• BMB Reports
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• v.57 no.6
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• pp.281-286
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• 2024

Adult hippocampal neurogenesis plays a pivotal role in maintaining cognitive brain function. However, this process diminishes with age, particularly in patients with neurodegenerative disorders. While small, non-coding microRNAs (miRNAs) are crucial for hippocampal neural stem (HCN) cell maintenance, their involvement in neurodegenerative disorders remains unclear. This study aimed to elucidate the mechanisms through which miRNAs regulate HCN cell death and their potential involvement in neurodegenerative disorders. We performed a comprehensive microarray-based analysis to investigate changes in miRNA expression in insulin-deprived HCN cells as an in vitro model for cognitive impairment. miR-150-3p, miR-323-5p, and miR-370-3p, which increased significantly over time following insulin withdrawal, induced pronounced mitochondrial fission and dysfunction, ultimately leading to HCN cell death. These miRNAs collectively targeted the mitochondrial fusion protein OPA1, with miR-150-3p also targeting MFN2. Data-driven analyses of the hippocampi and brains of human subjects revealed significant reductions in OPA1 and MFN2 in patients with Alzheimer's disease (AD). Our results indicate that miR-150-3p, miR-323-5p, and miR-370-3p contribute to deficits in hippocampal neurogenesis by modulating mitochondrial dynamics. Our findings provide novel insight into the intricate connections between miRNA and mitochondrial dynamics, shedding light on their potential involvement in conditions characterized by deficits in hippocampal neurogenesis, such as AD.

• Korean Journal of Biological Psychiatry
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• v.8 no.1
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• pp.3-19
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• 2001

Recent basic and clinical studies demonstrate a major role for neural plasticity in the etiology and treatment of depression and stress-related illness. The neural plasticity is reflected both in the birth of new cell in the adult brain(neurogenesis) and the death of genetically healthy cells(apoptosis) in the response to the individual's interaction with the environment. The neural plasticity includes adaptations of intracellular signal transduction pathway and gene expression, as well as alterations in neuronal morphology and cell survival. At the cellular level, repeated stress causes shortening and debranching of dendrite in the CA3 region of hippocampus and suppress neurogenesis of dentate gyrus granule neurons. At the molecular level, both form of structural remodeling appear to be mediated by glucocorticoid hormone working in concert with glutamate and N-methyl-D-aspartate(NMDA) receptor, along with transmitters such as serotonin and GABA-benzodiazepine system. In addition, the decreased expression and reduced level of brain-derived neurotrophic factor(BDNF) could contribute the atrophy and decreased function of stress-vulnerable hippocampal neurons. It is also suggested that atrophy and death of neurons in the hippocampus, as well as prefrontal cortex and possibly other regions, could contribute to the pathophysiology of depression. Antidepressant treatment could oppose these adverse cellular effects, which may be regarded as a loss of neural plasticity, by blocking or reversing the atrophy of hippocampal neurons and by increasing cell survival and function via up-regulation of cyclic adenosine monophosphate response element-binding proteins(CREB) and BDNF. In this article, the molecular and cellular mechanisms that underlie stress, depression, and action of antidepressant are precisely discussed.

• Biomolecules & Therapeutics
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• v.28 no.3
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• pp.282-291
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• 2020

Inhaled solvents such as toluene are of particular concern due to their abuse potential that is easily exposed to the environment. The inhalation of toluene causes various behavioral problems, but, the effect of short-term exposure of toluene on changes in emotional behaviors over time after exposure and the accompanying pathological characteristics have not been fully identified. Here, we evaluated the behavioral and neurochemical changes observed over time in mice that inhaled toluene. The mice were exposed to toluene for 30 min at a concentration of either 500 or 2,000 ppm. Toluene did not cause social or motor dysfunction in mice. However, increased anxiety-like behavior was detected in the short-term after exposure, and depression-like behavior appeared as delayed effects. The amount of striatal dopamine metabolites was significantly decreased by toluene, which continued to be seen for up to almost two weeks after inhalation. Additionally, an upregulation of serotonin 1A (5-HT_1A) receptor in the hippocampus and the substantia nigra, as well as reduced immunoreactivity of neurogenesis markers in the dentate gyrus, was observed in the mice after two weeks. These results suggest that toluene inhalation, even single exposure, mimics early anxiety-and delayed depression-like emotional disturbances, underpinned by pathological changes in the brain.

• International Journal of Oral Biology
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• v.33 no.2
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• pp.59-64
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• 2008

This study was designed to investigate the changes in the properties of the neuronal setm cells or progenitor cells associated with age-related decline in neurogenesis of the hippocampal dentate gyrus (DG). Active whole cells cycle marker Ki67 (a marker of whole cell cycle)-positive and S phase marker bromodeoxyuridine (BrdU)-positive. Neural stem cells gradually were reduced in the hippocampal subgranular zone (SGZ) in an age-dependant manner after birth (from P1 month to P1 year). The ratio of BrdUpositivecells/Ki67-positive cells was gradually enhanced in an age-dependent manner. The ratio of Ki67-positive cells/accu-mulating BrdU-positive cells at 3 hrs after BrdU injection was injected once a day for consecutive 5 days gradually decreased during ageing. TUNEL- and caspase 3 (apoptotic terminal caspase)-positive cells gradually decreased in the dentate SGZ during ageing and immunohistochemical findings of glial fibrillary acid protein (GFAP) were not changed during ageing. NeuN, a marker of mature neural cells, and BrdU-double positive cells gradually decreased in an age-dependent manner but differentiating ratio and survival rate of cells were not changed at 4 wks after BrdU injection once a day for consecutive 5 days. The number of BrdU-positive cells migrated from the hippocampal SGZ into granular layer and its migration speed was gradually declined during ageing. These results suggest that the adult neurogenesis in the mouse hippocampal DG gradually decrease through reducing proliferation of neural stem cells accompanying with cells cycle change and reduced cells migration rather than changes of differentiation.

• BMB Reports
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• v.56 no.4
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• pp.240-245
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• 2023

Glial cells play important roles during neurogenesis and in maintaining complex functions of the nervous system. Here, we report the characterization of a gene, Sdr, which contains a putative insulin-like growth factor receptor domain and is required to maintain critical nervous system functions in Drosophila. Sdr is expressed in glial cells during embryonic and larval stages of development, but its role in adult flies is poorly understood. As insulin signaling is important throughout the lifespan in human, we investigated the Sdr's role in adult flies. Our results demonstrate that Sdr is expressed on surface glial cells that surround the nervous system. Mutation of Sdr did not affect development but caused defects in locomotion and lifespan. Sdr mutants also showed increasingly severe defects in the blood-brain- and blood-retina-barriers as they aged. Therefore, we suggest a novel role of Sdr in maintaining the integrity of the blood-brain- and blood-retina-barriers in adult flies.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• v.34 no.6
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• pp.588-593
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• 2008

There are increasing reports regarding regeneration of the defected tissues using tissue engineering technique. In this technique, multipotential stem cells are essential. There are many potential sources of adult stem cells, such as bone marrow, umbilical cord blood, fat, muscle, dental tissues and skin. Among them, skin is highly accessible and easily obtained with a minimum of donor site complications. Moreover, skin is an abundant adult stem cell sources and has the potential for self-replication and immune privilege. In this study, we isolated skin-derived precursor cells (SKPs) from the ear of adult miniature pigs. In these SKPs, the expression of transcriptional factors, Oct-4, Sox-2, and Nanog were detected by RT-PCR. In vitro osteogenesis and adipogenesis were observed at 3 weeks after transdifferentiations as assayed by positive von Kossa and Oil-red O staining, respectively. In addition, expression of osteocalcin and osteonectin in the osteogenic differentiation medium and $PPAR{\gamma}2$ and aP2 in the adipogenic differentiation medium were detected by RT-PCR. In vitro neurogenesis of porcine SKPs was observed during 24 and 72 hours after treatment of neurogenic differentiation medium. The results of this study suggest that SKPs demonstrate the properties of pluripotence or multipotence and multi-lineage differentiation. This indicates that autogenous SKPs are a reliable and useful source of adult stem cells for regenerative medicine.

• Development and Reproduction
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• v.17 no.3
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• pp.179-186
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• 2013

Neural stem cells are found in adult mammalian brain regions including the subgranular zone (SGZ) of the dentate gyrus (DG) and the subventricular zone (SVZ). In addition to these two regions, other neurogenic regions are often reported in many species. Recently, the subcallosal zone (SCZ) has been identified as a novel neurogenic region where new neuroblasts are spontaneously generated and then, by Bax-dependent apoptosis, eliminated. However, the development of SCZ in the postnatal brain is not yet fully explored. The present study investigated the precise location and amount of neuroblasts in the developing brain. To estimate the importance of programmed cell death (PCD) for SCZ histogenesis, SCZ development in the Bax-knockout (KO) mouse was examined. Interestingly, an accumulation of extra neurons with synaptic fibers in the SCZ of Bax-KO mice was observed. Indeed, Bax-KO mice exhibited enhanced startle response to loud acoustic stimuli and reduced anxiety level. Considering the prevention of PCD in the SCZ leads to sensory-motor gating dysfunction in the Bax-KO mice, active elimination of SCZ neuroblasts may promote optimal brain function.

• BMB Reports
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• v.48 no.11
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• pp.599-608
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• 2015

Regeneration, a process of reconstitution of the entire tissue, occurs throughout life in the olfactory epithelium (OE). Regeneration of OE consists of several stages: proliferation of progenitors, cell fate determination between neuronal and non-neuronal lineages, their differentiation and maturation. How the differentiated cell types that comprise the OE are regenerated, is one of the central questions in olfactory developmental neurobiology. The past decade has witnessed considerable progress regarding the regulation of transcription factors (TFs) involved in the remarkable regenerative potential of OE. Here, we review current state of knowledge of the transcriptional regulatory networks that are powerful modulators of the acquisition and maintenance of developmental stages during regeneration in the OE. Advance in our understanding of regeneration will not only shed light on the basic principles of adult plasticity of cell identity, but may also lead to new approaches for using stem cells and reprogramming after injury or degenerative neurological diseases.

• BMB Reports
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• v.35 no.1
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• pp.87-93
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• 2002

Neural cell survival is an essential concern in the aging brain and many diseases of the central nervous system. Neural transplantation of the stem cells are already applied to clinical trials for many degenerative neurological diseases, including Huntington's disease, Parkinson's disease, and strokes. A critical problem of the neural transplantation is how to reduce their apoptosis and improve cell survival. Neurotrophic factors generally contribute as extrinsic cues to promote cell survival of specific neurons in the developing mammalian brains, but the survival factor for neural stem cell is poorly defined. To understand the mechanism controlling stem cell death and improve cell survival of the transplanted stem cells, we investigated the effect of plausible neurotrophic factors on stem cell survival. The neural stem cell, HiB5, when treated with PDGF prior to transplantation, survived better than cells without PDGF. The resulting survival rate was two fold for four weeks and up to three fold for twelve weeks. When transplanted into dorsal hippocampus, they migrated along hippocampal alveus and integrated into pyramidal cell layers and dentate granule cell layers in an inside out sequence, which is perhaps the endogenous pathway that is similar to that in embryonic neurogenesis. Promotion of the long term-survival and differentiation of the transplanted neural precursors by PDGF may facilitate regeneration in the aging adult brain and probably in the injury sites of the brain.

• Clinical and Experimental Pediatrics
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• v.57 no.3
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• pp.101-109
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• 2014

The use of glucocorticoids (GCs) in the perinatal period is suspected of being associated with adverse effects on long-term neurodevelopmental outcomes for preterm infants. Repeated administration of antenatal GCs to mothers at risk of preterm birth may adversely affect fetal growth and head circumference. Fetal exposure to excess GCs during critical periods of brain development may profoundly modify the limbic system (primarily the hippocampus), resulting in long-term effects on cognition, behavior, memory, co-ordination of the autonomic nervous system, and regulation of the endocrine system later in adult life. Postnatal GC treatment for chronic lung disease in premature infants, particularly involving the use of dexamethasone, has been shown to induce neurodevelopmental impairment and increases the risk of cerebral palsy. In contrast to studies involving postnatal dexamethasone, long-term follow-up studies for hydrocortisone therapy have not revealed adverse effects on neurodevelopmental outcomes. In experimental studies on animals, GCs has been shown to impair neurogenesis, and induce neuronal apoptosis in the immature brains of newborn animals. A recent study has demonstrated that dexamethasone-induced hypomyelination may result from the apoptotic degeneration of oligodendrocyte progenitors in the immature brain. Thus, based on clinical and experimental studies, there is enough evidence to advice caution regarding the use of GCs in the perinatal period; and moreover, the potential long-term effects of GCs on brain development need to be determined.