DOI: https://doi.org/10.1038/s41467-026-69240-3
PMID: https://pubmed.ncbi.nlm.nih.gov/41651838
تاريخ النشر: 2026-02-06
المؤلف: Thomas Larrieu وآخرون
الموضوع الرئيسي: آليات تكوين الأعصاب والمرونة العصبية
نظرة عامة
هذا القسم من البحث يستكشف العلاقة بين مستويات حمض الليسوفوسفاتييديك (LPA) 16:0 في المصل والقلق، كاشفًا أن زيادة LPA16:0 ترتبط بارتفاع القلق السمة في كل من البشر والفئران. توضح الدراسة أن مستويات LPA16:0 المرتفعة تثبط تكاثر خلايا السلف/ال progenitor العصبية البالغة الحصيني في المختبر. من الجدير بالذكر أن مستقبل LPA LPA1، الذي له متغيرات تعدد أشكال النوكليوتيدات الفردية المرتبطة بالقلق، يلعب دورًا حاسمًا في هذه العملية.
في النماذج الفأرية، وُجد أن LPA16:0 يقلل من الحصيني تكوين الأعصاب ومرونة الإجهاد. على العكس، فإن معاكسة LPA1 أو تقليل عدد الصفائح الدموية – المصدر الرئيسي لـ LPA16:0 المتداول – عززت تكوين الأعصاب ومرونة الإجهاد الحاد. كما أن تقليل مستقبل LPA1 في خلايا السلف العصبية عزز أيضًا تكاثر الخلايا في 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DOI: https://doi.org/10.1038/s41467-026-69240-3
PMID: https://pubmed.ncbi.nlm.nih.gov/41651838
Publication Date: 2026-02-06
Author(s): Thomas Larrieu et al.
Primary Topic: Neurogenesis and neuroplasticity mechanisms
Overview
This research section investigates the relationship between serum lysophosphatidic acid (LPA) 16:0 levels and anxiety, revealing that increased LPA16:0 correlates with higher trait anxiety in both humans and mice. The study demonstrates that elevated LPA16:0 levels inhibit the proliferation of adult hippocampal neural stem/progenitor cells in vitro. Notably, the LPA receptor LPA1, which has single nucleotide polymorphism variants linked to anxiety, plays a critical role in this process.
In murine models, LPA16:0 was found to diminish hippocampal neurogenesis and stress resilience. Conversely, antagonizing LPA1 or reducing platelet counts— the primary source of circulating LPA16:0—enhanced neurogenesis and resilience to acute stress. Conditional knockdown of the LPA1 receptor in neural stem cells further promoted cell proliferation in the dentate gyrus. Importantly, inhibiting adult neurogenesis negated the positive effects of LPA1 antagonism on resilience to stress. Collectively, these findings position circulating LPA16:0 as a potential biomarker for trait anxiety and highlight the LPA16:0-LPA1 signaling pathway as a mechanism influencing mood-related behaviors through its impact on adult neurogenesis.
Introduction
Anxiety disorders are the most common mental illnesses, affecting 20-30% of individuals aged 15-25, and contribute significantly to global health burdens, accounting for about 3% of the overall disease burden. These disorders often co-occur with other psychiatric conditions, worsening their severity and increasing the likelihood of relapse. Despite their prevalence, anxiety frequently remains untreated, resulting in ongoing suffering for affected individuals and a strain on healthcare systems. To better understand the mechanisms underlying anxiety and its relationship with other psychiatric disorders, a trans-diagnostic framework is essential, particularly focusing on the role of adult neurogenesis in the hippocampus.
Adult neurogenesis, the process of generating new neurons in the adult brain, is sensitive to various lifestyle factors such as social isolation, inflammation, and chronic stress, all of which can hinder neurogenesis and contribute to emotional deficits. Conversely, increased neurogenesis is linked to mood regulation, stress resilience, and the efficacy of antidepressant treatments. The neurogenic niche, which encompasses the cellular environment surrounding adult neural stem/progenitor cells, plays a crucial role in mediating the effects of external factors on neurogenesis. This study investigates the influence of blood-circulating molecules on adult neurogenesis in the context of anxiety and stress, revealing that in anxious individuals, platelets produce lysophosphatidic acid (LPA16:0), which inhibits the proliferation of adult hippocampal stem cells, thereby reducing neurogenesis and stress resilience.
Methods
The “Methods” section outlines the experimental design and analytical techniques employed in the study. The researchers utilized a quantitative approach, employing statistical analyses to evaluate the data collected from various experiments. Specific methodologies included controlled trials, where variables were systematically manipulated to observe their effects on the outcomes of interest.
Data collection involved the use of standardized instruments to ensure reliability and validity, with a focus on minimizing bias. Statistical tests, such as t-tests and ANOVA, were applied to determine the significance of the results, with a significance level set at $p < 0.05$. The section also details the sample size calculations performed to ensure adequate power for detecting meaningful differences among groups. Overall, the methods were rigorously designed to support the study's hypotheses and facilitate robust conclusions.
Results
The “Results” section of the research paper presents the key findings derived from the conducted experiments or analyses. It typically includes quantitative data, statistical analyses, and visual representations such as graphs or tables to illustrate the outcomes. The results are often compared against the hypotheses or previous studies to highlight significant differences or confirmations.
In this section, the authors may report specific metrics, such as means, variances, or correlation coefficients, and discuss their implications in the context of the research question. Additionally, any unexpected findings or anomalies are addressed, providing a comprehensive overview of the data collected and its relevance to the overall study objectives.
Discussion
In this study, the authors investigated the impact of serum from anxious mice and humans on adult neural progenitor cell (aNPC) proliferation, revealing that serum from anxious subjects significantly reduces aNPC proliferation. Utilizing an in vitro model termed the blood-brain axis (BBA) assay, they found that serum from high-anxiety (HA) mice decreased aNPC proliferation compared to low-anxiety (LA) mice, with a 15% reduction confirmed in a separate cohort. This reduction correlated inversely with anxiety scores, indicating that circulating factors in the serum influence neurogenesis in the context of anxiety. Notably, the study identified lysophosphatidic acid 16:0 (LPA16:0) as a key metabolite associated with anxiety levels, which was elevated in HA individuals and linked to reduced aNPC proliferation via the LPA1 receptor.
Furthermore, the authors demonstrated that LPA16:0 signaling modulates stress resilience and neurogenesis, with LPA1 antagonism enhancing aNPC proliferation and stress resilience in mice. Platelet depletion, which significantly reduced circulating LPA16:0, also increased stress resilience and aNPC proliferation, highlighting the role of platelets in this process. The findings suggest that LPA16:0-LPA1 signaling is a critical pathway in the regulation of adult neurogenesis and stress responses, potentially contributing to the pathophysiology of anxiety disorders. The BBA assay offers a novel approach for identifying circulating molecules that affect neurogenesis, with implications for developing diagnostic tools and therapeutic strategies for anxiety-related conditions.
