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The arachnoid barrier delineates the border between the central nervous system and dura mater. Although the arachnoid barrier creates a partition, communication between the central nervous system and the dura mater is crucial for waste clearance and immune surveillance 1 , 2 . How the arachnoid barrier balances separation and communication is poorly understood. Here, using transcriptomic data, we developed transgenic mice to examine specific anatomical structures that function as routes across the arachnoid barrier. Bridging veins create discontinuities where they cross the arachnoid barrier, forming structures that we termed arachnoid cuff exit (ACE) points. The openings that ACE points create allow the exchange of fluids and molecules between the subarachnoid space and the dura, enabling the drainage of cerebrospinal fluid and limited entry of molecules from the dura to the subarachnoid space. In healthy human volunteers, magnetic resonance imaging tracers transit along bridging veins in a similar manner to access the subarachnoid space. Notably, in neuroinflammatory conditions such as experimental autoimmune encephalomyelitis, ACE points also enable cellular trafficking, representing a route for immune cells to directly enter the subarachnoid space from the dura mater. Collectively, our results indicate that ACE points are a critical part of the anatomy of neuroimmune communication in both mice and humans that link the central nervous system with the dura and its immunological diversity and waste clearance systems. Arachnoid cuff exit points create openings in the arachnoid barrier enabling the drainage of cerebrospinal fluid and exchange of molecules and cells between the dura and the subarachnoid space, therefore physically connecting the brain and the dura.

The mechanisms behind molecular transport from cerebrospinal fluid to dural lymphatic vessels remain unknown. This study utilized magnetic resonance imaging along with cerebrospinal fluid tracer to visualize clearance pathways to human dural lymphatics in vivo. In 18 subjects with suspicion of various types of cerebrospinal fluid disorders, 3D T2-Fluid Attenuated Inversion Recovery, T1-black-blood, and T1 gradient echo acquisitions were obtained prior to intrathecal administration of the contrast agent gadobutrol (0.5 ml, 1 mmol/ml), serving as a cerebrospinal fluid tracer. Propagation of tracer was followed with T1 sequences at 3, 6, 24 and 48 h after the injection. The tracer escaped from cerebrospinal fluid into parasagittal dura along the superior sagittal sinus at areas nearby entry of cortical cerebral veins. The findings demonstrate that trans-arachnoid molecular passage does occur and suggest that parasagittal dura may serve as a bridging link between human brain and dural lymphatic vessels. Mechanisms behind molecular transport from cerebrospinal fluid to dural lymphatic vessels remain unknown. This study demonstrates that trans-arachnoid molecular passage does occur and suggests that parasagittal dura may serve as a bridging link between human brain and dural lymphatic vessels.

Sutures separate the flat bones of the skull and enable coordinated growth of the brain and overlying cranium. The coronal suture is most commonly fused in monogenic craniosynostosis, yet the unique aspects of its development remain incompletely understood. To uncover the cellular diversity within the murine embryonic coronal suture, we generated single-cell transcriptomes and performed extensive expression validation. We find distinct pre-osteoblast signatures between the bone fronts and periosteum, a ligament-like population above the suture that persists into adulthood, and a chondrogenic-like population in the dura mater underlying the suture. Lineage tracing reveals an embryonic Six2 + osteoprogenitor population that contributes to the postnatal suture mesenchyme, with these progenitors being preferentially affected in a Twist1 +/−; Tcf12 +/− mouse model of Saethre-Chotzen Syndrome. This single-cell atlas provides a resource for understanding the development of the coronal suture and the mechanisms for its loss in craniosynostosis. The development of the coronal suture remains incompletely understood. Here the authors perform scRNA-seq and expression validation to uncover the cellular diversity within the murine embryonic coronal suture, thus revealing possible mechanisms for its loss in craniosynostosis.

Realistic human head models are of great interest in traumatic brain injury research and in the forensic pathology courtroom and teaching. Due to a lack of biomechanical data, the human dura mater is underrepresented in head models. This study provides tensile data of 73 fresh human cranial dura mater samples retrieved from an area between the anterior middle and the posterior middle meningeal artery. Tissues were adapted to their native water content using the osmotic stress technique. Tensile tests were conducted under quasi-static uniaxial testing conditions with simultaneous digital image correlation. Human temporal dura mater is mechanically highly variable with regards to its elastic modulus of 70 ± 44 MPa, tensile strength of 7 ± 4 MPa, and maximum strain of 11 ± 3 percent. Mechanical properties of the dura mater did not vary significantly between side nor sex and decreased with the age of the cadaver. Both elastic modulus and tensile strength appear to have constant mechanical parameters within the first 139 hours post mortem. The mechanical properties provided by this study can help to improve computational and physical human head models. These properties under quasi-static conditions do not require adjustments for side nor sex, whereas adjustments of tensile properties accompanied with normal aging may be of interest.

There is increasing interest in how immune cells in the meninges—the membranes that surround the brain and spinal cord—contribute to homeostasis and disease in the central nervous system 1 , 2 . The outer layer of the meninges, the dura mater, has recently been described to contain both innate and adaptive immune cells, and functions as a site for B cell development 3 , 4 , 5 – 6 . Here we identify organized lymphoid structures that protect fenestrated vasculature in the dura mater. The most elaborate of these dural-associated lymphoid tissues (DALT) surrounded the rostral-rhinal confluence of the sinuses and included lymphatic vessels. We termed this structure, which interfaces with the skull bone marrow and a comparable venous plexus at the skull base, the rostral-rhinal venolymphatic hub. Immune aggregates were present in DALT during homeostasis and expanded with age or after challenge with systemic or nasal antigens. DALT contain germinal centre B cells and support the generation of somatically mutated, antibody-producing cells in response to a nasal pathogen challenge. Inhibition of lymphocyte entry into the rostral-rhinal hub at the time of nasal viral challenge abrogated the generation of germinal centre B cells and class-switched plasma cells, as did perturbation of B–T cell interactions. These data demonstrate a lymphoid structure around vasculature in the dura mater that can sample antigens and rapidly support humoral immune responses after local pathogen challenge. Dural-associated lymphoid tissues are lymphoid structures around vascular hubs in the dura mater that sample antigens and rapidly support humoral immune responses after local pathogen challenge.

The myodural bridge (MDB) is an anatomical structure located in the suboccipital region, consisting of a dense fibrous connective tissue bridge connecting the suboccipital muscles to the dura mater (DM). These fibres interweave with their originating muscles and the dura, forming a functional unit known as the “myodural bridge complex” (MDBC). Previous studies, employing plastination sections, gross dissection, histological staining, and electron microscopy, have confirmed the widespread and highly conserved presence of the MDB in mammals, birds, and reptiles. To further investigate the presence of the MDB across vertebrates, this study selected the African clawed frog ( Xenopus laevis ), a model amphibian species, as the subject of investigation. Morphological methods, including gross dissection, paraffin section staining, and scanning electron microscopy (SEM), were used to investigate the existence and characteristics of the MDB in this species. A total of 10 sexually Mature African clawed frogs were used for the study: 3 for gross dissection, 5 for histological staining, and 2 for SEM observation. The study confirmed the presence of the MDBC in adult African clawed frogs, located in the atlanto-occipital space, where it connects the perimysium of the longissimus dorsi muscle (LGD) and the interarcualis muscle (IAR) to the dorsal atlanto-occipital membrane (DAOM) and DM. The characteristics of the MDB in adult African clawed frogs were as follows: Its fibrous components consisted predominantly of collagen fibres, with type I and type III collagen being the most abundant and elastic fibres being almost absent. The fibres between the perimysium, DAOM, and DM are interwoven. Considering the unique physiological structure and evolutionary significance of amphibians, our findings extend the known distribution of the MDB across vertebrates, enhance our understanding of adaptive changes in the MDBC among different species, and support the hypothesis that the MDBC plays a regulatory role in cerebrospinal fluid (CSF) dynamics.

ABSTRACT Background Iatrogenic cerebral amyloid angiopathy (iCAA) is a recently identified clinico‐neuroradiological syndrome associated with medical procedures, particularly neurosurgical treatments involving cadaveric dura mater (e.g., Lyodura). iCAA can manifest as intracerebral hemorrhages, focal seizures, and cognitive impairment, with the risk following exposure currently unknown. We aim to evaluate the risk of developing iCAA in patients who underwent childhood neurosurgical treatment with Lyodura compared to those who did not. Methods This retrospective cohort study analyzed hospital records from the Christian‐Doppler University Hospital in Salzburg, along with mortality data provided by the Austrian Federal Institute of Statistics (Statistik Austria). The study included all patients aged 0–18 who underwent neurosurgical procedures between January 1970 and January 1996. The primary endpoint was the diagnosis of iCAA and iCAA‐related death. Results Of 569 pediatric neurosurgical patients, 388 (68%) were further analyzed. Four patients (1%) were diagnosed with probable iCAA at a median age of 42 years (IQR 40–47), with a median latency from surgery to symptom onset of 38 years (IQR 36–41). Only Lyodura recipients developed iCAA, with an incidence rate of 12% (OR 56, 95% CI: 6–2667). The overall incidence of symptomatic iCAA among recipients of any dura material was 5% (OR 19, 95% CI: 2–903). Conclusions Cadaveric dura mater, especially Lyodura, poses a long‐term risk for developing iCAA. Further research is needed to determine susceptibility factors in Lyodura‐exposed individuals.

Borrelia burgdorferi, the causative agent of Lyme disease, is a vector-borne bacterial infection that is transmitted through the bite of an infected tick. If not treated with antibiotics during the early stages of infection, disseminated infection can spread to the central nervous system (CNS). In non-human primates (NHPs) it has been demonstrated that the leptomeninges are among the tissues colonized by B. burgdorferi spirochetes. Although the NHP model parallels aspects of human borreliosis, a small rodent model would be ideal to study the trafficking of spirochetes and immune cells into the CNS. Here we show that during early and late disseminated infection, B. burgdorferi infects the meninges of intradermally infected mice, and is associated with concurrent increases in meningeal T cells. We found that the dura mater was consistently culture positive for spirochetes in transcardially perfused mice, independent of the strain of B. burgdorferi used. Within the dura mater, spirochetes were preferentially located in vascular regions, but were also present in perivascular, and extravascular regions, as late as 75 days post-infection. At the same end-point, we observed significant increases in the number of CD3+ T cells within the pia and dura mater, as compared to controls. Flow cytometric analysis of leukocytes isolated from the dura mater revealed that CD3+ cell populations were comprised of both CD4 and CD8 T cells. Overall, our data demonstrate that similarly to infection in peripheral tissues, spirochetes adhere to the dura mater during disseminated infection, and are associated with increases in the number of meningeal T cells. Collectively, our results demonstrate that there are aspects of B. burgdorferi meningeal infection that can be modelled in laboratory mice, suggesting that mice may be useful for elucidating mechanisms of meningeal pathogenesis by B. burgdorferi.

Mesenchymal progenitor cells (MPCs) have been recently identified in human and murine epidural fat and have been hypothesized to contribute to the maintenance/repair/regeneration of the dura mater. MPCs can secrete proteoglycan 4 (PRG4/lubricin), and this protein can regulate tissue homeostasis through bio-lubrication and immunomodulatory functions. MPC lineage tracing reporter mice ( Hic1) and human epidural fat MPCs were used to determine if PRG4 is expressed by these cells in vivo. PRG4 expression co-localized with Hic1 + MPCs in the dura throughout skeletal maturity and was localized adjacent to sites of dural injury. When Hic1 + MPCs were ablated, PRG4 expression was retained in the dura, yet when Prx1 + MPCs were ablated, PRG4 expression was completely lost. A number of cellular processes were impacted in human epidural fat MPCs treated with rhPRG4, and human MPCs contributed to the formation of epidural fat, and dura tissues were xenotransplanted into mouse dural injuries. We have shown that human and mouse MPCs in the epidural/dura microenvironment produce PRG4 and can contribute to dura homeostasis/repair/regeneration. Overall, these results suggest that these MPCs have biological significance within the dural microenvironment and that the role of PRG4 needs to be further elucidated.

The myodural bridge (MDB) was described as a dense fibrous tissue connecting the suboccipital musculature with the spinal dura mater. Now, the concept of the MDB was perceived as an exact anatomical structure likely essential for cerebrospinal fluid (CSF) circulation. The MDB has been shown to be universal across mammals, reptiles, and birds. To determine the existence of the MDB in other vertebrates on morphological study, representatives in amphibians and bony fishes were examined. It was found that the dense fibrous tissue connected the interarcuales muscle (IAR) and the spinal dura mater in the Xenopus laevis . In four examined fish species, somatic muscle fibers were directly anchored to the vertebral canal membrane. This observation led to the hypothesis that, during movement, these muscles may exert a pulling force on the membrane, generating negative pressure. It is speculated that this may serve as the driving force for CSF circulation. Thus, this connection suggests a functional similarity to the MDB observed in other vertebrate species. Based on this finding, the study proposes the MDB as a functionally analogous structure with a universal existence in amphibians and bony fishes.