Research Area

Adult Neurogenesis


Adult Neurogenesis Overview

Adult Neurogenesis

Adult neurogenesis refers to the formation of neurons from neural stem cells (NSCs) in certain brain regions, and the transformation of functional neurons into existing neural network loops of adult mammals. Ultimately, the novel neurons will be integrated into the circuits of the adult brain regions including the subventricular zone of the lateral ventricle (SVZ) and the subgranular zone of the hippocampal dentate gyrus (SGZ). SVZ produces type-3 progenitor cells (neuroblasts) that migrate along the Rostral Migratory Stream (RMS) to the olfactory bulb and participate in smell differentiation. SGZ produces granulosa cells that undergo functional integration into the existing neural circuits and form new synaptic connections in the hippocampus, which is critical for learning and memory formation. Under normal physiological conditions, neurogenesis is being in a relatively balanced state to maintain neuronal stability and brain function. However, certain factors such as exercise, aging, environmental enrichment and stress can cause changes in the rate of neurogenesis. Adult neurogenesis has great potential for the treatment and prevention of many neurological diseases.

Adult Neurogenesis Function

SVZ is the largest neurogenic niche lining the striatal wall of the lateral ventricles of the brain. In some specific "neurogenic" brain regions of SVZ, neurogenesis is more active. Four major cell types in the adult mammalian SVZ regions are involved in NSCs activities, ependymal E cells; subependymal GFAP + B cells, some of which are called CD133 + cells (both CD133 and GFAP proteins can be expressed); transitional expansion of cell C; type-A neuroblasts. The scientific community has not reach a conclusion on which cell types can be defined as neural stem cells. The GFAP expressing B cells are a group of astrocytes. When the B cells in SVZ are activated, they can differentiate into transitional expanded cells C. Those cells are intermediate progenitor cells, the most active cells in SVZ, and can rapidly divide into type-A neuroblasts. Type-A neuroblasts are the most abundant cells in SVZ and can express β-tubulin and polysialylated neuronal adhesion molecules (PSA-NCAM). β-tubulin is a molecular marker associated with migration, and PSA-NCAM is involved in regulating cell migration stability. Type-A neuroblasts migrate to the olfactory bulb through RMS, and the ependymal cells of SVZ set a concentration gradient through the pilus beat to guide the migration of type-A neuroblasts. Type-A neuroblasts then form a migration chain that migrates to different neuronal layers in the olfactory bulb and differentiates to form different neuronal subtypes. Studies have shown that very few of the type-A neuroblasts differentiate into dopaminergic para-balloon interneurons, while more than 90% of type-A neuroblasts differentiate into GABAergic granulosa cells. The mature granulosa cells and neurons integrate into the existing neural circuits in the olfactory bulb to perform signaling functions. Unlike the NSCs in the SVZ that are constantly active, NSCs in the adult mammalian hippocampus are generally at rest while retaining the potential for neurogenesis. Those NSCs are mainly distributed in the dentate gyrus between the hilus and the granule cell layer, namely the subgranular layer SGZ. SGZ is distributed with many types of NSCs, such as GFAP-cells, Nestin-cells, Sox2-cells, and radial glia-like (RGL) cells. In the case of RGL, monoclonal studies have found that RGL cells can self-renew, proliferate and differentiate to produce neurons and astrocytes. When adult SGZ neurogenesis occurs, RGL cells of SGZ undergo asymmetric division, forming intermediate precursor cells between the inner granule cell layer and the hippocampal region, and then the intermediate precursor cells differentiate into neuroblasts. The neuroblasts migrate tangentially along the SGZ to form immature neurons, while the immature neurons migrate radially into the granule cell layer and differentiate into dentate granule neurons. Newborn mature neurons produce dendrites and axons in the granule cell layer and integrate into existing neural circuits to participate in various functional activities of the hippocampus. With the deepening of the research, it has been found that the neurogenesis of the SGZ region exists not only in the embryonic stage of mammals but also in the adult stage. Various brain damages (such as cerebral ischemia, trauma, epilepsy, and depression.) can activate NSCs and promote neurogenesis. The hypothalamus is in the central region of the third ventricle and is composed of multiple nuclei or neurons. It acts as the third neurogenic region of the central nervous system, and is also the key area for neurogenesis. Studies find that neurogenesis also occurs in other areas except for the two major neurogenic regions of SVZ and SGZ in the hypothalamic region. Interestingly, even in the absence of external stimuli, large-scale cell proliferation occurs in the adult hypothalamic region. Meta-integration into the existing neural circuits of the hypothalamus plays a role. In addition, studies have indicated that there are neural progenitor cells (NPCs) in the hypothalamic parenchyma layer, and the proliferation of NPCs will be induced by different signaling molecules. The hypothalamus is the central regulator of homeostasis and important physiological activities such as eating, metabolism, growth, reproduction, and stress. Studies have found that diet can be involved in the regulation of neurogenesis in the hypothalamic region. The intake of high-fat foods inhibits the neurogenesis of the mesenchymal hypothalamus (MBH) and accelerates the apoptosis of progenitor cells. In addition, recent experimental studies have confirmed the presence of neurogenesis in the fourth ventricle of the mammalian brain. When the cells in the resting state of the fourth ventricle ependymal are exposed to vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), they can be activated to divide.

Adult Neurogenesis Research Status

Neurogenesis occurs throughout the entire life cycle of adult mammals, and it is regulated by the external environment and intrinsic genetic factors strictly. Recent studies have revealed some of the signaling pathways involved in the regulation of self-renewal, diffusion, differentiation, neuronal migration, and functional integration of NSCs, such as Wnt signaling pathway, Notch signaling pathway, and miR-30c/sema3A signaling pathway. These signaling pathways are involved in regulating adult neurogenesis from different levels. Wnt/β-catenin signaling pathway: The Wnt signaling pathway is a highly conserved signaling pathway involved in the development of the nervous system, including the formation of neural tubes, the development of dorsal root ganglia, and the development of the midbrain. Disruption of this signaling pathway will lead to the occurrence of diseases related to the nervous system, such as schizophrenia, psychological disorders, autism, and Alzheimer's disease. Wnt proteins involve in the development of many types of cells by autocrine and paracrine pathways. When the Wnt protein is deficient, a key regulator of the Wnt signaling pathway, glycogen synthase kinase-3β (GSK-3β), is activated. GSK-3β forms a degradation complex with axoin, adenomatous polyposis coli protein (APC), and β-Trcp protein, which causes β-catenin phosphorylation to be degraded by proteases. In the absence of Wnt protein, intracellular β-catenin will remain at a low level. When the Wnt protein forms a ternary complex with its receptor transmembrane frizzle (FRZ) and low-density lipoprotein receptor-related protein (LRP5/6), the dishevelled (DVL) will be phosphorylated. Phosphorylation of DVL results in the inactivation of GSK-3β, which causes the degradation pathway of β-catenin to be cleaved, resulting in the accumulation of β-catenin in the cytoplasm. Accumulated β-catenin enters the nucleus and binds to the TCF/LEF transcription factor, prompting a transcriptional expression of the Wnt target gene. Related studies have revealed the role of the Wnt signaling pathway in adult neurogenesis: injection of lentivirus in the hippocampus of adult mice results in a decrease in Wnt protein expression and a marked decrease in neurogenesis in the hippocampus, indicating that the Wnt signaling pathway has an important regulatory role of hippocampal neurogenesis. The Wnt signaling pathway also regulates the neurogenesis of the adult SVZ region. Overexpression of Wnt3A and Wnt5A proteins in SVZ promotes proliferation and differentiation of neural progenitor cells. In addition, the stable expression of β-catenin mediated by retrovirus can promote the proliferation of neural progenitor cells in the SVZ region and promote neurogenesis in the olfactory bulb. Although neurogenesis is restricted to several specific regions in adult mammals, it confers neuronal plasticity to a large extent. The triggering of adult neurogenesis is determined by the proliferation and differentiation status of NSCs. miRNAs are differentially expressed in specific tissue and have important regulatory roles in both embryonic and adult stages of neurogenesis. There is abundant miR-30c in the brain of adult mammals, and it is essential for cell proliferation and differentiation. The regulation of adult neurogenesis by miR-30c is accomplished by acting on the target protein Sema3A. Sema3A is a secreted protein that regulates the polarization and regeneration of neurons by inhibiting the formation of axons and promoting the growth of dendrites. Inhibition of axonal formation by sema3A is caused by down-regulation of protein kinase A (PKA) phosphorylation dependent on axonal stator LKB1 and GSK-3β. Cyclic guanosine monophosp (cGMP) and cyclic adenosine monophosphate (cAMP) are inversely related to the polarization of axons/dendrites. Sema3A regulates the formation of axons or dendrites by increasing cGMP activity and reducing the activity of cAMP and PKA. The Notch signaling pathway has a wide range of effects on the development of the nervous system, including cell proliferation, differentiation and apoptosis. The Notch receptor is a single transmembrane dimeric protein that, when activated, binds to Notch ligands in adjacent cells to form a complex. The complex is cleaved by γ-secretase and released into the intracellular domain (NICD). NICD then enters the nucleus and recombination signal binding protein-Jk (RBPJ) to form a complex NICD – RBPJ. The NICD-RPPJ complex can be used as a transcriptional activator to induce expression of the bHLH transcription factor. Down-regulation of RBPJ in the adult SVZ region will cause B-type cells to differentiate into transitional expanded cells C and neurons, resulting in excessive depletion of the NSC pool and premature cessation of the nerves. In SGZ of adult mammals, regulation of the Notch signaling pathway is critical for the amplification and self-renewal of nestin-expressing cells. Related studies have shown that overexpression of NICD in neural progenitor cells in the adult hippocampus leads to expansion of the NSC pool. During the life of an adult mammal, the Notch signaling pathway is critical for the maintenance of undifferentiated cell pools and the normal progression of neurogenesis.

Relationship with Diseases

  1. Alzheimer
    Alzheimer is a common mental disease. Its pathogenesis and treatment have always been a hot spot for scientists. At present, the clinical treatment of AD mainly relies on cholinergic drugs to delay the development of the disease. Hippocampus is one of the most vulnerable sites in the development of AD. Now studies find that much relationship between adult hippocampal neurogenesis and AD development. Promoting endogenous hippocampal neurogenesis in AD patients may be one of the new strategies in the future.
  2. Cerebral ischemia and reperfusion
    The different periods of cerebral ischemia-reperfusion and the different extents of injury have different effects on the adult central nervous system. In the acute phase of ischemia-reperfusion (1~3d), the adult central nervous system is inhibited. After that, the adult central nervous system is obviously enhanced and participates in the brain remodeling. The adult central nervous system has a promising future for the treatment of ischemic stroke.

References:

  1. Bergmann O, Spalding K L, Frisén J. Adult Neurogenesis in Humans. Cold Spring Harbor Perspectives in Biology. 2015, 7(7) a018994.
  2. Schoenfeld T J, Cameron H A. Adult Neurogenesis and Mental Illness. Neuropsychopharmacology Official Publication of the American College of Neuropsychopharmacology. 2014, 40(1):113-28.
  3. Yuan T F, Gu S, Shan C, et al. Oxidative Stress and Adult Neurogenesis. Stem Cell Reviews. 2015, 11(5):706.
  4. Geil C R, Hayes D M, Mcclain J A, et al. Alcohol and adult hippocampal neurogenesis: promiscuous drug, wanton effects. Progress in Neuropsychopharmacology & Biological Psychiatry. 2014, 54(15):103-113.
  5. Bond A M, Ming G, Song H. Adult Mammalian Neural Stem Cells and Neurogenesis: Five Decades Later. Cell Stem Cell. 2015, 17(4):385-395.

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