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Dentat girusta (DG) görülen yetişkin nörogenezininhipokampal bellek ağlarındaki işleve önemli bir katkı sunduğu kabuledilmektedir. Sunulan ayrık sayısal model DG'de bulunan nöral progenitör hücre(NPH) popülasyonlarında ve bu süreçlerin ürünlerindeki (immatür nöron, astrositve oligodendrosit popülasyonları) temporal değişimleri modellemeyiamaçlamaktadır. Süreçler toplam hacimde bir limitin olmadığı ve nörogeneziyönlendiren tüm kimyasal ve fiziksel düzenleyicilerin devamlı ulaşılabilirolduğu ideal bir ortamda tanımlanmıştır. Sistem üç temel seviyede bağımsızolarak çalışmaktadır. Her seviye nörogenez süreçlerindeki bir aşama olaraktanımlanmıştır ve popülasyonlar üç temel hücre tipinden oluşmaktadır: Tip I(radyal glia), tip II (geçici çoğalan hücre) ve tip III (nöroblast). Hücrekaderi, her hücre tipi için bir popülasyon limiti olan yarı-stokastik bir süreç(bir seçim) olarak sisteme eklenmiştir. Sunulan model, ayrık süreçleredayanmasına ve basitleştirilmiş bir yaklaşım izlemesine rağmen, yetişkinnörogenezinin sayısal bir taslağını başarılı şekilde üretmektedir ve farklımodülasyonlarla bir hipokampal trisinaptik devre ağına yerleştirilebilir., Adult neurogenesis in dentate gyrus (DG) is a prominentcontributor in the dynamics of hippocampal memory networks. This discrete modelaims to estimate the temporal changes in the neural progenitor cell (NPC) populations in DG, together with the productsof differentiation – immature neurons, astrocytes and oligodendrocytes. Thedynamics are described in an ideal environment, where there is no limit for thetotal volume and all required chemical and physical cues that directneurogenesis are continuously available. The system works independently onthree levels. Each level is defined as the dynamics in a stage of neurogenesiswith three types of NPCs: type I cell (radial glia), type II cell (transientlyamplifying cells) and type III cell (neuroblasts). Cell fate was introduced asa semi-stochastic process (a choice) with a population limit for each celltype. Although it is based on discrete processes and has a rather simplisticapproach, the simulations successfully provide a numerical template for adultneurogenesis, which can be further modified and implemented in a hippocampaltrisynaptic loop network.

The aim of the study was to evaluate the impact of second generation antiepileptic drug levetiracetam (LEV) with arachidonyl-2′-chloroethylamide (ACEA) on proliferating neural precursor cells in mouse brain. Additionally, we established the relationship between treatment with ACEA in combination with LEV and hippocampal neurogenesis in mouse brain. All experiments were performed on male CB57/BL mice injected i.p. with LEV (10 mg/kg), ACEA (10 mg/kg) and PMSF (30 mg/kg) for 10 days. Experiments were provided in two stages: stage 1- an acute response of proliferating neural precursor cells to ACEA and LEV administration (Ki-67 staining), stage 2 – a long term response to ACEA and LEV administration (BrDU, NeuN, GFAP staining). Results indicate that ACEA + PMSF and ACEA + PMSF + LEV significantly increased the total number of Ki-67 positive cells comparing to the control group. PMSF and LEV administered alone and in combination had no significant impact on cell proliferation compared to the control group. Results from neurogenesis study indicated that ACEA + PMSF administered alone and in combination with LEV increased the total number of BrDU cells compared to the control group, although LEV on its own decreased the number of BrDU cells. Moreover, the combination of ACEA + PMSF + LEV significantly increased the total number of newborn neurons compared to the control group. In turn, LEV significantly decreased the process of neurogenesis. Astrocytes were considerably reduced in all treated groups as compare to the control mice. These data provide substantial evidence that LEV administered chronically decreases the proliferation and differentiation of newly born cells while combination of LEV + ACEA significantly increases the level of newborn neurons in the dentate subgranular zone.

Neonatal hypoxic–ischemic (HI) brain injury likely represents the major cause of long-term neurodevelopmental disabilities in surviving babies. Despite significant investigations, there is not yet any known reliable treatment to reduce brain damage in suffering infants. Our recent studies in an animal model of HI revealed the therapeutic potential of a histone deacetylase inhibitor (HDACi). The neuroprotective action was connected with the stimulation of neurogenesis in the dentate gyrus subgranular zone. In the current study, we investigated whether HDACi—sodium butyrate (SB)—would also lead to neurogenesis in the subventricular zone (SVZ). By using a neonatal rat model of hypoxia–ischemia, we found that SB treatment stimulated neurogenesis in the damaged ipsilateral side, based on increased DCX labeling, and restored the number of neuronal cells in the SVZ ipsilateral to lesioning. The neurogenic effect was associated with inhibition of inflammation, expressed by a transition of microglia to the anti-inflammatory phenotype (M2). In addition, the administration of SB increased the activation of the TrkB receptor and the phosphorylation of the transcription factor—CREB—in the ipsilateral hemisphere. In contrast, SB administration reduced the level of HI-induced p75NTR. Together, these results suggest that BDNF–TrkB signaling plays an important role in SB-induced neurogenesis after HI. These findings provide the basis for clinical approaches targeted at protecting the newborn brain damage, which may prove beneficial for treating neonatal hypoxia–ischemia.

New neurons are continuously generated in the adult brain. This generation primarily occurs in the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the hippocampal dentate gyrus. In the SGZ, neural stem cells (NSCs) give rise to glutamatergic granule cells that integrate into the hippocampal circuitry. Reduction of neurogenesis in the hippocampus impairs learning and memory, which suggests that this process is important for adult hippocampal function. Indeed, the neurogenesis is reduced in the progression of aging, which is thought to contribute to age-related cognitive impairment. Although the mechanism of age-dependent decline in neurogenesis remains largely obscure, astrocytes are thought to play a vital role in regulating NSC proliferation and differentiation. Both astrocytes and NSCs secrete nucleotides to the extracellular space and extracellular nucleotides bind to their receptors on the surface of target cells. In this review, the recent knowledge on adult neurogenesis in the hippocampus is summarized briefly, and possible role of extracellular nucleotides in the age-dependent changes of the adult neurogenesis is discussed.

According to the previous research, metformin, a medication utilized for type 2 diabetes management, inhibits neural aging and reduces infarct size by enhancing angiogenesis in a mouse stroke model. What is more, metformin administration also promotes neural precursor cells proliferation, migration, as well as differentiation for newborn mice with hypoxia-ischemia brain injury. However, whether metformin regulates neurogenesis in an adult rat ischemia/reperfusion (I/R) model remains unclear. The current research found that metformin administration reduced neuronal damage in the CA1 area of hippocampus in a rat model of I/R. The number of neuronal nuclei positive neuron was significantly increased and glial fibrillary acidic protein positive astrocyte became obviously declined in the CA1 region in I/R rats treated with metformin. It was further demonstrated that metformin promoted neuroblasts proliferation and neuronal differentiation in the subgranular zone of the dentate gyrus and inhibited the formation of astrocyte. Our study indicates that activation of endogenous neuroblasts using metformin will become a favorable target in therapeutic intervention of cerebral ischemia injury models.

Reactive oxygen species (ROS) modulate the growth of neural stem/precursor cells (NS/PCs) and participate in hippocampus-associated learning and memory. However, the origin of these regulatory ROS in NS/PCs is not fully understood. In the present study, we found that Nox4, a ROS-producing NADPH oxidase family protein, is expressed in primary cultured NS/PCs and in those of the adult mouse brain. Nox inhibitors VAS 2870 and GKT137831 or Nox4 deletion attenuated bFGF-induced proliferation of cultured NS/PCs, while lentivirus-mediated Nox4 overexpression increased the production of H2O2, the phosphorylation of Akt, and the proliferation of cultured NS/PCs. Nox4 did not significantly affect the potential of cultured NS/PCs to differentiate into neurons or astrocytes. The histological and functional development of the hippocampus appeared normal in Nox4-/- mice. Although pathological and functional damages in the hippocampus induced by the neurotoxin trimethyltin were not significantly different between wild-type and Nox4-/- mice, the post-injury reactive proliferation of NS/PCs and neurogenesis in the subgranular zone (SGZ) of the dentate gyrus were significantly impaired in Nox4-/- animals. Restoration from the trimethyltin-induced impairment in recognition and spatial working memory was also significantly attenuated in Nox4-/- mice. Collectively, our findings suggest that Nox4 participates in NS/PC proliferation and neurogenesis in the hippocampus following injury, thereby helping to restore memory function.

Mounting evidence in the literature suggests that RNA-RNA binding protein aggregations can disturb neuronal homeostasis and lead to symptoms associated with normal aging as well as dementia. The specific ablation of cyclin A2 in adult neurons results in neuronal polyribosome aggregations and learning and memory deficits. Detailed histologic and ultrastructural assays of aged mice revealed that post-mitotic hippocampal pyramidal neurons maintain cyclin A2 expression and that proliferative cells in the dentate subgranular zone express cyclin A2. Cyclin A2 loss early during neural development inhibited hippocampal development through canonical/cell-cycle mechanisms, including prolonged cell cycle timing in embryonic hippocampal progenitor cells. However, in mature neurons, cyclin A2 colocalized with dendritic rRNA. Cyclin A2 ablation in adult hippocampus resulted in decreased synaptic density in the hippocampus as well as in accumulation of rRNA granules in dendrite shafts. We conclude that cyclin A2 functions in a noncanonical/non-cell cycle regulatory role to maintain adult pyramidal neuron ribostasis.

Melatonin is a pleiotropic molecule that, after a short-term sleep deprivation, promotes the proliferation of neural stem cells in the adult hippocampus. However, this effect has not been observed in long-term sleep deprivation. The precise mechanism exerted by melatonin on the modulation of neural stem cells is not entirely elucidated, but evidence indicates that epigenetic regulators may be involved in this process. In this study, we investigated the effect of melatonin treatment during a 96-hour sleep deprivation and analyzed the expression of epigenetic modulators predicted by computational text mining and keyword clusterization. Our results showed that the administration of melatonin under sleep-deprived conditions increased the MECP2 expression and reduced the SIRT1 expression in the dentate gyrus. We observed that let-7b, mir-132, and mir-124 were highly expressed in the dentate gyrus after melatonin administration, but they were not modified by sleep deprivation. In addition, we found more Sox2+/5-bromo-2′-deoxyuridine (BrdU)+ cells in the subgranular zone of the sleep-deprived group treated with melatonin than in the untreated group. These findings may support the notion that melatonin modifies the expression of epigenetic mediators that, in turn, regulate the proliferation of neural progenitor cells in the adult dentate gyrus under long-term sleep-deprived conditions. All procedures performed in this study were approved by the Animal Ethics Committee of the University of Guadalajara, Mexico (approval No. CI-16610) on January 2, 2016.

Traumatic brain injury is an important cause of mortality and morbidity all over the world. After the initial injury there is a cascade of cellular and molecular events that ultimately lead to cell death. Therapies aim not only to counteract these mechanisms but also to replenish the lost cell population in order to achieve a better recovery. The adult mammal brain in not as plastic as the postnatal, but it has at least two neurogenic regions that maintains physiological functions in the brain; the subgranular zone of the dentate gyrus of the hippocampus, which produces neurons that integrate locally, and the subventricular zone (SVZ) of the lateral ventricles, that produces neuroblasts that migrate through the rostral migratory stream (RMS) to the olfactory bulbs. Brain injuries, as well as neurodegenerative diseases, induce the SVZ to respond by increasing cell proliferation and migration to the injured areas. Here we report that SVZ cells migrate to the injured cortex after traumatic brain injury in mice, and that the physiological RMS migration is not impaired. We also show that Prokineticin 2 (PROK2), a chemokine important for the olfactory bulb neurogenesis by promoting the directional migration of neuroblasts, is induced in the injured cortex. Using PROK2 receptor antagonist and recombinant PROK2 we show for the first time that PROK2 can directionally attract SVZ cells in vitro and in vivo. The data we present here links one more element of the inflammatory process, PROK2 secreted by microglia, to the attempt to regenerate an acutely injured mammalian cortex.AbbreviationsSGZsubgranular zoneSVZsubventricular zoneRMSrostral migratory streamPROK2Prokineticin 2

HIF-1α is a hypoxia-inducible protein that regulates many cellular processes, including neural stem cell maintenance. Previous work demonstrated constitutive stabilization of HIF-1α in neural stem cells (NSCs) of the adult mouse subventricular zone (SVZ) and hippocampal subgranular zone (SGZ). Genetic inactivation of NSC-encoded HIF-1α in the adult SVZ results in gradual loss of NSCs, but whether HIF-1α is required for the maintenance of SGZ hippocampal progenitors and adult hippocampal neurogenesis has not been determined. Here we tested the hypothesis that HIF-1α plays an essential role in the maintenance of adult hippocampal neurogenesis using Nestin-CreER(T2)/R26R-YFP/Hif1a(fl/fl) triple transgenic mice, in which HIF-1α was genetically inactivated in nestin(+) hippocampal progenitors and their downstream progeny following tamoxifen exposure. We found that disruption of HIF-1α gene expression resulted in a marked 50% reduction of adult-generated dentate granule cells (DGCs) that was highly correlated with impaired hippocampal function, as assessed using two behavioral assays of pattern discrimination. These behavioral tests included the A-B contextual fear-conditioning task and the trial-unique, delayed nonmatching-to-location (TUNL) touch-screen operant chamber task. Our findings identify HIF-1α as a novel regulator of adult hippocampal neurogenesis under non-pathological conditions, and underscore the importance of neurogenesis for pattern discrimination learning.

Adult hippocampal neurogenesis is a finely tuned process regulated by extrinsic factors. Neuroinflammation is a hallmark of several pathological conditions underlying dysregulation of neurogenesis. In animal models, lipopolysaccharide (LPS)-induced neuroinflammation leads to a neurogenic decrease mainly associated to the early inflammatory response. However, it is not well understood how the neuroinflammatory response progresses over time and if neurogenesis continues to be diminished during the late neuroinflammatory response. Moreover, it is unknown if repeated intermittent administration of LPS along time induces a greater reduction in neurogenesis. We administered one single intraperitoneal injection of LPS or saline or four repeated injections (one per week) of LPS or saline to young-adult mice. A cohort of new cells was labeled with three 5-bromo-2-deoxyuridine injections (one per day) 4 days after the last LPS injection. We evaluated systemic and neuroinflammation-associated parameters and compared the effects of the late neuroinflammatory response on neurogenesis induced by each protocol. Our results show that 1) a single LPS injection leads to a late pro-inflammatory response characterized by microglial activation, moderate astrocytic reaction and increased interleukin-6 levels. This response correlates in time with decreased neurogenesis and 2) a repeated intermittent injection of LPS does not elicit a late pro-inflammatory response although activated microglia persists. The latter profile is not accompanied by a continued long-term hippocampal neurogenic decrease. Hereby, we provide evidence that the neuroinflammatory response is a dynamic process that progresses in a milieu-dependent manner and does not necessarily lead to a neurogenic decrease, highlighting the complex interaction between the immune system and neurogenesis.

Status epilepticus has been shown to activate the proliferation of neural stem cells in the hippocampus of the brain, while also causing a large amount of neuronal death, especially in the subgranular zone of the dentate gyrus and the subventricular zone. Simultaneously, proliferating stem cells tend to migrate to areas with obvious damage. Our previous studies have clearly confirmed the effect of sodium valproate on cognitive function in rats with convulsive status epilepticus. However, whether neurogenesis can play a role in the antiepileptic effect of sodium valproate remains unknown. A model of convulsive status epilepticus was established in Wistar rats by intraperitoneal injection of 3 mEq/kg lithium chloride, and intraperitoneal injection of pilocarpine 40 mg/kg after 18-20 hours. Sodium valproate (100, 200, 300, 400, 500, or 600 mg/kg) was intragastrically administered six times every day (4-hour intervals) for 5 days. To determine the best dosage, sodium valproate concentration was measured from the plasma. The effective concentration of sodium valproate in the plasma of the rats that received the 300-mg/kg intervention was 82.26 ± 11.23 μg/mL. Thus, 300 mg/kg was subsequently used as the intervention concentration of sodium valproate. The following changes were seen: Recording excitatory postsynaptic potentials in the CA1 region revealed high-frequency stimulation-induced long-term potentiation. Immunohistochemical staining for BrdU-positive cells in the brain revealed that sodium valproate intervention markedly increased the success rate and the duration of induced long-term potentiation in rats with convulsive status epilepticus. The intervention also reduced the number of newborn neurons in the subgranular area of the hippocampus and subventricular zone and inhibited the migration of newborn neurons to the dentate gyrus. These results indicate that sodium valproate can effectively inhibit the abnormal proliferation and migration of neural stem cells and newborn neurons after convulsive status epilepticus, and improve learning and memory ability.

Individuals with sleep apnea often exhibit changes in cognitive behaviors consistent with alterations in the hippocampus. It is hypothesized that adult neurogenesis in the dentate gyrus is an ongoing process that maintains normal hippocampal function in many mammalian species, including humans. However, the impact of chronic intermittent hypoxia (IH), a principal consequence of sleep apnea, on hippocampal adult neurogenesis remains unclear. Using a murine model, we examined the impact of 30 d of IH (IH30) on adult neurogenesis and synaptic plasticity in the dentate gyrus. Although IH30did not affect paired-pulse facilitation, IH30suppressed long-term potentiation (LTP). Immunohistochemical experiments also indicate that IH perturbs multiple aspects of adult neurogenesis. IH30increased the number of proliferating Sox2+neural progenitor cells in the subgranular zone yet reduced the number of doublecortin-positive neurons. Consistent with these findings, cell lineage tracing revealed that IH30increased the proportion of radial glial cells in the subgranular zone, yet decreased the proportion of adult-born neurons in the dentate gyrus. While administration of a superoxide anion scavenger during IH did not prevent neural progenitor cell proliferation, it mitigated the IH-dependent suppression of LTP and prevented adult-born neuron loss. These data demonstrate that IH causes both reactive oxygen species-dependent and reactive oxygen species-independent effects on adult neurogenesis and synaptic plasticity in the dentate gyrus. Our findings identify cellular and neurophysiological changes in the hippocampus that may contribute to cognitive and behavioral deficits occurring in sleep apnea.SIGNIFICANCE STATEMENTIndividuals with sleep apnea experience periods of intermittent hypoxia (IH) that can negatively impact many aspects of brain function. Neurons are continually generated throughout adulthood to support hippocampal physiology and behavior. This study demonstrates that IH exposure attenuates hippocampal long-term potentiation and reduces adult neurogenesis. Antioxidant treatment mitigates these effects indicating that oxidative signaling caused by IH is a significant factor that impairs synaptic plasticity and reduces adult neurogenesis in the hippocampus.

Ionizing radiation (IR) therapy is a major cancer treatment modality and an indispensable auxiliary treatment for primary and metastatic cancers, but invariably results in debilitating organ dysfunctions. IR-induced depletion of neural stem/progenitor cells in the subgranular zone of the dentate gyrus in the hippocampus where neurogenesis occurs is considered largely responsible for deficiencies such as learning, memory, and spatial information processing in patients subjected to cranial irradiation. Similarly, IR therapy-induced intestinal injuries such as diarrhea and malabsorption are common side effects in patients with gastrointestinal tumors and are believed to be caused by intestinal stem cell drop out. Hematopoietic stem cell transplantation is currently used to reinstate blood production in leukemia patients and pre-clinical treatments show promising results in other organs such as the skin and kidney, but ethical issues and logistic problems make this route difficult to follow. An alternative way to restore the injured tissue is to preserve the stem cell pool located in that specific tissue/organ niche, but stem cell response to ionizing radiation is inadequately understood at the molecular mechanistic level. Although embryonic and fetal hypersensity to IR has been very well known for many decades, research on embryonic stem cell models in culture concerning molecular mechanisms have been largely inconclusive and often in contradiction of the in vivo observations. This review will summarize the latest discoveries on stem cell radiosensitivity, highlighting the possible molecular and epigenetic mechanism(s) involved in DNA damage response and programmed cell death after ionizing radiation therapy specific to normal stem cells. Finally, we will analyze the possible contribution of stem cell-specific chromatin’s epigenetic constitution in promoting normal stem cell radiosensitivity.

Exposure to sterigmatocystin (STC) raises concerns on developmental neurological disorders. The present study investigated the effects of maternal oral STC exposure on postnatal hippocampal neurogenesis of offspring in rats. Dams were exposed to STC (1.7, 5.0, and 15.0 ppm in diet) from gestational day 6 until day 21 post-delivery (weaning), and offspring were maintained without STC exposure until adulthood on postnatal day (PND) 77, in accordance with OECD chemical testing guideline Test No. 426. On PND 21, 15.0-ppm STC decreased type-3 neural progenitor cell numbers in the subgranular zone (SGZ) due to suppressed proliferation. Increased γ-H2AX-immunoreactive (+) cell numbers in the SGZ and Ercc1 upregulation and Brip1 downregulation in the dentate gyrus suggested induction of DNA double-strand breaks in SGZ cells. Upregulation of Apex1 and Ogg1 and downregulation of antioxidant genes downstream of NRF2-Keap1 signaling suggested induction of oxidative DNA damage. Increased p21WAF1/CIP1+ SGZ cell numbers and suppressed cholinergic signaling through CHRNB2-containing receptors in GABAergic interneurons suggested potential neurogenesis suppression mechanisms. Multiple mechanisms involving N-methyl-d-aspartate (NMDA) receptor-mediated glutamatergic signaling and various GABAergic interneuron subpopulations, including CHRNA7-expressing somatostatin+ interneurons activated by BDNF-TrkB signaling, may be involved in ameliorating the neurogenesis. Upregulation of Arc, Ptgs2, and genes encoding NMDA receptors and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors suggested synaptic plasticity facilitation. On PND 77, ARC+ granule cells decreased, and Nos2 was upregulated following 15.0 ppm STC exposure, suggesting oxidative stress-mediated synaptic plasticity suppression. Inverse pattern in gene expression changes in vesicular glutamate transporter isoforms, Slc17a7 and Slc17a6, from weaning might also be responsible for the synaptic plasticity suppression. The no-observed-adverse-effect level of maternal oral STC exposure for offspring neurogenesis was determined to be 5.0 ppm, translating to 0.34-0.85 mg/kg body weight/day.

Neuron-restrictive silencing factor (NRSF) is a zinc-finger transcription factor that regulates expression of a diverse set of genes. However, NRSF function in brain development still remains elusive. In the present study, we generated NRSF-conditional knockout (NRSF-cKO) mice by hGFAP-Cre/loxp system to study the effect of NRSF deficiency on brain development. Results showed that NRSF conditional knockout caused a smaller hippocampus and a thinner granule cell layer (GCL) in mice. Moreover, the reduction and disarrangement of GFAP+ cells in subgranular zone (SGZ) of NRSF-cKO mice was accompanied with the decreased number of premature neurons, neural stem cells (NSCs) and neural progenitor cells (NPCs), as well as compromising the majority of mitotically active cells. The analysis of postnatal development of hippocampus indicated the existence of an abnormality at postnatal day (P) 8, rather than at P1, in NRSF-cKO mice, although the densities of Ki67+ cells with mitotic ability in dentate gyrus were relatively unaffected at P1 and P8. Meanwhile, NRSF deficiency led to abnormal organization of SGZ at P8 during postnatal development. RNA-Seq analysis revealed 79 deregulated genes in hippocampus of NRSF-cKO mice at P8, which were involved in p53 signal transduction, neuron migration and negative regulation of cell proliferation, etc. The deregulation of p53 pathway in NRSF-cKO mice at P1 and P8 was evidenced, of which p21/Cdkn1a was accumulated in a portion of NSCs and NPCs in hippocampus during postnatal development. Together, these results, for the first time, revealed that NRSF could significantly influence the postnatal development of hippocampus, especially the formation of SGZ.

Interventions for preventing cognitive dysfunction post traumatic brain injury (TBI) is limited. Given that adult hippocampal neurogenesis (AHN) after brain injury contributes to cognitive recovery, and that the AHN is potentially affected by nutritional factors, we asked whether fasting could promote AHN and thus ameliorates cognitive defects after TBI. Here we show that a one-month intermittent fasting (IF) regimen enhanced proliferation of neural stem cells (NSCs) in the subgranular zone (SGZ) of hippocampus 3 days post TBI, as well as improved cognitive performance in Morris water maze (MWM) test. Furthermore, an increase in hippocampal Npy expression was detected in IF group after injury, compared to the mice fed ad libitum (AL), and locally knock-down of Npy in vivo attenuated the aforementioned effects of IF in TBI. These findings suggest that IF promotes AHN following TBI by a mechanism involving enhancement of Npy expression, which may offer novel interventions that might prevent cognitive dysfunction caused by injury.

Postnatal and adult neurogenesis in the subventricular zone and subgranular zone of animals such as rodents and non-human primates has been observed with many different technical approaches. Since most techniques used in animals cannot be used in humans, the majority of human neurogenesis studies rely on postmortem immunohistochemistry. This technique is difficult in human tissue, due to poor and variable preservation of antigens and samples. Nevertheless, a survey of the literature reveals that most published studies provide evidence for childhood and adult neurogenesis in the human brain stem cell niches. There are some conflicting results even when assessing the same markers and when using the same antibodies. Focusing on immunohistochemical studies on post-mortem human sections, we discuss the relative robustness of the literature on adult neurogenesis. We also discuss the response of the subventricular and subgranular zones to human disease, showing that the two niches can respond differently and that the stage of disease impacts neurogenesis levels. Thus, we highlight strong evidence for adult human neurogenesis, discuss other work that did not find it, describe obstacles in analysis, and offer other approaches to evaluate the neurogenic potential of the subventricular and subgranular zones of Homo sapiens. This article is categorized under: Neurological Diseases > Stem Cells and Development Reproductive System Diseases > Stem Cells and Development.

The substantial clinical burden and disability after stroke injury urges the need to explore therapeutic solutions. Recent compelling evidence supports that neurogenesis persists in the adult mammalian brain and is amenable to regulation in both physiological and pathological situations. Its ability to generate new neurons implies a potential to contribute to recovery after brain injury. However, post-stroke neurogenic response may have different functional consequences. On the one hand, the capacity of newborn neurons to replenish the damaged tissue may be limited. In addition, aberrant forms of neurogenesis have been identified in several insult settings. All these data suggest that adult neurogenesis is at a crossroads between the physiological and the pathological regulation of the neurological function in the injured central nervous system (CNS). Given the complexity of the CNS together with its interaction with the periphery, we ultimately lack in-depth understanding of the key cell types, cell-cell interactions, and molecular pathways involved in the neurogenic response after brain damage and their positive or otherwise deleterious impact. Here we will review the evidence on the stroke-induced neurogenic response and on its potential repercussions on functional outcome. First, we will briefly describe subventricular zone (SVZ) neurogenesis after stroke beside the main evidence supporting its positive role on functional restoration after stroke. Then, we will focus on hippocampal subgranular zone (SGZ) neurogenesis due to the relevance of hippocampus in cognitive functions; we will outline compelling evidence that supports that, after stroke, SGZ neurogenesis may adopt a maladaptive plasticity response further contributing to the development of post-stroke cognitive impairment and dementia. Finally, we will discuss the therapeutic potential of specific steps in the neurogenic cascade that might ameliorate brain malfunctioning and the development of post-stroke cognitive impairment in the chronic phase. This work was supported by the grants from Spanish Ministry of Science and Innovation, PID2019-106581RB-I00 (MM); Leducq Foundation for Cardiovascular Research, TNE-19CVD01 (MM); Fundación La Caixa, HR17_00527 (MM); Instituto de Salud Carlos III and co-financed by the European Development Regional Fund “A Way to Achieve Europe,” PI20/00535 and RETICS RD16/0019/0009 (IL); by contracts FJC-039343-I (AG-C) from the Spanish Ministry of Science and Innovation; and FPU01405265 (VM) and FPU19/02989 (EF) from the Spanish Ministry of Universities. The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación (MCIN), and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (SEV-2015-0505). Sí

Purpose Despite major technical advances in hippocampus-sparing radiation therapy, radiation-induced injury to the neural stem cell compartment may affect neurocognitive functions. In the brain, glial cells modulate neuronal functions and are major mediators of neuroinflammation. In a preclinical mouse model with fractionated low-dose radiation (LDR), the complex response to radiation-induced injury was analyzed in the hippocampal stem cell compartment over a period of 6 months. Methods and Materials Adult and juvenile C57BL/6NCrl mice were exposed to low doses of ionizing radiation (IR; 20 fractions of 0.1 Gy, for up to 4 weeks) daily. At 72 hours and 1, 3, and 6 months after fractionated LDR, magnetic resonance imaging (9.4 T) was conducted to detect structural and functional abnormalities in the hippocampal region. Using immunofluorescence and histologic studies, neuroglia cells (astrocytes, microglia, oligodendrocytes) were quantified and neuroinflammatory responses were characterized in the hippocampal dentate gyrus. Using in vivo bromodeoxyuridine labeling, the cell fate of newly generated progenitor cells was tracked in the subgranular zone of the dentate gyrus during fractionated LDR. Results Low doses of IR induced long-lasting inflammatory responses with local increases of activated microglia and reactive astrocytes, which were most pronounced in the juvenile hippocampus within the first months after LDR. Glial activation with the consequent release of proinflammatory mediators increased local blood flow and vascular permeability in the hippocampal region. Cell fate mapping of progenitors located in the subgranular zone revealed a transient shift from neurogenesis to gliogenesis. Conclusions Glial cell activation and transient neuroinflammation may reflect radiation-induced neuronal damage in the hippocampal stem cell niche. The increased proliferative capacity of the developing brain may explain the enhanced hippocampal radiosensitivity, with stronger inflammatory reactions in the juvenile hippocampus. Thus, limiting the radiation dose to the hippocampal region is an important issue of clinical radiation therapy at all ages to preserve neurocognitive functions.

Neural stem cells (NSCs) persist into adulthood in the subgranular zone (SGZ) of the dentate gyrus in the hippocampus and in the ventricular-subventricular zone (V-SVZ) of the lateral ventricles, where they generate new neurons and glia cells that contribute to neural plasticity. A better understanding of the developmental process that enables NSCs to persist beyond development will provide insight into factors that determine the size and properties of the adult NSC pool and thus the capacity for life-long neurogenesis in the adult mammalian brain. We review current knowledge regarding the developmental origins of adult NSCs and the developmental process by which embryonic NSCs transition into their adult form. We also discuss potential mechanisms that might regulate proper establishment of the adult NSC pool, and propose future directions of research that will be key to unraveling how NSCs transform to establish the adult NSC pool in the mammalian brain.

Draxin belongs to the family of inhibitory axon-guiding factors that regulate neuronal migration and axonal spreading in the developing brain. This glycoprotein has recently been considered to play an important role both in hippocampal differentiation and adult neurogenesis in the dentate gyrus. Given that it has been reported that antipsychotic drugs may affect neurite growth and neurogenesis, we have therefore investigated whether chronic treatment with olanzapine modulates draxin immunoreactivity in the adult rat hippocampus. After analysis of local fluorescence intensity, we found a significant increase of draxin immunoexpression both in the subgranular zone (SGZ) and granular zone of the rat hippocampus following long-term olanzapine administration. This study reveals, for the first time, the modulatory effect of the atypical antipsychotic medication olanzapine on expression of the novel chemorepulsive protein draxin in the context of adult neurogenesis regulation. Moreover, this is the first report dealing with pharmacological aspects of draxin signaling. An elevated draxin expression may indirectly support a recently formulated hypothesis that olanzapine may drive adult neurogenesis via paracrine draxin-related signaling. This action of draxin is a new element in the neurogenesis mechanism that may be part of the action of second-generation antipsychotics in the treatment of schizophrenia, indicating more detailed molecular studies are urgently required to fully investigate these potential novel mechanisms of neurogenesis.

Adult neurogenesis is a highly regulated process during which new neurons are generated from neural stem cells in two discrete regions of the adult brain: the subventricular zone of the lateral ventricle and the subgranular zone of the dentate gyrus in the hippocampus. Defects of adult hippocampal neurogenesis have been linked to cognitive decline and dysfunction during natural aging and in neurodegenerative diseases, as well as psychological stress-induced mood disorders. Understanding the mechanisms and pathways that regulate adult neurogenesis is crucial to improving preventative measures and therapies for these conditions. Accumulating evidence shows that mitochondria directly regulate various steps and phases of adult neurogenesis. This review summarizes recent findings on how mitochondrial metabolism, dynamics, and reactive oxygen species control several aspects of adult neural stem cell function and their differentiation to newborn neurons. It also discusses the importance of autophagy for adult neurogenesis, and how mitochondrial and autophagic dysfunction may contribute to cognitive defects and stress-induced mood disorders by compromising adult neurogenesis. Finally, I suggest possible ways to target mitochondrial function as a strategy for stem cell-based interventions and treatments for cognitive and mood disorders.

We studied cell proliferation in the postnatal mouse brain between the ages of 2 and 30 months and identified four compartments with different densities of proliferating cells. The first identified compartment corresponds to the postnatal pallial neurogenic (PPN) zone in the telencephalon, the second to the subpallial postnatal neurogenic (SPPN) zone in the telencephalon, the third to the white matter bundles in the telencephalon, and the fourth to all brain parts outside of the other three compartments. We estimated that about 3.4 million new cells, including 0.8 million in the subgranular zone (SGZ) in the hippocampus, are produced in the PPN zone. About 21 million new cells, including 10 million in the subependymal zone (SEZ) in the lateral walls of the lateral ventricle and 2.7 million in the rostral migratory stream (RMS), are produced in the SPPN zone. The third and fourth compartments together produced about 31 million new cells. The analysis of cell proliferation in neurogenic zones shows that postnatal neurogenesis is the direct continuation of developmental neurogenesis in the telencephalon and that adult neurogenesis has characteristics of the late developmental process. As a developmental process, adult neurogenesis supports only compensatory regeneration, which is very inefficient.

The endocannabinoid system modulates adult hippocampal neurogenesis by promoting the proliferation and survival of neural stem and progenitor cells (NSPCs). Specifically, deleting cannabinoid receptors on NSPCs or the constitutive deletion of the endocannabinoid 2-arachidonoylglycerol (2-AG) producing enzyme diacylglycerol lipase alpha (DAGLa) disrupts adult neurogenesis. However, it is not known which cells are the producers of 2-AG relevant to neurogenesis. In this paper, we investigated the cellular source of endocannabinoids in the subgranular zone (SGZ) of the hippocampus, an important neurogenic niche. For this purpose, we used two complementary Cre-deleter mouse strains to delete DAGLa either in neurons or astroglia and NSPCs. Surprisingly, neurogenesis was not altered in mice with a deletion of Dagla in neurons (Syn-Dagla KO), although they are the main source for the endocannabinoids in the brain. In contrast, mice with a specific inducible deletion of Dagla in NPSCs and astrocytes (GLAST-CreERT2-Dagla KO) showed a strongly impaired neurogenesis with significantly reduced proliferation and survival of newborn cells. These results identify Dagla in NSPCs in the SGZ of dentate gyrus or in astrocytes, as the cellular source for 2-AG in adult hippocampal neurogenesis. In summary, 2-AG produced by progenitor cells or astrocytes in the SGZ regulates adult hippocampal neurogenesis.SummaryDAGLa in neuronal progenitor cells in the SGZ of dentate gyrus is identified as the cellular source for 2-AG in adult hippocampal neurogenesis.

Mild traumatic brain injuries (mTBIs) are prevalent worldwide. mTBIs can impair hippocampal-based functions such as memory and cause network hyperexcitability of the dentate gyrus (DG), a key entry point to hippocampal circuitry. One candidate for mediating mTBI-induced hippocampal cognitive and physiological dysfunction is injury-induced changes in the process of DG neurogenesis. There are conflicting results on how TBI impacts the process of DG neurogenesis; this is not surprising given that both the neurogenesis process and the post-injury period are dynamic, and that the quantification of neurogenesis varies widely in the literature. Even within the minority of TBI studies focusing specifically on mild injuries, there is disagreement about if and how mTBI changes the process of DG neurogenesis. Here we utilized a clinically-relevant rodent model of mTBI (lateral fluid percussion injury, LFPI), gold-standard markers and quantification of the neurogenesis process, and three time points post-injury to generate a comprehensive picture of how mTBI affects adult hippocampal DG neurogenesis. Male C57BL/6J mice (6-8 weeks old) received either sham surgery or mTBI via LFPI. Proliferating cells, neuroblasts/immature neurons, and surviving cells were quantified via stereology in DG subregions (subgranular zone [SGZ], outer granule cell layer [oGCL], molecular layer, and hilus) at short-term (3 days post-injury, dpi), intermediate (7 dpi), and long-term (31 dpi) time points. The data suggest this model of mTBI induces transient, sequential increases in ipsilateral SGZ/GCL proliferating cells, neuroblasts/immature neurons, and surviving cells which are suggestive of mTBI-induced neurogenesis. In contrast to these ipsilateral hemisphere findings, measures in the contralateral hemisphere were not increased in key neurogenic DG subregions after LFPI. Our work in this mTBI model is in line with most literature on other and more severe models of TBI in showing TBI stimulates the process of DG neurogenesis. However, as our DG data in mTBI provide temporal, subregional, and neurogenesis-stage resolution, these data are important to consider in regard to the functional importance of TBI-induction of the neurogenesis process and future work assessing the potential of replacing and/or repairing DG neurons in the brain after TBI.

Significance Generation of new neurons occurs normally in the adult brain in two locations: the subventricular zone (SVZ) in the walls of the lateral ventricles and the subgranular zone (SGZ) in the dentate gyrus (DG) of the hippocampus. Neurogenesis in the adult hippocampus has been implicated in cognitive functions such as learning, memory, and recovery of stress response. Imprinted genes are highly prevalent in the brain and have adult and developmental important functions. Genetic deletion of the imprinted gene Dlk1 from either parental allele shows that DLK1 is a key mediator of quiescence in adult hippocampal NSCs. Additionally, Dlk1 is exquisitely dosage sensitive in the brain with perturbations in levels resulting in impaired NSCs function and cognitive phenotypes., Neurogenesis in the adult brain gives rise to functional neurons, which integrate into neuronal circuits and modulate neural plasticity. Sustained neurogenesis throughout life occurs in the subgranular zone (SGZ) of the dentate gyrus in the hippocampus and is hypothesized to be involved in behavioral/cognitive processes such as memory and in diseases. Genomic imprinting is of critical importance to brain development and normal behavior, and exemplifies how epigenetic states regulate genome function and gene dosage. While most genes are expressed from both alleles, imprinted genes are usually expressed from either the maternally or the paternally inherited chromosome. Here, we show that in contrast to its canonical imprinting in nonneurogenic regions, Delta-like homolog 1 (Dlk1) is expressed biallelically in the SGZ, and both parental alleles are required for stem cell behavior and normal adult neurogenesis in the hippocampus. To evaluate the effects of maternally, paternally, and biallelically inherited mutations within the Dlk1 gene in specific behavioral domains, we subjected Dlk1-mutant mice to a battery of tests that dissociate and evaluate the effects of Dlk1 dosage on spatial learning ability and on anxiety traits. Importantly, reduction in Dlk1 levels triggers specific cognitive abnormalities that affect aspects of discriminating differences in environmental stimuli, emphasizing the importance of selective absence of imprinting in this neurogenic niche.

Adult hippocampal neurogenesis is implicated in antidepressant action in rodents and primates, yet relationships to human major depression (MDD) and antidepressant effects are unclear. In postmortem human hippocampus, we found doublecortin (DCX) protein and mRNA+ cells co-expressing neuronal but not astroglial or microglial markers. We defined neuroblasts as DCX+ cells located in the subgranular zone that co-expressed neuron-specific beta-tubulin (TUJ1) or lacked co-expression with neuronal nuclear marker (NeuN). Untreated MDD, regardless of clinical state, had fewer DCX-positive cells and neuroblasts in the rostral dentate gyrus compared with non-psychiatric controls. High-functioning, but not low-functioning, antidepressant-treated MDD, exhibited more DCX/TUJ1+ neuroblasts than untreated MDD. Groups did not differ in number of immature neurons, defined as DCX/NeuN+ cells in the inner granule cell layer. Deficient neuroblasts may be linked to hippocampal-dependent cognitive deficits in MDD. Similar neuroblast number between controls and higher-functioning antidepressant treated subjects warrants evaluation of neuroblasts as a treatment target.

Thyroid hormone (TH) signaling, a highly conserved pathway across vertebrates, is crucial for brain development and function throughout life. In the adult mammalian brain, including that of humans, multipotent neural stem cells (NSCs) proliferate and generate neuronal and glial progenitors. The role of TH has been intensively investigated in the two main neurogenic niches of the adult mouse brain, the subventricular and the subgranular zone. A key finding is that T3, the biologically active form of THs, promotes NSC commitment toward a neuronal fate. In this review, we first discuss the roles of THs in the regulation of adult rodent neurogenesis, as well as how it relates to functional behavior, notably olfaction and cognition. Most research uncovering these roles of TH in adult neurogenesis was conducted in rodents, whose genetic background, brain structure and rate of neurogenesis are considerably different from that of humans. To bridge the phylogenetic gap, we also explore the similarities and divergences of TH-dependent adult neurogenesis in non-human primate models. Lastly, we examine how photoperiodic length changes TH homeostasis, and how that might affect adult neurogenesis in seasonal species to increase fitness. Several aspects by which TH acts on adult NSCs seem to be conserved among mammals, while we only start to uncover the molecular pathways, as well as how other in- and extrinsic factors are intertwined. A multispecies approach delivering more insights in the matter will pave the way for novel NSC-based therapies to combat neurological disorders.

Chronic psychological stress is one of the most important triggers and environmental risk factors for neuropsychiatric disorders. Chronic stress can influence all organs via the secretion of stress hormones, including glucocorticoids by the adrenal glands, which coordinate the stress response across the body. In the brain, glucocorticoid receptors (GR) are expressed by various cell types including microglia, which are its resident immune cells regulating stress-induced inflammatory processes. To study the roles of microglial GR under normal homeostatic conditions and following chronic stress, we generated a mouse model in which the GR gene is depleted in microglia specifically at adulthood to prevent developmental confounds. We first confirmed that microglia were depleted in GR in our model in males and females among the cingulate cortex and the hippocampus, both stress-sensitive brain regions. Then, cohorts of microglial-GR depleted and wild-type (WT) adult female mice were housed for 3 weeks in a standard or stressful condition, using a chronic unpredictable mild stress (CUMS) paradigm. CUMS induced stress-related behavior in both microglial-GR depleted and WT animals as demonstrated by a decrease of both saccharine preference and progressive ratio breakpoint. Nevertheless, the hippocampal microglial and neural mechanisms underlying the adaptation to stress occurred differently between the two genotypes. Upon CUMS exposure, microglial morphology was altered in the WT controls, without any apparent effect in microglial-GR depleted mice. Furthermore, in the standard environment condition, GR depleted-microglia showed increased expression of pro-inflammatory genes, and genes involved in microglial homeostatic functions (such as Trem2, Cx3cr1 and Mertk). On the contrary, in CUMS condition, GR depleted-microglia showed reduced expression levels of pro-inflammatory genes and increased neuroprotective as well as anti-inflammatory genes compared to WT-microglia. Moreover, in microglial-GR depleted mice, but not in WT mice, CUMS led to a significant reduction of CA1 long-term potentiation and paired-pulse ratio. Lastly, differences in adult hippocampal neurogenesis were observed between the genotypes during normal homeostatic conditions, with microglial-GR deficiency increasing the formation of newborn neurons in the dentate gyrus subgranular zone independently from stress exposure. Together, these findings indicate that, although the deletion of microglial GR did not prevent the animal's ability to respond to stress, it contributed to modulating hippocampal functions in both standard and stressful conditions, notably by shaping the microglial response to chronic stress.

Neural stem cells (NSCs) of the central nervous system (CNS) follow a precisely timed sequence of neurogenesis and gliogenesis, before they generally vanish after birth. In the adult CNS residual NSCs can be detected in two neurogenic regions, the subependymal zone (SEZ) of the lateral ventricle and the subgranular zone (SGZ) in the dentate gyrus of the hippocampus. These regions present favorable environments for stem cells and are considered privileged niches for their persistence and differentiation. Niches comprise the stem cells, their progeny, specialized niche cells, and a specialized extracellular matrix (ECM) environment. Morphogens, cytokines, hormones, and glycoproteins contribute to a rich microenvironment that guides self-renewal and/or differentiation of stem cells. It has become evident that a subclass of ECM constituents is of particular importance for the structure and function of the stem cell niche, the proteoglycans (PGs). PGs can embody a considerable structural variability and intervene in many important cellular functions such as cell proliferation, migration, and differentiation. A better understanding of niche PGs and their regulatory roles will be valuable for the design of artificial growth support of stem cells. This chapter discusses recent insights into the composition and functions of PGs in the microenvironment of NSCs.

Neurogenesis is maintained in the mammalian brain throughout adulthood in two main regions: the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the hippocampal dentate gyrus. Adult neurogenesis is a process composed of multiple steps by which neurons are generated from dividing adult neural stem cells and migrate to be integrated into existing neuronal circuits. Alterations in any of these steps impair neurogenesis and may compromise brain function, leading to cognitive impairment and neurodegenerative diseases. Therefore, understanding the cellular and molecular mechanisms that modulate adult neurogenesis is the centre of attention of regenerative research. In this chapter, we review the main properties of the adult neurogenic niches.

Background. Valproic acid (anticonvulsant medication) has been found to inhibit histone deacetylase activity and suppress hippocampal neurogenesis, which causes memory impairment in both humans and rodents. The neurohormone melatonin, which regulates mammalian seasonal and circadian physiology, has recently been shown to have neuroprotective properties, counteracting memory impairment associated with VPA-caused hippocampal neurogenesis reduction. This study is aimed at investigating the molecular mechanisms of melatonin associated with VPA-induced hippocampal neurogenesis and memory impairment. Methods. Male Spraque-Dawley rats received VPA (300 mg/kg) twice daily or melatonin (8 mg/kg/day) or some rats were given melatonin for 14 days during VPA administration. Results. The VPA-treated rats showed a significant increase in malondialdehyde (MDA) levels in the hippocampus and p21-positive cells in the subgranular zone (SGZ) of the dentate gyrus (DG) but decreased superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx) activities. Moreover, VPA significantly decreased levels of nestin, Notchl, nuclear factor erythroid 2-related factor 2 (Nrf2), doublecortin (DCX), sex determining region Y-box 2 (SOX2), and brain-derived neurotrophic factor (BDNF). Conclusions. We found that melatonin was able to counteract these neurotoxic effects, acting as a neuroprotectant in VPA-induced memory hippocampal neurogenesis impairment by preventing intracellular oxidative stress and increasing antioxidant activity.

Cell survival during adult neurogenesis and the modulation of each step, namely, proliferation, lineage differentiation, migration, maturation, and functional integration of the newborn cells into the existing circuitry, is regulated by intrinsic and extrinsic factors. Transduction of extracellular niche signals triggers the activation of intracellular mechanisms that regulate adult neurogenesis by affecting gene expression. While the intrinsic factors include transcription factors and epigenetic regulators, the extrinsic factors are molecular signals that are present in the neurogenic niche microenvironment. These include morphogens, growth factors, neurotransmitters, and signaling molecules secreted as soluble factors or associated to the extracellular matrix. Among these molecular mechanisms are neurotrophins and neurotrophin receptors which have been implicated in the regulation of adult neurogenesis at different levels, with brain-derived neurotrophic factor (BDNF) being the most studied neurotrophin. In this chapter, we review the current knowledge about the role of neurotrophins in the regulation of adult neurogenesis in both the subventricular zone (SVZ) and the hippocampal subgranular zone (SGZ).

Brain organoids are in vitro three-dimensional (3D) self-organized neural structures, which promise to become relevant tools for disease modelling and drug screening. High-throughput drug screening assess a large amount of compounds using reliable and fast procedures. Organoids obtained from human induced pluripotent stem cells have high batch-to-batch variability, long differentiation time (10-20 weeks), and high cost required for production, thus limiting their use for standardized large-scale drug screening studies. Here, we developed, for the first time, a highly standardized, reproducible and fast (5 weeks) murine brain organoid model starting from multipotent neural stem cells (NSCs) isolated from embryonic subgranular zone (SGZ). Global transcriptome, protein expression, and cell metabolism data show that murine brain organoids progressively differentiate trough defined early, intermediate, and mature stages. During differentiation, brain organoids acquire a self-organized neural structure with a compact and interconnected neuronal layer at its edge. We measured neuronal activity on whole-brain organoids by combining electrophysiological techniques (patch-clamp and MEA recordings), transsynaptic tracing and calcium imaging analysis, and we found that, in less than 5 weeks of in vitro culture, these organoids own functional neurons organized in 3D networks with synaptic connections. Furthermore, we validated the potential of murine brain organoids to acquire a specific brain-region signature; by adding the morphogen WNT3a, we were able to generate brain organoids enriched in neurons with CA3 hippocampal region signature. Overall, our results showed the establishment of a novel fast, robust and reproducible murine 3D in vitro brain model that may represent a useful tool for high-throughput drug screening and disease modelling.

The adult brain harbors specific niches where stem cells undergo substantial plasticity and, in some regions, generate new neurons throughout life. This phenomenon is well known in the subventricular zone of the lateral ventricles and the subgranular zone of the hippocampus and has recently also been described in the hypothalamus of several rodent and primate species. After a brief overview of preclinical studies illustrating the pathophysiologic significance of hypothalamic neurogenesis in the control of energy metabolism, reproduction, thermoregulation, sleep, and aging, we review current literature on the neurogenic niche of the human hypothalamus. A comparison of the organization of the niche between humans and rodents highlights some common features, but also substantial differences, e.g., in the distribution and extent of the hypothalamic neural stem cells. Exploring the full dynamics of hypothalamic neurogenesis in humans raises a formidable challenge however, given among others, inherent technical limitations. We close with discussing possible functional role(s) of the human hypothalamic niche, and how gaining more insights into this form of plasticity could be relevant for a better understanding of pathologies associated with disturbed hypothalamic function.

Graphical abstract The dentate gyrus (DG) in rodent hippocampus is a site of neurogenesis. Newly developing neurons can be identified through immunostaining for doublecortin (DCX). We have found that genetic inactivation of the kinase activity of MSK1 (in red) results in an increase in the number of DCX-positive (DCX+) cells. This suggests that MSK1 negatively regulates neurogenesis in the subgranular zone, potentially to limit the number of new neurons in the dentate gyrus and maintain the stability of neuronal networks., Highlights • Neurogenesis in the subgranular zone of the hippocampal dentate gyrus was examined. • Ki-67 staining was not affected by the loss of MSK1 kinase activity. • DCX staining was increased in the MSK1 kinase dead mutant mouse. • MSK1 may negatively regulate neurogenesis to maintain stable neuronal networks., Neurogenesis in the subgranular zone (SGZ) of the adult hippocampus can be stimulated by a variety of means, including via exposure of experimental animals to an enriched environment that provides additional sensory, social, and motor stimulation. Tangible health and cognitive benefits accrue in enriched animals, including the amelioration of signs modelling psychiatric, neurological and neurodegenerative conditions that affect humans, which may in part be due to enhanced production of neurons. A key factor in the neuronal response to enrichment is the release of brain-derived neurotrophic factor (BDNF) and the activation of the Mitogen-Activated Protein Kinase (MAPK) cascade, which can lead to the stimulation of neurogenesis. Mitogen- and Stress-Activated protein Kinase 1 (MSK1) is a nuclear enzyme downstream of BDNF and MAPK that regulates transcription. MSK1 has previously been implicated in both basal and stimulated neurogenesis on the basis of studies with mice lacking MSK1 protein. In the present study, using mice in which only the kinase activity of MSK1 is lacking, we show that the rate of cellular proliferation in the SGZ (Ki-67 staining) is unaffected by the MSK1 kinase-dead (KD) mutation, and no different from controls levels after five weeks of enrichment. However, compared to wild-type mice, the number of doublecortin (DCX)-positive cells was greater in both standard-housed and enriched MSK1 KD mice. These observations suggest that, while MSK1 does not influence the basal rate of proliferation of neuronal precursors, MSK1 negatively regulates the number of cells destined to become neurons, potentially as a homeostatic control on the number of new neurons integrating into the dentate gyrus.

Glyphosate, the most used herbicide worldwide, has been suggested to induce neurotoxicity and behavioral changes in rats after developmental exposure. Studies of human glyphosate intoxication have reported adverse effects on the nervous system, particularly in substantia nigra (SN). Here we used matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry (IMS) to study persistent changes in peptide expression in the substantia nigra (SN) of 90-day-old adult male Wistar rats. The animals were perinatally exposed to 3% GBH (glyphosate-based herbicide) in drinking water (corresponding to 0.36% of glyphosate) starting at gestational day 5 and continued up to postnatal day 15 (PND15). Peptides are present in the central nervous system before birth and play a critical role in the development and survival of neurons, therefore, observed neuropeptide changes could provide better understanding of the GBH-induced long term effects on SN. The results revealed 188 significantly altered mass peaks in SN of animals perinatally exposed to GBH. A significant reduction of the peak intensity (P < 0.05) of several peptides from the opioid-related dynorphin family such as dynorphin B (57%), alpha-neoendorphin (50%), and its endogenous metabolite des-tyrosine alpha-neoendorphin (39%) was detected in the GBH group. Immunohistochemical analysis confirmed a decreased dynorphin expression and showed a reduction of the total area of dynorphin immunoreactive fibers in the SN of the GBH group. In addition, a small reduction of dynorphin immunoreactivity associated with non-neuronal cells was seen in the hilus of the hippocampal dentate gyrus. Perinatal exposure to GBH also induced an increase in the number of nestin-positive cells in the subgranular zone of the dentate gyrus. In conclusion, the results demonstrate long-term changes in the adult male rat SN and hippocampus following a perinatal GBH exposure suggesting that this glyphosate-based formulation may perturb critical developmental neuronal processes.

The adult brain retains endogenous neural stem/precursors cells (eNPCs) in two major neurogenic niches, the subgranular zone (SGZ) in the hippocampus and the subventricular zone (SVZ). While in humans and rodents the SGZ contributes to memory functions by generating new neurons that integrate into hippocampal circuitry, the role of eNPCs of the SVZ is less clear. SVZ-eNPCs contribute to the generation of new neurons fated to the olfactory bulb (OB) in rodents but not in humans where they are thought to contribute to striatal neurogenesis as a result of tissue damage.Here, we show in mice and humans a novel non-neurogenic physiological role of adult SVZ-eNPCs in supporting cognitive functions by regulating striatal neuronal activity. We first provide evidence that GABAergic transmission between parvalbumin-expressing fast-spiking interneurons (FSIs) and medium spiny neurons (MSNs) is tuned by SVZ-eNPCs via secretion of Insulin-Like Growth Factor Binding Protein Like 1 (IGFBPL-1) that, in turn, regulates the Insulin-Like Growth Factor (IGF-1) signalling cascade. Consistently, selective ablation of SVZ-eNPCs and in vivo disruption of the IGF-signalling determine the impairment of intrastriatal coherence. A finding associated with a higher failure rate of GABAergic transmission mediated by FSIs and with striatum-related behavioural dysfunctions impairing decision making. Human validation studies revealed IGFBPL-1 expression in the SVZ and in foetal and induced-pluripotent stem cell-derived NPCs as well as a strong correlation in neurological patients between SVZ pathological damage, reduction of striatum volume and impairment of information processing speed.All in all, our results highlight a novel non-neurogenic homeostatic role exerted by SVZ-eNPCs on striatal GABAergic neurons that might contribute to cognitive processes involving decisions-making tasks.

The continuous generation of new neurons occurs in at least two well-defined niches in the adult rodent brain. One of these areas is the subgranular zone of the dentate gyrus (DG) in the hippocampus. While the DG is associated with contextual and spatial learning and memory, hippocampal neurogenesis is necessary for pattern separation. Hippocampal neurogenesis begins with the activation of neural stem cells and culminates with the maturation and functional integration of a portion of the newly generated glutamatergic neurons into the hippocampal circuits. The neurogenic process is continuously modulated by intrinsic factors, one of which is neuroinflammation. The administration of lipopolysaccharide (LPS) has been widely used as a model of neuroinflammation and has yielded a body of evidence for unveiling the detrimental impact of inflammation upon the neurogenic process. This work aims to provide a comprehensive overview of the current knowledge on the effects of the systemic and central administration of LPS upon the different stages of neurogenesis and discuss their effects at the molecular, cellular, and behavioral levels.

Aim: Adult neurogenesis occurs in two major niches in the brain: the subgranular zone of the hippocampal formation and the ventricular-subventricular zone. Neurogenesis in both niches is reduced in ageing and neurological disease involving dementia. Exercise can rescue memory by enhancing hippocampal neurogenesis, but whether exercise affects adult neurogenesis in the ventricular-subventricular zone remains unresolved. Previously, we reported that exercise induces angiogenesis through activation of the lactate receptor HCA1. The aim of the present study is to investigate HCA1-dependent effects on neurogenesis in the two main neurogenic niches. Methods: Wild-type and HCA1 knock-out mice received high intensity interval exercise, subcutaneous injections of L-lactate, or saline injections, five days per week for seven weeks. Well-established markers for proliferating cells (Ki-67) and immature neurons (doublecortin), were used to investigate neurogenesis in the subgranular zone and the ventricular-subventricular zone. Results: We demonstrated that neurogenesis in the ventricular-subventricular zone is enhanced by HCA1 activation: Treatment with exercise or lactate resulted in increased neurogenesis in wild-type, but not in HCA1 knock-out mice. In the subgranular zone, neurogenesis was induced by exercise in both genotypes, but unaffected by lactate treatment. Conclusion: Our study demonstrates that neurogenesis in the two main neurogenic niches in the brain is regulated differently: Neurogenesis in both niches was induced by exercise, but only in the ventricular-subventricular zone was neurogenesis induced by lactate through HCA1 activation. This opens for a role of HCA1 in the physiological control of neurogenesis, and potentially in counteracting age-related cognitive decline.

In animal models with temporal lobe epilepsy (TLE), the status epilepticus (SE) leads to a dramatic increase in number of newly born neuron in the subgranular zone (SGZ) of dentate gyrus. How the SE confers a modulation in the dentate neurogenesis is mostly unknown. Gadd45b is involved in epigenetic gene activation by DNA demethylation. This study was performed to present a novel mechanism underling SE-induced dentate neurogenesis. A transient induction (12 hrs to 3 days) of Gadd45b was observed in dentate gyrus of mice after pilocarpine-induced SE. Labeling the dividing cells with BrdU, we next found that the induction of Gadd45b was required to increase the rate of cell proliferation in the dentate gyrus at 7 and 14 days after SE. Afterward, the DNA methylation levels for candidate growth factor genes critical for the adult neurogenesis were assayed with Sequenom MassARRAY Analyzer. The results indicated that Gadd45b was necessary for SE-induced DNA demethylation of specific promoters and expression of corresponding genes in the dentate gyrus, including brain-derived neurotrophic factor (BDNF) and fibroblast growth factor-2 (FGF-2). Using Timm staining, we further suggested that SE-induced Gadd45b might contribute to the subsequent mossy fiber sprouting (MFS) in the chronically epileptic hippocampus via epigenetic regulation of dentate neurogenesis at early stage after SE. Together, Gadd45b links pilocarpine-induced SE to epigenetic DNA modification of secreted factors in the dentate gyrus, leading to extrinsic modulation on the neurogenesis.