Adult Neurogenesis in the Mammalian Brain: Significant Answers and Significant Questions

Secreted Frizzled-Related Protein 3 Regulates Activity-Dependent Adult Hippocampal Neurogenesis

EDITORIAL article Front. Neurosci., 03 April 2012Sec. Neurogenesis Volume 6 - 2012 | https://doi.org/10.3389/fnins.2012.00041

Background Inflammatory bowel diseases (IBD), such as Crohn‘s disease and ulcerative colitis, are associated with neuropsychiatric comorbidities, including depression, anxiety, and Parkinson’s disease [1]. These are presumably mediated along the gut-immune-brain axis by the transition of inflammation across gastrointestinal and CNS-surrounding barriers, causing the activation of microglia [1]. Adult hippocampal neurogenesis, the generation of new neurons in the hippocampus throughout life, is impaired by peripheral inflammation [2] and linked to affective and neurodegenerative disorders [3]. In the context of IBD, adult hippocampal neurogenesis has only been investigated in chemically induced animal models mimicking ulcerative colitis, leading to heterogeneous results [1]. Methods In this study, we used the Casp8∆IEC ileocolitis mouse model which is characterized by a specific knockout of caspase 8 in intestinal epithelial cells, leading to ileocolitis that resembles Crohn’s disease [4]. We investigated the effects of ileocolitis on microglia and on adult neurogenesis in the hippocampal dentate gyrus (DG). The hippocampi of 14- and 24-week-old Casp8∆IEC mice were compared to wild-type (wt) mice using immunohistochemistry and immunofluorescence analyses. Microglial density and proliferation were assessed by quantifying ionized calcium-binding adapter molecule 1 (Iba1)+ and Iba1+Mcm2+ myeloid cells, respectively. Additionally, microglial phagocytic activation was examined by co-staining Iba1 with the lysosomal marker CD68. To evaluate adult hippocampal neurogenesis, progenitor cell proliferation and maturation were analyzed by quantifying Mcm2+ proliferating cells and doublecortin (DCX)+ neuroblasts in the DG. Cells undergoing cell death during maturation were quantified by co-staining DCX with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). Results Microglial density and proliferation in the dentate gyrus region were preserved between Casp8∆IEC and wt mice at both 14 and 24 weeks of age. Likewise, microglial activation state and phagocytosis remained unchanged between the two groups at both time points Adult hippocampal neurogenesis was maintained between the two groups. The proliferation and maturation of progenitor cells, as well as the rate of cell death during maturation in the dentate gyrus, remained similar between Casp8∆IEC and wt mice. Conclusion These results demonstrate that key aspects of hippocampal immune function and adult hippocampal neurogenesis are resilient to experimental ileocolitis induced by the deletion of Casp8 in intestinal epithelial cells. References (1)Masanetz RK, Winkler J, Winner B, Günther C, Süß P. The Gut-Immune-Brain Axis: An Important Route for Neuropsychiatric Morbidity in Inflammatory Bowel Disease. Int J Mol Sci. 2022;23(19):11111. Published 2022 Sep 21. doi:10.3390/ijms231911111 (2)Ekdahl CT, Claasen JH, Bonde S, Kokaia Z, Lindvall O. Inflammation is detrimental for neurogenesis in adult brain. Proc Natl Acad Sci U S A. 2003;100(23):13632-13637. doi:10.1073/pnas.2234031100 (3)Toda T, Parylak SL, Linker SB, Gage FH. The role of adult hippocampal neurogenesis in brain health and disease. Mol Psychiatry. 2019;24(1):67-87. doi:10.1038/s41380-018-0036-2 (4)Günther C, Martini E, Wittkopf N, et al. Caspase-8 regulates TNF-α-induced epithelial necroptosis and terminal ileitis. Nature. 2011;477(7364):335-339. Published 2011 Sep 14. doi:10.1038/nature10400

Adult neurogenesis occurs throughout life in restricted brain regions in mammals. However, the number of neural stem cells (NSCs) that generate new neurons steadily decreases with age, resulting in a decrease in neurogenesis. Transplantation of mesenchymal cells or cultured NSCs has been studied as a promising treatment in models of several brain injuries including cerebral infarction and cerebral contusion. Considering the problems of host-versus-graft reactions and the tumorigenicity of transplanted cells, the mobilization of endogenous adult NSCs should be more feasible for the treatment of these brain injuries. However, the number of adult NSCs in the adult brain is limited, and their mitotic potential is low. Here, we outline what we know to date about why the number of NSCs and adult neurogenesis decrease with age. We also discuss issues applicable to regenerative medicine.

In Vivo Clonal Analysis Reveals Self-Renewing and Multipotent Adult Neural Stem Cell Characteristics

Neuronal plasticity and antidepressant actions

Adult hippocampal neurogenesis in Alzheimer's disease: A roadmap to clinical relevance.

The Age of Olfactory Bulb Neurons in Humans

The term “adult neurogenesis” is used to describe the observation that, in the adult mammalian brain, new neurons are born from stem cells residing in discrete locations and these new neurons migrate, differentiate, and mature into newly integrated, functioning cells. By virtue of this definition, adult neurogenesis is a process, not an event, and as such, can be dissected and examined in evermore discrete components. In general, researchers seek a complete understanding of not only the details of these separate components but also the purpose and function of this process as a whole. Once the tools became available to monitor and measure adult neurogenesis, the interest in this process grew enormously, not the least because the birth and integration of new neurons in the adult brain constitute the most extreme cases of neuroplasticity in the adult brain. While the phenomenon is interesting enough to investigate and understand in the normal, healthy brain, the fact that this process is also disrupted in many disease states adds substantially to the numbers of those studying adult neurogenesis. As a result, a new way of looking at brain therapy has emerged that incorporates the potential of generating new neurons in the context of aging and disease into the search for a strategy for “self-repair.” The idea for this book originated from a meeting on adult neurogenesis in the adult brain held at the Banbury Conference Center at Cold Spring Harbor Laboratory in February 2006. In the secluded and intimate setting of this event, the

Neurogenesis in the mammalian adult brain is a well established phenomenon (for the recent reviews see Carpentier & Palmer, 2009; Kaneko & Sawamoto, 2009; Rodriguez & Verkhratsky, 2011) that is important in both young and aging brain (Galvan & Jin, 2007; Rao et al., 2006). The subventricular zone, subgranular layer of the dentate gyrus (DG), and cortex are the main sites of adult neurogenesis (Gould et al., 1999; Luskin & Boone, 1994; Palmer et al., 2000; Seki et al., 2007; Yoneyama et al., 2011). Newly-born neurons during adult neurogenesis have the ability to integrate into previously established neuronal networks (Kee et al., 2007; Markakis & Gage, 1999; Sandoval et al., 2011). Alteration of neurogenesis under different experimental and pathological conditions has been described to a great extent (Rodriguez & Verkhratsky, 2011; Sandoval et al., 2011; Winner et al., 2011; Yoneyama et al., 2011; Yu et al., 2009). Significant decreases of neurogenesis have been found in neurodevelopmental (Contestabile et al., 2007; Guidi et al., 2008, 2010) and in neurodegenerative diseases (Rodriguez & Verkhratsky, 2011). Numerous studies provide evidence that a lack of neurogenesis significantly diminishes plasticity in the adult brain and interferes with learning and memory (reviewed in Koehl & Abrous, 2011; Mongiat & Schinder, 2011). Different mechanisms have been proposed to regulate neurogenesis in the adult brain, including brain injury (Kernie & Parent, 2010; Moriyama et al., 2011), ischemia (Kernie & Parent, 2010; Kreuzberg et al., 2010), and inflammation (Voloboueva et al., 2010). One of the least studied factors that affects neurogenesis are chromosomal aberrations. Down syndrome (DS) results from the extra copy of chromosome 21 occurring with a prevalence of 1 in 733 live births (Canfield et al., 2006). Subjects with DS show developmental regression, diminished cognitive ability, and autonomic dysfunction (Antonarakis & Epstein, 2006; Chapman & Hesketh, 2000). The DS brain is severely affected showing a reduction in both overall size and of particular areas (frontal cortex, hippocampus, cerebellum, and brainstem) due to a reduced number of neurons (Aylward et al., 1997, 1999; Kesslak et al., 1994; Pinter et al., 2001; Raz et al., 1995; Wisniewski et al., 1984).

The topic of the Presidential Symposium at the 28th Annual Meeting of the Association for Chemoreception Sciences, on 29 April 2006, was ‘‘Why Have Neurogenesis in Adult Olfactory Systems?’’ This introductory paper plus the following 3 papers arose from the science presented in that symposium. Cell proliferation has long been known to occur in adult animals. It occurs in many tissues, including the epidermis and intestinal lining wherein it functions in the turnover and repair of tissue normally exposed to harsh environments. For many years, cell proliferation was thought to be absent from the nervous system of adult animals. This was the prevailing dogma until the 1960s, when radiolabeled molecules became more available for biological studies. This included tritiated thymidine, which could be used to label cells in the S-phase of the cell cycle. This provided a convenient and reliable marker of cells replicating their DNA and, at least in many cases, thus in the process of mitosis. This methodology allowed for claims of neurogenesis in brains of adult rodents in the 1960s by Altman and colleagues (e.g., Altman and Das 1966; Altman 1969). The claims were received with a mixture of skepticism, enthusiasm, and indifference, and they were not fully appreciated until later studies using the same and new techniques replicated and extended their findings. Now, with nonradiolabeled markers of DNA replication such as bromodeoxyuridine and antibodies for molecules specifically expressed in different phases of the cell cycle, identifying cell division in tissues is relatively simple and commonplace and has led to demonstrations of neurogenesis in the brains of adult animals representing an impressive phylogenetic range. Although adult neurogenesis is phylogenetically widespread in the brains of adult vertebrates, including representatives of the major classes of vertebrates—elasmobranchs, teleosts, amphibians, reptiles, birds, and mammals—it is limited to very few brain regions. The 2 vertebrate brain regions most recognized as sites of adult neurogenesis are the subventricular zone/olfactory bulb and the dentate gyrus of the hippocampus. Other areas in the adult mammalian brain, including the cortex, have been reported to undergo neurogenesis, but this topic is being debated. Adult neurogenesis occurs in other animal groups in addition to the vertebrates, most notably in some insects and crustaceans. In these groups as in the vertebrates, adult neurogenesis occurs only in limited parts of the nervous system and often associated with olfaction. In insects, it occurs in the mushroom bodies, which are large neuropils containing intrinsic interneurons called Kenyon cells. Kenyon cells are higher order multimodal integrators that receive their most prominent inputfromtheantennal lobes,whicharetheinsect’s primary olfactory neuropils. In crustaceans, adult neurogenesis principally occurs in 2 parts of the brain: the olfactory lobes and the optic lobes. Neurogenesis occurs not only in the brain but also in the peripheral olfactory systems of many animals, including vertebrates, crustaceans, and snails. A focus of research on adult neurogenesis is elucidating the cellular and molecular mechanisms of cell birth and migration (e.g., Merkle and Alvarez-Buylla 2006; Sawamoto et al. 2006). Receiving much less attention has been the ‘‘function’’ of olfactory neurogenesis in adults. Adult neurogenesis is certainly not limited to the olfactory system, but if adult neurogenesis occurs in a species, it is likely to occur in the olfactory pathway. Why is this so? What is different about olfaction that makes adult neurogenesis so prevalent? This led me to organize the 2006 AChemS Presidential Symposium on the topic, Why have adult olfactory neurogenesis? There are many reasons why adult animals might have olfactory neurogenesis. Many animals have indeterminate growth such that they increase in size throughout their life. Olfactory neurogenesis allows their olfactory system to keep pace with the increase in body surface. This effect, however, is not necessarily olfactory specific, as other parts of the body, including other sensory systems, may also expand with body size. A second reason for adult olfactory neurogenesis is that some animals respond to damage to or loss of the olfactory organ with regeneration and repair. Crustaceans are an excellent model of this. The olfactory organ is particularly susceptible to damage because its sensory function requires that it be intimately exposed to the external environment. Damage to and death of olfactory sensory neurons in such conditions are to be expected. So the continuous Chem. Senses doi:10.1093/chemse/bjm011

Neurogenesis involves generation of new neurons through finely tuned multistep processes, such as neural stem cell (NSC) proliferation, migration, differentiation, and integration into existing neuronal circuitry in the dentate gyrus of the hippocampus and subventricular zone. Adult hippocampal neurogenesis is involved in cognitive functions and altered in various neurodegenerative disorders, including Alzheimer disease (AD). Ethosuximide (ETH), an anticonvulsant drug is used for the treatment of epileptic seizures. However, the effects of ETH on adult hippocampal neurogenesis and the underlying cellular and molecular mechanism(s) are yet unexplored. Herein, we studied the effects of ETH on rat multipotent NSC proliferation and neuronal differentiation and adult hippocampal neurogenesis in an amyloid β (Aβ) toxin-induced rat model of AD-like phenotypes. ETH potently induced NSC proliferation and neuronal differentiation in the hippocampus-derived NSC in vitro. ETH enhanced NSC proliferation and neuronal differentiation and reduced Aβ toxin-mediated toxicity and neurodegeneration, leading to behavioral recovery in the rat AD model. ETH inhibited Aβ-mediated suppression of neurogenic and Akt/Wnt/β-catenin pathway gene expression in the hippocampus. ETH activated the PI3K·Akt and Wnt·β-catenin transduction pathways that are known to be involved in the regulation of neurogenesis. Inhibition of the PI3K·Akt and Wnt·β-catenin pathways effectively blocked the mitogenic and neurogenic effects of ETH. In silico molecular target prediction docking studies suggest that ETH interacts with Akt, Dkk-1, and GSK-3β. Our findings suggest that ETH stimulates NSC proliferation and differentiation in vitro and adult hippocampal neurogenesis via the PI3K·Akt and Wnt·β-catenin signaling.

Adult Neural Stem Cells Bridge Their Niche

New neurons are generated throughout life. This discovery has challenged firmly held concepts about the structural plasticity and regenerative capacity of the mammalian brain. In this special issue of the EJN, leaders in the field summarize and review recent advances aiming to understand the molecular mechanisms underlying adult neurogenesis and the impact of new neurons on brain function in health and disease. Below we discuss pivotal yet unsolved aspects of adult neurogenesis as well as potential future directions in the field.

Adult neurogenesis persists throughout life in restricted brain regions in mammals and is affected by various physiological and pathological conditions. The tumor suppressor gene Pten is involved in adult neurogenesis and is mutated in a subset of autism patients with macrocephaly; however, the link between the role of PTEN in adult neurogenesis and the etiology of autism has not been studied before. Moreover, the role of hippocampus, one of the brain regions where adult neurogenesis occurs, in development of autism is not clear. Here, we show that ablating Pten in adult neural stem cells in the subgranular zone of hippocampal dentate gyrus results in higher proliferation rate and accelerated differentiation of the stem/progenitor cells, leading to depletion of the neural stem cell pool and increased differentiation toward the astrocytic lineage at later stages. Pten-deleted stem/progenitor cells develop into hypertrophied neurons with abnormal polarity. Additionally, Pten mutant mice have macrocephaly and exhibit impairment in social interactions and seizure activity. Our data reveal a novel function for PTEN in adult hippocampal neurogenesis and indicate a role in the pathogenesis of abnormal social behaviors.