pages":"1-19"},"PeriodicalIF":2.3,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142866122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}