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Aging and various neurodegenerative diseases cause significant reduction in adult neurogenesis and simultaneous increase in quiescent neural stem cells (NSCs), which impact the brain's regenerative capabilities. To deal with this challenging issue, current treatments involve stem cell transplants or prevention of neurodegeneration; however, the efficacy or success of this process remains limited. Therefore, extensive and focused investigation is highly demanding to overcome this challenging task. Here, we have designed an efficient peptide-based EphA4 receptor-targeted ligand through an in silico approach. Further, this strategy involves chemical conjugation of the peptide with adipose tissue stem cell-derived EV (Exo-pep-11). Interestingly, our newly designed engineered EV, Exo-pep-11, targets NSC through EphA4 receptors, which offers promising therapeutic advantages by stimulating NSC proliferation and subsequent differentiation. Our result demonstrates that NSC successfully internalized Exo-pep-11 in both in vitro culture conditions as well as in the in vivo aging rats. We found that the uptake of Exo-pep-11 decreased by ∼2.3-fold when NSC was treated with EphA4 antibody before Exo-pep-11 incubation, which confirms the receptor-specific uptake of Exo-pep-11. Exo-pep-11 treatment also increases NSC proliferation by ∼1.9-fold and also shows ∼1.6- and ∼2.4-fold increase in expressions of Nestin and ID1, respectively. Exo-pep-11 also has the potential to increase neurogenesis in aging rats, which is confirmed by ∼1.6- and ∼1.5-fold increases in expressions of TH and Tuj1, respectively, in rat olfactory bulb. Overall, our findings highlight the potential role of Exo-pep-11 for prospective applications in combating age-related declines in NSC activity and neurogenesis.

Modulation of in vivo adult neurogenesis (AN) is an evolving concept in managing neurodegenerative diseases. CDRI-08, a bacoside-enriched fraction of Bacopa monnieri, has been demonstrated for its neuroprotective actions, but its effect on AN remains unexplored. This article describes the status of AN by monitoring neuronal stem cells (NSCs) proliferation, differentiation/maturation markers and BDNF-TrkB levels (NSCs signalling players) vs. the level of neurodegeneration and their modulations by CDRI-08 in the hippocampal dentate gyrus (DG) of male rats with moderate grade hepatic encephalopathy (MoHE). For NSC proliferation, 10 mg/kg b.w. 5-bromo-2'-deoxyuridine (BrdU) was administered i.p. during the last 3 days, and for the NSC differentiation study, it was given during the first 3 days to the control, the MoHE (developed by 100 mg/kg b.w. of thioacetamide i.p. up to 10 days) and to the MoHE male rats co-treated with 350 mg/kg b.w. CDRI-08. Compared with the control rats, the hippocampus DG region of MoHE rats showed significant decreases in the number of Nestin + /BrdU + and SOX2 + /BrdU + (proliferating) and DCX + /BrdU + and NeuN + /BrdU + (differentiating) NSCs. This was consistent with a similar decline in BDNF + /TrkB + NSCs. However, all these NSC marker positive cells were observed to be recovered to their control levels, with a concordant restoration of total cell numbers in the DG of the CDRI-08-treated MoHE rats. The findings suggest that the restoration of hippocampal AN by CDRI-08 is consistent with the recovery of BDNF-TrkB-expressing NSCs in the MoHE rat model of neurodegeneration., (© 2024 International Society for Developmental Neuroscience.)

In a recent study, Shvedov and colleagues used live two-photon imaging in transgenic zebra finches to reveal migration patterns of neuroblasts through the complex environment of the postembryonic brain. This study highlights the value of ubiquitin C/green fluorescent protein (UBC-GFP) transgenic zebra finches in studying adult neurogenesis and advances our understanding of dispersed long-distance neuronal migration in the adult brain, shedding light on this understudied phenomenon. [ABSTRACT FROM AUTHOR]

6 Hochgerner H, Zeisel A, Lonnerberg P, Linnarsson S. Conserved properties of dentate gyrus neurogenesis across postnatal development revealed by single-cell RNA sequencing. Keywords: adult neurogenesis EN adult neurogenesis 1 3 3 02/27/23 20230201 NES 230201 Adult neurogenesis, the process of generating functional neurons from neural progenitors (Figure 1A), occurs throughout the lifetime in the hippocampus of almost all mammals examined, including humans.[[1]] Adult hippocampal neurogenesis plays critical roles in learning and memory, cognition, and affective behaviours, whereas its dysfunction has been associated with many neurological and psychiatric disorders, such as Alzheimer's disease (Figure 1B).[[1]] Studies in rodents have revealed distinct molecular, cellular, physiological, and neuronal circuitry properties of immature neurons (imNs) generated during adult neurogenesis compared to their mature counterparts (mNs), which are considered the foundation for the functional role of adult hippocampal neurogenesis.[2] Limited knowledge of imNs in adult humans represents a major roadblock to harness their potential in clinical applications for brain disorders and regenerative medicine. Moreover, studying the pathology and pathogenesis underlying adult human neurogenesis and imNs in neuropsychiatric disorders has important implications for understanding disease mechanisms. [Extracted from the article]

Early life adversity (ELA) increases the risk of developing neuropsychiatric illnesses such as anxiety disorders. However, the mechanisms connecting these negative early life experiences to illness later in life remain unclear. In rodents, plasticity mechanisms, specifically adult neurogenesis in the ventral hippocampus, have been shown to be altered by ELA and important for buffering against detrimental stress-induced outcomes. The current study sought to explore whether adult neurogenesis contributes to ELA-induced changes in avoidance behavior. Using the GFAP-TK transgenic model, which allows for the inhibition of adult neurogenesis, and CD1 littermate controls, we subjected mice to an ELA paradigm of maternal separation and early weaning (MSEW) or control rearing. We found that mice with intact adult neurogenesis showed no behavioral changes in response to MSEW. After reducing adult neurogenesis, however, male mice previously subjected to MSEW had an unexpected decrease in avoidance behavior. This finding was not observed in female mice, suggesting that a sex difference exists in the role of adult-born neurons in buffering against ELA-induced changes in behavior. Taken together with the existing literature on ELA and avoidance behavior, this work suggests that strain differences exist in susceptibility to ELA and that adult-born neurons may play a role in regulating adaptive behavior.

The majority of adult neural stem cells (aNSCs) are in a distinct metabolic state of reversible cell cycle exit also known as quiescence. The rate of aNSC activation determines the number of new neurons generated and directly influences the long-term maintenance of neurogenesis. Despite its relevance, it is still unclear how aNSC quiescence is regulated. Many factors contribute to this, like aNSC heterogeneity, the lack of reliable quiescence markers, the complexity of the neurogenic niches or the intricacy of the transcriptional and post-transcriptional mechanisms involved. In this perspective article I discuss possible solutions to these problems. But, first and foremost, I believe we require a model that goes beyond a simple transition toward activation. Instead, we must acknowledge the full complexity of aNSC states, which include not only activation but also differentiation and survival as behavioural outcomes. I propose a model where aNSCs dynamically transition through a cloud of highly interlinked cellular states driven by intrinsic and extrinsic cues. I also show how a new perspective enables us to integrate current results into a coherent framework leading to the formulation of new testable hypothesis. This model, like all others, is still far from perfect and will be reshaped by future findings. I believe that having a more complete view of aNSC transitions and embracing their complexity will bring us closer to understand how aNSC activity and neurogenesis are controlled throughout life.

Background: Self-renewal and proliferation of neural progenitor cells occur throughout humans' lives. However, aging, stress, and degenerative diseases can hinder or stop the process. If you can accelerate neurogenesis in adults, this is a promising way to recover from neurodegeneration and cognitive impairments. As the demand for a safer and natural therapeutic product has increased over the past decade, medicinal plants seem to be a viable alternative to synthetic medicines. Since early human civilization, various herbs have been used as medicines and are still a basis for different modern medications. With the advancements in science, researchers can isolate the active compounds in an herb and predict these herbs' line of action when used as a drug. Our current knowledge of medicinal plants with neurological functions is many, but only a few are scientifically validated. Method: A review of the scientific literature explaining plants' bioactive compounds that show neurogenesis was executed. All published data till the year 2021 have been taken to consideration. PubMed, Scopus, ScienceDirect, and Google Scholar directories were used to explore literature published using relevant keywords. Results: Plants like Panax ginseng, Lycium barbarum, Acorus tatarinowii, Curcuma longa, Salvia miltiorrhiza, Centella asiatica, Bacopa monnieri, Ginkgo biloba, Cuscuta japonica, Radix Astragali, Hericium erinaceus and Banisteriopsis caapi have shown to induce neurogenesis. Conclusions: The information on plants compiled in this review pertains to those with a therapeutic value that can be used for drug development to cope with neurodegenerative diseases and memory impairment.

The vertebrate eye is a vital sensory organ that has long fascinated scientists, but the details of how this organ evolved are still unclear. The vertebrate eye is distinct from the simple photoreceptive organs of other non-vertebrate chordates and there are no clear transitional forms of the eye in the fossil record. To investigate the evolution of the eye we can examine the eyes of the most ancient extant vertebrates, the hagfish and lamprey. These jawless vertebrates are in an ideal phylogenetic position to study the origin of the vertebrate eye but data on eye/retina development in these organisms is limited. New genomic and gene expression data from hagfish and lamprey suggest they have many of the same genes for eye development and retinal neurogenesis as jawed vertebrates, but functional work to determine if these genes operate in retinogenesis similarly to other vertebrates is missing. In addition, hagfish express a marker of proliferative retinal cells (Pax6) near the margin of the retina, and adult retinal growth is apparent in some species. This finding of eye growth late into hagfish ontogeny is unexpected given the degenerate eye phenotype. Further studies dissecting retinal neurogenesis in jawless vertebrates would allow for comparison of the mechanisms of retinal development between cyclostome and gnathostome eyes and provide insight into the evolutionary origins of the vertebrate eye.

Cell cycle proteins play essential roles in regulating embryonic and adult neurogenesis in the mammalian brain. A key example is the Retinoblastoma protein (Rb) whose loss disrupts the whole neurogenic program during brain development, but only results in increased progenitor proliferation in the adult subventricular zone (SVZ) and compromised long-term neuronal survival in the adult olfactory bulb (OB). Whether this holds true of neurogenesis in the aged brain remains unknown. In this study, we find no evidence of irregular proliferation or early commitment defects in the mid-aged (12-month-old) and old-aged (20-month-old) SVZ following tamoxifen-inducible Rb knockout (Rb iKO) in mice. However, we highlight a striking defect in early maturation of Rb-deficient migrating neuroblasts along the rostral migratory stream (RMS), followed by massive decline in neuronal generation inside the aged OB. In the absence of Rb, we also show evidence of incomplete cell cycle re-entry (CCE) along with DNA damage in the young OB, while we find a similar trend towards CCE but no clear signs of DNA damage or neurodegenerative signatures (pTau or Synuclein accumulation) in the aged OB. However, such phenotype could be masked by the severe maturation defect reported above in addition to the natural decline in adult neurogenesis with age. Overall, we show that Rb is required to prevent CCE and DNA damage in adult-born OB neurons, hence maintain neuronal survival. Moreover, while loss of Rb alone is insufficient to trigger seeding of neurotoxic species, this study reveals age-dependent non-monotonic dynamics in regulating neurogenesis by Rb.

Most mammals have sensory tactile hairs, also known as whiskers or vibrissae. Traditionally, whiskers are associated with diverse survival skills, including tactile discrimination, distance assessment, food acquisition, gap crossing, and social interaction. Vibrissae functions are processed in the somatosensorial cortex, commonly referred to as the barrel cortex. Hence, most of the whisker-related research has been focused on this cortical region. However, increasing evidence indicates that the vibrissal system modulates several aspects of hippocampal physiology. This graphical review aims to summarize cumulative evidence indicating that whiskers regulate the neural function and cellularity in several hippocampal subfields. Interestingly, lack of whiskers notably affects neuronal firing in CA1 and CA3 hippocampal subfields, alters spatial mapping, impairs navigational skills, modifies cytoarchitecture, and reduces the adult neurogenesis in the dentate gyrus. This evidence extends our understanding of how whiskers are related to hippocampal function and offers insights to explore novel associations between whisker functions and neural plasticity in the hippocampus.

In the dentate gyrus of the adult hippocampus new neurons are generated from neural precursor cells through different stages including proliferation and differentiation of neural progenitor cells and maturation of newborn neurons. These stages are controlled by the expression of specific transcription factors and epigenetic mechanisms, which together orchestrate the progression of the neurogenic process. However, little is known about the involvement of histone posttranslational modifications, a crucial epigenetic mechanism in embryonic neurogenesis that regulates fate commitment and neuronal differentiation. During embryonic development, the repressive modification trimethylation of histone H3 on lysine 9 (H3K9me3) contributes to the cellular identity of different cell-types. However, the role of this modification and its H3K9 methyltransferases has not been elucidated in adult hippocampal neurogenesis. We determined that during the stages of neurogenesis in the adult mouse dentate gyrus and in cultured adult hippocampal progenitors (AHPs), there was a dynamic change in the expression and distribution of H3K9me3, being enriched at early stages of the neurogenic process. A similar pattern was observed in the hippocampus for the dimethylation of histone H3 on lysine 9 (H3K9me2), another repressive modification. Among H3K9 methyltransferases, the enzymes Suv39h1 and Suv39h2 exhibited high levels of expression at early stages of neurogenesis and their expression decreased upon differentiation. Pharmacological inhibition of these enzymes by chaetocin in AHPs reduced H3K9me3 and concomitantly decreased neuronal differentiation while increasing proliferation. Moreover, Suv39h1 and Suv39h2 knockdown in newborn cells of the adult mouse dentate gyrus by retrovirus-mediated RNA interference impaired neuronal differentiation of progenitor cells. Our results indicate that H3K9me3 and H3K9 methyltransferases Suv39h1 and Suv39h2 are critically involved in the regulation of adult hippocampal neurogenesis by controlling the differentiation of neural progenitor cells.

The majority of adult neural stem cells (aNSCs) are in a distinct metabolic state of reversible cell cycle exit also known as quiescence. The rate of aNSC activation determines the number of new neurons generated and directly influences the long-term maintenance of neurogenesis. Despite its relevance, it is still unclear how aNSC quiescence is regulated. Many factors contribute to this, like aNSC heterogeneity, the lack of reliable quiescence markers, the complexity of the neurogenic niches or the intricacy of the transcriptional and post-transcriptional mechanisms involved. In this perspective article I discuss possible solutions to these problems. But, first and foremost, I believe we require a model that goes beyond a simple transition toward activation. Instead, we must acknowledge the full complexity of aNSC states, which include not only activation but also differentiation and survival as behavioural outcomes. I propose a model where aNSCs dynamically transition through a cloud of highly interlinked cellular states driven by intrinsic and extrinsic cues. I also show how a new perspective enables us to integrate current results into a coherent framework leading to the formulation of new testable hypothesis. This model, like all others, is still far from perfect and will be reshaped by future findings. I believe that having a more complete view of aNSC transitions and embracing their complexity will bring us closer to understand how aNSC activity and neurogenesis are controlled throughout life. [ABSTRACT FROM AUTHOR]

Maternal intake of omega-3 (n-3 PUFAs) and omega-6 (n-6 PUFAs) polyunsaturated fatty acids impacts hippocampal neurogenesis during development, an effect that may extend to adulthood by altering adult hippocampal neurogenesis (AHN). The n-3 PUFAs and n-6 PUFAs are precursors of inflammatory regulators that potentially affect AHN and glia. Additionally, n-3 PUFA dietary supplementation may present a sexually dimorphic action in the brain. Therefore, we postulated that dietary n-6/n-3 PUFA balance shapes the adult DG in a sex-dependent manner influencing AHN and glia. We test our hypothesis by feeding adult female and male mice with n-3 PUFA balanced or deficient diets. To analyze the immunomodulatory potential of the diets, we injected mice with the bacterial endotoxin lipopolysaccharide (LPS). LPS reduced neuroblast number, and its effect was exacerbated by the n-3 PUFA-deficient diet. The n-3 PUFA-deficient diet reduced the DG volume, AHN, microglia number, and surveilled volume. The diet effect on most mature neuroblasts was exclusively significant in female mice. Colocalization and multivariate analysis revealed an association between microglia and AHN, as well as the sexual dimorphic effect of diet. Our study reveals that female mice are more susceptible than males to the effect of dietary n-6/n-3 PUFA ratio on AHN and microglia. [ABSTRACT FROM AUTHOR]

Decline in episodic memory is one of the hallmarks of aging and represents one of the most important health problems facing Western societies. A key structure in episodic memory is the hippocampal formation and the dentate gyrus in particular, as the continuous production of new dentate granule neurons in this brain region was found to play a crucial role in memory and age-related decline in memory. As such, understanding the molecular processes that regulate the relationship between adult neurogenesis and aging of memory function holds great therapeutic potential. Recently, we found that Vang-Gogh like 2 (Vangl2), a core component of the Planar Cell Polarity (PCP) signaling pathway, is enriched in the dentate gyrus of adult mice. In this context, we sought to evaluate the involvement of this member of the Wnt/PCP pathway in both adult neurogenesis and memory abilities in adult and middle-aged mice. Using a heterozygous mouse model carrying a dominant-negative mutation in the Vangl2 gene, called Looptail (Vangl2Lp), we show that alteration in Vangl2 expression decreases the survival of adult-born granule cells and advances the onset of a decrease in cognitive flexibility. The inability of mutant mice to erase old irrelevant information to the benefit of new relevant ones highlights a key role of Vangl2 in interference-based forgetting. Taken together, our findings show that Vangl2 activity may constitute an interesting target to prevent age-related decline in hippocampal plasticity and memory. [ABSTRACT FROM AUTHOR]

Adult neurogenesis has been profusely studied in central nervous system. However, its presence in enteric nervous system remains elusive although it has been recently demonstrated in mice and intimately linked to glial cells. Moreover, primary cilium is an important organelle in central adult neurogenesis. In the present study, we analysed some parallelisms between central and enteric nervous system (ENS) in humans based on ultrastructural and immunohistochemical techniques. Thus, we described the presence of primary cilia in some subtypes of glial cells and Interstitial Cells of Cajal (ICCs) and we performed 3-D reconstructions to better characterise their features. Besides, we studied the expression of several adult neurogenesis-related proteins. Immature neuron markers were found in human ENS, supporting the existence of adult neurogenesis. However, only ICCs showed proliferation markers. Hence, we propose a new paradigm where ICCs would constitute the original neural stem cells which, through asymmetrical cell division, would generate the new-born neurons. [ABSTRACT FROM AUTHOR]

Distinct neural stem cells (NSCs) reside in different regions of the subventricular zone (SVZ) and generate multiple olfactory bulb (OB) interneuron subtypes in the adult brain. However, the molecular mechanisms underlying such NSC heterogeneity remain largely unknown. Here, we show that the basic helix-loop-helix transcription factor Olig2 defines a subset of NSCs in the early postnatal and adult SVZ. Olig2-expressing NSCs exist broadly but are most enriched in the ventral SVZ along the dorsoventral axis complementary to dorsally enriched Gsx2-expressing NSCs. Comparisons of Olig2-expressing NSCs from early embryonic to adult stages using single cell transcriptomics reveal stepwise developmental changes in their cell cycle and metabolic properties. Genetic studies further show that cross-repression contributes to the mutually exclusive expression of Olig2 and Gsx2 in NSCs/progenitors during embryogenesis, but that their expression is regulated independently from each other in adult NSCs. Finally, lineage-tracing and conditional inactivation studies demonstrate that Olig2 plays an important role in the specification of OB interneuron subtypes. Altogether, our study demonstrates that Olig2 defines a unique subset of adult NSCs enriched in the ventral aspect of the adult SVZ. [ABSTRACT FROM AUTHOR]

Objective: More than half of patients with depression display eating disorders, such as bulimia nervosa and anorexia nervosa. Feeding centers are located in the hypothalamus, and hypothalamic adult neurogenesis has an important role in feeding and energy balance. Antidepressants, which can regulate adult neurogenesis in the hippocampus, olfactory bulb, and neocortex, are used for eating disorders, but it is unclear whether antidepressants change hypothalamic adult neurogenesis. In this study, we used immunohistological analysis to assess effects of the antidepressant fluoxetine (FLX) on hypothalamic adult neurogenesis of adult mice. Results: Expressions of the proliferating cell marker, Ki67, and the neural stem cell marker, nestin, were significantly decreased in the hypothalamus by FLX. As regard to postmitotic cells, the number of the neural marker, NeuN, positive cells was significantly upregulated by FLX, but that of the astrocytic marker, S100B, positive cells was significantly reduced by FLX. The number of the oligodendrocyte marker, Olig2, positive cells was not changed by FLX. Interestingly, FLX treatment did not affect the total number of newly generated cells in the hypothalamus, comparing that in controls. These results suggest that FLX treatment influence hypothalamic adult neurogenesis and shift the balance between the numbers of neurons and astrocytes under studied conditions. [ABSTRACT FROM AUTHOR]

An integral component of neural ontogeny and plasticity is the ongoing generation of new neurons from precursor cells throughout the lifespan in virtually all animals with a nervous system. In mammals, postnatal neurogenesis has been documented in the cerebellum, olfactory bulb, hippocampus, striatum, substantia nigra, hypothalamus, and amygdala. Germinal centers of new neuron production in the adult brain have been identified in the neuroepithelium of the subventricular zone and the dentate gyrus. One of the earliest lines of evidence gathered came from studies on the production of cerebellar microneurons in the external germinal layer of rodents and carnivores in the 1960s and 1970s. The undeniable pioneer of that research was the insightful developmental neurobiologist Joseph Altman (1925–2016). This Cerebellar Classic is devoted to the groundbreaking work of Altman and his graduate student and, subsequently, fellow faculty member, Gopal Das (1933–1991), on postnatal neurogenesis using tritiated thymidine autoradiography to tag newly formed neurons in the cerebellum of cats. Perseverant to their ideas and patiently working in West Lafayette (Indiana), they were the founders of two fields that brought about paradigm shifts and led to an explosive growth in brain research: adult neurogenesis and neural tissue transplantation. [ABSTRACT FROM AUTHOR]

Adult neurogenesis is the ongoing generation of functional new neurons from neural progenitor cells (NPCs) in the mammalian brain. However, this process declines with aging, which is implicated in the recession of brain function and neurodegeneration. Understanding the mechanism of adult neurogenesis and stimulating neurogenesis will benefit the mitigation of neurodegenerative diseases. Autophagy, a highly conserved process of cellular degradation, is essential for maintaining cellular homeostasis and normal function. Whether and how autophagy affects adult neurogenesis remains poorly understood. In present study, we revealed a close connection between impaired autophagy and adult neurogenetic decline. Expression of autophagy-related genes and autophagic activity were significantly declined in the middle-adult subventricular/subgranular zone (SVZ/SGZ) homogenates and cultured NPCs, and inhibiting autophagy by siRNA interference resulted in impaired proliferation and differentiation of NPCs. Conversely, stimulating autophagy by rapamycin not only revitalized the viability of middle-adult NPCs, but also facilitated the neurogenesis in middle-adult SVZ/SGZ. More importantly, autophagic activation by rapamycin also ameliorated the olfactory sensitivity and cognitional capacities in middle-adult mice. Taken together, our results reveal that compromised autophagy is involved in the decline of adult neurogenesis, which could be reversed by autophagy activation. It also shed light on the regulation of adult neurogenesis and paves the way for developing a therapeutic strategy for aging and neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Soluble amyloid precursor protein-alpha (sAPPα) is a regulator of neuronal and memory mechanisms, while also having neurogenic and neuroprotective effects in the brain. As adult hippocampal neurogenesis is impaired in Alzheimer's disease, we tested the hypothesis that sAPPα delivery would rescue adult hippocampal neurogenesis in an APP/PS1 mouse model of Alzheimer's disease. An adeno-associated virus-9 (AAV9) encoding murine sAPPα was injected into the hippocampus of 8-month-old wild-type and APP/PS1 mice, and later two different thymidine analogues (XdU) were systemically injected to label adult-born cells at different time points after viral transduction. The proliferation of adult-born cells, cell survival after eight weeks, and cell differentiation into either neurons or astrocytes was studied. Proliferation was impaired in APP/PS1 mice but was restored to wild-type levels by viral expression of sAPPα. In contrast, sAPPα overexpression failed to rescue the survival of XdU+-labelled cells that was impaired in APP/PS1 mice, although it did cause a significant increase in the area density of astrocytes in the granule cell layer across both genotypes. Finally, viral expression of sAPPα reduced amyloid-beta plaque load in APP/PS1 mice in the dentate gyrus and somatosensory cortex. These data add further evidence that increased levels of sAPPα could be therapeutic for the cognitive decline in AD, in part through restoration of the proliferation of neural progenitor cells in adults. [ABSTRACT FROM AUTHOR]

The hippocampus encodes spatial and contextual information involved in memory and learning. The incorporation of new neurons into hippocampal networks increases neuroplasticity and enhances hippocampal-dependent learning performances. Only few studies have described hippocampal abnormalities after spinal cord injury (SCI) although cognitive deficits related to hippocampal function have been reported in rodents and even humans. The aim of this study was to characterize in further detail hippocampal changes in the acute and chronic SCI. Our data suggested that neurogenesis reduction in the acute phase after SCI could be due to enhanced death of amplifying neural progenitors (ANPs). In addition, astrocytes became reactive and microglial cells increased their number in almost all hippocampal regions studied. Glial changes resulted in a non-inflammatory response as the mRNAs of the major pro-inflammatory cytokines (IL-1β, TNFα, IL-18) remained unaltered, but CD200R mRNA levels were downregulated. Long-term after SCI, astrocytes remained reactive but on the other hand, microglial cell density decreased. Also, glial cells induced a neuroinflammatory environment with the upregulation of IL-1β, TNFα and IL-18 mRNA expression and the decrease of CD200R mRNA. Neurogenesis reduction may be ascribed at later time points to inactivation of neural stem cells (NSCs) and inhibition of ANP proliferation. The number of granular cells and CA1 pyramidal neurons decreased only in the chronic phase. The release of pro-inflammatory cytokines at the chronic phase might involve neurogenesis reduction and neurodegeneration of hippocampal neurons. Therefore, SCI led to hippocampal changes that could be implicated in cognitive deficits observed in rodents and humans. [ABSTRACT FROM AUTHOR]

Carriers of the fragile X premutation (PM) can develop a variety of early neurological symptoms, including depression, anxiety and cognitive impairment as well as being at risk for developing the late-onset fragile X-associated tremor/ataxia syndrome (FXTAS). The absence of effective treatments for FXTAS underscores the importance of developing efficacious therapies to reduce the neurological symptoms in elderly PM carriers and FXTAS patients. A recent preliminary study reported that weekly infusions of Allopregnanolone (Allop) may improve deficits in executive function, learning and memory in FXTAS patients. Based on this study we examined whether Allop would improve neurological function in the aged CGG knock-in (CGG KI) dutch mouse, B6.129P2(Cg)-Fmr1tm2Cgr/Cgr, that models much of the symptomatology in PM carriers and FXTAS patients. Wild type and CGG KI mice received 10 weekly injections of Allop (10 mg/kg, s.c.), followed by a battery of behavioral tests of motor function, anxiety, and repetitive behavior, and 5-bromo-2′-deoxyuridine (BrdU) labeling to examine adult neurogenesis. The results provided evidence that Allop in CGG KI mice normalized motor performance and reduced thigmotaxis in the open field, normalized repetitive digging behavior in the marble burying test, but did not appear to increase adult neurogenesis in the hippocampus. Considered together, these results support further examination of Allop as a therapeutic strategy in patients with FXTAS.

Adult hippocampal neurogenesis (AHN) is important for multiple cognitive functions. We sort to establish a minimal or non-invasive radiation approach to ablate AHN using guinea pigs as an animal model. 125I seeds with different radiation dosages (1.0, 0.8, 0.6, 0.3 mCi) were implanted unilaterally between the scalp and skull above the temporal lobe for 30 and 60 days, with the radiation effect on proliferating cells, immature neurons, and mature neurons in the hippocampal formation determined by assessment of immunolabeled (+) cells for Ki67, doublecortin (DCX), and neuron-specific nuclear antigen (NeuN), as well as Nissl stain cells. Spatially, the ablation effect of radiation occurred across the entire rostrocaudal and largely the dorsoventral dimensions of the hippocampus, evidenced by a loss of DCX+ cells in the subgranular zone (SGZ) of dentate gyrus (DG) in the ipsilateral relative to contralateral hemispheres in reference to the 125I seed implant. Quantitatively, Ki67+ and DCX+ cells at the SGZ in the dorsal hippocampus were reduced in all dosage groups at the two surviving time points, more significant in the ipsilateral than contralateral sides, relative to sham controls. NeuN+ neurons and Nissl-stained cells were reduced in the granule cell layer of DG and the stratum pyramidale of CA1 in the groups with 0.6-mCi radiation for 60 days and 1.0 mCi for 30 and 60 days. Minimal cranial trauma was observed in the groups with 0.3– 1.0-mCi radiation at 60 days. These results suggest that extracranial radiation with 125I seed implantation can be used to deplete HAN in a radioactivity-, duration-, and space-controllable manner, with a “non-invasive” stereotactic ablation achievable by using 125I seeds with relatively low radioactivity dosages.

Objective: Proopiomelanocortin (POMC) neurons of the hypothalamic arcuate nucleus are essential regulators of energy balance. Selective loss of POMC production in these cells results in extreme obesity and metabolic comorbidities. Neurogenesis occurs in the adult hypothalamus, but it remains uncertain whether functional POMC neurons emerge in physiologically significant numbers during adulthood. Here, we tested whether Rax-expressing precursors generate POMC neurons in adult mice and rescue the metabolic phenotype caused by congenital hypothalamic POMC deficiency. Methods: Initially, we identified hypothalamic Rax-expressing cell types using wild-type and Rax-CreERT2:Ai34D mice. Then we generated compound Rax-CreERT2:ArcPomcloxTB/loxTB mice in which endogenous hypothalamic Pomc expression is silenced, but can be restored by tamoxifen administration selectively in neurons derived from Rax+ progenitors. The number of POMC neurons generated by Rax+ progenitors in adult mice and their axonal projections was determined. The metabolic effects of these neurons were assessed by measuring food intake, bodyweight, and body composition, along with glucose and insulin levels. Results: We found that Rax is expressed by tanycytes and a previously unrecognized cell type in the hypothalamic parenchyma of adult mice. Rax+ progenitors generated ~10% of the normal adult hypothalamic POMC neuron population within two weeks of tamoxifen treatment. The same rate and steady state of POMC neurogenesis persisted from young adult to aged mice. These new POMC neurons established terminal projections to brain regions that were involved in energy homeostasis. Mice with Rax+ progenitor-derived POMC neurons had reduced body fat mass, improved glucose tolerance, increased insulin sensitivity, and decreased bodyweight in proportion to the number of new POMC neurons. Conclusions: These data demonstrate that Rax+ progenitors generate POMC neurons in sufficient numbers during adulthood to mitigate the metabolic abnormalities of hypothalamic POMC-deficient mice. The findings suggest that adult hypothalamic neurogenesis is a robust phenomenon in mice that can significantly impact energy homeostasis.

The perception and discriminating of odors are sensory activities that are an integral part of our daily life. The first brain region where odors are processed is the olfactory bulb (OB). Among the different cell populations that make up this brain area, interneurons play an essential role in this sensory activity. Moreover, probably because of their activity, they represent an exception compared to other parts of the brain, since OB interneurons are continuously generated in the postnatal and adult period. In this review, we will focus on periglomerular (PG) cells which are a class of interneurons found in the glomerular layer of the OB. These interneurons can be classified into distinct subtypes based on their neurochemical nature, based on the neurotransmitter and calcium-binding proteins expressed by these cells. Dopaminergic (DA) periglomerular cells and calretinin (CR) cells are among the newly generated interneurons and play an important role in the physiology of OB. In the OB, DA cells are involved in the processing of odors and the adaptation of the bulbar network to external conditions. The main role of DA cells in OB appears to be the inhibition of glutamate release from olfactory sensory fibers. Calretinin cells are probably the best morphologically characterized interneurons among PG cells in OB, but little is known about their function except for their inhibitory effect on noisy random excitatory signals arriving at the main neurons. In this review, we will mainly describe the electrophysiological properties related to the excitability profiles of DA and CR cells, with a particular view on the differences that characterize DA mature interneurons from cells in different stages of adult neurogenesis.

Summary: GABA can depolarize immature neurons close to the action potential (AP) threshold in development and adult neurogenesis. Nevertheless, GABAergic synapses effectively inhibit AP firing in newborn granule cells of the adult hippocampus as early as two weeks post-mitosis. The underlying mechanisms are largely unclear. Here, we analyze GABAergic inputs in newborn hippocampal granule cells mediated by soma-targeting parvalbumin and dendrite-targeting somatostatin interneurons. Surprisingly, both interneuron subtypes activate α5-subunit-containing GABAA receptors (α5-GABAARs) in young neurons, showing a nonlinear voltage dependence with increasing conductance around the AP threshold. By contrast, in mature cells, parvalbumin interneurons mediate linear GABAergic synaptic currents lacking α5-subunits, while somatostatin interneurons continue to target nonlinear α5-GABAARs. Computational modeling shows that the voltage-dependent amplification of α5-GABAAR opening in young neurons is crucial for inhibition of AP firing to generate balanced and sparse firing activity, even with depolarized GABA reversal potential.

Recent epidemiological and intervention studies have suggested that polyphenol-rich plant food consumption reduced the risk of cognitive decline. However, the findings were tentative and by no means definitive. In the present study, we examined the impact of short-term oral administration of cinnamtannin A2 (A2), an (−)-epicatechin tetramer, on adult hippocampal neurogenesis and cognitive function in mice. Mice received supplementation with vehicle (20% glycerol) or 100 μg/kg A2 for 10 days. Then, we conducted the open field test, the object location test, and the novel object test. In the open field test, the A2-treated group tended to spend more time in the center of the arena, compared to the vehicle-treated group. The A2-treated group spent significantly more time exploring objects placed in different locations, compared to the vehicle-treated group. There were no significant differences between groups in the object preference index or in the novel object test. In addition, A2 administration significantly increased the number of hippocampal bromodeoxyuridine-labeled cells in the dentate gyrus, but not in the CA1 or CA3 regions. These results suggested that short-term administration of A2 may impact spatial memory by enhancing neurogenesis in the dentate gyrus of adult mice. [Display omitted] • Ten daily gavage doses of cinnamtannin A2 (A2) increased exploration behavior in mice. • A2 enhanced mouse spatial memory detected with the object location test. • A2 increased BrdU-positive cells in hippocampal dentate gyrus, but not CA1 or CA3. [ABSTRACT FROM AUTHOR]

Carriers of the fragile X premutation (PM) can develop a variety of early neurological symptoms, including depression, anxiety and cognitive impairment as well as being at risk for developing the late-onset fragile X-associated tremor/ataxia syndrome (FXTAS). The absence of effective treatments for FXTAS underscores the importance of developing efficacious therapies to reduce the neurological symptoms in elderly PM carriers and FXTAS patients. A recent preliminary study reported that weekly infusions of Allopregnanolone (Allop) may improve deficits in executive function, learning and memory in FXTAS patients. Based on this study we examined whether Allop would improve neurological function in the aged CGG knock-in (CGG KI) dutch mouse, B6.129P2(Cg)-Fmr1tm2Cgr/Cgr, that models much of the symptomatology in PM carriers and FXTAS patients. Wild type and CGG KI mice received 10 weekly injections of Allop (10 mg/kg, s.c.), followed by a battery of behavioral tests of motor function, anxiety, and repetitive behavior, and 5-bromo-2′-deoxyuridine (BrdU) labeling to examine adult neurogenesis. The results provided evidence that Allop in CGG KI mice normalized motor performance and reduced thigmotaxis in the open field, normalized repetitive digging behavior in the marble burying test, but did not appear to increase adult neurogenesis in the hippocampus. Considered together, these results support further examination of Allop as a therapeutic strategy in patients with FXTAS. [ABSTRACT FROM AUTHOR]

Adult hippocampal neurogenesis (AHN) is important for multiple cognitive functions. We sort to establish a minimal or non-invasive radiation approach to ablate AHN using guinea pigs as an animal model. 125I seeds with different radiation dosages (1.0, 0.8, 0.6, 0.3 mCi) were implanted unilaterally between the scalp and skull above the temporal lobe for 30 and 60 days, with the radiation effect on proliferating cells, immature neurons, and mature neurons in the hippocampal formation determined by assessment of immunolabeled (+) cells for Ki67, doublecortin (DCX), and neuron-specific nuclear antigen (NeuN), as well as Nissl stain cells. Spatially, the ablation effect of radiation occurred across the entire rostrocaudal and largely the dorsoventral dimensions of the hippocampus, evidenced by a loss of DCX+ cells in the subgranular zone (SGZ) of dentate gyrus (DG) in the ipsilateral relative to contralateral hemispheres in reference to the 125I seed implant. Quantitatively, Ki67+ and DCX+ cells at the SGZ in the dorsal hippocampus were reduced in all dosage groups at the two surviving time points, more significant in the ipsilateral than contralateral sides, relative to sham controls. NeuN+ neurons and Nissl-stained cells were reduced in the granule cell layer of DG and the stratum pyramidale of CA1 in the groups with 0.6-mCi radiation for 60 days and 1.0 mCi for 30 and 60 days. Minimal cranial trauma was observed in the groups with 0.3– 1.0-mCi radiation at 60 days. These results suggest that extracranial radiation with 125I seed implantation can be used to deplete HAN in a radioactivity-, duration-, and space-controllable manner, with a "non-invasive" stereotactic ablation achievable by using 125I seeds with relatively low radioactivity dosages. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases, characterized by progressive neural loss, have been some of the most challenging medical problems in aging societies. Treatment strategies such as symptom management have little impact on disease progression, while intervention with specific disease mechanisms may only slow down disease progression. One therapeutic strategy that has the potential to reverse the disease phenotype is to replenish neurons and rebuild the pathway lost to degeneration. Although it is generally believed that the central nervous system has lost the capability to regenerate, increasing evidence indicates that the brain is more plastic than previously thought, containing perhaps the biggest repertoire of cells with latent neurogenic programs in the body. This review focuses on key advances in generating new neurons through in situ neuronal reprogramming, which is tied to fundamental questions regarding adult neurogenesis, cell source, and mechanisms for neuronal reprogramming, as well as the ability of new neurons to integrate into the existing circuitry. [ABSTRACT FROM AUTHOR]

Background: The coexistence of magnetite within protein aggregates in the brain is a typical pathologic feature of Alzheimer's disease (AD), and the formation of amyloid-β (Aβ) plaques induces critical impairment of cognitive function.Objective: This study aimed to investigate the therapeutic effect of proton stimulation (PS) targeting plaque magnetite in the transgenic AD mouse brain.Methods: A proton transmission beam was applied to the whole mouse brain at a single entrance dose of 2 or 4 Gy to test the effect of disruption of magnetite-containing Aβ plaques by electron emission from magnetite. The reduction in Aβ plaque burden and the cognitive function of the PS-treated mouse group were assayed by histochemical analysis and memory tests, respectively. Aβ-magnetite and Aβ fibrils were treated with PS to investigate the breakdown of the amyloid protein matrix.Results: Single PS induced a 48-87%reduction in both the amyloid plaque burden and ferrous-containing magnetite level in the early-onset AD mouse brain while saving normal tissue. The overall Aβ plaque burden (68-82%) and (94-97%) hippocampal magnetite levels were reduced in late onset AD mice that showed improvements in cognitive function after PS compared with untreated AD mice (p < 0.001). Analysis of amyloid fibrils after exposure to a single 2 or 4 Gy proton transmission beam demonstrated that the protein matrix was broken down only in magnetite-associated Aβ fibrils.Conclusion: Single PS targeting plaque magnetite effectively decreases the amyloid plaque burden and the ferrous-containing magnetite level, and this effect is useful for memory recovery. [ABSTRACT FROM AUTHOR]

• Complement C3 negatively regulates the survival and migration of adult born hippocampal neurons, independent of C3a/C3aR signalling. • Complement C3aR is required for normal morphological development of immature neuronal progenitors in the adult hippocampal niche. • Lack of C3 impairs behavioural inhibition and cognitive flexibility. • Lack of C3aR enhances pattern separation without impacting cognitive flexibility. Adult hippocampal neurogenesis (AHN) is a form of ongoing plasticity in the brain that supports specific aspects of cognition. Disruptions in AHN have been observed in neuropsychiatric conditions presenting with inflammatory components and are associated with impairments in cognition and mood. Recent evidence highlights important roles of the complement system in synaptic plasticity and neurogenesis during neurodevelopment and in acute learning and memory processes. In this work we investigated the impact of the complement C3/C3aR pathway on AHN and its functional implications for AHN-related behaviours. In C3 −/− mice, we found increased numbers and accelerated migration of adult born granule cells, indicating that absence of C3 leads to abnormal survival and distribution of adult born neurons. Loss of either C3 or C3aR affected the morphology of immature neurons, reducing morphological complexity, though these effects were more pronounced in the absence of C3aR. We assessed functional impacts of the cellular phenotypes in an operant spatial discrimination task that assayed AHN sensitive behaviours. Again, we observed differences in the effects of manipulating C3 or C3aR, in that whilst C3aR −/− mice showed evidence of enhanced pattern separation abilities, C3 −/− mice instead demonstrated impaired behavioural flexibility. Our findings show that C3 and C3aR manipulation have distinct effects on AHN that impact at different stages in the development and maturation of newly born neurons, and that the dissociable cellular phenotypes are associated with specific alterations in AHN-related behaviours. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) comprises a group of multifactorial neurodevelopmental disorders primarily characterized by deficits in social interaction and repetitive behavior. Although the onset is typically in early childhood, ASD poses a lifelong challenge for both patients and caretakers. Adult neurogenesis (AN) is the process by which new functional neurons are created from neural stem cells existing in the post‐natal brain. The entire event is based on a sequence of cellular processes, such as proliferation, specification of cell fate, maturation, and ultimately, synaptic integration into the existing neural circuits. Hence, AN is implicated in structural and functional brain plasticity throughout life. Accumulating evidence shows that impaired AN may underlie some of the abnormal behavioral phenotypes seen in ASD. In this review, we approach the interconnections between the molecular pathways related to AN and ASD. We also discuss existing therapeutic approaches targeting such pathways both in preclinical and clinical studies. A deeper understanding of how ASD and AN reciprocally affect one another could reveal important converging pathways leading to the emergence of psychiatric disorders. [ABSTRACT FROM AUTHOR]

As a master regulator of the dynamic process of adult neurogenesis, timely expression and regulation of the orphan nuclear receptor Tailless (Tlx) is essential. However, there is no study yet to directly investigate the essential role of precise spatiotemporal expressed Tlx. Here, we generated a conditional gain of Tlx expression transgenic mouse model, which allowed the extended Tlx expression in neural stem cells (NSCs) and their progeny by mating with a TlxCreERT2 mouse line. We demonstrate that extended expression of Tlx induced the impaired generation of mature neurons in adult subventricular zone and subgranular zone. Furthermore, we elucidated for the first time that this mutation decreased the endogenous expression of Sox2 by directly binding to its promoter. Restoration experiments further confirmed that Sox2 partially rescued these neuron maturation defects. Together, these findings not only highlight the importance of shutting‐off Tlx on time in controlling NSC behavior, but also provide insights for further understanding adult neurogenesis and developing treatment strategies for neurological disorders. [ABSTRACT FROM AUTHOR]

Adult mouse hippocampal neural stem cells (NSCs) generate new neurons that integrate into existing hippocampal networks and modulate mood and memory. These NSCs are largely quiescent and are stimulated by niche signals to activate and produce neurons. Wnt/β-catenin signalling acts at different steps along the hippocampal neurogenic lineage, but whether it has a direct role in the regulation of NSCs remains unclear. Here, we used Wnt/β-catenin reporters and transcriptomic data from in vivo and in vitro models to show that adult NSCs respond to Wnt/β-catenin signalling. Wnt/β-catenin stimulation instructed the neuronal differentiation of proliferating NSCs and promoted the activation or differentiation of quiescent NSCs in a dose-dependent manner. However, deletion of β-catenin in NSCs did not affect either their activation or maintenance of their stem cell characteristics. Together, these results indicate that, although NSCs do respond to Wnt/β-catenin stimulation in a dosedependent and state-specific manner, Wnt/β-catenin signalling is not cell-autonomously required to maintain NSC homeostasis, which reconciles some of the contradictions in the literature as to the role of Wnt/β-catenin signalling in adult hippocampal NSCs. [ABSTRACT FROM AUTHOR]

The perception and discriminating of odors are sensory activities that are an integral part of our daily life. The first brain region where odors are processed is the olfactory bulb (OB). Among the different cell populations that make up this brain area, interneurons play an essential role in this sensory activity. Moreover, probably because of their activity, they represent an exception compared to other parts of the brain, since OB interneurons are continuously generated in the postnatal and adult period. In this review, we will focus on periglomerular (PG) cells which are a class of interneurons found in the glomerular layer of the OB. These interneurons can be classified into distinct subtypes based on their neurochemical nature, based on the neurotransmitter and calcium-binding proteins expressed by these cells. Dopaminergic (DA) periglomerular cells and calretinin (CR) cells are among the newly generated interneurons and play an important role in the physiology of OB. In the OB, DA cells are involved in the processing of odors and the adaptation of the bulbar network to external conditions. The main role of DA cells in OB appears to be the inhibition of glutamate release from olfactory sensory fibers. Calretinin cells are probably the best morphologically characterized interneurons among PG cells in OB, but little is known about their function except for their inhibitory effect on noisy random excitatory signals arriving at the main neurons. In this review, we will mainly describe the electrophysiological properties related to the excitability profiles of DA and CR cells, with a particular view on the differences that characterize DA mature interneurons from cells in different stages of adult neurogenesis. [ABSTRACT FROM AUTHOR]

Increased physical activity has shown positive effects on various hippocampal memory functions through accumulating evidence that physical exercise and higher cardiorespiratory fitness can enhance human performance on nonspatial mnemonic discrimination tasks that rely on hippocampal pattern separation. However, there is less direct evidence of exercise effects on spatial pattern separation in humans, despite evidence for this association in rodent models. We examined the influence of strenuous exercise habits on spatial mnemonic discrimination among 176 young adults. We used a delayed match-/non-match-to-sample (same/different) task to assess pattern separation for spatial locations across varying degrees of similarity. Participants who reported regularly engaging in strenuous exercise three or more times per week performed significantly better than those who reported engaging in strenuous exercise fewer than three times per week, even when pattern separation tasks involved higher spatial similarity. These apparent exercise effects were observed for female, but not male, participants. These findings support likely benefits of strenuous exercise habits for human spatial pattern separation skills, and they suggest a need to explore potential interaction effects of exercise and gender. [ABSTRACT FROM AUTHOR]

Chronic exposure to stress disturbs the homeostasis of the brain, thus, deleteriously affecting the neurological circuits. In literature, there are investigations about the stress-related alterations in behavioral response and adult neurogenesis; however, an effective combating strategy to evade stress is still at stake. Hence, the present study is designed to investigate the effect of an enriched environment in alleviating the anxiety/depressive-like behavioral response and enhancing the adult neurogenesis in the hippocampal region of rats exposed to chronic immobilization stress. The rats were exposed to chronic immobilization stress (IS) for 4 h/day followed by the enriched environment (EE) for 2 h/day for 28 days, and finally, the hippocampal region was dissected out after the behavioral analyses. IS group showed increased behavioral despair to tail suspension test, decrement in the activity for light/dark box test, and less grooming activity towards splash test. In contrast, IS + EE rats exhibited a decrease in the activity of tail suspension test and an increase in the behavioral response to light/dark box test and splash test. The in vitro assessment of primary cultures of neurospheres from the IS group resulted in decreased levels of proliferation in the cell number and metabolic activity of both MTT assay and lactate levels. IS + EE group revealed an increase in the growth curve of neurospheres and higher metabolic activities of MTT and lactate. The IS cultures had reduced neurite length, while the neurite outgrowths were increased in IS + EE group. The IS group showed significant reduction in the protein and mRNA levels of nestin, GFAP, CD11b, MOG, and synaptophysin, whereas the IS + EE cultures exhibited significant increase in the levels of these stem cell markers. Our data highlight the positive impact of EE against stress-related behavioral changes in rats exposed to chronic immobilization stress perhaps by interfering with the differentiation of neurospheres and neurogenesis. [ABSTRACT FROM AUTHOR]

Adult neural stem cells reside in specialized niches. In the ventricular-subventricular zone (V-SVZ), quiescent neural stem cells (qNSCs) become activated (aNSCs), and generate transit amplifying cells (TACs), which give rise to neuroblasts that migrate to the olfactory bulb. The vasculature is an important component of the adult neural stem cell niche, but whether vascular cells in neurogenic areas are intrinsically different from those elsewhere in the brain is unknown. Moreover, the contribution of pericytes to the neural stem cell niche has not been defined. Here, we describe a rapid FACS purification strategy to simultaneously isolate primary endothelial cells and pericytes from brain microregions of nontransgenic mice using CD31 and CD13 as surface markers. We compared the effect of purified vascular cells from a neurogenic (V-SVZ) and non-neurogenic brain region (cortex) on the V-SVZ stem cell lineage in vitro. Endothelial and pericyte diffusible signals from both regions differentially promote the proliferation and neuronal differentiation of qNSCs, aNSCs, and TACs. Unexpectedly, diffusible cortical signals had the most potent effects on V-SVZ proliferation and neurogenesis, highlighting the intrinsic capacity of non-neurogenic vasculature to support stem cell behavior. Finally, we identify PlGF-2 as an endothelial-derived mitogen that promotes V-SVZ cell proliferation. This purification strategy provides a platform to define the functional and molecular contribution of vascular cells to stem cell niches and other brain regions under different physiological and pathological states.

Within the adult mouse subventricular zone (SVZ), neural stem cells (NSCs) produce neuroblasts and oligodendrocyte precursor cells (OPCs). T 3 , the active thyroid hormone, influences renewal and commitment of SVZ progenitors. However, how regulators of T 3 availability affect these processes is less understood. Using Mct8/Dio2 knockout mice, we investigated the role of MCT8, a TH transporter, and DIO2, the T 3 -generating enzyme, in regulating adult SVZ-neurogliogenesis. Single-cell RNA-Seq revealed Mct8 expression in various SVZ cell types in WT mice, while Dio2 was enriched in neurons, astrocytes, and quiescent NSCs. The absence of both regulators in the knockout model dysregulated gene expression, increased the neuroblast/OPC ratio and hindered OPC differentiation. Immunostainings demonstrated compromised neuroblast migration reducing their supply to the olfactory bulbs, impairing interneuron differentiation and odor discrimination. These findings underscore the pivotal roles of MCT8 and DIO2 in neuro- and oligodendrogenesis, offering targets for therapeutic avenues in neurodegenerative and demyelinating diseases. [Display omitted] • MCT8 and DIO2 are pivotal for proper neuro- oligodendrogenesis in the adult murine SVZ. • Lack of MCT8 and DIO2 alters the transcriptomic landscape in the adult SVZ. • MCT8 and DIO2 absence leads to decreased migration from SVZ-derived progenitors. • MCT8 and DIO2 absence leads to an altered neuroarchitecture in the olfactory bulbs. • Lack of MCT8 and DIO2 leads to reduced olfactory memory and discrimination. [ABSTRACT FROM AUTHOR]