Introduction: 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. Methods: 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. Results: 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 hours), 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 hours 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. Conclusions: 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.

Fuxin Lu

Celeste Yen

Chase D. Corley

Jeffrey G. McDonald

Tiina Manninen

Nicholas R. Stewart

Christina M. Zhu

Donna M. Ferriero

Xiangning Jiang

Developmental Neuroscience

《DEVELOPMENTAL NEUROSCIENCE》是一本多学科期刊，发表论文涵盖无脊椎动物、脊椎动物和人类大脑发育的所有阶段。重点放在发表有助于我们理解正常发育机制以及异常大脑发育的遗传和环境原因的基础研究和转化研究。因此，该杂志为医生和生物学家提供了有价值的信息。为了满足读者快速增长的信息需求，该杂志将报告发育神经科学进展和进展的原创论文与简明的小型评论相结合，及时概述关键主题、新见解和正在进行的争议。 《发育神经科学》的编辑水准很高。我们致力于只发表对该领域做出重大贡献的高质量、完整的论文。

Developmental Neuroscience is a multidisciplinary journal that publishes research papers covering all stages of brain development in invertebrates, vertebrates, and humans. The journal focuses on both basic and translational research that helps us understand the genetic and environmental factors influencing normal and abnormal brain development. As such, it provides valuable information for both clinicians and biologists. To meet the growing information needs of readers, the journal combines original papers with concise mini-reviews, offering timely overviews of key topics, new insights, and ongoing controversies in the field of developmental neuroscience. The editorial standards of Developmental Neuroscience are very high, and we are committed to publishing only high-quality, comprehensive papers that make significant contributions to the field.

《Developmental Neuroscience》是一本多学科期刊，发表涵盖无脊椎动物、脊椎动物及人类大脑发育各个阶段的研究论文。期刊重点关注基础研究和转化研究，这些研究有助于我们理解正常及异常大脑发育的遗传和环境因素。因此，该期刊为医生和生物学家提供了宝贵的信息。为了满足读者日益增长的信息需求，期刊结合了原创论文和简明的小型评论，及时概述发育神经科学领域的最新进展、关键主题、新见解及正在进行的争议。《Developmental Neuroscience》的编辑水准极高，我们致力于只发表对该领域做出重大贡献的高质量、完整的论文。

Category	Quartile
医学	4
医学, 发育生物学	4
医学, 神经科学	4

Dysregulation of brain cholesterol biosynthetic pathway following hypoxia-ischemia in neonatal mice

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