• BMB Reports
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• v.56 no.9
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• pp.520-525
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• 2023

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive decline. Several recent studies demonstrated that impaired adult neurogenesis could contribute to AD-related cognitive impairment. Adult subventricular zone (SVZ) neurogenesis, which occurs in the lateral ventricles, plays a crucial role in structural plasticity and neural circuit maintenance. Alterations in adult SVZ neurogenesis are early events in AD, and impaired adult neurogenesis is influenced by the accumulation of intracellular Aβ. Although Aβ-overexpressing transgenic 5XFAD mice are an AD animal model well representative of Aβ-related pathologies in the brain, the characterization of altered adult SVZ neurogenesis following AD progression in 5XFAD mice has not been thoroughly examined. Therefore, we validated the characterization of adult SVZ neurogenesis changes with AD progression in 2-, 4-, 8-, and 11-monthold male 5XFAD mice. We first investigated the Aβ accumulation in the SVZ using the 4G8 antibody. We observed intracellular Aβ accumulation in the SVZ of 2-month-old 5XFAD mice. In addition, 5XFAD mice exhibited significantly increased Aβ deposition in the SVZ with age. Next, we performed a histological analysis to investigate changes in various phases of adult neurogenesis, such as quiescence, proliferation, and differentiation, in SVZ. Compared to age-matched wild-type (WT) mice, quiescent neural stem cells were reduced in 5XFAD mice from 2-11 months of age. Moreover, proliferative neural stem cells were decreased in 5XFAD mice from 2 to 8 months of age. Furthermore, differentiations of neuroblasts were diminished in 5XFAD mice from 2-11 months of age. Intriguingly, we found that adult SVZ neurogenesis was reduced with aging in healthy mice. Taken together, our results revealed that impairment of adult SVZ neurogenesis appears with aging or AD progression.

• The Korean Journal of Physiology and Pharmacology
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• v.22 no.2
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• pp.145-153
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• 2018

The subgranular zone (SGZ) of hippocampal dentate gyrus (HDG) is a primary site of adult neurogenesis. Toll-like receptors (TLRs), are involved in neural system development of Drosophila and innate immune response of mammals. TLR2 is expressed abundantly in neurogenic niches such as adult mammalian hippocampus. It regulates adult hippocampal neurogenesis. However, the role of TLR2 in adult neurogenesis is not well studied in global or focal cerebral ischemia. Therefore, this study aimed to investigate the role of TLR2 in adult neurogenesis after photochemically induced cerebral ischemia. At 7 days after photothrombotic ischemic injury, the number of bromodeoxyuridine (BrdU)-positive cells was increased in both TLR2 knock-out (KO) mice and wild-type (WT) mice. However, the increment rate of BrdU-positive cells was lower in TLR2 KO mice compared to that in WT mice. The number of doublecortin (DCX) and neuronal nuclei (NeuN)-positive cells in HDG was decreased after photothrombotic ischemia in TLR2 KO mice compared to that in WT mice. The survival rate of cells in HDG was decreased in TLR2 KO mice compared to that in WT mice. In contrast, the number of cleaved-caspase 3 (apoptotic marker) and the number of GFAP (glia marker)/BrdU double-positive cells in TLR2 KO mice were higher than that in WT mice. These results suggest that TLR2 can promote adult neurogenesis from neural stem cell of hippocampal dentate gyrus through increasing proliferation, differentiation, and survival from neural stem cells after ischemic injury of the brain.

• Development and Reproduction
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• v.17 no.4
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• pp.461-467
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• 2013

Nesfatin-1/NUCB2, which is associated with the control of appetite and energy metabolism, was reported for the first time to be expressed in the hypothalamus. However, recent studies have shown that nesfatin-1/NUCB2 was expressed not only in the hypothalamus, but also in various tissues including digestive and reproductive organs. We also demonstrated that nesfatin-1/NUCB2 was expressed in the reproductive organs, pituitary gland, heart, lung, and gastrointestinal tract of the adult mouse. However, little is known about nesfatin-1/NUCB2 expression in fetal and neonatal mice. Therefore, we examined here the distribution of nesfatin-1/NUCB2 in various organs of fetal and neonatal mice and compared them with the distribution in adult mice. As a result of immunohistochemical staining, nesfatin-1/NUCB2 protein was expressed relatively higher in the lung, kidney, heart, and liver compared to other organs in the fetus. Western blot results also showed that nesfatin-1/NUCB2 protein was detected in the lung, kidney, heart, and stomach. Next, we compared the expression levels of nesfatin-1/NUCB2 mRNA in the fetus and neonate with the expression levels in both male and female adult mice. The expression levels in heart, lung, stomach, and kidney were higher compared with other organs in fetal and neonatal mice and in both male and female adult mice. Interestingly, the expression of nesfatin-1/NUCB2 mRNA in the kidney was dramatically increased in male and female adult mice compared to fetal and neonatal mice. These results indicate that nesfatin-1/NUCB2 may regulate the development and physiological function of mouse organs. In the future, we need more study on the function of nesfatin-1/NUCB2, which is highly expressed in the heart, lung, and kidney during mouse development.

• Korean Journal of Veterinary Research
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• v.38 no.4
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• pp.679-685
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• 1998

We have studied, by a nonisotopic in situ DNA end-labeling (ISEL) technique, frequency of apoptosis in the external granular layer (EGL) of the cerebellum after whole-body irradiation of newborn mice and intestinal crypt cell of adult mice by gamma-rays from $^{60}Co$. The extent of changes following 2 Gy(10.9 Gy/min) was studied at 2, 4, 6, 8, 12, or 24h after exposure. The maximal frequency was found 4-8h after exposure. The mice that received 0.18, 0.36, 0.54, 1.08, 1.98, or 3.96 Gy were examined 6h after irradiation. Measurements performed after irradiation showed a dose-related increase in apoptotic cells in each of the mice studied. The dose-response curves were analyzed by a linear-quadratic model; frequency(%) of apoptotic cell in the newborn mice cerebellum was ($13.49{\pm}1.175$)D+$(-1.52{\pm}0.334)D^2$+0.048($r^2=0.981$, D = dose in Gy) and frequency(number per crypt) of apoptotic cell in the intestinal crypt of adult mice was ($3.857{\pm}0.420$)D+$(-0.535{\pm}0.120)D^2$+0.155($r^2=0.952$, D = dose in Gy). It provides the basis required for a better understanding of results which will be obtained in any further studies for biological responses of radiation using newborn and adult mice.

• Molecules and Cells
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• v.39 no.8
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• pp.603-610
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• 2016

Recently, an increasing number of studies have focused on the effects of CD4+ T cell on cognitive function. However, the changes of Th2 cytokines in restricted CD4+ T cell receptor (TCR) repertoire model and their effects on the adult hippocampal neurogenesis and memory are not fully understood. Here, we investigated whether and how the mice with restricted CD4+ repertoire TCR exhibit learning and memory impairment by using OT-II mice. OT-II mice showed decreased adult neurogenesis in hippocampus and short- and long- term memory impairment. Moreover, Th2 cytokines in OT-II mice are significantly increased in peripheral organs and IL-4 is significantly increased in brain. Finally, IL-4 treatment significantly inhibited the proliferation of cultured adult rat hippocampal neural stem cells. Taken together, abnormal level of Th2 cytokines can lead memory dysfunction via impaired adult neurogenesis in OT-II transgenic.

• Korean Journal of Biological Psychiatry
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• v.27 no.1
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• pp.27-35
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• 2020

Objectives Ketamine has been reported to have antidepressant effects or psychotomimetic effects. The aim of this study was to investigate the behavioral effects of ketamine treatment at various sub-anesthetic doses in adolescent and adult naïve mice. Methods In each experiment for adolescent and adult mice, a total of 60 male Institute of Cancer Research mice were randomly divided into 6 groups, which were intraperitoneally treated with physiological saline, 10, 20, 30, 40, and 50 mg/kg ketamine for consecutive 3 days. At 1 day after last injection, the locomotor and depressive-like behaviors were evaluated in mice, using open field test (OFT) and forced swim test (FST), respectively. Results In case of adolescent mice, ketamine dose was negatively correlated with total distance traveled in the OFT (Spearman's rho = -0.27, p = 0.039). In case of adult mice, we found significant positive correlation between ketamine dose and duration of immobility in the FST (Spearman's rho = 0.45, p < 0.001). Immobility time in the 50 mg/kg ketamine-treated mice was significantly higher compared to the saline-treated mice (Dunnett's post-hoc test, p = 0.012). Conclusions We found that the repeated treatment with ketamine could decrease the locomotor or prolong the duration of immobility in mice as the dose of ketamine increased. Our findings suggest that sub-anesthetic doses of ketamine might induce schizophrenia-like negative symptoms but not antidepressant effects in naïve laboratory animals.

• Journal of Veterinary Clinics
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• v.14 no.1
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• pp.30-36
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• 1997

It is well estabilished that IL-4, IL-6, $IFN{\gamma}$ and immunoglobulin production are increased as a consequence of advancing age, and endothelial cells increase their expression of pro-inflammatory surface protein, such as ICAM-1, as a consequence of contact with inflammatory cytokines, including IL-1, $TNF{\alpha} or INF{\gamma}.$ This study was designed to define the relationship between age-associated changes of cytokines and immunoglobulin production and ICAM-1 expression in aged mice. Serum from aged mice had elevated IL-6 and immunoglobulin levels compared to mature adult controls and activation-induced production of $IFN{\gamma}$ of splenocytes from aged mice were increased above normal adult level. By immunoperoxidase staining, ICAM-1 in hearts of normal adult mice was expressed occasionally at low levels, but in aged mice, the number of positive blood vessels for ICAM-1 were increased and also the immunoreactivity were stronger. Therefore, these finding indicate that the altered expression of ICAM-1 eith normal aging may actually be correlative to these age-related changes in cytokiness and immunoglobulin production.

• BMB Reports
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• v.57 no.4
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• pp.182-187
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• 2024

Neural stem cells (NSCs) in the adult hippocampus divide infrequently; the endogenous molecules modulating adult hippocampal neurogenesis (AHN) remain largely unknown. Here, we show that ErbB3 binding protein 1 (Ebp1), which plays important roles in embryonic neurodevelopment, acts as an essential modulator of adult neurogenic factors. In vivo analysis of Ebp1 neuron depletion mice showed impaired AHN with a low number of hippocampal NSCs and neuroblasts. Ebp1 leads to transcriptional repression of Bmp4 and suppression of Ascl1 promoter methylation in the dentate gyrus of the adult hippocampus reflecting an unusually high level of Bmp4 and low Ascl1 level in neurons of Ebp1-deficient mice. Therefore, our findings suggests that Ebp1 could act as an endogenous modulator of the interplay between Bmp4 and Ascl1/Notch signaling, contributing to AHN.

• IMMUNE NETWORK
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• v.14 no.2
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• pp.100-106
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• 2014

Infection with invasive Shigella species results in intestinal inflammation in humans but no symptoms in adult mice. To investigate why adult mice are resistant to invasive shigellae, 6~8-week-old mice were infected orally with S. flexneri 5a. Shigellae successfully colonized the small and large intestines. Mild cell death was seen but no inflammation. The infected bacteria were cleared 24 hours later. Microarray analysis of infected intestinal tissue showed that several genes that are involved with the sphingosine-1-phosphate (S1P) signaling pathway, a lipid mediator which mediates immune responses, were altered significantly. Shigella infection of a human intestinal cell line modulated host S1P-related genes to reduce S1P levels. In addition, co-administration of S1P with shigellae could induce inflammatory responses in the gut. Here we propose that Shigella species have evasion mechanisms that dampen host inflammatory responses by lowering host S1P levels in the gut of adult mice.

• International Journal of Oral Biology
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• v.34 no.4
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• pp.191-197
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• 2009

Somatostatin (SST) is a known neuromodulator of the central nervous system. The substantia gelatinosa (SG) of the trigeminal subnucleus caudalis (Vc) receives many thinmyelinated $A{\delta}$-fiber and unmyelinated C primary afferent fibers and is involved in nociceptive processing. Many studies have demonstrated that SST plays a pivotal role in pain modulation in the spinal cord. However, little is yet known about the direct effects of SST on the SG neurons of the Vc in adult mice. In our present study, we investigated the direct membrane effects of SST and a type 2 SST receptor agonist, seglitide (SEG), on the SG neurons of the Vc using a gramicidin-perforated current clamp in adult mice. The majority (53%, n = 27/51) of the adult SG neurons were hyperpolarized by SST (300 nM) but no differences were found in the hyperpolarization response rate between males and females. When SST was applied successively, the second response was smaller ($76{\pm}9.5%$, n=19), suggesting that SST receptors are desensitized by repeated application. SST-induced hyperpolarization was also maintained under conditions where presynaptic events were blocked ($75{\pm}1.0%$, n=5), suggesting that this neuromodulator exerts direct effects upon postsynaptic SG neurons. SEG was further found to induce membrane hyperpolarization of the SG neurons of the Vc. These results collectively demonstrate that SST inhibits the SG neuronal activities of the Vc in adult mice with no gender bias, and that these effects are mediated via a type 2 SST receptor, suggesting that this is a potential target for orofacial pain modulation.