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EN
Memory is a process that encompasses three basic elements: encoding, consolidation and retrieval. The concept of multiple memory systems is now widely accepted. The question concerning the contribution of new neurons to learning has been recognized for a long time. There are also numerous associations between neurogenesis and learning. Experience-related changes that affect neurogenesis, such as stress or environmental enrichment, also affect learning. This paper also presents some methods of improving memory.
EN
The main aim of the paper is to show that many previously forgotten discoveries within the field of neuroscience own their rediscovery and renaissance to the refinement of tools provided by the technological advances. Most spectacular is the advancement of brain imaging techniques, which provide hard data that support for evidence for previously neglected presumptions and ideas. Neuroplasticity is an example of such a long ignored historical discovery. One reason for that neglect is that it stood in contradiction to beliefs and theories prevailing at the first half of the twenties century. The idea of neuronal plasticity is not disputed any longer since it has found confirmation not only in a dramatic development of neuroimaging but also in the advancement of neurobiology. Most authors concentrate upon neuronal plasticity, recent studies, however, have produced a wealth of information regarding neurogenesis, in which astrocytes have proved to play a significant role. The significance of adult neurogenesis for learning and memory and for treatment of depression is outlined. Moreover, it was observed that neuroplasticity benefits patients suffering from obsessive-compulsive disorder (OCD) who undergo effective, evidence-based treatment. Convincing examples of brain plasticity brings also clinical practice, which often unveils the appearance of hitherto hidden artistic abilities in people who have suffered from brain damage. In addition, the possibilities of altering the brain functions by mental force alone are discussed. Thus, the paper reveals that many “controversial” ideas were confirmed by contemporary studies forcing changes in a traditional view on brain works.
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We study the mechanisms of neurogenesis in order to implement them for neuronal repair. I will present unpublished work about the molecular function of Trnp1, a novel nuclear protein, with key roles in promoting neural stem cell self‑renewal and neurogenesis. Trnp1 shows unprecedented functions in regulating several nuclear processes by its N-terminal intrinsically disordered region, which is highly conserved in mammals. I will then show that Trnp1 is also critical for direct neuronal reprogramming and provide an update on the recent breakthrough in direct glia-to-neuron conversion after brain injury. I will then move on to discuss the integration of replaced neurons into the circuitry of the murine cerebral cortex – that normally does not integrate new neurons at adult stages – and present unpublished data about the mechanisms regulating this integration. Taken together, our knowledge about basic mechanisms of neurogenesis allows us to make great strides towards neuronal repair.
EN
Deep brain stimulation (DBS) is a neuromodulation method that modulates neuronal activity. A trend in the treatment of Alzheimer’s disease (AD) is targeting key points of neural circuits with DBS. Here, we explored the effects of DBS targeted to the entorhinal cortex (EC) on neurons in the hippocampal CA1 in a mouse model of preclinical AD. Specifically, we recorded field potential signals from CA1 in preclinical AD mice after DBS of the EC (1 h/day for 21 days of 100 lA, 90 ls, 10 Hz, biphasic square wave pulse) with in-vivo electrophysiology and evaluated corresponding changes in behavior with the open field task and Morris water maze (MWM) task. We also assessed changes in pathological markers and neurogenesis in the hippocampus with immunohistological staining. DBS of the EC increased theta and gamma power and modulated theta in the high gamma band (50-100 Hz) in preclinical AD mice. After DBS of the EC, these mice performed better in the MWM task and exhibited reduced deposition of beta-amyloid and neuronal changes including significant increases in proliferating neurons and immature neurons. This is the first study to target the EC with DBS and analyze resulting neural oscillations in the hippocampal CA1 in a model of preclinical AD. The findings support the use of DBS as a potential treatment for AD.
EN
Genomic imprinting is a normal process causing genes to be expressed from only one of the two parental chromosome homologues according to their parental origin. Imprinted genes function in a range of developmental processes. In recent years, data has emerged indicating discordance of imprinting between mouse and man, polymorphic imprinting between different individuals and tissue-specific imprinting within individuals. This suggests that imprinting might be an adaptable and dynamic process with the potential to act as a mechanism regulating gene dosage in different developmental contexts. Delta-like homologue 1 (Dlk1) is a paternally expressed imprinted gene that encodes both a transmembrane protein and a secreted isoform generated by alternative splicing, and is an atypical member of the Notch/Delta/Serrate family of developmental signalling molecules. Although widely expressed during embryonic development, only a few tissues including neurogenic regions of the brain retain Dlk1 expression in adults. Analysis of neurogenesis in the SVZ of Dlk1 mutant mice shows a reduction in the numbers of stem cells in vivo and an impairment of newborn neurons incorporated into the olfactory bulb as well as fewer primary neurospheres in vitro suggesting that normal levels of Dlk1 are necessary for the life-long maintenance of neural stem cells (NSCs). Within the SVZ, DLK1 is a niche factor secreted by astrocytes and that membrane-bound DLK1 is required in NSCs to respond to it. In contrast to the neighbouring Gtl2 gene, we observe specific absence of Dlk1 imprinting in the stem cell and astrocyte populations in the SVZ niche indicating that the mechanism conferring biallelic expression can override the imprint selectively at Dlk1 to control normal neurogenesis in the adult brain. This neurogenic requirement for both the maternally and paternally expressed alleles of the canonically imprinted Dlk1 gene supports the hypothesis that control of gene dosage by absence of imprinting is an important developmental process. We are testing the hypothesis that other imprinted genes important in neurogenesis may also modulate imprinting to control gene dosage.
EN
Until the second half of the twentieth century there was a view that central nervous system, after its evolution, was unable to any further regeneration. Moreover, it was said that neurogenesis (the development of nerve tissues) of an adult (postnatal) did not exist. However, in the course of time, some findings indicated that the process of new neurons was continuously formed in mature brains of primates as well as human beings. A breakthrough discovery of active, proliferating neural stem cells existing in a fully developed brain has given grave possibilities to modern neuroscience. The process of neurogenesis among adults is an extraordinary phenomenon. It plays an important role in a few processes. There is also evidence that neurogenesis may help answer the hippocampus to stress and prevent any onset of depression. Nowadays, it is identified to be three areas in the adult mammalian brain where processes of cell proliferation take place. These areas are: subventricular zone (SVZ), subgranular zone (SGZ) and posterior periventricular area (PPv). By excessive formating new tissues circulatory system is the opposite to the nervous system. Although the latter is the complex biological system with its cytostructure, neural network, the location of the functional centers and its integration it has a poor ability to regeneration. Because of the complexity of the central nervous system a few disorders can be distinguished such as: multiple sclerosis, ischemic stroke, Alzheimer’s disease, Parkinson’s disease or brain tumors. At present stem cells are matters of interest to scientists. Not only are stem cells being observed by researchers but also they are to be conducted studies on. The end result of these findings could be primarily usable for CNS regenerative therapies.
PL
Do drugiej połowy XX wieku panował pogląd, że po okresie rozwoju ośrodkowy układ nerwowy pozbawiony jest jakiejkolwiek zdolności regeneracyjnej, a neurogeneza (neurogenesis, „narodziny neuronów”) wieku dorosłego (postnatalnego) z całą pewnością nie istnieje. Odkrycie w dojrzałym mózgu aktywnych proliferacyjnie nerwowych komórek macierzystych (neural stem cells, NSCs) otworzyło nowe możliwości między innymi dla neurologii. Proces neurogenezy osób dorosłych jest unikatowym zjawiskiem i odgrywa znaczącą rolę w różnych procesach. Wiele obserwacji wskazuje także na to, że proces neurogenezy może wspomagać odpowiedź formacji hipokampa na stres i zapobiegać między innymi wystąpieniu depresji. W chwili obecnej w mózgu dorosłych ssaków zidentyfikowano trzy obszary, gdzie mają miejsce procesy proliferacji komórkowej. Są to: strefa przykomorowa (subventricular zone, SVZ), strefa przyziarnista (subgranular zone, SGZ) oraz tylna strefa okołokomorowa (posterior periventricular area, PPv). Tkanką podlegającą bardzo sprawnej regeneracji jest układ krwionośny. Jest to przeciwieństwo układu nerwowego, który przez to, że jest bardzo skomplikowanym systemem biologicznym pod względem cytoarchitektury, sieci neuronalnej, lokalizacji ośrodków funkcjonalnych oraz integracji, posiada słabą zdolność do regeneracji. Zaburzenia tak złożonego systemu są widoczne w takich schorzeniach ośrodkowego układu nerwowego, jak: stwardnienie rozsiane, udar niedokrwienny mózgu, choroba Alzheimera, choroba Parkinsona, stwardnienie zanikowe boczne czy guzy mózgu. Naukowcy nie poprzestali na identyfikacji komórek macierzystych w mózgu, prowadzonych jest obecnie wiele badań poświęconych potencjalnemu wykorzystaniu komórek macierzystych o różnym pochodzeniu w nowych terapiach regeneracyjnych chorób ośrodkowego układu nerwowego.
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Content available Komórki macierzyste w neurologii
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EN
Human brain is a very complex biological system considering its cytoarchitecture, neuronal network, localisation of functional regions and integration. Until second half of the XX century it was believed that CNS is deprived of regenerative processes. At present there are many studies that confirm constant formation of new neurones in the human brain. However, this process of cell exchange is far less effective in comparison with the regeneration and functional renewal of other tissues of our organism. In the following article we present current data on local neurogenesis in the adult brain. There are at least 3 regions of CNS where cell proliferembrioation takes place: subventricular zone – SVZ, subgranular zone – SGZ and posterior periventricular area – PPv. It has been estimated that single radial glial cell, which is the progenitor of cells residing in the aforementioned regions of the brain, would be enough to form 4×107 of new brains. Other tissues of our organism could become another source of stem cells for brain regeneration. This solution is tempting when we consider a theory of peripheral blood stem cells that reside in different organ niches. Injured tissue produces higher amounts of chemokines such as SDF-1 or LIF that causes increased migration of stem cells towards the “calling- for-help” organ. The last part of the article presents the progress that has been made in regeneration therapies of certain neurological disorders: cerebral stroke, Parkinson’s disease, multiple sclerosis, spinal cord injuries, amyotrophic lateral sclerosis, Huntigton’s disease and Alzheimer’s disease.
PL
Mózg człowieka jest bardzo skomplikowanym biologicznym systemem pod względem cytoarchitektury, sieci neuronalnej, lokalizacji ośrodków funkcjonalnych oraz integracji. Do drugiej połowy XX wieku panował pogląd, że po okresie rozwoju OUN jest pozbawiony jakiejkolwiek zdolności regeneracyjnej. Istnieje obecnie wiele badań potwierdzających fakt, iż w dorosłym mózgu ludzi ma miejsce ciągły proces tworzenia się nowych neuronów, chociaż oczywiście proces wymiany komórek ośrodkowego układu nerwowego prezentuje się nie najlepiej w porównaniu z regeneracją i funkcjonalną odnową, które mają miejsce w innych organach naszego organizmu. W poniższym artykule przedstawione zostały aktualne dane dotyczące miejscowej neurogenezy w dojrzałym mózgu. W mózgu człowieka znajdują się przynajmniej 3 obszary, gdzie mają miejsce procesy proliferacji komórkowej: strefa przykomorowa (subventricularzone, SVZ), strefa przyziarnista (subgranularzone, SGZ), oraz tylna strefa okołokomorowa (posterior periventricular area, PPv). Wyliczono, że pojedyncza komórka gleju radialnego, której mitotyczni potomkowie rezydują w wymienionych strefach rozrodczych, wystarczyłaby do utworzenia 4x107 mózgów. Innym źródłem odnowy dla mózgu mogłyby stać się komórki macierzyste pozyskiwane z innych tkanek naszego organizmu. Takie rozwiązanie znajduje swoje uzasadnienie w ramach teorii o krążących w krwi obwodowej komórkach macierzystych zasiedlających poszczególne nisze narządowe. Znacznie upraszczając, uszkodzony narząd wydziela zwiększoną ilość chemoatraktantów, takich jak SDF-1 czy LIF, i tym przyciąga do siebie zwiększoną ilość komórek macierzystych. W dalszej części artykułu przedstawiono postęp, jaki dokonał się w terapiach regeneracyjnych w przypadku niektórych schorzeń neurologicznych: udaru mózgu, choroby Parkinsona, stwardnienia rozsianego, urazów rdzenia, stwardnienia zanikowego bocznego, choroby Huntingtona oraz choroby Alzheimera.
EN
The brain is a structure of great variability during the ontogenetic human life. In the first period of life, changes in its structure and activities are due to the processes of development and maturation. Then, due to the remarkable synaptic plasticity, individual brain centres adapt to the requirements of the environment in which the man lives, and his lifestyle. After the age of 40 years, apoptosis, the process of programmed cell death of neurons begins. In a state of disease, the process of necrosis or aponecrosis may cause additional destruction of neurons. The process of neurogenesis based on local or transplanted brain stem cells has a repairing effect in the damaged structures, but may be also associated with psychiatric and neurological diseases. Underlying processes of neuroprotection include antioxidant, anti-inflammatory, anti-apoptotic processes and antidestructive action of Ca. Phytotherapy based on compounds of plant origin has been found to have a supporting function in neuroprotection. In recent years, particular attention is paid to neuroprotective properties of pentacyclic triterpenes and their derivatives. The article presents neuroprotective properties of ursolic, oleanolic, maslinic, asiatic, betulinic, boswellic acid and triterpene saponins from Bupleurum and Panax ginseng. Ginseng saponins additionally increase neurogenesis in the brain. The possibility of using these triterpene compounds in the treatment of many neurological and psychiatric diseases has been suggested. However, it should be pointed out that the direction of their action may depend on the dosage, they may have a different effect on various types of neurons, and they can interact with other drugs used simultaneously. Most of the experiments using triterpenes were performed on animals or cell cultures. Further studies in humans are required to further determine triterpene effect in humans.
PL
Ludzki mózg to struktura wykazująca ogromną zmienność w ciągu życia osobniczego. W pierwszym okresie zmiany budowy i czynności spowodowane są procesami rozwoju i dojrzewania. Następnie, dzięki niezwykłej plastyczności synaptycznej, poszczególne ośrodki mózgu przystosowują się do wymagań środowiska, w jakim człowiek funkcjonuje, i do stylu jego życia. Po 40. roku życia włącza się proces zaprogramowanej śmierci neuronów, czyli apoptozy, a w stanie choroby neurony mogą ginąć w procesie nekrozy lub aponekrozy. Neurogeneza na bazie miejscowych albo transplantowanych komórek macierzystych mózgu pełni funkcję naprawczą w powstałych uszkodzeniach, ale może także mieć związek z chorobami psychicznymi i neurologicznymi. U podstaw neuroprotekcji leżą procesy antyoksydacyjne, przeciwzapalne, antyapoptotyczne i przeciwdziałające destrukcyjnemu działaniu jonów wapnia. Wspierającą funkcję w działaniu neuroprotekcyjnym mogą mieć związki pochodzenia roślinnego, podawane w ramach fitoterapii. W ostatnich latach zwrócono uwagę na neuroprotekcyjne właściwości pentacyklicznych triterpenów i ich pochodnych. W pracy omówiono właściwości neuroprotekcyjne kwasu ursolowego, oleanolowego, maslinowego, asjatowego, betulinowego, bosweliowego oraz saponin triterpenowych pozyskiwanych z roślin Bupleurum i Panax ginseng. Saponiny ginseng dodatkowo nasilają neurogenezę w mózgu. Sugeruje się potencjał stosowania wymienionych związków w terapii wielu chorób neurologicznych i psychicznych – z kilkoma zastrzeżeniami: 1) kierunek działania może zależeć od dawki; 2) związki te mogą różnie działać na neurony różnych rodzajów; 3) mogą istnieć niekorzystne interakcje z innymi lekami stosowanymi równocześnie. Większość doświadczeń z użyciem triterpenów wykonano na zwierzętach bądź w hodowlach komórkowych, zagadnienie wymaga więc dalszych badań na ludziach.
EN
The goal of regenerative medicine is to ameliorate irreversible destruction of brain tissue by harnessing the power of stem cells in the process of neurogenesis. Several types of stem cells, including mesenchymal stem cells, hematopoietic stem cells, as well as neural cells differentiated from embryonic stem cell lines, have been proposed as potential therapeutic vehicles. In this review paper we will discuss a perspective of stem cell therapies for neurological disorders with special emphasis on potential application of cells isolated from adult tissues. In support of this our group found that murine bone marrow contains a mobile population of Oct-4+CXCR4+SSEA-1+Sca-1+lin–CD45– very small embryonic-like stem cells (VSELs) that are mobilized into peripheral blood in a murine stroke model. The number of these cells in circulation increases also after pharmacological mobilization by administration of granulocyte colony stimulating factor (G-CSF). Recently we found that VSELs are present in various non-hematopoietic adult organs and, interestingly, our data indicate that the brain contains a high number of cells that display the VSEL phenotype. Based on our published data both in human and mice we postulate that VSELs are a mobile population of epiblast/germ line-derived stem cells and play an important role as an organ-residing reserve population of pluripotent stem cells that give rise to stem cells committed to particular organs and tissues - including neural tissue. In conclusion human VSELs could be potentially harnessed in regenerative medicine as a source of stem cells for neurogenesis.
EN
In adult mammals cells generated in the subventricular zone (SVZ) migrate to olfactory bulbs (OB). Functional significance of this continuous neurogenesis is not clear. We injected opossums (Monodelphis domestica) for seven consecutive days with a 5HT1A agonist (8-OH-DPAT or buspirone), or its antagonist WAY100635. One hour after each of these injections bromodeoxyuridine (BrdU), a marker of dividing cells was also injected. Two months later, when newly generated neurons settled in the OB and matured the ability of these opossums to detect hidden food by olfactory cues was tested. Afterwards, numbers of BrdU-labeled cell nuclei in their OB were counted and a phenotype of labeled cells established. In all groups investigated the majority of new cells differentiated into neurons (55-76%) and a lower proportion into astroglia (6-12%). Numbers of BrdU-labeled cells differed depending on the applied treatment: both agonists of the 5HT1A receptor increased these numbers, while its antagonist decreased them. The increased number of new OB interneurons did not change the time required for finding all three food items and therefore did not improve the opossums' performance in this test of the olfactory perception. However, opossums that had the reduced number of new generated OB cells searched longer for each food item and in consequence took three times longer to find all three crickets, than did opossums from other groups. In conclusion, lower numbers of new neurons in the opossums OB correlated with their worse behavioral performance in a test based on olfactory perception.
EN
The phenomena of neural differentiation in vitro and neurogenesis in vivo involve a numerous cellular proteins to create the differentiation signaling pathways. The role of the cellular isoform of prion protein PrPc – a product of the PRNP gene, seems also to be connected with a process of neural differentiation. The primary investigations in this field revealed increase of PRNP gene expression during both neurogenesis and neural differentiation in vitro; however, the majority of results were obtained with the use of animal models or cancer- derived cell lines. The latest experiments using neural stem/progenitor cells as an experimental models, seem to confirm the previous results, suggesting participation of PrPc in a neural differentiation. On the basis of the further analyses, PrPc appears to be a part of differentiation signaling pathways. Moreover, PrPc activity may contribute to acquire and maintain the functions specific for neurons. Surprisingly, the prion protein- -deficient cells are still able to differentiate into neurons, although the process of differentiation is delayed. The controversy nevertheless persists about expression of PRNP gene during glial cells differentiation that is reflected in inconsistent published results, beginning with hypothesis postulating the importance of “astrocytic” PrPc for neural differentiation, ending with data presenting no PrPc expression in glial lineage. Studying the literature data does not allow to create the uniform PRNP expression pattern during neural differentiation. It rather seems to be an individual feature, which should be considered in the broader context of particular cell type and the specificity of metabolic processes accompanying neural differentiation in vitro or neurogenesis in vivo.
PL
Różnicowanie neuralne in vitro lub proces neurogenezy in vivo to zjawiska angażujące szereg białek komórkowych, będących ogniwami szlaków sygnalizacyjnych sterujących tymi procesami. Białkiem, którego funkcja również wydaje się związana z procesem różnicowania, jest białko prionu, izoforma komórkowa PrP1 - produkt genu PRNP. Pionierskie badania w tej dziedzinie ujawniły wzrost poziomu ekspresji genu PRNf podczas neurogenezy czy też różnicowania neuronalnego in vitro, aczkolwiek większość wyników uzyskane z wykorzystaniem modeli neurogenezy zwierząt lub linii komórkowych pochodzenia nowotworowego. Najnowsze badania, w których jako model eksperymentalny wykorzystywane są neuralne komórki macierzyste/progenitorowe, potwierdzają zarysowany uprzednio obraz, sugerując udział PrPc w różnicowaniu neuronalnym. Kolejne analizy, będące próbą sprecyzowania funkcji PrPc w tym zjawisku, ukazują to białko jako potencjalne ogniwo szlaków sygnalizacyjnych sterujących procesami różnicowania. Co więcej, wydaje się, iż PrPc jest białkiem, którego aktywność związana jest z nabywaniem oraz realizowaniem przez komórki funkcji specyficznych dla neuronów. Komórki pozbawione białka PrPc nadal są jednak zdolne do różnicowania neuronalnego, chociaż proces ten jest opóźniony. Kwestią kontrowersyjną jest natomiast ekspresja genu PRNP w trakcie różnicowania komórek glejowych, czego dowodem jest brak spójnych doniesień, poczynając od danych sugerujących, iż obecność PrPc w astrocytach jest niezbędna dla prawidłowego przebiegu różnicowania neuralnego, na wynikach definitywnie wykluczających obecność PrPc w linii glejowej kończąc. Analiza danych z literatury nie pozwala więc stworzyć uniwersalnego wzorca ekspresji genu PRNP w procesie różnicowania neuralnego. Wydaje się, iż jest to cecha, którą należy rozpatrywać indywidualnie dla danego typu komórek oraz konkretnego procesu metabolicznego, towarzyszącego zjawiskom tak złożonym, jak proces różnicowania neuralnego in vitro czy neurogeneza in vivo.
16
Content available remote Modeling the neurovascular niche: Implications for recovery from (CNS) injury
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Organotypic hippocampal cultures are used as an alternative model for studying molecular mechanism(s) of neurogenesis after combined oxygen-glucose deprivation (OGD) mimicking ischemic conditions. The aim of the present work was to investigate the effect of OGD on stem/progenitor cells proliferation and/or differentiation in the hippocampus. Our attention was primarily focused on the relationship between neurogenesis-associated processes and activity of matrix metalloproteinases (MMPs). Cell proliferation was detected by using BrdU incorporation. Newly generated BrdU (+) cells were identified by labeling with specific cell markers. In order to check the activity and localization of MMPs we conducted in situ zymography in conjunction with immunohistochemistry. In our experimental conditions OGD-insult followed by 24 h of recovery caused the damage of neuronal cells in CA1. At 1 week cell death appears all over the hippocampus. We found that expected stimulation of endogenous neurogenesis fails as a source of compensation for the lost neurons in OGD-treated cultures. The modulation of culture microenvironment after ischemia favors the dominant proliferation of glial cells expressed by the enhancement of newly-generated oligodendrocyte progenitors. In addition, during our study we also detected some BrdU labeled nuclei encapsulated by GFAP positive processes. However, the majority of BrdU positive cells expressed microglial specific stain, particularly pronounced in CAlarea. The OGD-promoted responses involved activation of metalloproteinases, which matches the progression of gliogenesis. On the other hand, the high activity of MMPs associated with microglial cells implicate their involvement in the mechanism participating in OGD-induced cell damage.
EN
P5 ATPases (ATP13A1 through ATP13A5) are found in all eukaryotes. They are currently poorly characterized and have unknown substrate specificity. Recent evidence has linked two P5 ATPases to diseases of the nervous system, suggesting possible importance of these proteins within the nervous system. In this study we determined the relative expression of mouse P5 ATPases in development using quantitative real time PCR. We have shown that ATP13A1 and ATP13A2 were both expressed similarly during development, with the highest expression levels at the peak of neurogenesis. ATP13A3 was expressed highly during organogenesis with one of its isoforms playing a more predominant role during the period of neuronal development. ATP13A5 was expressed most highly in the adult mouse brain. We also assessed the expression of these genes in various regions of the adult mouse brain. ATP13A1 to ATP13A4 were expressed differentially in the cerebral cortex, hippocampus, brainstem and cerebellum while levels of ATP13A5 were fairly constant between these brain regions. Moreover, we demonstrated expression of the ATP13A4 protein in the corresponding brain regions using immunohistochemistry. In summary, this study furthers our knowledge of P5-type ATPases and their potentially important role in the nervous system.
EN
In the central nervous system (CNS) generation of new neurons continues throughout adulthood, when it is limited to the olfactory bulb and hippocampus. The knowledge regarding the function of newly-generated neurons remains limited and is vigorously investigated using diverse approaches. Among these are genetically modified mice, most of them of knock-out type (KO). Results from 23 diverse KO mouse models demonstrate the importance of particular proteins (growth factors, nitric oxide synthases, receptors, cyclins/cyclin-associated proteins, transcription factors, etc.) in adult neurogenesis (ANGE) as well as separate it from developmental neurogenesis. These results bring us closer to revealing the function of newly generated neurons in adult brains.
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