Cerebral organoids are 3D stem cell-derived models that can be utilized to study the human brain. The current consensus is that cerebral organoids consist of cells derived from the neuroectodermal ...lineage. This limits their value and applicability, as mesodermal-derived microglia are important players in neural development and disease. Remarkably, here we show that microglia can innately develop within a cerebral organoid model and display their characteristic ramified morphology. The transcriptome and response to inflammatory stimulation of these organoid-grown microglia closely mimic the transcriptome and response of adult microglia acutely isolated from post mortem human brain tissue. In addition, organoid-grown microglia mediate phagocytosis and synaptic material is detected inside them. In all, our study characterizes a microglia-containing organoid model that represents a valuable tool for studying the interplay between microglia, macroglia, and neurons in human brain development and disease.
Following the decline of neurogenesis at birth, progenitors of the subventricular zone (SVZ) remain mostly in a quiescent state in the adult human brain. The mechanisms that regulate this quiescent ...state are still unclear. Here, we isolate CD271
progenitors from the aged human SVZ for single-cell RNA sequencing analysis. Our transcriptome data reveal the identity of progenitors of the aged human SVZ as late oligodendrocyte progenitor cells. We identify the Wnt pathway antagonist SFRP1 as a possible signal that promotes quiescence of progenitors from the aged human SVZ. Administration of WAY-316606, a small molecule that inhibits SFRP1 function, stimulates activation of neural stem cells both in vitro and in vivo under homeostatic conditions. Our data unravel a possible mechanism through which progenitors of the adult human SVZ are maintained in a quiescent state and a potential target for stimulating progenitors to re-activate.
Myeloid cells are suggested as an important player in Alzheimer´s disease (AD). However, its continuum of phenotypic and functional changes across different body compartments and their use as a ...biomarker in AD remains elusive. Here, we perform multiple state-of-the-art analyses to phenotypically and metabolically characterize immune cells between peripheral blood (n = 117), cerebrospinal fluid (CSF, n = 117), choroid plexus (CP, n = 13) and brain parenchyma (n = 13). We find that CSF cells increase expression of markers involved in inflammation, phagocytosis, and metabolism. Changes in phenotype of myeloid cells from AD patients are more pronounced in CP and brain parenchyma and upon in vitro stimulation, suggesting that AD-myeloid cells are more vulnerable to environmental changes. Our findings underscore the importance of myeloid cells in AD and the detailed characterization across body compartments may serve as a resource for future studies focusing on the assessment of these cells as biomarkers in AD.
The habenula plays a key role in various motivated and pathological behaviors and is composed of molecularly distinct neuron subtypes. Despite progress in identifying mature habenula neuron subtypes, ...how these subtypes develop and organize into functional brain circuits remains largely unknown. Here, we performed single-cell transcriptional profiling of mouse habenular neurons at critical developmental stages, instructed by detailed three-dimensional anatomical data. Our data reveal cellular and molecular trajectories during embryonic and postnatal development, leading to different habenular subtypes. Further, based on this analysis, our work establishes the distinctive functional properties and projection target of a subtype of Cartpt+ habenula neurons. Finally, we show how comparison of single-cell transcriptional profiles and GWAS data links specific developing habenular subtypes to psychiatric disease. Together, our study begins to dissect the mechanisms underlying habenula neuron subtype-specific development and creates a framework for further interrogation of habenular development in normal and disease states.
In view of important neurobiological functions of the cell adhesion molecule contactin-6 (Cntn6) that have emerged from studies on null-mutant mice and autism spectrum disorders patients, we set out ...to examine pathways underlying functions of Cntn6 using a proteomics approach. We identified the cell adhesion GPCR latrophilin-1 (Lphn1, a.k.a. CIRL1/CL, ADGRL1) as a binding partner for Cntn6 forming together a heteromeric
-complex. Lphn1 expression in cultured neurons caused reduction in neurite outgrowth and increase in apoptosis, which was rescued by coexpression of Cntn6. In cultured neurons derived from
mice, Lphn1 knockdown reduced apoptosis, suggesting that the observed apoptosis was Lphn1-dependent. In line with these data, the number of apoptotic cells was increased in the cortex of
mice compared to wild-type littermate controls. These results show that Cntn6 can modulate the activity of Lphn1 by direct binding and suggests that Cntn6 may prevent apoptosis thereby impinging on neurodevelopment.
Context
Climate change can directly affect habitats within ecological networks, but may also have indirect effects on network quality by inducing land use change. The relative impact of indirect ...effects of climate change on the quality of ecological networks currently remains largely unknown.
Objectives
The objective of this study was to determine the relative impact of direct and indirect effects of climate change on a network of breeding habitat of four meadow bird species (Black-tailed godwit, Common redshank, Eurasian oystercatcher and Northern lapwing) in the Netherlands.
Methods
Habitat models were developed that link meadow bird breeding densities to three habitat characteristics that are sensitive to environmental change (landscape openness, land use and groundwater level). These models were used to assess the impact of scenarios of landscape change with and without climate change on meadow bird breeding habitat quality for a case study area in the peat meadow district of the Netherlands.
Results
All scenarios led to significantly reduced habitat quality for all species, mainly as a result of conversion of grassland to bioenergy crops, which reduces landscape openness. Direct effects of climate change on habitat quality were largely absent, indicating that especially human adaptation to climate change rather than direct effects of climate change was decisive for the degradation of ecological network quality for breeding meadow birds.
Conclusions
We conclude that scenario studies exploring impacts of climate change on ecological networks should incorporate both land use change resulting from human responses to climate change and direct effects of climate change on landscapes.
Meadow bird species in the Netherlands have shown a long-term decline in numbers. This has been generally attributed to agricultural intensification, but in addition an increase of disturbing ...elements may have played a role in the decline. In this review we compiled data from literature to explore to what extent breeding by meadow birds (Eurasian Oystercatcher Haematopus ostralegus, Northern Lapwing Vanellus vanellus, Black-tailed Godwit Limosa limosa) is limited by disturbing landscape elements. We considered elements that can be considered ‘view-obstructing’ (like trees or houses), and those that can be considered ‘flat’ (canal, road or railway). Our review shows that breeding birds keep a distance to both types of landscape elements, with distances ranging over 1 km for highways and village edges. Roads with high traffic intensity caused the largest disturbance. Eurasian Oystercatcher was most tolerant to the presence of landscape elements, and Black-tailed Godwit least tolerant.
Objectives This study attempted to determine the factors that best predict the duration of absence from work among employees with common mental disorders. Methods A cohort of 188 employees, of whom ...102 were teachers, on sick leave with common mental disorders was followed for 1 year. Only information potentially available to the occupational physician during a first consultation was included in the predictive model. The predictive power of the variables was tested using Cox's regression analysis with a stepwise backward selection procedure. The hazard ratios (HR) from the final model were used to deduce a simple prediction rule. The resulting prognostic scores were then used to predict the probability of not returning to work after 3,6, and 12 months. Calculating the area under the curve from the ROC (receiver operating characteristic) curve tested the discriminative ability of the prediction rule. Results The final Cox's regression model produced the following four predictors of a longer time until return to work: age older than 50 years HR 0.5, 95% confidence interval (95% CI) 0.3-0.8, expectation of duration absence longer than 3 months (HR 0.5,95% CI 0.3-0.8), higher educational level (HR 0.5,95% CI 0.3-0.8), and diagnosis depression or anxiety disorder (HR 0.7, 95% CI 0.4-0.9). The resulting prognostic score yielded areas under the curves ranging from 0.68 to 0.73, which represent acceptable discrimination of the rule. Conclusions A prediction rule based on four simple variables can be used by occupational physicians to identify unfavorable cases and to predict the duration of sickness absence.
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