Mispatterned motile cilia beating causes flow blockage in the epileptic brain

Beating of motile cilia at the brain ventricular surface generates rapid flow in an evolutionary conserved pattern mediating the transport of cerebrospinal fluid, but its functional importance has yet to be demonstrated. Here we show disturbance of this transport may contribute to seizure susceptibility. Mice haploinsufficient for FoxJ1, transcription factor regulating motile cilia exhibited cilia-driven flow blockage and increased seizure susceptibility. Mutations in two epilepsy-associated kinases, Cdkl5 and Yes1, in mice resulted in similar cilia-driven flow blockage and increased seizure susceptibility. We showed this arises from disorganized cilia polarity associated with disruption in the highly organized basal body anchoring meshwork. Together these findings suggest mispatterning of cilia-generated flow may contribute to epilepsy and thus might account for seizures unresponsive to current seizure medications.

Topological Analysis of the Brainstem of the Australian Lungfish Neoceratodus forsteri

This paper presents a survey of the cell masses in the brainstem of the Australian lungfish <i>Neoceratodus forsteri</i>, based on<i></i>transversely cut Bodian-stained serial sections, supplemented by immunohistochemical data from the recent literature. This study is intended to serve a double purpose. First it concludes and completes a series of publications on the structure of the brainstem in representative species of all groups of anamniote vertebrates. Within the framework of this comparative program the cell masses in the brainstem and their positional relations are analyzed in the light of the Herrick-Johnston concept, according to which the brainstem nuclei are arranged in four longitudinal, functional zones or columns, the boundaries of which are marked by ventricular sulci. The procedure employed in this analysis essentially involves two steps: first, the cell masses and large individual cells are projected upon the ventricular surface, and next, the ventricular surface is flattened out, that is, subjected to a one-to-one continuous topological transformation [J Comp Neurol. 1974;156:255–267]. The second purpose of the present paper is to complement our mapping of the longitudinal zonal arrangement of the cell masses in the brainstem of <i>Neoceratodus</i>with a subdivision in transversely oriented neural segments. Five longitudinal rhombencephalic sulci – the sulcus medianus inferior, the sulcus intermedius ventralis, the sulcus limitans, the sulcus intermedius dorsalis and the sulcus medianus superior – and four longitudinal mesencephalic sulci – the sulcus tegmentalis medialis, the sulcus tegmentalis lateralis, the sulcus subtectalis and the sulcus lateralis mesencephali – could be distinguished. Two obliquely oriented grooves, present in the isthmic region – the sulcus isthmi dorsalis and ventralis – deviate from the overall longitudinal pattern of the other sulci. Although in <i>Neoceratodus</i> most neuronal perikarya are situated within a diffuse periventricular gray, 45 cell masses could be delineated. Ten of these are primary efferent or motor nuclei, eight are primary afferent or sensory centers, six are considered to be components of the reticular formation and the remaining 21 may be interpreted as “relay” nuclei. The topological analysis showed that in most of the rhombencephalon the gray matter is arranged in four longitudinal zones or areas, termed area ventralis, area intermedioventralis, area intermediodorsalis and area dorsalis. The sulcus intermedius ventralis, the sulcus limitans, and the sulcus intermedius dorsalis mark the boundaries between these morphological entities. These longitudinal zones coincide largely, but not entirely, with the functional columns of Herrick and Johnston. The most obvious incongruity is that the area intermediodorsalis contains, in addition to the viscerosensory nucleus of the solitary tract, several general somatosensory and special somatosensory centers. The isthmus region does not exhibit a clear morphological zonal pattern. The mesencephalon is divisible into a ventral, primarily motor zone and a dorsal somatosensory zone. The boundary between these zones is marked by the sulcus tegmentalis lateralis, which may be considered as an isolated rostral extremity of the sulcus limitans. The results of this study are summarized in a “classical” topological map, as well as in a “modernized” version of this map, in which neuromere borders are indicated.

Structural and Clinical Correlates of a Periventricular Gradient of Neuroinflammation in Multiple Sclerosis

Objectives:To explore in-vivo innate immune cell activation as a function of the distance from ventricular CSF in patients with Multiple Sclerosis (MS) using [18F]-DPA714 PET, and to investigate its relationship with periventricular microstructural damage, evaluated by magnetization transfer ratio (MTR), and with trajectories of disability worsening.Methods:Thirty-seven MS patients and nineteen healthy controls underwent MRI and [18F]-DPA714 TSPO dynamic PET, from which individual maps of voxels characterized by innate immune cell activation (DPA+) were generated. White matter (WM) was divided in 3mm-thick concentric rings radiating from the ventricular surface toward the cortex, and the percentage of DPA+ voxels and mean MTR were extracted from each ring. Two-year trajectories of disability worsening were collected to identify patients with and without recent disability worsening.Results:The percentage of DPA+ voxels was higher in patients compared to controls in the periventricular WM (p=6.10e-6), and declined with increasing distance from ventricular surface, with a steeper gradient in patients compared to controls (p=0.001). This gradient was found both in periventricular lesions and normal-appearing WM. In the total WM, it correlated with a gradient of microstructural tissue damage measured by MTR (rs=-0.65, p=1.0e-3). When compared to clinically stable patients, patients with disability worsening were characterized by a higher percentage of DPA+ voxels in the periventricular normal-appearing WM (p=0.025).Conclusions:Our results demonstrate that in MS the innate immune cell activation predominates in periventricular regions and associates with microstructural damage and disability worsening. This could result from the diffusion of pro-inflammatory CSF-derived factors into surrounding tissues.

Comprehensive characterization of migration profiles of murine cerebral cortical neurons during development using FlashTag labeling

SummaryIn mammalian cerebral neocortex, different regions have different cytoarchitecture, neuronal birthdates and functions. In most regions, neuronal migratory profiles have been speculated similar to each other based on observations using thymidine analogues. Few reports investigated regional migratory differences from mitosis at the ventricular surface. Here, in mice, we applied FlashTag technology, in which dyes are injected intraventricularly, to describe migratory profiles. We revealed a mediolateral regional difference in migratory profiles of neurons that is dependent on the developmental stages, e.g., neurons labeled at E12.5-15.5 reached their destination earlier dorsomedially than dorsolaterally even where there were underlying ventricular surfaces, reflecting sojourning below the subplate. This difference was hardly recapitulated by thymidine analogues, which visualize neurogenic gradient, suggesting biological significance different from neurogenic gradient. These observations advance understanding of cortical development, portraying strength of FlashTag in studying migration, and are thus a resource for studies of normal and abnormal neurodevelopment.

Persistent Cyfip1 expression is required to maintain the adult subventricular zone neurogenic niche

ABSTRACTNeural stem cells (NSCs) persist throughout life in the subventricular zone (SVZ) niche of the lateral ventricles as B1 cells. Maintaining this population of NSCs depends on the balance between quiescence and self-renewing or self-depleting proliferation. Interactions between B1 cells and the surrounding niche are important in regulating this balance, but the mechanisms governing these processes have not been fully elucidated in adult mammals. The cytoplasmic FMRP-interacting protein (CYFIP1) regulates apical-basal polarity in the embryonic brain. Loss of Cyfip1 during embryonic development in mice disrupts the embryonic niche and affects cortical neurogenesis. However, a direct role for Cyfip1 in the regulation of adult NSCs has not been established. Here, we demonstrate that Cyfip1 expression is preferentially localized to B1 cells in the adult SVZ. Loss of Cyfip1 in the embryonic mouse brain results in altered adult SVZ architecture and expansion of the adult B1 cell population at the ventricular surface. Furthermore, acute deletion of Cyfip1 in adult NSCs results in a rapid change in adherens junction proteins as well as increased proliferation and the number of B1 cells at the ventricular surface. Together, these data indicate that CYFIP1 plays a critical role in the formation and maintenance of the adult SVZ niche and, furthermore, deletion of Cyfip1 unleashes the capacity of adult B1 cells for symmetric renewal to increase the adult NSC pool.SIGNIFICANCENeural stem cells (NSCs) persist in the subventricular zone (SVZ) of the lateral ventricles in adult mammals and their population is determined by the balance between quiescence and self-depleting or renewing cell division. The mechanisms regulating their biology are not fully understood. This study establishes that the cytoplasmic FMRP interacting protein 1 (Cyfip1) regulates NSC fate decisions in the adult SVZ and NSCs that are quiescent or typically undergo self-depleting divisions retain the ability to self-renew in the adult. This contributes to our understanding of how adult NSCs are regulated throughout life and has potential implications for human brain disorders.