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The societal implication of sex and gender (SG) differences in brain are profound, as they influence brain development, behavior, and importantly, the presentation, prevalence, and therapeutic response to diseases. Technological advances have enabled speed up identification and characterization of SG differences during development and in psychopathologies. The main aim of this review is to elaborate on new technological advancements, such as genomics, imaging, and emerging biobanks, coupled with bioinformatics analyses of data generated from these technologies have facilitated the identification and characterization of SG differences in the human brain through development and psychopathologies. First, a brief explanation of SG concepts is provided, along with a developmental and evolutionary context. We then describe physiological SG differences in brain activity and function, and in psychopathologies identified through imaging techniques. We further provide an overview of insights into SG differences using genomics, specifically taking advantage of large cohorts and biobanks. We finally emphasize how bioinformatics analyses of big data generated by emerging technologies provides new opportunities to reduce SG disparities in health outcomes, including major challenges. [ABSTRACT FROM AUTHOR]

Background: The immune system of human and mouse neonates is relatively immature. However, innate lymphoid cells (ILCs), commonly divided into the subsets ILC1, ILC2, and ILC3, are already present in the placenta and other fetal compartments and exhibit higher activity than what is seen in adulthood. Recent reports have suggested the potential role of ILCs, especially ILC2s, in spontaneous preterm labor, which is associated with brain damage and subsequent long-term neurodevelopmental deficits. Therefore, we hypothesized that ILCs, and especially ILC2s, play a role in preterm brain injury. Methods: C57Bl/6J mice at postnatal day 6 were subjected to hypoxia-ischemia (HI) insult induced by left carotid artery ligation and subsequent exposure to 10% oxygen in nitrogen. The presence of ILCs and ILC2s in the brain was examined at different time points after HI. The contribution of ILC2s to HI-induced preterm brain damage was explored using a conditionally targeted ILC2-deficient mouse strain (Rorα fl/fl IL7r Cre ), and gray and white-matter injury were evaluated at 7 days post-HI. The inflammatory response in the injured brain was assessed using immunoassays and immunochemistry staining. Results: Significant increases in ILCs and ILC2s were observed at 24 h, 3 days, and 7 days post-HI in the injured brain hemisphere compared with the uninjured hemisphere in wild-type mice. ILC2s in the brain were predominantly located in the meninges of the injured ipsilateral hemispheres after HI but not in the brain parenchyma. Overall, we did not observe changes in cytokine/chemokine levels in the brains of Rorα fl/fl IL7r Cre mice compared with wild type animals apart from IL-13. Gray and white-matter tissue loss in the brain was not affected after HI in Rorα fl/fl IL7r Cre mice. Correspondingly, we did not find any differences in reactive microglia and astrocyte numbers in the brain in Rorα fl/fl IL7r Cre mice compared with wild-type mice following HI insult. Conclusion: After HI, ILCs and ILC2s accumulate in the injured brain hemisphere. However, ILC2s do not contribute to the development of brain damage in this mouse model of preterm brain injury. [ABSTRACT FROM AUTHOR]

Highlights • A novel image segmentation method for quantification of myelinated fibers in brain sections. • The developed algorithm converted to a program called" MyelinQ". • The program is automated, consistent and easy-to-use. • The method revealed that a viral mimic causes significant hypomyelination in neonatal mouse brain. Abstract The developing brain is very susceptible to environmental insults, and very immature infants often suffer from long-term neurological syndromes associated with white matter injuries such as periventricular leukomalacia. Infection and inflammation are important risk factors for neonatal brain white matter injuries, but the evaluation of white matter injury in animal models, especially the quantification of myelinated axons, has long been problematic due to the lack of ideal measurement methods. Here, we present an automated segmentation method, which we call MyelinQ, for the quantification of myelinated white matter in immunohistochemical DAB-stained sections of the neonatal mouse brain. Using MyelinQ, we show that a viral infection mimic agent, the Toll-like receptor 3 ligand Poly I:C, causes significant hypomyelination of white matter in the cortical and hippocampal fimbria regions, but not in the striatal caudoputamen region. We showed that MyelinQ can reliably produce results that are comparable to a method used in our previous publications. However, in comparison to the conventional method, MyelinQ has the advantages of being automated, objective and accurate. MyelinQ can analyze white matter in various specific brain regions and therefore provides a useful platform for the quantification of myelin and the evaluation of white matter injuries in animal models. MyelinQ and its code together with instructions for use can be found at: https://github.com/parham-ap/myelinq. [ABSTRACT FROM AUTHOR]

Abnormal myelination underlies the pathology of white matter diseases such as preterm white matter injury and multiple sclerosis. Osteopontin (OPN) has been suggested to play a role in myelination. Murine OPN mRNA is translated into a secreted isoform (sOPN) or an intracellular isoform (iOPN). Whether there is an isoform-specific involvement of OPN in myelination is unknown. Here we generated mouse models that either lacked both OPN isoforms in all cells (OPN-KO) or lacked sOPN systemically but expressed iOPN specifically in oligodendrocytes (OLs-iOPN-KI). Transcriptome analysis of isolated oligodendrocytes from the neonatal brain showed that genes and pathways related to increase of myelination and altered cell cycle control were enriched in the absence of the two OPN isoforms in OPN-KO mice compared to control mice. Accordingly, adult OPN-KO mice showed an increased axonal myelination, as revealed by transmission electron microscopy imaging, and increased expression of myelin-related proteins. In contrast, neonatal oligodendrocytes from OLs-iOPN-KI mice compared to control mice showed differential regulation of genes and pathways related to the increase of cell adhesion, motility, and vasculature development, and the decrease of axonal/neuronal development. OLs-iOPN-KI mice showed abnormal myelin formation in the early phase of myelination in young mice and signs of axonal degeneration in adulthood. These results suggest an OPN isoform-specific involvement, and a possible interplay between the isoforms, in myelination, and axonal integrity. Thus, the two isoforms of OPN need to be separately considered in therapeutic strategies targeting OPN in white matter injury and diseases., (© 2023 The Authors. FASEB BioAdvances published by Wiley Periodicals LLC on behalf of The Federation of American Societies for Experimental Biology.)

The meninges are important for brain development and pathology. Using single-cell RNA sequencing, we have generated the first comprehensive transcriptional atlas of neonatal mouse meningeal leukocytes under normal conditions and after perinatal brain injury. We identified almost all known leukocyte subtypes and found differences between neonatal and adult border-associated macrophages, thus highlighting that neonatal border-associated macrophages are functionally immature with regards to immune responses compared with their adult counterparts. We also identified novel meningeal microglia-like cell populations that may participate in white matter development. Early after the hypoxic-ischemic insult, neutrophil numbers increased and they exhibited increased granulopoiesis, suggesting that the meninges are an important site of immune cell expansion with implications for the initiation of inflammatory cascades after neonatal brain injury. Our study provides a single-cell resolution view of the importance of meningeal leukocytes at the early stage of development in health and disease., (© 2021 Zelco et al.; Published by Cold Spring Harbor Laboratory Press.)

Hypoxic-ischaemic encephalopathy remains a global health burden. Despite medical advances and treatment with therapeutic hypothermia, over 50% of cooled infants are not protected and still develop lifelong neurodisabilities, including cerebral palsy. Furthermore, hypothermia is not used in preterm cases or low resource settings. Alternatives or adjunct therapies are urgently needed. Exendin-4 is a drug used to treat type 2 diabetes mellitus that has also demonstrated neuroprotective properties, and is currently being tested in clinical trials for Alzheimer's and Parkinson's diseases. Therefore, we hypothesized a neuroprotective effect for exendin-4 in neonatal neurodisorders, particularly in the treatment of neonatal hypoxic-ischaemic encephalopathy. Initially, we confirmed that the glucagon like peptide 1 receptor (GLP1R) was expressed in the human neonatal brain and in murine neurons at postnatal Day 7 (human equivalent late preterm) and postnatal Day 10 (term). Using a well characterized mouse model of neonatal hypoxic-ischaemic brain injury, we investigated the potential neuroprotective effect of exendin-4 in both postnatal Day 7 and 10 mice. An optimal exendin-4 treatment dosing regimen was identified, where four high doses (0.5 µg/g) starting at 0 h, then at 12 h, 24 h and 36 h after postnatal Day 7 hypoxic-ischaemic insult resulted in significant brain neuroprotection. Furthermore, neuroprotection was sustained even when treatment using exendin-4 was delayed by 2 h post hypoxic-ischaemic brain injury. This protective effect was observed in various histopathological markers: tissue infarction, cell death, astrogliosis, microglial and endothelial activation. Blood glucose levels were not altered by high dose exendin-4 administration when compared to controls. Exendin-4 administration did not result in adverse organ histopathology (haematoxylin and eosin) or inflammation (CD68). Despite initial reduced weight gain, animals restored weight gain following end of treatment. Overall high dose exendin-4 administration was well tolerated. To mimic the clinical scenario, postnatal Day 10 mice underwent exendin-4 and therapeutic hypothermia treatment, either alone or in combination, and brain tissue loss was assessed after 1 week. Exendin-4 treatment resulted in significant neuroprotection alone, and enhanced the cerebroprotective effect of therapeutic hypothermia. In summary, the safety and tolerance of high dose exendin-4 administrations, combined with its neuroprotective effect alone or in conjunction with clinically relevant hypothermia make the repurposing of exendin-4 for the treatment of neonatal hypoxic-ischaemic encephalopathy particularly promising.