Lab life, seasons and chromosome fusions restrict non-cell-autonomously proliferation and neurogenesis, but not oligodendrogenesis, in mice and voles

Lab life, seasons and chromosome fusions restrict non-cell-autonomously proliferation and neurogenesis, but not oligodendrogenesis, in mice and voles | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Lab life, seasons and chromosome fusions restrict non-cell-autonomously proliferation and neurogenesis, but not oligodendrogenesis, in mice and voles Athanasia Rapti, Theodosia Androutsopoulou, Evangelia Andreopoulou, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5299693/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 28 May, 2025 Read the published version in Scientific Reports → Version 1 posted 11 You are reading this latest preprint version Abstract Environmental and behavioral factors have been shown, in experimental settings, to affect neurogenesis in the mouse brain. We found that the density of proliferating neural stem/ progenitor cells (NSPCs) and of neuroblasts was significantly lower in the Subependymal Zone stem cell niche of lab mice when compared with mice and pine voles captured in the wild, with seasonal variation observed only in voles. Moreover, levels of proliferation and neurogenesis were found to decrease in proportion to the decrease in the numbers of chromosomes (from the typical 2n = 40 down to 2n = 26) caused by Robertsonian fusions. In contrast, oligodendroglial progenitors and microglial cells were unaffected by wildlife, seasons and chromosomal fusions. When NSPCs were grown in cultures no differences were detected, suggesting that environmental and genetic effects are mediated by non-cell-autonomous mechanisms. These “real-world” data provide a platform for the identification of systemic factors and genetic loci that control postnatal brain neurogenesis. Biological sciences/Developmental biology/Neurogenesis/Adult neurogenesis Biological sciences/Neuroscience/Stem cells in the nervous system/Glial stem cells Biological sciences/Neuroscience/Stem cells in the nervous system/Neural stem cells Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction In mammals, postnatal brain neural stem and progenitor cells (pbNSPCs) cluster within specialized microenvironments called stem cell niches. They remain in quiescence and infrequently transit towards mitotic activation, giving rise to transit amplifying progenitors that subsequently generate committed neuronal or glial progenitors (Delgado et al., 2021 ; Kalamakis et al., 2019 ; Obernier et al., 2018 ). A well-described niche in rodents and humans is located at the subependymal zone (SEZ) of the lateral ventricles (also known as ventricular-subventricular zone) (Obernier and Alvarez-Buylla, 2019 ). In mice and rats, the bulk of the SEZ niche is located in a narrow layer of cells adjacent to the ventricular ependyma, at the striatal side of the lateral ventricles, and can be identified based on the expression of markers of cell proliferation, such as PCNA (Fig. 1 A, C) and of immature neuronal identity, such as Doublecortin (Dcx, Fig. 1 B) (Kazanis et al., 2010 , 2017 ). A distinct pool of brain progenitors, called Oligodendrocyte Progenitor Cells (OPCs), can be also detected based on the co-expression of proliferation markers and markers of oligodendroglial lineage identity, such as Olig2 or PDGFRα (Bruggen et al., 2022 ; Foerster et al., 2024 ; Kazanis et al., 2017 ). OPCs are scattered throughout the brain parenchyma, with the corpus callosum (CC) being a white matter tract particularly rich in them (Bottes and Jessberger, 2021 ; Franklin and ffrench-Constant, 2017 ; Young et al., 2013 ). A wide range of ecological and behavioral factors have been shown, in lab settings and each one separately, to control the behavior of pbNSPCs, including: pregnancy (Chaker et al., 2023 ), physical exercise (Nicolis di Robilant et al., 2019; Pons-Espinal et al., 2019 ), stress (Mirescu and Gould, 2006 ), environmental enrichment (Körholz et al., 2018 ; Plane et al., 2008 ), social interaction (Lopes et al., 2023 ), night/day duration (Gengatharan et al., 2021 ), olfactory stimuli (for the rodent SEZ) (Rochefort et al., 2002 ) and the microbiome (Dohm-Hansen et al., 2022 ). An even wider list of diffusible (local and long-range) molecules, cell-to-cell signals and metabolic factors have been, again experimentally, proposed to regulate pbNSPCs (Obernier and Alvarez-Buylla, 2019 ). Such experimental animal work is important in basic research but can be less valid for translational biomedical research, as it relies on the use of animals maintained and handled in highly controlled conditions and with the role of each factor explored individually. Hence, it is imperative to dissect mechanisms and factors that regulate pbNSPCs in wild rodent populations, the life of which integrates the multiple parameters listed above. To achieve this, it is necessary to identify appropriate wild animal comparator populations that -in the absence of experimental manipulation and easy access to large animal numbers- will enable the link of descriptive information with genetic and metabolic data. As a first step towards this direction, we generated “real world” data comparing neurogenesis and oligodendrogenesis in the SEZ and the CC in brain samples obtained from laboratory and wild populations of Mus musculus domesticus (house mice). To increase the strength of the analysis, we enriched our samples in two ways: firstly, by including a fossorial species, the Microtus thomasi (Thomas’s pine voles), which is found in open fields and was captured in underground burrows (Supplemental Fig. 1 and Supplemental Table 1). Secondly, we sampled populations of wild mice with karyotypes that deviate from the typical 2n = 40 due to the naturally occurring phenomenon of Robertsonian fusions (Rb). As the typical mouse chromosomes are acrocentric, the fusion of two of them can result in the formation of metacentric chromosomes (Gerton, 2024 ), leading to established mouse populations with lower numbers of chromosomes, down to 2n = 26 (Mitsainas and Giagia-Aathanasopoulou, 2005). Rb lead to the reorganization of chromatin; albeit, without major loss of genetic material (Piálek et al., 2005 ). So far, there is no evidence of phenotypic alterations caused by Rb in mice (Wang et al., 2023 ); however, this phenomenon leads to higher levels of genetic differentiation through effects to meiotic recombination (Marín-García et al., 2024 ) and is regarded as a speciation factor because it leads to the genetic isolation of mouse populations by inhibiting the flow of genetic material (Britton-Davidian et al., 2000 ; Ferguson-Smith and Trifonov, 2007 ; Garagna et al., 2014 ) and has been linked to infertility in humans (Gerton, 2024 ). We focused our analysis on the SEZ, which is positioned and structured in a way that allows the integration of multiple, peripheral and local, stimuli derived via the cerebrospinal fluid, the vasculature, astrocytic syncytia, neuronal activity and the extracellular matrix (Douet et al., 2013 ; Kazanis, 2009 ; Silva-Vargas et al., 2016 ; Taranov et al., 2024 ; Tavazoie et al., 2008 ) and on the OPC-rich adjacent CC. In this way we were able to investigate, within the same anatomical areas, both neurogenesis and oligodendrogenesis, as well as the behavior of two distinct pools of brain progenitors, pbNSPCs and OPCs. Results Numbers of proliferating cells and of neuroblasts, in the SEZ, are reduced in lab mice and show seasonal variation in pine voles To assess the behavior of pbNSPCs of the SEZ, we calculated the density and the percentage of proliferating cells (immunopositive for PCNA), as well as the density and the percentage of neuroblasts (immunopositive for Doublecortin) at the dorsolateral horn of the SEZ, a hotspot of pbNSPCs (Mirzadeh et al., 2008 ) and the site of convergence for neuroblasts and oligodendroblasts ahead of their outward migration via the rostral migratory stream (Capilla-Gonzalez et al., 2013 ). All PCNA + cells were found to co-express the transcription factor Sox2; thus, they were all considered to be pbNSPCs (Fig. 1 A,E). Firstly, we compared lab and wild mice (all bearing the typical 2n = 40 karyotype) and we found that the density and the percentage of proliferating cells and the density of neuroblasts were significantly higher in wild mice (Fig. 1 F-G, Suppl. Figure 2A,B), indicating that maintenance in lab facilities restricts proliferation and generation of neuroblasts in the SEZ. To test more for the effect of habitat, we looked in the SEZ of the Microtus thomasi , a fossorial rodent that spends a significant fraction of its life in confined spaces and relies more on the use of olfaction (Kirkpatrick et al., 1994 ). The less investigated Microtus thomasi SEZ had a structure similar to that of the mouse and the rat niche, as has been shown in the Microtus ochrogaster (Castro et al., 2020 ), apart from the detection of individual proliferating cells located in the striatum (Fig. 1 E), deeper than the 30–50µm distance from the ventricular wall in which all proliferating cells are found in mice and rats, respectively (Kazanis and ffrench-Constant, 2012 ). Notably, a clear dichotomy in PCNA + and Dcx + cell densities was observed in the samples we analysed, with the season of capture (autumn versus spring), being the only factor separating the two sub-populations (Fig. 1 F-G). To ascertain appropriate comparisons, we also separated lab mice in spring and autumn pools and no seasonal variation was found in PCNA + and Dcx + cells. In voles, the SEZ was significantly richer in proliferating cells and neuroblasts in spring, with Microtus s pring pbNSPCs exhibiting a behavior similar to that of wild 2n = 40(autumn) mice, while the Microtus autumn population exhibited pbNSPC behavior similar to that of lab mice (the percentage of Dcx + cells was even significantly lower) (Fig. 1 , Suppl. Figure 2A-B). Overall, these data reveal that the proliferative and neurogenic activity, per unit of SEZ, varies within a similar “low/high” range in mice and voles, and is directly affected by lab or wild habitat in mice and by seasons in the Microtus . Numbers of proliferating cells and of neuroblasts in the SEZ are corelated to the number of chromosomes Based on previous work (Mitsainas and Giagia-Athanasopoulou, 2005 ) and on explorative new collections, we sampled wild mice populations with non-typical karyotypes, from different sites in Greece. We included in our analysis mice with 2n = 37, 30, 28, 27 and 26 chromosomes (Suppl. Table 1 and Suppl. Figure 1, Fig. 2 A-B). From one site (#7, in Mavroneri, Suppl. Figure 1) we were not able to karyotype all mice, but as we have established well that mice found there belong to populations with 2n ≤ 30 (Suppl. Table 1), we grouped them as a separate Wild 2n ≤ 30 pool. When the densities and percentages of PCNA + and Dcx + cells were plotted against the number of chromosomes, a surprising pattern was revealed, with both parameters found to decrease in proportion to the reduction in the numbers of chromosomes (Fig. 2 C-F, Suppl Fig. 2C-F). The correlation was tested separately for mice captured in spring and autumn and was found to be very strong, with Pearson’s correlation values higher than 0.90. One-way ANOVA analyses revealed that, besides Wild 2n = 40 mice, Wild 2n = 37 mice had also significantly higher densities of PCNA + and Dcx + cells in the SEZ when compared to lab mice (Fig. 2 C-F, Suppl Fig. 2C-F). Wild mice with karyotypes 2n ≤ 30 showed no differences compared to lab mice and had significantly less PCNA + and Dcx + cells than Wild 2n = 40 and Wild 2n = 37 mice. The season was not found to affect the densities or percentages of PCNA + and Dcx + cells in wild mice (p > 0.05, post-hoc analyses for all Wild autumn versus all Wild spring mice as well as for Wild 2n ≤ 30(autumn) versus Wild 2n ≤ 30(spring) ), as was the case for lab mice. Oligodendrocyte progenitor cells are not affected by ecological factors and by changes in chromosome numbers To assess if the effects we identified on the neurogenic output of the SEZ were also visible to its oligodendrogenic output we calculated the density of Olig2 + oligodendroblasts in the dorsoventral horn of the niche (Fig. 3A-C). Moreover, we extended our analysis to the supraventricular CC. Because in the CC Olig2 is expressed both in OPCs and in mature oligodendrocytes, we focused on the mitotic fraction of OPCs, i.e. the cells co-expressing Olig2 and PCNA (Fig. 4 A-F). We also counted Sox2 + cells, as the expression of this transcription factor is undetectable in mature cells of the nervous system but is retained in cells with neural progenitor identity of the brain parenchyma (Niu et al., 2015 )(Fig. 4 G-I). Our analysis revealed that the density of Olig2 + cells in the SEZ and of mitotic Olig2 + cells in the CC were unaffected by species, habitat, or karyotype in the same groups that showed differences in PCNA + and Dcx + cells (Figs. 3, 4 ). On the other hand, the density of Sox2-expressing cells in the CC was significantly decreased in lab mice, compared to wild mice and to the Microtus autumn (Fig. 4 G-I). A strong Pearson’s correlation between the decreasing densities of Sox2 + cells and the decreasing number of chromosomes was apparent as was observed for PCNA + and Dcx + cells in the SEZ (Fig. 4 H-I). No differences in the behavior of pbNSPCs across experimental groups in vitro The significant differences in the activity of SEZ pbNSPCs in animals living in diverse habitats but also in mice harboring chromosomal fusions, could be caused by hard-wired, cell autonomous, differences, or by changes in external factors regulating their behavior. To test for this in the most direct way, in some animals one brain hemisphere was included in the histological analyses, while the other was used for the isolation of SEZ-derived pbNSPCs and their culture in the form of free-floating colonies known as neurospheres. One-week old primary, or twice passaged (tertiary), neurospheres were dissociated and cells were plated on glass coverslips. After two days in pro-proliferation conditions, their mitotic activity (percentage of Ki67 + cells) and their NSPC profile (percentage of nestin + cells in mouse cultures and of Sox2 + cells in Microtus samples, because they failed to produce positive immunostaining for nestin) were assessed. In addition, tertiary mouse neurosphere cells were plated on glass coverslips and were analyzed after five days in pro-differentiation conditions for the presence of GFAP + astrocytes and βΙΙΙ-tubulin + neurons. The cell culture analyses revealed that pbNSPCs exhibited similar in vitro behavior irrespective of species, karyotype, season, and lifestyle (Fig. 5 ). Ecological and genetic factors do not alter the immediate NSPC cellular microenvironment The absence of differences in the in vitro behavior of pbNSPCs strongly indicated that the effects observed in vivo are instructed by external factors. To assess if these changes were correlated to changes in the immediate cellular microenvironment of the SEZ or of the CC, we looked at microglial (Iba1+) cells that act as regulators of pbNSPCs (Shigemoto-Mogami et al., 2014 ; Solano Fonseca et al., 2016 ; Xavier et al., 2015 ). We found that the density of Iba1 + cells remained stable across all groups (Fig. 3D-E, Fig. 4 J-K). We also calculated the pool of what we termed “supporting cells” of the SEZ, i.e. the cells of the niche that do not belong in the pbNSPC lineage, by subtracting from the total number of cells (all DAPI + nuclei) the numbers of all PCNA + and Dcx + cells. This pool of cells includes mainly ependymal and endothelial cells, as well as differentiated astrocytes (Mirzadeh et al., 2008 ; Shen et al., 2008 ). Notably, we found that the population of supporting SEZ cells remained also unaffected (Suppl Fig. 3). Discussion The behavior (e.g. proliferation, differentiation, survival/maturation) and regulation of pbNSPCs, especially in their niches, has been investigated extensively in mice maintained in animal facilities, under tightly controlled conditions that differ substantially from the natural habitats of these rodents. Accumulating evidence suggests that environmental enrichment (Plane et al., 2008 ; Rochefort et al., 2002 ), increased physical activity (Horowitz et al., 2020 ; Pons-Espinal et al., 2019 ) and high social interactions (Körholz et al., 2018 ) are correlated with increased levels of neurogenesis, mainly in the hippocampal niche. Based on the above, and hypothesizing that the behavior of pbNSPCs in lab mice might be critically different comparing to wild mice, we decided to investigate the SEZ stem cell niche that is located and structured in a way that enables the integration of signals originating from multiple pathways (Kazanis, 2009 ; Obernier and Alvarez-Buylla, 2019 ; Silva-Vargas et al., 2016 ; Tavazoie et al., 2008 ). Indeed, our data revealed that proliferation and neurogenesis in SEZ pbNSPCs are affected by life conditions and were decreased (by approximately 50%-70%) in lab mice when compared to wild animals. This sets a new, significantly higher, translational “standard” when interpreting the therapeutic potential of experimental manipulations that lead to increased levels of neurogenesis, with the behavior of pbNSPCs in wild mice offering a “real mouse world” comparator. Wild mice provide a unique opportunity to generate valid, unbiased from experimental handling, information, especially because even mild interventions can affect the mouse characteristics (Geiger et al., 2018 ) or the vole’s neurogenic activity (Castro et al., 2020 ). To achieve this, it is essential to identify multiple, well-defined, wild populations that will allow the extraction of key conclusions by linking genetic and molecular data with descriptive data, as has been done with human samples (Al-Dalahmah et al., 2024 ; Kim et al., 2024 ; Kukanja et al., 2024 ). Here, we identify interesting comparator groups either at the cellular or at the animal level. At the cellular level, the divergent behavior of neuronal and of oligodendroglial lineage progenitors most probably underlines the divergent roles and evolutionary adaptations of the two cell lineages. The former have acquired a dependence on the niche microenvironment wherein their activity is tightly regulated (Delgado et al., 2014 , 2021 ; Marqués-Torrejón et al., 2021 ; Sanai et al., 2004 ; Takei, 2019 ) and the latter have adapted to life in the parenchyma (Agathou et al., 2013 ; Anesti et al., 2022 ) exhibiting persistent generation of myelin (Young et al., 2013 ); albeit, remain responsive to life-style changes, such as piano playing (Bengtsson et al., 2005 ; Scholz et al., 2009 ). In contrast, Sox2 + neural progenitors located in the CC showed behavior similar to that of neural progenitors in the SEZ. The identification of cell pools with convergent/divergent aspects of behavior in the same brain areas can enrich the analytical resolution of methods incorporating anatomical elements (such as spatial transcriptomics). At the populations level, we show that the density of pbNSPCs in the SEZ exhibits seasonal variation in the Microtus , but not in mice, an observation that can be used to extract key metabolic information by identifying systemic factors with similar seasonal fluctuations. This discrepancy could reflect the fact that wild mice populate humanized habitats, characterized by higher stability, throughout the year, in terms of temperature, abundance of food and the presence of predators, while the Microtus’ ethology involves seasonal variation in physical, reproductive and food scavenging activity. Because two of the three voles captured in spring had lower body weight, indicating younger age, when also checked for a possible correlation between body weight and density of PCNA + cells, this turned to be negative (Pearson’s analysis ρ=-0.43), while a t-test for the density of PCNA + cells in individuals with body weight 20g gave no significant result (p = 0.09). It should be noted that, overall, we found no significant differences in the gross cyto-architecture of the SEZ between lab mice, wild mice and voles and the same was observed when comparing mice and rats (Kazanis and ffrench-Constant, 2012 ). This suggests that valid comparisons can be drawn by investigating species that belong to the same order (rodentia) and that differences in the behavior and organization of postnatal brain progenitors require longer phylogenetic distances (Jessberger and Gage, 2014 ). Importantly, the observation that the differences identified between lab and wild rodents are not hard-wired and cell-autonomous, allows to focus on metabolic/ systemic targets. Accumulating evidence has shown that circulation (Horowitz et al., 2020 ; Katsimpardi et al., 2014 ) and choroid plexus-derived (Delgado et al., 2014 ; Silva-Vargas et al., 2016 ; Taranov et al., 2024 ) factors are important in the control of pbNSPCs and our data offer a unique opportunity to expand such analyses using “real world” data (e.g. metabolic and inflammatory profiles). Based on the significant differences observed in vivo and to the limited number of wild animal samples, the in vitro assays we employed were purposedly crude (e.g. cells were grown in abundance of EGF and FGF2, or in the total absence of these factors), as the aim was not to assess the numbers of neural stem cells in the parent SEZ, or the detailed response of cells to different factors (Ávila-González et al., 2023 ). The most unexpected observation was the strong correlation between the decrease in the number of chromosomes and the decrease in the density of pbNSPCs in the SEZ. A mechanistical explanation for this will require additional analyses, such as G-banded chromosome staining, or some type of NGS and ATAC sequence analyses, which can now be performed on archived material. Gene silencing due to “position effect variegation” has been described in mice (Pedram et al., 2006 ); however, rather than focusing on individual genes, the involvement of pericentromeric and of telomeric chromatin seems to offer a more valid target. These are the chromosome areas quantitively affected by Rb and they have been implicated in the control of stem cell proliferation (Del Rosario et al., 2019 ; Nishide and Hirano, 2014 ) and of the age-related decline in stem cell function (Jaskelioff et al., 2011 ; Lobanova et al., 2017 ). In terms of basic biology, our data reveal a key feature of the regulation of pbNSPCs and of the SEZ function in rodents. The fact that the Microtus niche becomes almost void of progenitors in the autumn, only to be replenished in spring, indicates that living conditions affect the proliferative activity of pbNSPCs, possibly acting at the top of the hierarchy, at the quiescence-to-mitotic activation transition of neural stem cells (Kalamakis et al., 2019 ). At the same time, the fact that the density of supporting niche cells (ependyma, endothelium) remains similar across species, karyotypes, lifestyle (even in the lab animals that experience many generations of hypoactivity), and seasons, strongly suggests that the structure of the niche is independent of any fluctuations of neurogenic activity. These findings might reconciliate previous observations on the human SEZ, that has been reported to become depleted of pbNSPC activity during infancy (McClenahan et al., 2021 ; Sanai et al., 2004 ; Takei, 2019 ) but also to be able to respond in cases of degeneration, even in the elderly (Ekonomou et al., 2011 , 2012 ). Further histological analysis of niche elements, such as the vasculature, will consolidate this architectural stability and can lead to the calculation of a “maximum capacity” for pbNSPC density per niche unit. One methodological limitation of this study is that the age of wild animals could not be reliably determined. The only animal groups with certified ages were the laboratory mice (2 to 4 months). We could only be sure that wild mice were adult (post-1 month old), based on their body size, and that the females were not pregnant, a condition recently reported to affect neurogenesis in the SEZ (Chaker et al., 2023 ). Neurogenesis (and more widely the activity of tissue-specific stem cells) decreases over ageing in lab animals (Neumann et al., 2019 ; Shook et al., 2012 ). Therefore, lab animals included in the study were at the peak of neurogenesis age, while wild mice were not younger than lab mice, rather a mixture of different ages (old, or sick wild animals are not very active; thus, are more rarely captured and are under-represented). In conclusion, the overall results indicate that it is highly unlikely that the age of wild mice might have confounded our results, as the activity of pbNSPCs was found to be both increased and decreased (compared to the age-grouped young adult lab mice) in different groups of wild mice; whilst at the same time, microglial cells and OPCs showed different patterns of behavior. Another possible confounding factor in this type of work is the possible lack of genetic variation, if individuals captured at one site belong to the same family. In this study there was no implementation of strict distribution rules, such as the use of grids employed in field work destined for the assessment of the diversity of fauna and flora, and all captured individuals were included. Supplemental table 1 and supplemental Fig. 1 provide details that inform regarding possible family relations between individuals. The 4 Wild 2n = 40 mice were captured at 4 different locations; thus, have no family relations to each other. The 4 Wild 2n = 37 mice were captured at the same location and time. Nevertheless, our analysis revealed a wide range of values, especially in the density of PCNA + and Dcx + cells in their SEZs, whilst the grouping of R586 and R599 observed in the density of PCNA+, Dcx + and Olig2 + cells is not repeated when looking at the density of Iba1 + cells. The 6 Wild 2n = 30 mice were captured as two groups: R613, R614, R617 and R619 in location #5 and Wild4, Wild6 in the very distant location #7. Wild6 measurements do not show segregation from the other individuals of the same group (Wild 2n = 30, SPRING ). Furthermore, Wild4 and Wild6 show: a) similar patterns in the density of PCNA + and Dcx + cells in the SEZ, b) moderately different patterns in the density of Olig2 + and Iba1 + cells in the SEZ, c) strongly different patterns in nestin+, GFAP + and βIIItubulin + cells in cultures. The other 12 wild mice were also captured at Mavroneri (location #7 in the map) in the same barn and were trapped at the same time, apart from Wild13 that was captured almost a year later. There is no direct evidence on family relations amongst the individuals that share the same numbers of chromosomes, but the co-existence of individuals with different karyotypes strongly indicates fluidity of populations. Voles were captured in two, distant, areas. The species lives in highly complicated burrows, that can extend to more than 25m in total length (Rekouti, 2018 ). Each network is usually inhabited by one male/female pair, although coexistence of additional adults has been reported (Eisenberg, 1963 ) and social exposure has been shown to affect neurogenesis in Microtus ochrogaster (Ávila-González et al., 2023 ). Only one adult was captured per burrow; thus, limiting the possibility of 1st or 2nd degree relations. Conclusions The worth of field-work expeditions to capture wild mice, rats and voles and the benefit of gathering descriptive information in the absence of experimental manipulation depend on two conditions: a) availability of methods and b) choice of the appropriate comparators. By generating single-cell analysis data in supercentenarians (Hashimoto et al., 2019 ), astronauts (Kim et al., 2024 ) or multiple sclerosis patients (Kukanja et al., 2024 ; Smets et al., 2021 ) -and their respective controls- or by systematically linking data acquired via multimodal brain imaging, cognitive tests and a range of biochemical analyses in order to cluster individuals across a large-scale dataset (Tian et al., 2023 ), novel information on the biological processes of ageing or disease has been discovered. Similarly to above, we identified rodent populations with divergent behavior of pbNSPCs. In this way, the homogenizing effects of laboratorization/domestication (Geiger et al., 2018 ; KOIZUMI et al., 2018 ) can be brought into “real life” context and novel information can be generated by linking high throughput analyses to descriptive data. Notably, the strong correlation between phenotype and chromosome fusions can only be explained by proportional changes in chromatin structure (genetic or epigenetic) that should be feasible to detect; thus, providing a valuable tool to study the control of gene expression, even in a non-physiological context. Materials and Methods Animals, euthanasia method and bone marrow karyotyping Lab mice were of the Bl6CBAC and of the 129sv backgrounds. All animals were between 2 and 4 months of age, inbred at the designated animal facility of the University of Patras (EL13 BIOexp-04), maintained in steady light/dark cycle (12/12 h) with free access to food and water. Animal breeding, maintenance and handling was performed in accordance with the European Communities Council Directive Guidelines (86/609/EEC) for the care and use of Laboratory animals as implemented in Greece by the Presidential Decree 56/2013 and approved and scrutinized by the local Prefectural Animal Care and Use Committee (Protocol number: 118188/432/21-05-2020). Wild mice ( Mus musculus domesticus ) were trapped alive with Sherman traps in a variety of humanized habitats, e.g. storage buildings and farms. Thomas’s pine voles ( Microtus thomasi ) were trapped alive with wire custom-made, rectangular traps of 5x6x20cm size. Bait (usually pieces of carrot) was put deep in the trap, with an additional piece positioned at the opening, under a shutter. The traps were set, fully aligned and at the same depth, at the open ends of tunnels, to resemble an extension of the burrow. The underground burrows were located in cultivated and uncultivated fields. Both taxa are common in nature and not under threat or protection by national or international decrees. All field procedures involving these wild animals were in compliance with guidelines, approved by the American Society of Mammalogists (Sikes and Gannon, 2011 ). The captured animals were brought to the lab and were maintained for the minimal possible duration (typically 2 to 7 days, with the exception of the wild 2n = 30−26 subgroup that was analyzed in spring) under standard animal house conditions and free access to water and food. All animals were subjected to colchicine pretreatment (0.025%, 2µl/g of body weigh) 45min prior to euthanasia. Euthanasia was performed by final (non-recovering) anesthesia, with ketamine overdose and subsequent intracardially perfusion with fresh, ice-cold saline (50ml per animal). For karyotyping using bone marrow cells, chromosome preparations were obtained using a modified version of the direct bone marrow method (Hsu and Patton, 1969 ), incubating cell preparations with a hypotonic solution of KCl (0.75M; 30min at 37 o C), followed by fixation in Carnoy’s solution (3:1 methanol : glacial acetic acid). Slides were prepared by the standard air-drying technique. Metaphasic chromosomes were photographed in brightfield using the 100X objective of an Axioskop 2 Plus Zeiss microscope and a Zeiss mrc5 digital camera. Numbers of chromosomes were counted, in at least 3 metaphases. No animals were excluded and all protocols and analyses were planned and performed in compliance with the ARRIVE guidelines, as described in https://arriveguidelines.org/arrive-guidelines . Cell cultures, immunocytochemistry and pbNSPC karyotyping For pbNSPC cultures, the subependymal zone of one brain hemisphere was dissected under the stereoscope using anatomical landmarks, as performed previously (Kazanis et al., 2017 ) and was dissociated using accutase. Cells were plated in 6-well plates with proliferation medium (high glucose DMEM, FGF2 and EGF at 20ng/ml, 2% B27 and 1% N2 supplements) and were allowed to grow as 3D free-floating aggregates called neurospheres. For the immunocytochemical analysis, the primary neurospheres were dissociated and plated on poly-D-lysine coated glass coverslips. Cells were fixed with 2% PFA after 48h. Immunofluorescence was performed with standard protocols (Kazanis et al., 2017 ), using the following primary antibodies: chicken anti-nestin (Abcam, 1/200, ab134017), mouse anti-nestin (Abcam, 1/200, ab6142), rabbit anti-Ki67 (Abcam, 1/500, [SP6] ab16667), goat anti-GFAP (Abcam, 1/700, ab53554), goat anti-Sox2 (Santa Cruz, 1/200, sc-17320), mouse anti-βΙΙΙ tubulin (Abcam, 1/500, Abcam, ab7751). Appropriate secondary antibodies (Biotium) were used, and nuclei were counterstained with Dapi (Merck). For karyotyping, neurosphere cells, of higher than two passages, were dissociated. After 48h they were dissociated again, cells were incubated for 8.5h with 10µg/ml colchicine and were karyotyped with the bone marrow protocol, adjusted for pbNSPCs. Tissue handling for immunohistochemistry After the intracardial perfusion with saline, the tissue was fixed in 4% PFA (4 o C, overnight), cryopreserved in 30% sucrose and frozen at -80 o C. 14µm-thick coronal cryo-sections were obtained (Leica) and were immunostained using standard protocols (Kazanis et al., 2017 ), using the following antibodies: mouse anti-PCNA (Abcam, 1/500, [PC10] ab29), rabbit anti-Dcx (Abcam, 1/500, ab18723), goat anti-Iba1 (Abcam, 1/1000, AB5076), rabbit anti-Olig2 (Millipore, 1/300, AB9610), goat anti-Sox2 (Santa Cruz, 1/200, sc-17320). Appropriate secondary antibodies (Biotium) were used and nuclei were counterstained with Dapi (Merck). Imaging and cell count Tissue sections and cells on coverslips were photographed with a Leica TCS SP8 confocal microscope, using the 40X objective and the Leica Application Suite X software. For SEZ measurements, at least two coronal sections, at different rostro-caudal levels (typically 1.2 and 0.8mm from bregma) were imaged, with at least 2 optical fields at the “dorsal horn” domain of the niche (as shown in Fig. 1 A). Cells were counted manually at a depth of 30µm (mice and microtus) or 50µm (rats) from the ventricular wall; that we have previously shown to contain the SEZ (Kazanis and ffrench-Constant, 2012 ), as well as deeper in the initial segment of the rostral migratory stream. Cell densities are given as cells/mm 2 . For cell cultures, at least 10 optical fields were photographed per coverslip. It should be noted that nestin immunoreactivity could not be detected in Microtus cells, using two different antibodies (Abcam, chicken and mouse anti-nestin). For corpus callosum measurements, the same sections and methods were used, by photographing callosal areas adjacent to the lateral ventricles. Statistics All cell counts were performed blind as to the experimental group and the karyotype and from multiple investigators. Statistical analyses were performed using IBM SPSS statistics (for 2-way and 1-way ANOVA, followed by the Tukey post-hoc analysis, whenever necessary). Scatter plots were generated, and regression and Pearson’s correlation analyses were performed using Microsoft Office Excel. Declarations Declaration of interest The authors declare no competing interests. Author Contribution AR: Data curation, Formal Analysis, Methodology, Validation, Visualization, Writing –review & editingTA: Data curation, Formal Analysis, Validation, Visualization, Writing –review & editingEA, MM, GL, MA, KM, MC, PS: Data curation, Formal Analysis, ValidationGM: Data curation, Formal Analysis, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing –review & editingIK: Conceptualization, Data curation, Formal Analysis, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing – original draft, review & editing Data Availability The datasets used and analysed during the current study are available from the corresponding author on reasonable request. Materials availability This study did not generate new unique reagents. References Agathou, S., Káradóttir, R. T. & Kazanis, I. Niche derived oligodendrocyte progenitors: a source of rejuvenation or complementation for local oligodendrogenesis? 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KAZANIS","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAvElEQVRIiWNgGAWjYBACNh7m459/VMD5CcRoYUtjZjhDihYGHh4zZsY2UrTw8Rwwe1w4z05et4H54QfGtjQiHMbbkG48c1uy4bYDbMYSjG05RGjhZzggwbvtAOO2AwxmDIxtFcRoYWyQ4J1zwH7bAfZvRGrhbWaT5m04kLjtAA/IFmIcxnOM2XDGseTkbYd5iiUSzhHhffme/I8PPtTY2W473r7xw4eyZMJaEICZgbiIHAWjYBSMglFABAAAi440hwu+jvgAAAAASUVORK5CYII=","orcid":"","institution":"University of Westminster","correspondingAuthor":true,"prefix":"","firstName":"ILIAS","middleName":"","lastName":"KAZANIS","suffix":""}],"badges":[],"createdAt":"2024-10-20 18:38:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5299693/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5299693/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-025-01670-3","type":"published","date":"2025-05-28T15:57:56+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":69833478,"identity":"8ace39f8-afb7-4fe6-b62e-bb6b211e7e76","added_by":"auto","created_at":"2024-11-25 15:51:14","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":137249,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eEffects of habitat and species on proliferation and neurogenesis in the SEZ niche\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e(A-C) Microphotograph of the “dorsal horn” of the lab mouse SEZ, after immuno-fluorescence on brain sections for PCNA (nuclear staining, in red, in A) and Sox2 (nuclear staining, in green, B). [Merged image in C. Scale bar: 100μm. The yellow arrow indicates a PCNA+ cell with low Sox2 immunoreactivity. The white arrow indicates a PCNA+ cell with high Sox2 immunoreactivity] (D) Detail of the “dorsal horn” of the SEZ in a Wild\u003csup\u003e2n=40\u003c/sup\u003e mouse showing Dcx+ cells (cytoplasmic staining in red). [scale bar: 15μm] (E) Image of the total dorsoventral SEZ area in a \u003cem\u003eMicrotus thomasi\u003c/em\u003e individual (autumn collection) after immunostaining for Sox2 (in green), PCNA (in red) and GFAP (in white). The SEZ has a typical for rodents (mice and rats) structure, with Sox2 expression in ependymal cells (indicative examples of ependymal cell groups indicated with yellow arrows). An “ectopic” PCNA+ cell, located deeper in the striatum, is indicated with a white arrow. Note that the density of PCNA+ cells is significantly decreased at the “dorsal horn” area, indicated by the white star (compare with the area shown in Figure 1A). [scale bar: 50μm] (F-G) Scatter plot graphs of the density of PCNA+ and of Dcx+ cells according to life conditions (lab or wild), species and season. [Individual values are shown with different colours and shapes, as explained in Suppl. Figure 1. Mean values are shown with red lines and error bars depict the SEM. Comparisons between groups were performed using one-way ANOVA, followed by Tukey’s \u003cem\u003epost-hoc \u003c/em\u003eanalysis.]\u003c/p\u003e","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-5299693/v1/006663af0f03193eb60694b3.png"},{"id":69833474,"identity":"b13d6375-6c74-420f-ba5f-293650813f04","added_by":"auto","created_at":"2024-11-25 15:51:14","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":57469,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eEffects of chromosomal fusions, leading to changes in chromosome numbers, on proliferation and neurogenesis in the SEZ niche\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e(A-B) High magnification images of metaphasic chromosomes from wild\u003csup\u003e2n=40\u003c/sup\u003e (in A, without G-band staining) and wild\u003csup\u003e2n=30\u003c/sup\u003e (in B, with G-band staining) \u003cem\u003eM. m. domesticus \u003c/em\u003eindividuals. (C-F) Scatter plot graphs showing the density of PCNA+ and Dcx+ cells within the SEZ of wild mice populations with different numbers of chromosomes, separately for autumn (C,D) and spring (E,F) collections. [Individual values are shown with different colours and shapes, as explained in Suppl. Figure 1. Mean values are shown with red lines and error bars depict the SEM. Comparisons with lab mice (#), with Wild\u003csup\u003e2n=40\u003c/sup\u003e (\u0026amp;) or Wild\u003csup\u003e2n=37\u003c/sup\u003e (*) were performed using one-way ANOVA followed by Tukey’s \u003cem\u003epost-hoc \u003c/em\u003eanalysis. The polynomial equation describing each plot, the R-squared value, as well as the Pearson’s correlation (ρ) are shown at the upper right of each graph.]\u003c/p\u003e","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-5299693/v1/a8a0829a2c810b4a2993ec40.png"},{"id":69833475,"identity":"d05ad85a-a1f1-4b95-ad6b-d28654bbd078","added_by":"auto","created_at":"2024-11-25 15:51:14","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":46306,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eEffects of habitat, species, seasons and of chromosome numbers on the density of oligodendroblasts and microglial cells in the SEZ\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e(A) Detail of the “dorsal horn” of the SEZ in a Wild\u003csup\u003e2n=40\u003c/sup\u003e mouse, with a typical Iba1+ microglial cell (in green, indicated by a yellow arrowhead) and an Olig2+ cell (in white, indicated by a white arrow). PCNA nuclear staining is in red. [scale bar: 15μm] (B-E) Scatter plot graphs showing the density of Olig2+ (oligodendroblasts) and Iba1+ (microglia) cells within the SEZ of lab mice, wild mice populations with different numbers of chromosomes and \u003cem\u003eMicrotus thomasi\u003c/em\u003e. [Individual values are shown with different colours and shapes, as explained in Suppl. Figure 1. Mean values are shown with red lines and error bars depict the SEM. Comparisons were performed using one-way ANOVA followed by Tukey’s \u003cem\u003epost-hoc \u003c/em\u003eanalysis. “n.s.”: not significant]\u003c/p\u003e","description":"","filename":"Onlinefloatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-5299693/v1/72120f2dfb7d4bc8ff3e16c5.png"},{"id":69833480,"identity":"bcb6b0fc-1f34-4a0f-9172-43073ca80127","added_by":"auto","created_at":"2024-11-25 15:51:14","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":154148,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eEffects of habitat, species, seasons and of chromosome numbers on the density of different cell types in the CC\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e(A) Image of the supraventricular CC with cells immunopositive for Iba1 (in white; a typical example is indicated by the yellow arrow with the area outlined in A3 shown in higher magnification), PCNA (in red) and Olig2 (in green). The analysis was focused on proliferating Olig2+ cells (examples indicated by white arrows). (B) Image of the supraventricular CC with cells immunopositive for Sox2 (in green; note the numerous immunopositive ependymal cells at the ventricular wall and the typical cytoarchitecture of the corpus callosum, with chains of nuclei) and PCNA (in red). [scale bar: 50μm in A; 40μm in B] (C-K) Scatter plot graphs showing the density of Olig2+PCNA+ double positive cells (C,D), the percentage of mitotic Olig2+ cells within the pool of Olig2+ cells (E,F), the density of Sox2+ cells (G-I) and of Iba1+ cells (J,K). [Individual values are shown with different colours and shapes, as explained in Suppl. Figure 1. Mean values are shown with red lines and error bars depict the SEM. Comparisons to “lab mice” (#) were performed using one-way ANOVA followed by Tukey’s \u003cem\u003epost-hoc \u003c/em\u003eanalysis. The polynomial equation describing the plots, the R-squared value, as well as the Pearson’s correlation (ρ) are shown at the upper right in (G-I) and only the Pearson’s correlation (ρ) in (D)]\u003c/p\u003e","description":"","filename":"Onlinefloatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-5299693/v1/44d19d6541fbfcb9eb1e8d14.png"},{"id":69833477,"identity":"430fd915-6051-4c1c-98d2-9c242418f713","added_by":"auto","created_at":"2024-11-25 15:51:14","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":108162,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eIn vitro behavior of SEZ pbNSPCs\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e(A-D) Images of pbNSCs, immunostained for different cell-type markers. Expression of Sox2 (A1, in green) and Ki67 (A2, in red) in Microtus-derived primary neurosphere cells. (B) Expression of nestin (B1, in green) and Ki67 (B2, in red) in lab mouse-derived primary neurosphere cells. (C) Expression of βΙΙΙ-tubulin (in red) in Wild\u003csup\u003e2n=30\u003c/sup\u003e mouse-derived tertiary neurosphere cells. (D) Expression of GFAP (in green) in Wild\u003csup\u003e2n=30\u003c/sup\u003e mouse-derived tertiary neurosphere cells. [scale bars: 40μm in A, C; 10μm in B; 15μm in D] (E-I) Scatter plot graphs showing the percentages of Ki67+ cells (in E,F), of Nestin+ cells (in G,H), and of Sox2+ cells (in I) in primary and tertiary cultures of pbNSCs isolated from mice or Microtus (in I). [Individual values are shown with different colours and shapes, as explained in Suppl. Figure 1. Mean values are shown with red lines and error bars depict the SEM. Comparisons were performed using one-way ANOVA followed by Tukey’s \u003cem\u003epost-hoc \u003c/em\u003eanalysis]\u003c/p\u003e","description":"","filename":"Onlinefloatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-5299693/v1/41d928f2af3b731fdb96173c.png"},{"id":83782983,"identity":"bf71bc89-46c8-4b02-b2e8-2144e05388ae","added_by":"auto","created_at":"2025-06-02 16:09:37","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1946182,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5299693/v1/588bddd4-f6ff-4173-b705-2291dea20afa.pdf"},{"id":69834458,"identity":"4dcb34ca-8947-44aa-bd29-697597d7edfc","added_by":"auto","created_at":"2024-11-25 15:59:15","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":869596,"visible":true,"origin":"","legend":"","description":"","filename":"Raptietal.SupplementaryMaterial.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5299693/v1/3b7a93d0be7b713f6eeeb988.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Lab life, seasons and chromosome fusions restrict non-cell-autonomously proliferation and neurogenesis, but not oligodendrogenesis, in mice and voles","fulltext":[{"header":"Introduction","content":"\u003cp\u003eIn mammals, postnatal brain neural stem and progenitor cells (pbNSPCs) cluster within specialized microenvironments called stem cell niches. They remain in quiescence and infrequently transit towards mitotic activation, giving rise to transit amplifying progenitors that subsequently generate committed neuronal or glial progenitors (Delgado et al., \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Kalamakis et al., \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Obernier et al., \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). A well-described niche in rodents and humans is located at the subependymal zone (SEZ) of the lateral ventricles (also known as ventricular-subventricular zone) (Obernier and Alvarez-Buylla, \u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). In mice and rats, the bulk of the SEZ niche is located in a narrow layer of cells adjacent to the ventricular ependyma, at the striatal side of the lateral ventricles, and can be identified based on the expression of markers of cell proliferation, such as PCNA (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA, C) and of immature neuronal identity, such as Doublecortin (Dcx, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB) (Kazanis et al., \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e2010\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). A distinct pool of brain progenitors, called Oligodendrocyte Progenitor Cells (OPCs), can be also detected based on the co-expression of proliferation markers and markers of oligodendroglial lineage identity, such as Olig2 or PDGFRα (Bruggen et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Foerster et al., \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2024\u003c/span\u003e; Kazanis et al., \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). OPCs are scattered throughout the brain parenchyma, with the corpus callosum (CC) being a white matter tract particularly rich in them (Bottes and Jessberger, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Franklin and ffrench-Constant, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; Young et al., \u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e2013\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eA wide range of ecological and behavioral factors have been shown, in lab settings and each one separately, to control the behavior of pbNSPCs, including: pregnancy (Chaker et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2023\u003c/span\u003e), physical exercise (Nicolis di Robilant et al., 2019; Pons-Espinal et al., \u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e2019\u003c/span\u003e), stress (Mirescu and Gould, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e2006\u003c/span\u003e), environmental enrichment (K\u0026ouml;rholz et al., \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e2018\u003c/span\u003e; Plane et al., \u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e2008\u003c/span\u003e), social interaction (Lopes et al., \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2023\u003c/span\u003e), night/day duration (Gengatharan et al., \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2021\u003c/span\u003e), olfactory stimuli (for the rodent SEZ) (Rochefort et al., \u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e2002\u003c/span\u003e) and the microbiome (Dohm-Hansen et al., \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). An even wider list of diffusible (local and long-range) molecules, cell-to-cell signals and metabolic factors have been, again experimentally, proposed to regulate pbNSPCs (Obernier and Alvarez-Buylla, \u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). Such experimental animal work is important in basic research but can be less valid for translational biomedical research, as it relies on the use of animals maintained and handled in highly controlled conditions and with the role of each factor explored individually. Hence, it is imperative to dissect mechanisms and factors that regulate pbNSPCs in wild rodent populations, the life of which integrates the multiple parameters listed above. To achieve this, it is necessary to identify appropriate wild animal comparator populations that -in the absence of experimental manipulation and easy access to large animal numbers- will enable the link of descriptive information with genetic and metabolic data.\u003c/p\u003e \u003cp\u003eAs a first step towards this direction, we generated \u0026ldquo;real world\u0026rdquo; data comparing neurogenesis and oligodendrogenesis in the SEZ and the CC in brain samples obtained from laboratory and wild populations of \u003cem\u003eMus musculus domesticus\u003c/em\u003e (house mice). To increase the strength of the analysis, we enriched our samples in two ways: firstly, by including a fossorial species, the \u003cem\u003eMicrotus thomasi\u003c/em\u003e (Thomas\u0026rsquo;s pine voles), which is found in open fields and was captured in underground burrows (Supplemental Fig.\u0026nbsp;1 and Supplemental Table\u0026nbsp;1). Secondly, we sampled populations of wild mice with karyotypes that deviate from the typical 2n\u0026thinsp;=\u0026thinsp;40 due to the naturally occurring phenomenon of Robertsonian fusions (Rb). As the typical mouse chromosomes are acrocentric, the fusion of two of them can result in the formation of metacentric chromosomes (Gerton, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e2024\u003c/span\u003e), leading to established mouse populations with lower numbers of chromosomes, down to 2n\u0026thinsp;=\u0026thinsp;26 (Mitsainas and Giagia-Aathanasopoulou, 2005). Rb lead to the reorganization of chromatin; albeit, without major loss of genetic material (Pi\u0026aacute;lek et al., \u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e2005\u003c/span\u003e). So far, there is no evidence of phenotypic alterations caused by Rb in mice (Wang et al., \u003cspan citationid=\"CR77\" class=\"CitationRef\"\u003e2023\u003c/span\u003e); however, this phenomenon leads to higher levels of genetic differentiation through effects to meiotic recombination (Mar\u0026iacute;n-Garc\u0026iacute;a et al., \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e2024\u003c/span\u003e) and is regarded as a speciation factor because it leads to the genetic isolation of mouse populations by inhibiting the flow of genetic material (Britton-Davidian et al., \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2000\u003c/span\u003e; Ferguson-Smith and Trifonov, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2007\u003c/span\u003e; Garagna et al., \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e2014\u003c/span\u003e) and has been linked to infertility in humans (Gerton, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e2024\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eWe focused our analysis on the SEZ, which is positioned and structured in a way that allows the integration of multiple, peripheral and local, stimuli derived via the cerebrospinal fluid, the vasculature, astrocytic syncytia, neuronal activity and the extracellular matrix (Douet et al., \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2013\u003c/span\u003e; Kazanis, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2009\u003c/span\u003e; Silva-Vargas et al., \u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e2016\u003c/span\u003e; Taranov et al., \u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e2024\u003c/span\u003e; Tavazoie et al., \u003cspan citationid=\"CR75\" class=\"CitationRef\"\u003e2008\u003c/span\u003e) and on the OPC-rich adjacent CC. In this way we were able to investigate, within the same anatomical areas, both neurogenesis and oligodendrogenesis, as well as the behavior of two distinct pools of brain progenitors, pbNSPCs and OPCs.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eNumbers of proliferating cells and of neuroblasts, in the SEZ, are reduced in lab mice and show seasonal variation in pine voles\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo assess the behavior of pbNSPCs of the SEZ, we calculated the density and the percentage of proliferating cells (immunopositive for PCNA), as well as the density and the percentage of neuroblasts (immunopositive for Doublecortin) at the dorsolateral horn of the SEZ, a hotspot of pbNSPCs (Mirzadeh et al., \u003cspan class=\"CitationRef\"\u003e2008\u003c/span\u003e) and the site of convergence for neuroblasts and oligodendroblasts ahead of their outward migration via the rostral migratory stream (Capilla-Gonzalez et al., \u003cspan class=\"CitationRef\"\u003e2013\u003c/span\u003e). All PCNA\u0026thinsp;+\u0026thinsp;cells were found to co-express the transcription factor Sox2; thus, they were all considered to be pbNSPCs (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eA,E).\u003c/p\u003e\n\u003cp\u003eFirstly, we compared lab and wild mice (all bearing the typical 2n\u0026thinsp;=\u0026thinsp;40 karyotype) and we found that the density and the percentage of proliferating cells and the density of neuroblasts were significantly higher in wild mice (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eF-G, Suppl. Figure 2A,B), indicating that maintenance in lab facilities restricts proliferation and generation of neuroblasts in the SEZ. To test more for the effect of habitat, we looked in the SEZ of the \u003cem\u003eMicrotus thomasi\u003c/em\u003e, a fossorial rodent that spends a significant fraction of its life in confined spaces and relies more on the use of olfaction (Kirkpatrick et al., \u003cspan class=\"CitationRef\"\u003e1994\u003c/span\u003e). The less investigated \u003cem\u003eMicrotus thomasi\u003c/em\u003e SEZ had a structure similar to that of the mouse and the rat niche, as has been shown in the \u003cem\u003eMicrotus ochrogaster\u003c/em\u003e (Castro et al., \u003cspan class=\"CitationRef\"\u003e2020\u003c/span\u003e), apart from the detection of individual proliferating cells located in the striatum (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eE), deeper than the 30\u0026ndash;50\u0026micro;m distance from the ventricular wall in which all proliferating cells are found in mice and rats, respectively (Kazanis and ffrench-Constant, \u003cspan class=\"CitationRef\"\u003e2012\u003c/span\u003e). Notably, a clear dichotomy in PCNA\u0026thinsp;+\u0026thinsp;and Dcx\u0026thinsp;+\u0026thinsp;cell densities was observed in the samples we analysed, with the season of capture (autumn versus spring), being the only factor separating the two sub-populations (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eF-G). To ascertain appropriate comparisons, we also separated lab mice in spring and autumn pools and no seasonal variation was found in PCNA\u0026thinsp;+\u0026thinsp;and Dcx\u0026thinsp;+\u0026thinsp;cells. In voles, the SEZ was significantly richer in proliferating cells and neuroblasts in spring, with \u003cem\u003eMicrotus\u003c/em\u003e\u003csup\u003e\u003cem\u003es\u003c/em\u003epring\u003c/sup\u003e pbNSPCs exhibiting a behavior similar to that of wild\u003csup\u003e2n\u0026thinsp;=\u0026thinsp;40(autumn)\u003c/sup\u003e mice, while the \u003cem\u003eMicrotus\u003c/em\u003e\u003csup\u003e\u003cem\u003eautumn\u003c/em\u003e\u003c/sup\u003e population exhibited pbNSPC behavior similar to that of lab mice (the percentage of Dcx\u0026thinsp;+\u0026thinsp;cells was even significantly lower) (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, Suppl. Figure 2A-B). Overall, these data reveal that the proliferative and neurogenic activity, per unit of SEZ, varies within a similar \u0026ldquo;low/high\u0026rdquo; range in mice and voles, and is directly affected by lab or wild habitat in mice and by seasons in the \u003cem\u003eMicrotus\u003c/em\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNumbers of proliferating cells and of neuroblasts in the SEZ are corelated to the number of chromosomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBased on previous work (Mitsainas and Giagia-Athanasopoulou, \u003cspan class=\"CitationRef\"\u003e2005\u003c/span\u003e) and on explorative new collections, we sampled wild mice populations with non-typical karyotypes, from different sites in Greece. We included in our analysis mice with 2n\u0026thinsp;=\u0026thinsp;37, 30, 28, 27 and 26 chromosomes (Suppl. Table 1 and Suppl. Figure 1, Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eA-B). From one site (#7, in Mavroneri, Suppl. Figure\u0026nbsp;1) we were not able to karyotype all mice, but as we have established well that mice found there belong to populations with 2n\u0026thinsp;\u0026le;\u0026thinsp;30 (Suppl. Table\u0026nbsp;1), we grouped them as a separate Wild\u003csup\u003e2n\u0026thinsp;\u0026le;\u0026thinsp;30\u003c/sup\u003e pool. When the densities and percentages of PCNA\u0026thinsp;+\u0026thinsp;and Dcx\u0026thinsp;+\u0026thinsp;cells were plotted against the number of chromosomes, a surprising pattern was revealed, with both parameters found to decrease in proportion to the reduction in the numbers of chromosomes (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eC-F, Suppl Fig.\u0026nbsp;2C-F). The correlation was tested separately for mice captured in spring and autumn and was found to be very strong, with Pearson\u0026rsquo;s correlation values higher than 0.90. One-way ANOVA analyses revealed that, besides Wild\u003csup\u003e2n\u0026thinsp;=\u0026thinsp;40\u003c/sup\u003e mice, Wild\u003csup\u003e2n\u0026thinsp;=\u0026thinsp;37\u003c/sup\u003e mice had also significantly higher densities of PCNA\u0026thinsp;+\u0026thinsp;and Dcx\u0026thinsp;+\u0026thinsp;cells in the SEZ when compared to lab mice (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eC-F, Suppl Fig.\u0026nbsp;2C-F). Wild mice with karyotypes 2n\u0026thinsp;\u0026le;\u0026thinsp;30 showed no differences compared to lab mice and had significantly less PCNA\u0026thinsp;+\u0026thinsp;and Dcx\u0026thinsp;+\u0026thinsp;cells than Wild\u003csup\u003e2n\u0026thinsp;=\u0026thinsp;40\u003c/sup\u003e and Wild\u003csup\u003e2n\u0026thinsp;=\u0026thinsp;37\u003c/sup\u003e mice. The season was not found to affect the densities or percentages of PCNA\u0026thinsp;+\u0026thinsp;and Dcx\u0026thinsp;+\u0026thinsp;cells in wild mice (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05, \u003cem\u003epost-hoc\u003c/em\u003e analyses for all Wild\u003csup\u003eautumn\u003c/sup\u003e versus all Wild\u003csup\u003espring\u003c/sup\u003e mice as well as for Wild\u003csup\u003e2n\u0026thinsp;\u0026le;\u0026thinsp;30(autumn)\u003c/sup\u003e versus Wild\u003csup\u003e2n\u0026thinsp;\u0026le;\u0026thinsp;30(spring)\u003c/sup\u003e), as was the case for lab mice.\u003c/p\u003e\n\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003eOligodendrocyte progenitor cells are not affected by ecological factors and by changes in chromosome numbers\u003c/h2\u003e\n \u003cp\u003eTo assess if the effects we identified on the neurogenic output of the SEZ were also visible to its oligodendrogenic output we calculated the density of Olig2\u0026thinsp;+\u0026thinsp;oligodendroblasts in the dorsoventral horn of the niche (Fig. 3A-C). Moreover, we extended our analysis to the supraventricular CC. Because in the CC Olig2 is expressed both in OPCs and in mature oligodendrocytes, we focused on the mitotic fraction of OPCs, i.e. the cells co-expressing Olig2 and PCNA (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eA-F). We also counted Sox2\u0026thinsp;+\u0026thinsp;cells, as the expression of this transcription factor is undetectable in mature cells of the nervous system but is retained in cells with neural progenitor identity of the brain parenchyma (Niu et al., \u003cspan class=\"CitationRef\"\u003e2015\u003c/span\u003e)(Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eG-I). Our analysis revealed that the density of Olig2\u0026thinsp;+\u0026thinsp;cells in the SEZ and of mitotic Olig2\u0026thinsp;+\u0026thinsp;cells in the CC were unaffected by species, habitat, or karyotype in the same groups that showed differences in PCNA\u0026thinsp;+\u0026thinsp;and Dcx\u0026thinsp;+\u0026thinsp;cells (Figs. 3, \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e). On the other hand, the density of Sox2-expressing cells in the CC was significantly decreased in lab mice, compared to wild mice and to the \u003cem\u003eMicrotus\u003c/em\u003e\u003csup\u003eautumn\u003c/sup\u003e (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eG-I). A strong Pearson\u0026rsquo;s correlation between the decreasing densities of Sox2\u0026thinsp;+\u0026thinsp;cells and the decreasing number of chromosomes was apparent as was observed for PCNA\u0026thinsp;+\u0026thinsp;and Dcx\u0026thinsp;+\u0026thinsp;cells in the SEZ (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eH-I).\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eNo differences in the behavior of pbNSPCs across experimental groups in vitro\u003c/h3\u003e\n\u003cp\u003eThe significant differences in the activity of SEZ pbNSPCs in animals living in diverse habitats but also in mice harboring chromosomal fusions, could be caused by hard-wired, cell autonomous, differences, or by changes in external factors regulating their behavior. To test for this in the most direct way, in some animals one brain hemisphere was included in the histological analyses, while the other was used for the isolation of SEZ-derived pbNSPCs and their culture in the form of free-floating colonies known as neurospheres. One-week old primary, or twice passaged (tertiary), neurospheres were dissociated and cells were plated on glass coverslips. After two days in pro-proliferation conditions, their mitotic activity (percentage of Ki67\u0026thinsp;+\u0026thinsp;cells) and their NSPC profile (percentage of nestin\u0026thinsp;+\u0026thinsp;cells in mouse cultures and of Sox2\u0026thinsp;+\u0026thinsp;cells in \u003cem\u003eMicrotus\u003c/em\u003e samples, because they failed to produce positive immunostaining for nestin) were assessed. In addition, tertiary mouse neurosphere cells were plated on glass coverslips and were analyzed after five days in pro-differentiation conditions for the presence of GFAP\u0026thinsp;+\u0026thinsp;astrocytes and \u0026beta;\u0026Iota;\u0026Iota;\u0026Iota;-tubulin\u0026thinsp;+\u0026thinsp;neurons. The cell culture analyses revealed that pbNSPCs exhibited similar \u003cem\u003ein vitro\u003c/em\u003e behavior irrespective of species, karyotype, season, and lifestyle (Fig. \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e\n\u003ch3\u003eEcological and genetic factors do not alter the immediate NSPC cellular microenvironment\u003c/h3\u003e\n\u003cp\u003eThe absence of differences in the \u003cem\u003ein vitro\u003c/em\u003e behavior of pbNSPCs strongly indicated that the effects observed \u003cem\u003ein vivo\u003c/em\u003e are instructed by external factors. To assess if these changes were correlated to changes in the immediate cellular microenvironment of the SEZ or of the CC, we looked at microglial (Iba1+) cells that act as regulators of pbNSPCs (Shigemoto-Mogami et al., \u003cspan class=\"CitationRef\"\u003e2014\u003c/span\u003e; Solano Fonseca et al., \u003cspan class=\"CitationRef\"\u003e2016\u003c/span\u003e; Xavier et al., \u003cspan class=\"CitationRef\"\u003e2015\u003c/span\u003e). We found that the density of Iba1\u0026thinsp;+\u0026thinsp;cells remained stable across all groups (Fig. 3D-E, Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eJ-K). We also calculated the pool of what we termed \u0026ldquo;supporting cells\u0026rdquo; of the SEZ, i.e. the cells of the niche that do not belong in the pbNSPC lineage, by subtracting from the total number of cells (all DAPI\u0026thinsp;+\u0026thinsp;nuclei) the numbers of all PCNA\u0026thinsp;+\u0026thinsp;and Dcx\u0026thinsp;+\u0026thinsp;cells. This pool of cells includes mainly ependymal and endothelial cells, as well as differentiated astrocytes (Mirzadeh et al., \u003cspan class=\"CitationRef\"\u003e2008\u003c/span\u003e; Shen et al., \u003cspan class=\"CitationRef\"\u003e2008\u003c/span\u003e). Notably, we found that the population of supporting SEZ cells remained also unaffected (Suppl Fig.\u0026nbsp;3).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe behavior (e.g. proliferation, differentiation, survival/maturation) and regulation of pbNSPCs, especially in their niches, has been investigated extensively in mice maintained in animal facilities, under tightly controlled conditions that differ substantially from the natural habitats of these rodents. Accumulating evidence suggests that environmental enrichment (Plane et al., \u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e2008\u003c/span\u003e; Rochefort et al., \u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e2002\u003c/span\u003e), increased physical activity (Horowitz et al., \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; Pons-Espinal et al., \u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e2019\u003c/span\u003e) and high social interactions (K\u0026ouml;rholz et al., \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e2018\u003c/span\u003e) are correlated with increased levels of neurogenesis, mainly in the hippocampal niche. Based on the above, and hypothesizing that the behavior of pbNSPCs in lab mice might be critically different comparing to wild mice, we decided to investigate the SEZ stem cell niche that is located and structured in a way that enables the integration of signals originating from multiple pathways (Kazanis, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2009\u003c/span\u003e; Obernier and Alvarez-Buylla, \u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Silva-Vargas et al., \u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e2016\u003c/span\u003e; Tavazoie et al., \u003cspan citationid=\"CR75\" class=\"CitationRef\"\u003e2008\u003c/span\u003e). Indeed, our data revealed that proliferation and neurogenesis in SEZ pbNSPCs are affected by life conditions and were decreased (by approximately 50%-70%) in lab mice when compared to wild animals. This sets a new, significantly higher, translational \u0026ldquo;standard\u0026rdquo; when interpreting the therapeutic potential of experimental manipulations that lead to increased levels of neurogenesis, with the behavior of pbNSPCs in wild mice offering a \u0026ldquo;real mouse world\u0026rdquo; comparator.\u003c/p\u003e \u003cp\u003eWild mice provide a unique opportunity to generate valid, unbiased from experimental handling, information, especially because even mild interventions can affect the mouse characteristics (Geiger et al., \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2018\u003c/span\u003e) or the vole\u0026rsquo;s neurogenic activity (Castro et al., \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). To achieve this, it is essential to identify multiple, well-defined, wild populations that will allow the extraction of key conclusions by linking genetic and molecular data with descriptive data, as has been done with human samples (Al-Dalahmah et al., \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2024\u003c/span\u003e; Kim et al., \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2024\u003c/span\u003e; Kukanja et al., \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e2024\u003c/span\u003e). Here, we identify interesting comparator groups either at the cellular or at the animal level. At the cellular level, the divergent behavior of neuronal and of oligodendroglial lineage progenitors most probably underlines the divergent roles and evolutionary adaptations of the two cell lineages. The former have acquired a dependence on the niche microenvironment wherein their activity is tightly regulated (Delgado et al., \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2014\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Marqu\u0026eacute;s-Torrej\u0026oacute;n et al., \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Sanai et al., \u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e2004\u003c/span\u003e; Takei, \u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e2019\u003c/span\u003e) and the latter have adapted to life in the parenchyma (Agathou et al., \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2013\u003c/span\u003e; Anesti et al., \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2022\u003c/span\u003e) exhibiting persistent generation of myelin (Young et al., \u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e2013\u003c/span\u003e); albeit, remain responsive to life-style changes, such as piano playing (Bengtsson et al., \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2005\u003c/span\u003e; Scholz et al., \u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e2009\u003c/span\u003e). In contrast, Sox2\u0026thinsp;+\u0026thinsp;neural progenitors located in the CC showed behavior similar to that of neural progenitors in the SEZ. The identification of cell pools with convergent/divergent aspects of behavior in the same brain areas can enrich the analytical resolution of methods incorporating anatomical elements (such as spatial transcriptomics).\u003c/p\u003e \u003cp\u003eAt the populations level, we show that the density of pbNSPCs in the SEZ exhibits seasonal variation in the \u003cem\u003eMicrotus\u003c/em\u003e, but not in mice, an observation that can be used to extract key metabolic information by identifying systemic factors with similar seasonal fluctuations. This discrepancy could reflect the fact that wild mice populate humanized habitats, characterized by higher stability, throughout the year, in terms of temperature, abundance of food and the presence of predators, while the \u003cem\u003eMicrotus\u0026rsquo;\u003c/em\u003e ethology involves seasonal variation in physical, reproductive and food scavenging activity. Because two of the three voles captured in spring had lower body weight, indicating younger age, when also checked for a possible correlation between body weight and density of PCNA\u0026thinsp;+\u0026thinsp;cells, this turned to be negative (Pearson\u0026rsquo;s analysis ρ=-0.43), while a t-test for the density of PCNA\u0026thinsp;+\u0026thinsp;cells in individuals with body weight\u0026thinsp;\u0026lt;\u0026thinsp;10g versus body weight\u0026thinsp;\u0026gt;\u0026thinsp;20g gave no significant result (p\u0026thinsp;=\u0026thinsp;0.09). It should be noted that, overall, we found no significant differences in the gross cyto-architecture of the SEZ between lab mice, wild mice and voles and the same was observed when comparing mice and rats (Kazanis and ffrench-Constant, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e2012\u003c/span\u003e). This suggests that valid comparisons can be drawn by investigating species that belong to the same order (rodentia) and that differences in the behavior and organization of postnatal brain progenitors require longer phylogenetic distances (Jessberger and Gage, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e2014\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eImportantly, the observation that the differences identified between lab and wild rodents are not hard-wired and cell-autonomous, allows to focus on metabolic/ systemic targets. Accumulating evidence has shown that circulation (Horowitz et al., \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; Katsimpardi et al., \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e2014\u003c/span\u003e) and choroid plexus-derived (Delgado et al., \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2014\u003c/span\u003e; Silva-Vargas et al., \u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e2016\u003c/span\u003e; Taranov et al., \u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e2024\u003c/span\u003e) factors are important in the control of pbNSPCs and our data offer a unique opportunity to expand such analyses using \u0026ldquo;real world\u0026rdquo; data (e.g. metabolic and inflammatory profiles). Based on the significant differences observed \u003cem\u003ein vivo\u003c/em\u003e and to the limited number of wild animal samples, the \u003cem\u003ein vitro\u003c/em\u003e assays we employed were purposedly crude (e.g. cells were grown in abundance of EGF and FGF2, or in the total absence of these factors), as the aim was not to assess the numbers of neural stem cells in the parent SEZ, or the detailed response of cells to different factors (\u0026Aacute;vila-Gonz\u0026aacute;lez et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2023\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe most unexpected observation was the strong correlation between the decrease in the number of chromosomes and the decrease in the density of pbNSPCs in the SEZ. A mechanistical explanation for this will require additional analyses, such as G-banded chromosome staining, or some type of NGS and ATAC sequence analyses, which can now be performed on archived material. Gene silencing due to \u0026ldquo;position effect variegation\u0026rdquo; has been described in mice (Pedram et al., \u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e2006\u003c/span\u003e); however, rather than focusing on individual genes, the involvement of pericentromeric and of telomeric chromatin seems to offer a more valid target. These are the chromosome areas quantitively affected by Rb and they have been implicated in the control of stem cell proliferation (Del Rosario et al., \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Nishide and Hirano, \u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e2014\u003c/span\u003e) and of the age-related decline in stem cell function (Jaskelioff et al., \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Lobanova et al., \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2017\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn terms of basic biology, our data reveal a key feature of the regulation of pbNSPCs and of the SEZ function in rodents. The fact that the \u003cem\u003eMicrotus\u003c/em\u003e niche becomes almost void of progenitors in the autumn, only to be replenished in spring, indicates that living conditions affect the proliferative activity of pbNSPCs, possibly acting at the top of the hierarchy, at the quiescence-to-mitotic activation transition of neural stem cells (Kalamakis et al., \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). At the same time, the fact that the density of supporting niche cells (ependyma, endothelium) remains similar across species, karyotypes, lifestyle (even in the lab animals that experience many generations of hypoactivity), and seasons, strongly suggests that the structure of the niche is independent of any fluctuations of neurogenic activity. These findings might reconciliate previous observations on the human SEZ, that has been reported to become depleted of pbNSPC activity during infancy (McClenahan et al., \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Sanai et al., \u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e2004\u003c/span\u003e; Takei, \u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e2019\u003c/span\u003e) but also to be able to respond in cases of degeneration, even in the elderly (Ekonomou et al., \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2011\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2012\u003c/span\u003e). Further histological analysis of niche elements, such as the vasculature, will consolidate this architectural stability and can lead to the calculation of a \u0026ldquo;maximum capacity\u0026rdquo; for pbNSPC density per niche unit.\u003c/p\u003e \u003cp\u003eOne methodological limitation of this study is that the age of wild animals could not be reliably determined. The only animal groups with certified ages were the laboratory mice (2 to 4 months). We could only be sure that wild mice were adult (post-1 month old), based on their body size, and that the females were not pregnant, a condition recently reported to affect neurogenesis in the SEZ (Chaker et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). Neurogenesis (and more widely the activity of tissue-specific stem cells) decreases over ageing in lab animals (Neumann et al., \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Shook et al., \u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e2012\u003c/span\u003e). Therefore, lab animals included in the study were at the peak of neurogenesis age, while wild mice were not younger than lab mice, rather a mixture of different ages (old, or sick wild animals are not very active; thus, are more rarely captured and are under-represented). In conclusion, the overall results indicate that it is highly unlikely that the age of wild mice might have confounded our results, as the activity of pbNSPCs was found to be both increased and decreased (compared to the age-grouped young adult lab mice) in different groups of wild mice; whilst at the same time, microglial cells and OPCs showed different patterns of behavior.\u003c/p\u003e \u003cp\u003eAnother possible confounding factor in this type of work is the possible lack of genetic variation, if individuals captured at one site belong to the same family. In this study there was no implementation of strict distribution rules, such as the use of grids employed in field work destined for the assessment of the diversity of fauna and flora, and all captured individuals were included. Supplemental table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and supplemental Fig.\u0026nbsp;1 provide details that inform regarding possible family relations between individuals. The 4 Wild\u003csup\u003e2n\u0026thinsp;=\u0026thinsp;40\u003c/sup\u003e mice were captured at 4 different locations; thus, have no family relations to each other. The 4 Wild\u003csup\u003e2n\u0026thinsp;=\u0026thinsp;37\u003c/sup\u003e mice were captured at the same location and time. Nevertheless, our analysis revealed a wide range of values, especially in the density of PCNA\u0026thinsp;+\u0026thinsp;and Dcx\u0026thinsp;+\u0026thinsp;cells in their SEZs, whilst the grouping of R586 and R599 observed in the density of PCNA+, Dcx\u0026thinsp;+\u0026thinsp;and Olig2\u0026thinsp;+\u0026thinsp;cells is not repeated when looking at the density of Iba1\u0026thinsp;+\u0026thinsp;cells. The 6 Wild\u003csup\u003e2n\u0026thinsp;=\u0026thinsp;30\u003c/sup\u003e mice were captured as two groups: R613, R614, R617 and R619 in location #5 and Wild4, Wild6 in the very distant location #7. Wild6 measurements do not show segregation from the other individuals of the same group (Wild\u003csup\u003e2n\u0026thinsp;=\u0026thinsp;30, SPRING\u003c/sup\u003e). Furthermore, Wild4 and Wild6 show: a) similar patterns in the density of PCNA\u0026thinsp;+\u0026thinsp;and Dcx\u0026thinsp;+\u0026thinsp;cells in the SEZ, b) moderately different patterns in the density of Olig2\u0026thinsp;+\u0026thinsp;and Iba1\u0026thinsp;+\u0026thinsp;cells in the SEZ, c) strongly different patterns in nestin+, GFAP\u0026thinsp;+\u0026thinsp;and βIIItubulin\u0026thinsp;+\u0026thinsp;cells in cultures. The other 12 wild mice were also captured at Mavroneri (location #7 in the map) in the same barn and were trapped at the same time, apart from Wild13 that was captured almost a year later. There is no direct evidence on family relations amongst the individuals that share the same numbers of chromosomes, but the co-existence of individuals with different karyotypes strongly indicates fluidity of populations. Voles were captured in two, distant, areas. The species lives in highly complicated burrows, that can extend to more than 25m in total length (Rekouti, \u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). Each network is usually inhabited by one male/female pair, although coexistence of additional adults has been reported (Eisenberg, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e1963\u003c/span\u003e) and social exposure has been shown to affect neurogenesis in \u003cem\u003eMicrotus ochrogaster\u003c/em\u003e (\u0026Aacute;vila-Gonz\u0026aacute;lez et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). Only one adult was captured per burrow; thus, limiting the possibility of 1st or 2nd degree relations.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThe worth of field-work expeditions to capture wild mice, rats and voles and the benefit of gathering descriptive information in the absence of experimental manipulation depend on two conditions: a) availability of methods and b) choice of the appropriate comparators. By generating single-cell analysis data in supercentenarians (Hashimoto et al., \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e2019\u003c/span\u003e), astronauts (Kim et al., \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2024\u003c/span\u003e) or multiple sclerosis patients (Kukanja et al., \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e2024\u003c/span\u003e; Smets et al., \u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e2021\u003c/span\u003e) -and their respective controls- or by systematically linking data acquired via multimodal brain imaging, cognitive tests and a range of biochemical analyses in order to cluster individuals across a large-scale dataset (Tian et al., \u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e2023\u003c/span\u003e), novel information on the biological processes of ageing or disease has been discovered. Similarly to above, we identified rodent populations with divergent behavior of pbNSPCs. In this way, the homogenizing effects of laboratorization/domestication (Geiger et al., \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2018\u003c/span\u003e; KOIZUMI et al., \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e2018\u003c/span\u003e) can be brought into \u0026ldquo;real life\u0026rdquo; context and novel information can be generated by linking high throughput analyses to descriptive data. Notably, the strong correlation between phenotype and chromosome fusions can only be explained by proportional changes in chromatin structure (genetic or epigenetic) that should be feasible to detect; thus, providing a valuable tool to study the control of gene expression, even in a non-physiological context.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eAnimals, euthanasia method and bone marrow karyotyping\u003c/h2\u003e \u003cp\u003eLab mice were of the Bl6CBAC and of the 129sv backgrounds. All animals were between 2 and 4 months of age, inbred at the designated animal facility of the University of Patras (EL13 BIOexp-04), maintained in steady light/dark cycle (12/12 h) with free access to food and water. Animal breeding, maintenance and handling was performed in accordance with the European Communities Council Directive Guidelines (86/609/EEC) for the care and use of Laboratory animals as implemented in Greece by the Presidential Decree 56/2013 and approved and scrutinized by the local Prefectural Animal Care and Use Committee (Protocol number: 118188/432/21-05-2020). Wild mice (\u003cem\u003eMus musculus domesticus\u003c/em\u003e) were trapped alive with Sherman traps in a variety of humanized habitats, e.g. storage buildings and farms. Thomas\u0026rsquo;s pine voles (\u003cem\u003eMicrotus thomasi\u003c/em\u003e) were trapped alive with wire custom-made, rectangular traps of 5x6x20cm size. Bait (usually pieces of carrot) was put deep in the trap, with an additional piece positioned at the opening, under a shutter. The traps were set, fully aligned and at the same depth, at the open ends of tunnels, to resemble an extension of the burrow. The underground burrows were located in cultivated and uncultivated fields. Both taxa are common in nature and not under threat or protection by national or international decrees. All field procedures involving these wild animals were in compliance with guidelines, approved by the American Society of Mammalogists (Sikes and Gannon, \u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e2011\u003c/span\u003e). The captured animals were brought to the lab and were maintained for the minimal possible duration (typically 2 to 7 days, with the exception of the wild\u003csup\u003e2n\u0026thinsp;=\u0026thinsp;30\u0026minus;26\u003c/sup\u003e subgroup that was analyzed in spring) under standard animal house conditions and free access to water and food. All animals were subjected to colchicine pretreatment (0.025%, 2\u0026micro;l/g of body weigh) 45min prior to euthanasia.\u003c/p\u003e \u003cp\u003eEuthanasia was performed by final (non-recovering) anesthesia, with ketamine overdose and subsequent intracardially perfusion with fresh, ice-cold saline (50ml per animal).\u003c/p\u003e \u003cp\u003eFor karyotyping using bone marrow cells, chromosome preparations were obtained using a modified version of the direct bone marrow method (Hsu and Patton, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e1969\u003c/span\u003e), incubating cell preparations with a hypotonic solution of KCl (0.75M; 30min at 37\u003csup\u003eo\u003c/sup\u003eC), followed by fixation in Carnoy\u0026rsquo;s solution (3:1 methanol : glacial acetic acid). Slides were prepared by the standard air-drying technique. Metaphasic chromosomes were photographed in brightfield using the 100X objective of an Axioskop 2 Plus Zeiss microscope and a Zeiss mrc5 digital camera. Numbers of chromosomes were counted, in at least 3 metaphases. No animals were excluded and all protocols and analyses were planned and performed in compliance with the ARRIVE guidelines, as described in \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://arriveguidelines.org/arrive-guidelines\u003c/span\u003e\u003cspan address=\"https://arriveguidelines.org/arrive-guidelines\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eCell cultures, immunocytochemistry and pbNSPC karyotyping\u003c/h2\u003e \u003cp\u003eFor pbNSPC cultures, the subependymal zone of one brain hemisphere was dissected under the stereoscope using anatomical landmarks, as performed previously (Kazanis et al., \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e2017\u003c/span\u003e) and was dissociated using accutase. Cells were plated in 6-well plates with proliferation medium (high glucose DMEM, FGF2 and EGF at 20ng/ml, 2% B27 and 1% N2 supplements) and were allowed to grow as 3D free-floating aggregates called neurospheres. For the immunocytochemical analysis, the primary neurospheres were dissociated and plated on poly-D-lysine coated glass coverslips. Cells were fixed with 2% PFA after 48h. Immunofluorescence was performed with standard protocols (Kazanis et al., \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e2017\u003c/span\u003e), using the following primary antibodies: chicken anti-nestin (Abcam, 1/200, ab134017), mouse anti-nestin (Abcam, 1/200, ab6142), rabbit anti-Ki67 (Abcam, 1/500, [SP6] ab16667), goat anti-GFAP (Abcam, 1/700, ab53554), goat anti-Sox2 (Santa Cruz, 1/200, sc-17320), mouse anti-βΙΙΙ tubulin (Abcam, 1/500, Abcam, ab7751). Appropriate secondary antibodies (Biotium) were used, and nuclei were counterstained with Dapi (Merck). For karyotyping, neurosphere cells, of higher than two passages, were dissociated. After 48h they were dissociated again, cells were incubated for 8.5h with 10\u0026micro;g/ml colchicine and were karyotyped with the bone marrow protocol, adjusted for pbNSPCs.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eTissue handling for immunohistochemistry\u003c/h2\u003e \u003cp\u003eAfter the intracardial perfusion with saline, the tissue was fixed in 4% PFA (4\u003csup\u003eo\u003c/sup\u003eC, overnight), cryopreserved in 30% sucrose and frozen at -80\u003csup\u003eo\u003c/sup\u003eC. 14\u0026micro;m-thick coronal cryo-sections were obtained (Leica) and were immunostained using standard protocols (Kazanis et al., \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e2017\u003c/span\u003e), using the following antibodies: mouse anti-PCNA (Abcam, 1/500, [PC10] ab29), rabbit anti-Dcx (Abcam, 1/500, ab18723), goat anti-Iba1 (Abcam, 1/1000, AB5076), rabbit anti-Olig2 (Millipore, 1/300, AB9610), goat anti-Sox2 (Santa Cruz, 1/200, sc-17320). Appropriate secondary antibodies (Biotium) were used and nuclei were counterstained with Dapi (Merck).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eImaging and cell count\u003c/h2\u003e \u003cp\u003eTissue sections and cells on coverslips were photographed with a Leica TCS SP8 confocal microscope, using the 40X objective and the Leica Application Suite X software. For SEZ measurements, at least two coronal sections, at different rostro-caudal levels (typically 1.2 and 0.8mm from bregma) were imaged, with at least 2 optical fields at the \u0026ldquo;dorsal horn\u0026rdquo; domain of the niche (as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). Cells were counted manually at a depth of 30\u0026micro;m (mice and microtus) or 50\u0026micro;m (rats) from the ventricular wall; that we have previously shown to contain the SEZ (Kazanis and ffrench-Constant, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e2012\u003c/span\u003e), as well as deeper in the initial segment of the rostral migratory stream. Cell densities are given as cells/mm\u003csup\u003e2\u003c/sup\u003e. For cell cultures, at least 10 optical fields were photographed per coverslip. It should be noted that nestin immunoreactivity could not be detected in Microtus cells, using two different antibodies (Abcam, chicken and mouse anti-nestin). For corpus callosum measurements, the same sections and methods were used, by photographing callosal areas adjacent to the lateral ventricles.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eStatistics\u003c/h2\u003e \u003cp\u003eAll cell counts were performed blind as to the experimental group and the karyotype and from multiple investigators. Statistical analyses were performed using IBM SPSS statistics (for 2-way and 1-way ANOVA, followed by the Tukey \u003cem\u003epost-hoc\u003c/em\u003e analysis, whenever necessary). Scatter plots were generated, and regression and Pearson\u0026rsquo;s correlation analyses were performed using Microsoft Office Excel.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eDeclaration of interest\u003c/h2\u003e \u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAR: Data curation, Formal Analysis, Methodology, Validation, Visualization, Writing \u0026ndash;review \u0026amp; editingTA: Data curation, Formal Analysis, Validation, Visualization, Writing \u0026ndash;review \u0026amp; editingEA, MM, GL, MA, KM, MC, PS: Data curation, Formal Analysis, ValidationGM: Data curation, Formal Analysis, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing \u0026ndash;review \u0026amp; editingIK: Conceptualization, Data curation, Formal Analysis, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing \u0026ndash; original draft, review \u0026amp; editing\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets used and analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003ch3\u003eMaterials availability\u003c/h3\u003e\n\u003cp\u003eThis study did not generate new unique reagents.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAgathou, S., K\u0026aacute;rad\u0026oacute;ttir, R. 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Oligodendrocyte Dynamics in the Healthy Adult CNS: Evidence for Myelin Remodeling. \u003cem\u003eNeuron\u003c/em\u003e. \u003cb\u003e77\u003c/b\u003e, 873\u0026ndash;885. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.neuron.2013.01.006\u003c/span\u003e\u003cspan address=\"10.1016/j.neuron.2013.01.006\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2013).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-5299693/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5299693/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eEnvironmental and behavioral factors have been shown, in experimental settings, to affect neurogenesis in the mouse brain. We found that the density of proliferating neural stem/ progenitor cells (NSPCs) and of neuroblasts was significantly lower in the Subependymal Zone stem cell niche of lab mice when compared with mice and pine voles captured in the wild, with seasonal variation observed only in voles. Moreover, levels of proliferation and neurogenesis were found to decrease in proportion to the decrease in the numbers of chromosomes (from the typical 2n\u0026thinsp;=\u0026thinsp;40 down to 2n\u0026thinsp;=\u0026thinsp;26) caused by Robertsonian fusions. In contrast, oligodendroglial progenitors and microglial cells were unaffected by wildlife, seasons and chromosomal fusions. When NSPCs were grown in cultures no differences were detected, suggesting that environmental and genetic effects are mediated by non-cell-autonomous mechanisms. These \u0026ldquo;real-world\u0026rdquo; data provide a platform for the identification of systemic factors and genetic loci that control postnatal brain neurogenesis.\u003c/p\u003e","manuscriptTitle":"Lab life, seasons and chromosome fusions restrict non-cell-autonomously proliferation and neurogenesis, but not oligodendrogenesis, in mice and voles","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-11-25 15:51:09","doi":"10.21203/rs.3.rs-5299693/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-12-23T09:39:13+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-12-20T14:37:42+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"8139850916513081290718871722809661003","date":"2024-12-14T13:18:43+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-29T16:07:04+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"90655161128624951139692799979414683897","date":"2024-11-22T14:15:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"336544480463642108900585434443286556156","date":"2024-11-13T09:31:18+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-11-11T05:43:36+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-11-11T05:18:46+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-11-11T04:45:02+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-11-07T10:20:20+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-10-20T18:28:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"54545574-00de-4913-a4a7-199f67325697","owner":[],"postedDate":"November 25th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":40631015,"name":"Biological sciences/Developmental biology/Neurogenesis/Adult neurogenesis"},{"id":40631016,"name":"Biological sciences/Neuroscience/Stem cells in the nervous system/Glial stem cells"},{"id":40631017,"name":"Biological sciences/Neuroscience/Stem cells in the nervous system/Neural stem cells"}],"tags":[],"updatedAt":"2025-06-02T16:03:32+00:00","versionOfRecord":{"articleIdentity":"rs-5299693","link":"https://doi.org/10.1038/s41598-025-01670-3","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2025-05-28 15:57:56","publishedOnDateReadable":"May 28th, 2025"},"versionCreatedAt":"2024-11-25 15:51:09","video":"","vorDoi":"10.1038/s41598-025-01670-3","vorDoiUrl":"https://doi.org/10.1038/s41598-025-01670-3","workflowStages":[]},"version":"v1","identity":"rs-5299693","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5299693","identity":"rs-5299693","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}