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Temporal niche partitioning is a crucial strategy for sympatric species to avoid predation and competition for habitat space and food resources. This study investigated the effect of the gut microbiota on the metabolic rhythms of two sympatric gerbil species (Meriones unguiculatus and Meriones meridianus) to test the hypothesis that the oscillatory patterns of microbiota may not fully mirror those of the host's metabolism. Experiment 1 compared the circadian metabolic and gut microbiota rhythms of M. unguiculatus (n = 12) and M. meridianus (n = 12) and measured the subjects' body temperatures and environmental temperature preferences. In Experiment 2.1, six M. meridianus gerbils were treated with antibiotics, and in Experiment 2.2, 21 M. unguiculatus gerbils (seven per treatment) were randomly gavaged with saline or a gut microbiota suspension from either M. unguiculatus or M. meridianus; their metabolic rhythms were subsequently measured. The results showed that the two gerbils had different metabolic phenotypes that determined activity heterogeneity and contributed to their coexistence. The relative abundances of Bacteroidetes, Actinobacteria, and Cyanobacteria in M. meridianus varied rhythmically in parallel with the daily metabolic rate, which was significantly higher at night than during the day. The rhythm of the metabolic rate was not noticeable in M. unguiculatus. However, in M.unguiculatus, the relative abundances of Firmicutes, Bacteroidetes, Proteobacteria, and Verrucomicrobia were significantly higher during the day than at night, while Cyanobacteria exhibited the opposite pattern. Antibiotic treatment significantly weakened the metabolic rhythms of M. meridianus, and the circadian rhythms slowly recovered after stopping antibiotic gavage. However, after transplanting M. meridianus' gut microbiota into M. unguiculatus, the metabolic rate of M. unguiculatus was not significantly different from that of the control groups. Our hypothesis was partly supported: the microbiota was only partially involved in regulating the metabolic rhythms of gerbils, and other factors could compensate for the effect of the gut microbiota on host metabolic rhythms. This finding underscores the complexity of host-microbiota interactions and highlights the need for further exploration into the multifaceted mechanisms governing host metabolic regulation., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aging causes changes in liver morphophysiology, altering hepatocyte morphology and organ function. Due to its antioxidant and anti-inflammatory properties, coconut oil has been used as a therapeutic agent in diets, in an attempt to attenuate alterations in the liver naturally caused by aging. Herein, we evaluated the effects of coconut oil consumption during aging on Mongolian gerbil liver morphophysiology. The animals were divided into three experimental groups: the gerbils in the Adult Control Group (AC) were euthanized at 3 months of age, the gerbils in the Old Control Group (OC) at 15 months of age, and the gerbils in the Coconut Oil Group (CO) received 0.1 ml/day of coconut oil for 12 months and were euthanized at 15 months of age. Prolonged consumption of coconut oil during aging prevented the animals and the liver from gaining mass. However, the other results showed that coconut oil intensified the morphophysiological alterations of aging, promoting an increase in the hepatocyte cytoplasm and nuclei. In addition, an increase in blood vessels, reticular fibers, lipid droplets, and lipofuscin granules were observed in the CO group. Finally, the results also demonstrated that coconut oil promotes an increase in lipid peroxidation, indicated by an increase in MDA levels. We therefore conclude that coconut oil has the potential to intensify the morphophysiological alterations that occur in the liver during aging., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

In photoperiod-sensitive wild animals, the secretion of melatonin (MT) is modulated by external photoperiod, and MT affects inflammation and the ageing process. The beneficial effects of MT in delaying the progress of ageing have been reported in laboratory mice and rats. However, little is known about MT in wild mammals. In the current study, we investigated energy metabolism, microbial community structure and colon homeostasis in ageing Mongolian gerbils (Meriones unguiculatus) through exogenous supplementation of MT to test the hypothesis that MT has beneficial effects on gut homeostasis in ageing gerbils. Exogenous MT supplementation had no effect on energy metabolism in Mongolian gerbils but reduced the levels of circulating tumor necrosis factor-α (TNF-α), immune globulin G (IgG) and corticosterone (CORT). The increase in the level of inflammation in ageing animals was related to changes in the structure and diversity of the gut microbiota. At the genus level, the relative abundance of Prevotella, Treponema, Corynebacterium, and Sphingomonas was increased in ageing animals and decreased significantly by the treatment of MT. Christensenella and Lactobacillus were attenuated in ageing animals, and tended to be enhanced by MT treatment. Functions related to glycosphingolipid biosynthesis-ganglio series and lipopolysaccharide biosynthesis (metabolisms of cofactors, vitamins and glycan) were increased in ageing animals and decreased significantly by the treatment of MT. Our data suggest that a supplement of MT could improve colon homeostasis through changing the composition of gut microbiota and reducing inflammation in ageing gerbils., Competing Interests: Declaration of competing interest The information presented in this manuscript is original and has not been submitted for publication anywhere else. All the authors listed have approved the manuscript and have no competing interests., (Copyright © 2023. Published by Elsevier Inc.)

The nonapeptide system modulates a diversity of social behaviors, including aggression, parental care, affiliation, sexual behavior, and pair bonding. Such social behaviors are regulated through oxytocin and vasopressin activation of the oxytocin receptor (OXTR) and vasopressin V1a receptor (AVPR1A) in the brain. Nonapeptide receptor distributions have been mapped for several species, however, studies have demonstrated that there is substantial variation across species. Mongolian gerbils (Meriones unguiculatus) are an excellent organism for studying family dynamics, social development, pair bonding, and territorial aggression. Although an increasing number of studies are examining the neural mechanisms of social behavior in Mongolian gerbils, nonapeptide receptor distributions have yet to be characterized for this species. Here we conducted receptor autoradiography to map distributions of OXTR and AVPR1A binding throughout the basal forebrain and midbrain of female and male Mongolian gerbils. Further, we assessed whether gonadal sex influenced binding densities in brain regions important for social behavior and reward, however, we observed no effects of sex on OXTR or AVPR1A binding densities. These findings provide mapping distributions of nonapeptide receptors in male and female Mongolian gerbils, laying a foundation for future studies that seek to manipulate the nonapeptide system to examine nonapeptide-mediated social behavior., (Copyright © 2023 IBRO. Published by Elsevier Ltd. All rights reserved.)

The Zwicker tone illusion - an auditory phantom percept after hearing a notched noise stimulus - can serve as an interesting model for acute tinnitus. Recent mechanistic models suggest that the underlying neural mechanisms of both percepts are similar. To date it is not clear if animals do perceive the Zwicker tone, as up to now no behavioral paradigms are available to objectively assess the presence of this phantom percept. Here we introduce, for the first time, a modified version of the gap pre-pulse inhibition of the acoustic startle reflex (GPIAS) paradigm to test if it is possible to induce a Zwicker tone percept in our rodent model, the Mongolian gerbil. Furthermore, we developed a new aversive conditioning learning paradigm and compare the two approaches. We found a significant increase in the GPIAS effect when presenting a notched noise compared to white noise gap pre-pulse inhibition, which is consistent with the interpretation of a Zwicker tone percept in these animals. In the aversive conditioning learning paradigm, no clear effect could be observed in the discrimination performance of the tested animals. When investigating the first 33% of the correct conditioned responses, an effect of a possible Zwicker tone percept can be seen, i.e. animals show identical behavior as if a pure tone was presented, but the paradigm needs to be further improved. Nevertheless, the results indicate that Mongolian gerbils are able to perceive a Zwicker tone and can serve as a neurophysiological model for human tinnitus generation., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The extremely species-rich genus Trypanosoma has recently been divided into 16 subgenera, most of which show fairly high host specificity, including the subgenus Herpetosoma parasitizing mainly rodents. Although most Herpetosoma spp. are highly host-specific, the best-known representative, Trypanosoma lewisi, has a cosmopolitan distribution and low host specificity. The present study investigates the general diversity of small mammal trypanosomes in East and Central Africa and the penetration of invasive T. lewisi into communities of native rodents. An extensive study of blood and tissue samples from Afrotropical micromammals (1528 rodents, 135 shrews, and five sengis belonging to 37 genera and 133 species) captured in the Central African Republic, Ethiopia, Kenya, Malawi, Mozambique, Tanzania, and Zambia revealed 187 (11.2%) trypanosome-positive individuals. The prevalence of trypanosomes in host genera ranged from 2.1% in Aethomys to 37.1% in Lemniscomys. The only previously known trypanosome detected in our dataset was T. lewisi, newly found in Ethiopia, Kenya, and Tanzania in a wide range of native rodent hosts. Besides T. lewisi, 18S rRNA sequencing revealed 48 additional unique Herpetosoma genotypes representing at least 15 putative new species, which doubles the known sequence-based diversity of this subgenus, and approaches the true species richness in the study area. The other two genotypes represent two new species belonging to the subgenera Ornithotrypanum and Squamatrypanum. The trypanosomes of white-toothed shrews (Crocidura spp.) form a new phylogroup of Herpetosoma, unrelated to flagellates previously detected in insectivores. With 13 documented species, Ethiopia was the richest region for trypanosome diversity, which corresponds to the very diverse environments and generally high biodiversity of this country. We conclude that besides T. lewisi, the subgenus Herpetosoma is highly host-specific (e.g., species parasitizing the rodent genera Acomys and Gerbilliscus). Furthermore, several newly detected trypanosome species are specific to their endemic hosts, such as brush-furred mice (Lophuromys), dormice (Graphiurus), and white-toothed shrews (Crocidura)., (Copyright © 2022. Published by Elsevier Ltd.)

Leishmania RNA virus (LRV) is a double-strand RNA virus that was first detected in members of the Leishmania viannia in the New World. The present study aimed to investigate the presence of LRV in the Leishmania species isolated from cutaneous leishmaniasis (CL) patients and rodents as reservoirs in Isfahan province an old zoonotic CL focus, center of Iran. Totally, 85 samples were collected from CL patients (n = 80) and rodent reservoirs (n = 5) from different regions of Isfahan province. Species identification was determined using the PCR-RFLP method. Viral dsRNA was extracted and for observation of 5.3 kb dsRNA on an agarose gel. The presence of LRV was surveyed using the Semi-nested PCR method. For phylogenetic analyzes, 6 samples of 13 isolates were sequenced and a phylogenetic tree was drawn by MEGA7 version 7.0.26. Of 80 Leishmania isolates recovered from the patients with CL, 79 and only one were identified as L. major and L. tropica, respectively. Also, the PCR assays detected four L. major and one L. turanica in five assessed Rhombomys opimus as the rodent reservoirs. LRV was detected only in Leishmania species isolated from 13 species of 85 (15.3%) CL including (L. major, n = 12) and (L. tropica, n = 1). Phylogenetic analysis showed that they were belonged to LRV2 and had the highest similarity with Iranian reference LRV2 in GenBank. Our results showed that the LRV2 was present in cutaneous Leishmania species in Isfahan province is the most historical and touristic province of Iran. In the study LRV was not reported from rodent reservoirs, it may be due to the small sample size. Phylogenetic analysis of current sequences demonstrated that these isolates belong to the registered LRV2 of the Old World., (Copyright © 2022. Published by Elsevier B.V.)

Localization of sound sources in the environment requires neurons that extract interaural timing differences (ITD) in low-frequency hearing animals from fast and precisely timed converging inputs from both ears. In mammals, this is accomplished by neurons in the medial superior olive (MSO). MSO neurons receive converging excitatory input from both the ipsilateral and contralateral cochlear nuclei and glycinergic, inhibitory input by way of interneurons in the medial and lateral nuclei of the trapezoid body (MNTB and LNTB, respectively). Key features of the ITD circuit are MSO neurons with symmetric dendrites that segregate inputs from the ipsilateral and contralateral ears and preferential distribution of glycinergic inputs on MSO cell bodies. This circuit for ITD is well characterized in gerbils, a mammal with a prominent MSO and a low-frequency hearing range similar to humans. However, the organization of this circuit in the human MSO has not been characterized. This is further complicated by limited understanding of the human LNTB. Nonetheless, we hypothesized that the ITD circuit characterized in laboratory animals is similarly arranged in the human MSO. Herein, we utilized neuron reconstructions and immunohistochemistry to investigate the distribution of glutamatergic and glycinergic inputs onto human MSO neurons. Our results indicate that human MSO neurons have simple, symmetric dendrites and that glycinergic inputs outnumber glutamatergic inputs on MSO cell bodies and proximal dendrites. Together these results suggest that the human MSO utilizes similar circuitry to other mammals with excellent low-frequency hearing., (Copyright © 2021 IBRO. Published by Elsevier Ltd. All rights reserved.)

Ultrasonic vocalizations (USVs) play an important role in parent-infant interactions during the neonatal period of rodents because of the pups' need to be suckled and protected by their parents. However, studies on the effects of USVs on parental care are focused on maternal behavior, and little data on paternal care are available, with especially few investigations in midday gerbils. In this study, we examined the effects of early social deprivation (ED) on offspring due to USVs and parental behavior responses in midday gerbils (Meriones meridianus). The results indicated that the number of USVs in ED gerbils increased on postnatal day nine (40 calls/minute), whereas the number of gerbils in the parental care (PC) group remained high for up to 2 weeks (46.6 calls/minute), before decreasing. The number of USVs and duration of single syllables from postnatal day 3 to 21 in ED pups were significantly lower than those in PC pups. ED increased maternal licking, grooming behavior, and nest-building, but decreased huddling and exploring behavior. Similarly, ED increased paternal behavior, like nest-building, but reduced exploring and self-grooming. Overall, gerbil pups displayed high levels of USVs and various syllable types before weaning. ED significantly reduced the number of USVs and syllable types, but increased maternal licking, grooming, and paternal nest-building behavior., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The morbidity and mortality of coxsackievirus A10 (CVA10)-associated hand, foot, and mouth disease (HFMD) have been increasing in recent years, while few studies on the vaccine and animal model of CVA10 have been reported. Here, we first established a CVA10-infected gerbil model and employed it to evaluate the immunoprotective effect of an inactivated CVA10 vaccine. The results showed that gerbils up to the age of 14 days were fully susceptible to CVA10, and all died within five days post-infection by intraperitoneal inoculation. Lethargy, wasting, hind-limb paralysis, and even death could be observed in the CVA10-infected gerbils. Pathological examination suggested that CVA10 has a strong tropism toward muscle tissue, and muscle bundle fracture and muscular fibers necrosis were observed in the limb muscles. Additionally, active immunization results showed that gerbils immunized with the inactivated CVA10 vaccine were 100 % protected from lethal CVA10 challenge. The antisera from vaccinated gerbils also showed high neutralizing titers against CVA10. Based on these results, the CVA10-infected gerbil model was a suitable tool for analyzing the pathogenesis of CVA10 and assessing the protective efficacy of CVA10 candidate vaccines., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Quinestrol and levonorgestrel (EP-1, at a ratio of 1:2) are often used as anti-fertility compounds (sterilants) in rodents. As most of the research has focused on the sterility and damage caused in parental reproductive organs, there is little research on the effect of these contraceptive hormones on maternal behavior and offspring's early development. In this study, we examined maternal behavior after treatment with different doses of EP-1 (10 ml/kg) at postnatal days 3 and 10, separately. Various parameters were measured after treatment, including oxytocin expression, serum levels of estradiol and luteinizing hormone (LH), ovary damage after weaning of offspring, as well as the development and ultrasonic vocalizations (USVs) of midday gerbil (Meriones meridianus) offspring. At postnatal days 5 and 12, the EP-1 increased maternal licking, grooming, and retrieving behavior, while reducing contacting behavior. Oxytocin expression in the hypothalamic paraventricular and supraoptic nuclei increased, while the levels of estradiol and LH decreased. The ovaries and the development of follicles were clearly affected by the treatment. The EP-1 significantly reduced the pups' body weight, the amount and pulse duration of USVs, whereas the frequency range variation of USVs was increased. Overall, treatment with EP-1 during lactation significantly affected maternal behavior and impaired offspring early development in the midday gerbil., Competing Interests: Declaration of interest All authors agree with the results and conclusions in this study and agree to publish. There are no conflicts of interest to declare., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Neospora caninum is a causative and transmissible agent of dog and bovine neosporosis. The resulting reproductive failures in infected cattle lead to significant economic losses worldwide. However, there is no satisfactory treatment or vaccine currently available to combat this pathogen. Thus, the development of appropriate vaccines to manage its infection and transmission is urgently needed. In this study, we expressed Rous sarcoma virus-like particles (RSV-LP) that displayed dual N. caninum antigens in silkworms. The antigen candidates are modified by adding a transmembrane domain of GP64 protein from Bombyx mori nucleopolyhedrovirus (BmNPV) to the C-terminus of surface antigen 1 (NcSAG1) and SAG1-related sequence 2 (NcSRS2). The NcSRS2 alone or the NcSAG1/NcSRS2 bivalent form displaying RSV-LPs were purified using sucrose density gradient centrifugation. These purified VLPs were then used for immunizations in gerbils, Meriones unguiculatus, to evaluate the anti-N. caninum effects in vivo. The results demonstrated that antigens displaying RSV-LPs in immunized gerbils produced the antigen-specific antibody, leading to a relatively lower parasite load after infections of N. caninum. To the best of our knowledge, this is the first study to present an RSV-LP vaccine displaying bivalent antigens from neosporosis. Taken together, our strategy suggests that silkworm-expressed virus-like particles (VLPs) are promising bivalent vaccine candidates against N. caninum infections., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

A suitable animal model of CVA16 infection is crucial in order to understand its pathogenesis and to help develop antiviral vaccines or screen therapeutic drugs. The neonatal mouse model has a short sensitivity period to CA16 infection, which is a major limitation. In this study, we demonstrate that adult (60-day-old) gerbils are susceptible to CVA16 infection at high doses (10 8.0 TCID 50 ). A clinical isolate strain of CVA16 was inoculated intraperitoneally into adult gerbils, which subsequently developed significant clinical symptoms, including hind limb weakness, paralysis of one or both hind limbs, tremors, and eventual death from neurological disorders. Real-time RT-PCR revealed that viral loads in the spinal cord and brainstem were higher than those in other organs/tissues. Histopathological changes, such as neuronal degeneration, neuronal loss, and neuronophagia, were observed in the spinal cord, brainstem, and heart muscle, along with necrotizing myositis. Gerbils receiving both prime and boost immunizations of alum adjuvant inactivated vaccine exhibited no clinical signs of disease or mortality following challenge by CVA16, whereas 80% of control animals showed obvious clinical signs, including slowness, paralysis of one or both hind limbs, and eventual death, suggesting that the CVA16 vaccine can fully protect gerbils against CVA16 challenge. These results demonstrate that an adult gerbil model provides us with a useful tool for studying the pathogenesis and evaluating antiviral reagents of CVA16 infection. The development of this animal model would also be conducive to screening promising CVA16 vaccine candidates as well as further vaccination evaluation., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Agmatine (AgM, 100 mg/kg i.p.) effect was tested in parallel at two animal models of cerebral ischemia - rat MCAO model (60'/24 h, 60'/48 h, 90'/24 h, 90'/48 h) and gerbil global ischemia (10') model, administrated 5 min after reperfusion. Aim was to evaluate AgM effect on functional outcome 24 and 48 h after MCAO on neurological and sensor-motor function, and coordination in rats. AgM administration significantly reduced infarct volume, improved neurological score and improved post-ischemic oxidative status. Results of behavioral tests (cylinder test, beam walking test, and adhesive removal test) have shown very effective functional recovery after AgM administration. Efficiency of AgM administration in gerbils was observed in forebrain cortex, striatum, hippocampus, and cerebellum at the level of each examined oxidative stress parameter (nitric oxide level, superoxide production, superoxide dismutase activity, and index of lipid peroxidation) measured in four different time points starting at 3 h up to 48 h after reperfusion. The highest levels were obtained 6 h after the insult. The most sensitive oxidative stress parameter to AgM was nitric oxide. Additionally, we performed pharmacological analysis of AgM on rat isolated common carotid arteries. The findings imply that mixed population of potassium channels located on the smooth muscle cells was involved in common carotid artery response to AgM, with predominance of inward rectifying K + channels. In our comparative experimental approach, judged by behavioral, biochemical, as well as pharmacological data, the AgM administration showed an effective reduction of ischemic neurological damage and oxidative stress, hence indicating a direction towards improving post-stroke recovery., (Copyright © 2019. Published by Elsevier Inc.)

The present study evaluates the role of social factors in the transition from infanticidal to paternal male behavior and its association with T concentration, presence of estrogen receptor alpha (ERα) and androgen receptor (AR) in the olfactory bulb (OB), medial preoptic area (mPOA) and medial amygdala (MeA) of Mongolian gerbils (Meriones unguiculatus). This study included thirty-six sexually inexperienced males displaying aggressive behavior toward foreign pups. The selected animals were mated and organized into four groups. The paternal behavior tests were performed on the day of copulation (DCOPUL), during cohabitation with a pregnant female (CPREG), on the day of birth (DBIRTH), and on day 6 postpartum (DPP6). Eight sexually inexperienced males (CTL (male-male cohabitation) were used as control. After paternal behavior tests, blood samples were obtained to quantify T by radioimmunoassay; the brains were removed and analyzed for immunoreactivity (ir) of ERα and AR. All males of the DCOPUL, DBIRTH, and DPP6 groups exhibited paternal behavior, whereas the males of CPREG and CTL groups were aggressive with the pups. Paternal behavior was associated with high T concentrations, and the presence of ERα-ir and AR-ir in the OB, MeA, and mPOA. These results suggest that the transition from aggressive to paternal response to pups is facilitated by copulation, and that in this transition is involved an increase in T concentration. Moreover, the presence of ERα-ir and AR-ir in the OB, mPOA, and MeA could indicate that estrogenic and androgenic pathways participate in the regulation of paternal behavior of the Mongolian gerbils., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Bartonellae bacteria are associated with several re-emerging human diseases. These vector-borne pathogens have a global distribution, yet data on Bartonella prevalence and diversity in the Arabian Peninsula are limited. In this study we assessed the Bartonella infection status of the Baluchistan gerbil (Gerbillus nanus), a species associated with pastoral communities throughout the Middle East region, using a multi-gene PCR screening approach. The results demonstrated that 94 (68.1%) of the 138 gerbils trapped on a monthly basis, over a period of one year, were PCR-positive. Sequencing of the gltA gene region confirmed the presence of four discrete Bartonella lineages (I-IV) and high levels of co-infection (33.0%). Each of the four lineages, varied in overall abundance (7.5%-47.9%) and had discernible seasonal peaks. Bartonella status was significantly correlated with ectoparasite presence, but not with sex, nor with season. Statistical analyses further revealed that co-infected individuals had a significantly higher relative body condition. Multi-locus sequence analysis (MLSA) performed with a concatenated dataset of three genetic loci (gltA, nuoG, and rpoB), 1452 nucleotides (nt) in length confirmed that lineage IV, which occurred in 24 PCR-positive animals (25.5%), is most closely related to zoonotic B. elizabethae. The remaining three lineages (I-III) formed a monophyletic clade which, on the basis of gltA was shown to contain bartonellae from diverse Gerbillinae species from the Middle East, suggestive of a gerbil-associated species complex in this region. Lineage I was identical to a Candidatus B. sanaae strain identified previously in Bushy-tailed jirds (Sekeetamys calurus) from Egypt, wherease MLSA indicate that lineages II and III are novel. The high levels of infection and co-infection, together with the presence of multiple Bartonella lineages indicate that Gerbillus nanus is likely a natural reservoir of Bartonella in the Arabian Peninsula., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Enterovirus 71 (EV71) is one of the major pathogens causing hand, foot, and mouth disease (HFMD) with neurological and systemic complications worldwide, and it is mostly discovered in infants and young children. It is of great significance to establish suitable animal models of EV71 infection on research of distribution and pathogenesis of the virus. In this study, we established a successful infection of a non-mouse-adapted isolate of EV71 via oral route in 7-day-old Mongolian gerbil (Meriones unguiculatus), all of which were paralyzed and died within 10 days post infection. Analysis of virus loads in twelve tissues showed that virus was first detected in intestine, blood, heart, lung, and muscle one day post-infection, and then in the rest of the tissues/organs within the next few days, among which thymus, spleen, spinal cord and muscles had the highest virus titer at 5 days post infection. Pathological examination showed that severe necrosis was observed in skeletal muscle and spinal cord, and edema was observed in both heart and lung. Comparisons of host gene expression of various tissues from infected and non-infected gerbils revealed a general up-regulation of genes related to anti-viral response and a viral receptor gene (sialic acid-linked glycans), as well as a tissue(gut)-specific up-regulation of genes related to neuronal communication. Collectively, our results showed that EV71 could induce severe neurological complications as well as massive tissue damage all over the body, which indicates that oral infection of 7-day gerbils can be a suitable animal model to study the infection of EV71 in human., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Exercise improves cognitive impairments induced by transient cerebral ischemia, and modulates synaptic adhesion molecules. In this study, we investigated effects of long-term treadmill exercise on cognitive impairments and its relation to changes of synaptic cell adhesion molecule (SynCAM) 1/2/3 in the hippocampus after 5 min of transient cerebral ischemia in aged gerbils. Animals were assigned to sedentary and exercised groups, given treadmill exercise for 4 consecutive weeks from 5 days after transient ischemia, and evaluated cognitive function through passive avoidance test and Morris water maze test. SynCAM 2 protein levels were determined in the hippocampus by western blot. In addition, neuronal and synaptic changes were examined by NeuN immunohistochemistry, and SynCAM 1/2/3 and MAP2 double immunofluorescence, respectively. We found that transient cerebral ischemia led to neuronal death in the CA1 area and dentate gyrus, and impaired -memory function; however, 4 weeks of treadmill exercise improved ischemia-induced memory impairment. In addition, SynCAM 1/2/3 and SynCAM 2 expression in the hippocampus was significantly decreased in the sedentary group after transient cerebral ischemia; however, SynCAM 1/2/3 expressionand and SynCAM 2 protein level was significantly increased in the ischemic group with exercise. These results suggest that long-term treadmill exercise improves memory impairment through the restoration of decreased SynCAM 1/2/3 expression in the hippocampus induced by transient cerebral ischemia in the aged gerbil., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Pseudorabies virus (PRV), a neurovirulent α-herpesvirus, spreads between neurons at synaptic connections. PRV-infected neurons have been shown to exhibit functional deficits with the attenuated PRV152 Bartha strain negatively influencing neuronal functioning in in vitro model systems. However, the impact of this attenuated PRV152 Bartha strain on the native central nervous system has not been fully explored. Using a combination of in vivo stereotactic injections and post-hoc in vitro whole-cell recordings, we investigated the functional impact of PRV152 Bartha in the auditory system of juvenile Mongolian gerbils. The specificity of this virus strain to spread exclusively trans-synaptically in a retrograde fashion and the well-defined structure of the ascending auditory brainstem pathways allowed us to determine the physiological alterations in primary and secondary infected neurons. We find at primary and secondary infections sites, the inferior colliculus (IC) and dorsal nucleus of the lateral lemniscus respectively, a reduced excitability of infected cells. The loss of excitability is manifested by an increase in current threshold and a loss of action potential generation. The minor changes in the approximated passive membrane parameters induced by the infection cannot explain the full loss in excitability, indicating that channel densities and properties have changed. This impact on neuronal functioning might contribute to the lethal neurovirulent effects of PRV viruses as vital neuronal circuits might cease activity. Since the detrimental effects of the attenuated PRV152 Bartha strain are reduced compared to wild-type strains, it comprises an excellent tool to study the neuropathological mechanisms of viral infections., (Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.)

The potential contribution of auditory synaptopathy to age dependent hearing loss was studied in groups of young and old gerbils. The analysis of the number of inner hair cell ribbon synapses in aged gerbils (37.9±3.3months of age) revealed only a relatively small (11-17%) loss in the basal two thirds of the cochlea, while a more pronounced reduction was identified towards the apex (almost 40%) when compared to a group of young gerbils (9.5±3.2months of age). Mean threshold elevation in the old gerbils was around 25dB at 2 and 10kHz. Frequency-specific behavioral thresholds and ribbon synapse counts were not significantly correlated for the middle and basal regions of the cochlea, despite thresholds varying over a 45dB SPL range. This suggests that besides a small age-dependent loss of ribbon synapses, additional cochlear pathologies, most likely a decreased endocochlear potential, contribute to peripheral hearing loss in old gerbils., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Proline rich Akt substrate (PRAS40) is a component of mammalian target of rapamycin complex 1 (mTORC1) and is known to play an important role against reactive oxygen species-induced cell death. However, the precise function of PRAS40 in ischemia remains unclear. Thus, we investigated whether Tat-PRAS40, a cell-permeable fusion protein, has a protective function against oxidative stress-induced hippocampal neuronal (HT-22) cell death in an animal model of ischemia. We showed that Tat-PRAS40 transduced into HT-22 cells, and significantly protected against cell death by reducing the levels of H2O2 and derived reactive species, and DNA fragmentation as well as via the regulation of Bcl-2, Bax, and caspase 3 expression levels in H2O2 treated cells. Also, we showed that transduced Tat-PARS40 protein markedly increased phosphorylated RRAS40 expression levels and 14-3-3σ complex via the Akt signaling pathway. In an animal ischemia model, Tat-PRAS40 effectively transduced into the hippocampus in animal brain and significantly protected against neuronal cell death in the CA1 region. We showed that Tat-PRAS40 protein effectively transduced into hippocampal neuronal cells and markedly protected against neuronal cell damage. Therefore, we suggest that Tat-PRAS40 protein may be used as a therapeutic protein for ischemia and oxidative stress-induced brain disorders., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Our previous study demonstrated that quercetin-metabolite-enriched plasma (QP) but not quercetin itself upregulates peroxisome proliferator-activated receptor gamma (PPAR-γ) expression to induce G2/M arrest in A549 cells. In the present study, we incubated A549 cells with QP as well as quercetin-3-glucuronide (Q3G) and quercetin-3'-sulfate (Q3'S), two major metabolites of quercetin, to investigate the effects of quercetin metabolites on cell invasion and migration, the possible mechanisms and the role of PPAR-γ. We also compared the effects of QP with those of quercetin and troglitazone (TGZ), a PPAR-γ ligand. The results showed that QP significantly suppressed cell invasion and migration, as well as matrix metalloproteinases (MMPs)-2 activity and expression in a dose-dependent manner. The effects of 10% QP on those parameters were similar to those of 10μM quercetin and 20μM TGZ. However, QP and TGZ rather than quercetin itself increased the expressions of nm23-H1 and tissue inhibitor of metalloproteinase (TIMP-2). Furthermore, we demonstrated that Q3G and Q3'S also inhibited the protein expression of MMP-2. GW9662, a PPAR-γ antagonist, significantly diminished such an effect of Q3G and Q3'S. Silencing PPAR-γ expression in A549 cells also significantly diminished the suppression effect of Q3G and Q3'S on MMP-2 expression. Taken together, our study demonstrated that QP inhibited cell invasion and migration through nm23-H1/TIMP-2/MMP-2 associated mechanisms. The upregulation of PPAR-γ by quercetin metabolites such as Q3G and Q3'S could play an important role in the effects of QP., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The larval stages of the cestodes Echinococcus multilocularis and Echinococcus granulosus cause the important zoonoses known as larval echinococcoses. These larvae are protected by a unique, massive, mucin-based structure known as the laminated layer. The mucin glycans of the E. granulosus laminated layer are core 1- or core 2-based O-glycans in which the core Galpβ1-3 residue can initiate a chain comprising one to three additional Galpβ1-3 residues, a motif not known in mammalian carbohydrates. This chain can be capped with a Galpα1-4 residue, and can be ramified with GlcNAcpβ1-6 residues. These, as well as the GlcNAcpβ1-6 residue in core 2, can be decorated with the Galpα1-4Galpβ1-4 disaccharide. Here we extend our analysis to the laminated layer of E. multilocularis, showing that the non-decorated cores, together with Galpβ1-3(Galpα1-4Galpβ1-4GlcNAcpβ1-6)GalNAc, comprise over 96% of the glycans in molar terms. This simple laminated layer glycome is exhibited by E. multilocularis grown either in vitro or in vivo. Interestingly, all the differences with the complex laminated layer glycome found in E. granulosus may be explained in terms of strongly reduced activity in E. multilocularis of a putative glycosyltransferase catalysing the elongation with Galpβ1-3. Comparative inter-species analysis of available genomic and transcriptomic data suggested a candidate for this enzyme, amongst more than 20 putative (non-core 1) Gal/GlcNAc β1-3 transferases present in each species as a result of a taeniid-specific gene expansion. The candidate gene was experimentally verified to be transcribed at much higher levels in the larva of E. granulosus than that of E. multilocularis., (Copyright © 2016 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved.)

Ischemic tolerance (IT) is induced by a variety of insults to the brain (e.g., nonfatal ischemia, heat and hypoxia) and it provides a strong neuroprotective effect. Although the mechanisms are still not fully elucidated, Ca(2+) is regarded as a key mediator of IT. Ryanodine receptors (RyRs) are located in the sarcoplasmic/endoplasmic reticulum membrane and are responsible for the release of Ca(2+) from intracellular stores. In brain, neuronal RyRs are thought to play a role in various neuropathological conditions, including ischemia. The purpose of the present study was to investigate the involvement of RyRs in IT. Pretreatment with a RyR antagonist, dantrolene (25mg/kg, i.p), blocked IT in a gerbil global ischemia model, while a RyR agonist, caffeine (100mg/kg, i.p), stimulated the production of IT. In vitro, using rat hippocampal cells, short-term oxygen/glucose deprivation induced preconditioning and RyR antagonists, dantrolene (50 and 100 μM) and ryanodine (100 and 200 μM) prevented it. RyR protein and mRNA levels were transiently decreased after induction of IT. These results suggest that RyRs are involved in the induction of ischemic tolerance., (Copyright © 2016 Elsevier Inc. All rights reserved.)

To better understand how desert rodents adapt to water scarcity, we examined urine osmolality, renal distribution and expression of aquaporins (AQPs) in Mongolian gerbils (Meriones unguiculatus) during 7 days of water deprivation (WD). Urine osmolality of the gerbils during WD averaged 7503 mOsm kg(-1). Renal distributions of AQP1, AQP2, and AQP3 were similar to that described in other rodents. After the 7 day WD, renal AQP2 was up-regulated, while resting metabolic rate and total evaporative water loss decreased by 43% and 36%, respectively. Our data demonstrated that Mongolian gerbils showed high urine concentration, renal AQPs expression and body water conservation to cope with limited water availability, which may be critical for their survival during dry seasons in cold deserts., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Tinnitus often occurs after exposure to loud noise. This raises the question of whether repeated exposure to noise increases the risk of developing tinnitus. We thus studied tinnitus development after repeated acoustic overstimulation using startle and auditory brainstem-response techniques applied to Mongolian gerbils. Noise with bandwidths ranging from 0.25 up to 0.5 oct were used for repeated acoustic overstimulation. Auditory brainstem response measurements revealed similar threshold shifts in both groups of up to about 30 dB directly after the acoustic overstimulation. We identified an upper limit in threshold values, which was independent of the baseline values before the noise exposure. Several weeks after the acoustic overstimulation, animals with the noise bandwidth of 0.25 oct showed a permanent threshold shift, while animals of the group with the 0.5-oct noise band featured only a temporary threshold shift. We thus conclude that the threshold shift directly after noise exposure cannot be used as an indicator for the upcoming threshold level several weeks later. By using behavioral measurements, we investigated the frequency-dependent development of tinnitus-related changes in both groups and one group with 1-oct noise bandwidth. The number of animals that show tinnitus-related changes was highest in animals that received noise with the bandwidth 0.5 oct. This number was, in contrast to the number of animals in the 0.25-oct bandwidth, not significantly increased after repeated overstimulation. The frequency distribution of tinnitus-related changes ranged from 4 to 20 kHz. In the group with the narrow-band noise (0.25 oct) changes center at one frequency range from 10 to 12 kHz. In the group with the broader noise band (0.5 oct), however, two peaks at 8-10 kHz and at 16-18 kHz were found, which suggests that different mechanisms underlie the tinnitus development., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Physical exercise is a non-pharmacological treatment for affective disorders. The mechanisms of its effects are unknown although some suggest a relationship to synchronization of circadian rhythms. One way to explore mechanisms is to utilize animal models. We previously demonstrated that the diurnal fat sand rat is an advantageous model for studying the interactions between photoperiods and mood. The current study was designed to evaluate the effects of voluntary exercise on activity rhythms and anxiety and depression-like behaviors in sand rats as a step towards better understanding of the underlying mechanisms. Male sand rats were housed in short photoperiod (SP; 5h light/19 h dark) or neutral light (NP; 12h light/12h dark) regimens for 3 weeks and divided into subgroups with or without running wheels. Activity was monitored for 3 additional weeks and then animals were tested in the elevated plus-maze, the forced swim test and the social interaction test. Activity rhythms were enhanced by the running wheels. As hypothesized, voluntary exercise had significant effects on SP animals' anxiety- and depression-like behaviors but not on NP animals. Results are discussed in the context of interactions between physical exercise, circadian rhythms and mood. We suggest that the sand rat model can be used to explore the underlying mechanism of the effects of physical exercise for mood disorders., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Previous studies have shown that hepatitis E virus (HEV) can be transmitted between rats, pigs, cattle, rabbits, chicken, cats, and deer. Because wild and domestic rodents have anti-HEV antibodies, they are considered potential reservoirs of HEV. In the current study, Mongolian gerbils were experimentally infected with swine hepatitis E virus and the effects of this infection were investigated. After inoculation with HEV, the liver-to-body weight ratio increased at 7 dpi. Mongolian gerbils demonstrated significant increase (p<0.05) in Aspartate Transaminase (AST), alanine transaminase (ALT) and total bilirubin (T-BIL) concentrations in the sera, and HEV IgG was detected at 21 days post-inoculation (dpi). Real-time PCR revealed that the copies of HEV RNA in the liver were detected at 7 dpi, and peaked at 28 dpi at a concentration of 7.73 logs g(-1). Using both light and electron microscopy, hepatic lesions were observed in the HEV inoculated animals. In the experimental group, characteristic viral hepatitis lesions were prominent in the liver. HEV antigen was detected in the liver by immunohistochemistry, and HEV ORF3 antigen was detectable in liver by Western blot. These results clearly demonstrate that viral load of HEV in livers was dynamic, and ultrastructural hepatic injury in HEV infected Mongolian gerbils and anti-HEV IgG positive seroconversion were observed during infection., (Copyright © 2015 Elsevier B.V. All rights reserved.)

In an effort to develop a new gastro-retentive drug delivery system (GRDDS) without a large amount of additives, 75% clarithromycin (CAM) loaded fine granules were prepared with three different hydrophobic binders by high-shear melt granulation and their properties were evaluated. Granules containing the higher hydrophobic binder showed sustained drug release and were able to float over 24h. The synchrotron X-ray CT measurement indicated that both the high hydrophobicity of the binder and the void space inside the granules might be involved in their buoyancy. In an in vivo experiment, the floating granules more effectively eradicated Helicobacter pylori than a CAM suspension by remaining in the stomach for a longer period. In short, CAM highly-loaded gastro-floating fine granules can enhance the eradication efficiency of H. pylori compared with CAM alone., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Parker's sperm competition model predicts a negative relationship between pre-copulatory (social status) and post-copulatory (sperm quality and quantity) sexually selected traits, however, empirical studies have revealed considerable inconsistency in this relationship. We hypothesized that there was a trade-off between pre- and post-copulatory sexually selected traits, and hormones (corticosterone, CORT; testosterone, T) orchestrate this relationship. In this study, we measured energetic parameters in the dominant-subordinate Mongolian gerbils (Meriones unguiculatus), whose relationship was established under chronic social encounters in a neutral arena, and then tested the relationship between their social status and sperm quality and quantity. Our results showed that dominant males initiated attack sooner and displayed more aggression, self-grooming and locomotion behaviors in daily social encounters across seven consecutive days. Dominant gerbils also had more and better quality of sperm than that of subordinate males, yet showed no significant differences in energy intake and RMR in comparison with subordinate individuals. In addition, dominant males had higher concentrations of serum T than subordinate males, whereas the concentrations of CORT showed a reverse pattern. The frequency and duration of aggression (indicative of social status) increased with elevated T concentrations. Sperm quality in terms of number and activity were associated with higher concentrations of serum T in dominant gerbils, whereas small sperm counts and poor-quality sperm were associated with relatively higher concentrations of serum CORT in subordinate gerbils. Together, our data indicated that there was no trade-off between pre- and post-copulatory sexually selected traits but hormones orchestrated the relationship between these traits in male Mongolian gerbils., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Ischemic preconditioning (IPC) provides neuroprotection against subsequent severe ischemic injury by activating specific mechanisms. In this study, we tested the hypothesis that IPC attenuates postischemic neuronal death via heme oxygenase-1 (HO-1). Animals used in this study were randomly assigned to 4 groups; sham-operated group, ischemia-operated group, IPC plus (+) sham-operated group and IPC+ischemia-operated group. IPC was induced by subjecting gerbils to 2min of ischemia followed by 1 day of recovery. A significant loss of neurons was observed in pyramidal neurons of the hippocampal CA1 region (CA1) in the ischemia-operated groups at 5 days postischemia. In the IPC+ischemia-operated groups, CA1 pyramidal neurons were well protected. The level of HO-1 protein and its activity increased significantly in the CA1 of the IPC+sham-operated group, and the level and activity was maintained in all the time after ischemia-reperfusion compared with the ischemia-operated groups. HO-1 immunoreactivity was induced in the CA1 pyramidal neurons in both IPC+sham-operated- and IPC+ischemia-operated groups. We also found that levels or immunoreactivities of superoxide anion, 8-hydroxy-2'-deoxyguanosine and 4-hydroxy-2-nonenal were significantly decreased in the CA1 of both IPC+sham-operated- and IPC+ischemia-operated groups. Whereas, treatment with zinc protoporphyrin IX (a HO-1 inhibitor) into the IPC+ischemia-operated groups did not preserve the IPC-mediated increase of HO-1 and lost beneficial effects of IPC by inhibiting ischemia-induced DNA damage and lipid peroxidation. In brief, IPC protects CA1 pyramidal neurons from ischemic injury by upregulating HO-1, and we suggest that the enhancement of HO-1 expression by IPC may be a legitimate strategy for a therapeutic intervention of cerebral ischemic damage., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The present study investigates the neuroprotective effects of d-allose, a rare sugar, against ischemia/reperfusion injury in a gerbil model. Transient forebrain ischemia was induced by occlusion of the bilateral common carotid arteries for 5 min. D-Allose was intravenously injected before and after ischemia (200 mg/kg). Extracellular glutamate and lactate release from the gerbil brain, and PO₂ profiles were monitored during ischemia and reperfusion. We also examined neuronal death and oxidative damage in the hippocampus one week after ischemia reperfusion, and investigated functional outcome. D-Allose administration suppressed glutamate and lactate release compared to vehicle controls. Brain damage, 8-OHdG levels (a marker of oxidative stress) and locomotor activities were significantly decreased by D-allose treatment. The present results suggest that d-allose reduces delayed neuronal death and behavioral deficits after transient ischemia by changing cerebral metabolism and inhibiting oxidative stress., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Vaccination is an effective means of preventing infectious diseases, including those caused by Helicobacter pylori. In this study, we constructed a novel multi-epitope vaccine, CTB-UE, composed of the cholera toxin B subunit and tandem copies of the B and Th cell epitopes from the H. pylori urease A and B subunits. We evaluated the therapeutic efficacy of the multi-epitope vaccine CTB-UE against H. pylori infection in a Mongolian gerbil model and studied its immuno-protective mechanisms. The experimental results indicated that urease activity, H. pylori colonisation density, the levels of IL-8 and TNF-α in the serum, and the levels of COX-2 and NAP in gastric tissue were significantly lower and the IgG level in the serum and the IFN-γ level in spleen lymphocytes were significantly higher in the vaccinated group compared with the model control group; additionally, gastric mucosal inflammation was notably alleviated following vaccination. The results showed that CTB-UE had a good therapeutic effect on H. pylori infection. The immuno-protective mechanism was closely related to the immune response mediated by microRNA-155, the expression of which was strongly up-regulated after CTB-UE administration. The expression levels of the microRNA-155 target proteins IFN-γRα, AID, and PU.1 were significantly down-regulated; these results indicated that CTB-UE induced an immune response biased towards Th1 cells by up-regulating microRNA-155 to inhibit IFN-γRα expression and induced a humoral immune response towards B cells by up-regulating microRNA-155 to inhibit PU.1 and AID expression. These results demonstrate that the multi-epitope vaccine CTB-UE may be a promising therapeutic vaccine against H. pylori infection and is a new therapeutic tool for human use., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Indicators of an age-dependent down-regulation of GABA (gamma amino butyric acid) have been well-documented in the inferior colliculus (IC) of several rat strains. In the present study, we performed a quantitative light microscopic analysis of GABA-immunostained IC sections to characterize the effect of age on the cross-sectional area of the IC, the number and density of GABAergic cells and the expression of GABA in gerbils. Compared to young gerbils, a significant shrinkage of the IC but no loss of GABAergic cells was found resulting in an increased density of GABAergic cells in old gerbils. The expression of GABA in neurons and the neuropil of the IC did not differ between young and old gerbils. The results in the gerbil differ considerably from age-dependent changes described for the rat IC, showing clear species-specific differences., (Copyright © 2014 Elsevier Inc. All rights reserved.)

We describe a method to use point-stiffness (PtSt) measurements, i.e., indentation measurements, to obtain elastic moduli of different organ of Corti (OC) tissues. A detailed finite element (FE) model of the OC is used to account for geometric effects in the indentation measurements. We also present a sensitivity analysis, performed within a Bayesian estimation framework, that can be used to improve experimental design. The sensitivity analysis shows that the basilar membrane (BM) PtSt is most sensitive to changes in the BM properties and to changes in the pillar cells (PC) properties. This result suggests that the BM and the PC dominate the macromechanics of the OC. The most likely values of the Young׳s modulus predicted for the middle turn for the BM arcuate, BM pectinate, and the PC are found to be 935 KPa (range 640-1360 KPa), 300 KPa (range 190-460 KPa), and 3 GPa (range 1-9 GPa), respectively., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

We have recently identified disorganized muscle protein-1 (DIM-1) in one of the proinflammatory fractions of the human filaria Brugia malayi adult worm. The present study was undertaken to characterize B. malayi DIM-1 (DIM-1bm) and explore its vaccine potential. In this study we cloned and expressed the DIM-1bm gene, investigated its sequence homology with other nematodes, constructed in silico structural model, purified the recombinant DIM-1bm (rDIM-1bm) protein, and studied the effect of immunization with rDIM-1bm on the establishment of B. malayi infection in Mastomys coucha. DIM-1bm showed similarity with DIM-1 of Caenorhabditis elegans, Ascaris suum and Loa loa. Structural modeling revealed three immunoglobulin domains in DIM-1bm indicating that it is a member of immunoglobulin superfamily (IgSF) and 'blastn' results showed that DIM-1bm coding sequence (CDS) have almost no homology with human and mouse nucleotide sequences. Immunization with rDIM-1bm partially protected M. coucha against establishment of infection as inferred by a low recovery of microfilariae (37-64%) and parasite burden (∼50%). The enhanced activity of macrophages, and IFN-γ and NO responses, and elevated levels of specific IgG, IgG1, IgG2a and IgG2b correlated with parasitological findings. This is the first report on cloning, expression, structural modeling and purification of rDIM-1bm and its ability to partially prevent establishment of B. malayi infection. DIM-1bm's almost complete lack of homology with the human counterpart makes it an attractive protein for exploring its vaccine potential., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Precise regulation of the chloride homeostasis crucially determines the action of inhibitory transmitters GABA and glycine and thereby endows neurons or even discrete neuronal compartments with distinct physiological responses to the same transmitters. In mammals, the signaling mediated by GABAA/glycine receptors shifts during early postnatal life from depolarization to hyperpolarization, due to delayed maturation of the chloride homeostasis system. While the activity of the secondary active, K(+)-Cl(-)-extruding cotransporter KCC2, renders GABA/glycine hyperpolarizing in auditory brainstem nuclei of altricial rodents, the mechanisms contributing to the initially depolarizing transmembrane gradient for Cl(-) in respective neurons remained unknown. Here we used gramicidin-perforated patch recordings, non-invasive Cl(-) and Ca(2+) imaging, and immunohistochemistry to identify the Cl(-)-loading transporter that renders depolarizing effects of GABA/glycine in early postnatal life of spherical bushy cells in the cochlear nucleus of gerbil. Our data identify the 1Na(+):1K(+):2Cl(-) cotransporter 1 (NKCC1) as the major Cl(-)-loader responsible for depolarizing action of GABA/glycine at postnatal days 3-5 (P3-5). Extracellular GABA/muscimol elicited calcium signaling through R-, L-, and T-type channels, which was dependent on bumetanide- and [Na(+)]e-sensitive Cl(-) accumulation. The "adult like", low intracellular Cl(-) concentration is established during the second postnatal week, through a mechanism engaging the NKCC1-down regulation between P5 and P15 and ongoing KCC2-mediated Cl(-)-extrusion., (Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.)

The tetanus toxin C (TTC) fragment capacity of being transported in a retrograde way through motoneurons and its nontoxic nature opens the door to a new promising therapeutic strategy for neurodegenerative diseases. In this study, the TTC effect was tested for the first time in animal model of global cerebral ischemia induced by 10-min occlusion of both common carotid arteries. The aim was to evaluate the effect of TTC gene therapy treatment on the development and expression of global cerebral ischemia/reperfusion-induced oxidative stress and motor hyperactivity in Mongolian gerbils. Several oxidative stress and motor behavioral parameters were investigated between 2 h and 14 days after reperfusion. Neuroprotective efficiency of TTC was observed in the forebrain cortex, striatum, hippocampus, and cerebellum at the level of each examined oxidative stress parameter (nitric oxide level, superoxide production, superoxide dismutase activity, and index of lipid peroxidation). Additionally, TTC significantly decreased ischemia-induced motor hyperactivity based on tested parameters (locomotion, stereotypy, and rotations). As judged by biochemical as well as behavioral data, treatment with TTC for the first time showed neuroprotective efficiency by reduction of ischemia-induced oxidative stress and motor hyperactivity and can be a promising strategy for ischemia-induced neuronal damage treatment., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Methylglyoxal (MG), a metabolite of glucose, is the major precursor of protein glycation and induces apoptosis. MG is associated with neurodegeneration, including oxidative stress and impaired glucose metabolism, and is efficiently metabolized to S-D-lactoylglutathione by glyoxalase (GLO). Although GLO has been implicated as being crucial in various diseases including ischemia, its detailed functions remain unclear. Therefore, we investigated the protective effect of GLO (GLO1 and GLO2) in neuronal cells and an animal ischemia model using Tat-GLO proteins. Purified Tat-GLO protein efficiently transduced into HT-22 neuronal cells and protected cells against MG- and H2O2-induced cell death, DNA fragmentation, and activation of caspase-3 and mitogen-activated protein kinase. In addition, transduced Tat-GLO protein increased D-lactate in MG- and H2O2-treated cells whereas glycation end products (AGE) and MG levels were significantly reduced in the same cells. Gerbils treated with Tat-GLO proteins displayed delayed neuronal cell death in the CA1 region of the hippocampus compared with a control. Furthermore, the combined neuroprotective effects of Tat-GLO1 and Tat-GLO2 proteins against ischemic damage were significantly higher than those of each individual protein. Those results demonstrate that transduced Tat-GLO protein protects neuronal cells by inhibiting MG- and H2O2-mediated cytotoxicity in vitro and in vivo. Therefore, we suggest that Tat-GLO proteins could be useful as a therapeutic agent for various human diseases related to oxidative stress including brain diseases., (© 2013 Elsevier Inc. All rights reserved.)

The last two decades have provided a large weight of preclinical data implicating the neurokinin-1 receptor (NK1) and its cognate ligand substance P (SP) in a broad range of both central and peripheral disease conditions. However, to date, only the NK1 receptor antagonist aprepitant has been approved as a therapeutic and this is to prevent chemotherapy-induced nausea & vomiting (CINV). The belief remained that the full therapeutic potential of NK1 receptor antagonists had yet to be realized; therefore clinical evidence that NK1 receptor antagonists may be effective in major depression disorder, resulted in a significant further investment in discovering novel CNS penetrant druggable NK1 receptor antagonists to address this condition. At GlaxoSmithKline after the discovery of casopitant, that went on to demonstrate efficacy as a novel antidepressant in the clinic, additional novel analogues of this NK1 receptor antagonist were designed to further enhance its drug developability characteristics. Herein, we therefore describe the discovery process and the vivo pharmacological and pharmacokinetic profile of the new NK1 receptor antagonist 3a (also called orvepitant), selected as clinical candidate and further progressed into clinical studies for major depressive disorder. Moreover, molecular modeling studies enabled us to improve the pharmacophore model of the NK1 receptor antagonists with the identification of a region able to accommodate a variety of heterocycle moieties., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The multivalent vaccine BmHAT, consisting of the Brugia malayi infective larval (L3) antigens heat shock protein12.6 (HSP12.6), abundant larval transcript-2 (ALT-2) and tetraspanin large extra cellular loop (TSP-LEL), was shown to be protective in rodent models from our laboratory. We hypothesize that since these antigens were identified using protective antibodies from immune endemic normal individuals, the multivalent vaccine can be augmented by natural L3 infections providing protection to the vaccinated host. This hypothesis was tested using single dose of DNA and protein or protein alone of the BmHAT vaccination in gerbils followed by live trickle L3 infection as booster dose. Vaccine-induced protection in gerbils was determined by worm establishment, micropore chamber assay and by antibody dependant cell cytotoxicity (ADCC) assay. Results were compared with the traditional prime-boost vaccination regimen. Gerbils vaccinated with BmHAT and boosted with L3 trickle infection were protected 51% (BmHAT DNA-protein) and 48% (BmHAT protein) respectively. BmHAT vaccination plus L3 trickle booster generated significant titer of antigen-specific IgG antibodies comparable to the traditional prime boost vaccination approach. BmHAT vaccination plus L3 trickle booster also generated antigen-specific cells in the spleen of vaccinated animals and these cells secreted predominantly IFN-γ and IL-4 in response to the vaccine antigens. These studies thus show that single dose of BmHAT multivalent vaccination followed by L3 trickle booster infection can confer significant protection against lymphatic filariasis., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objective: The purpose of the present study was to investigate the effect of dopamine as a possible regulator of epithelial Na(+) channel (ENaC) in the Reissner's membrane (RM)., Methods: RM was freshly dissected from the gerbil cochlea, and short-circuit current (Isc) was measured using the voltage-sensitive vibrating probe technique. The dopamine receptor expression was examined using immunohistochemistry., Results: The results showed that dopamine induced activation of the amiloride-sensitive Isc, but not after pre-treatment with amiloride. The D1-like receptor antagonist SCH-23390, but not the D2-like receptor antagonist sulpiride, decreased the stimulatory effect of dopamine on RM. The effect of dopamine on Na(+) transport via ENaC was still observed after blockade of the Na(+)-K(+)-ATPase by ouabain. D1 receptor immunoreactivity was observed in RM, stria vascularis and spiral ganglion., Conclusion: Na(+) transport in RM is activated by dopamine possibly via D1-like receptors, and intracellular mechanisms other than cAMP-mediated pathway may be involved., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

In experimental cerebral ischemia, melanocortin MC4 receptor agonists induce neuroprotection and neurogenesis with subsequent long-lasting functional recovery. Here we investigated the molecular mechanisms underlying melanocortin-induced neurogenesis. Gerbils were subjected to transient global cerebral ischemia, then they were treated every 12 h, and until sacrifice, with 5-bromo-2'-deoxyuridine (BrdU; to label proliferating cells), and the melanocortin analog [Nle(4),d-Phe(7)]α-melanocyte-stimulating hormone (NDP-α-MSH) or saline. NDP-α-MSH increased hippocampus dentate gyrus (DG) expression of Wnt-3A, β-catenin, Sonic hedgehog (Shh), Zif268, interleukin-10 (IL-10) and doublecortin (DCX), as detected at days 3, 6 and 10 after the ischemic insult. Further, an elevated number of BrdU immunoreactive cells was found at days 3 and 10, and an improved histological picture with reduced neuronal loss at day 10, associated with learning and memory recovery. Pharmacological blockade of the Wnt-3A/β-catenin and Shh pathways, as well as of melanocortin MC4 receptors, prevented all effects of NDP-α-MSH. These data indicate that, in experimental brain ischemia, treatment with melanocortins acting at MC4 receptors induces neural stem/progenitor cell proliferation in the DG by promptly and effectively triggering the canonical Wnt-3A/β-catenin and Shh signaling pathways. Activation of these pathways is associated with up-regulation of the repair factor Zif268 and the neurogenesis facilitating factor IL-10, and it seems to address mainly toward a neuronal fate, as indicated by the increase in DCX positive cells., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Baicalin, a flavonoid compound isolated from the plant Scutellaria baicalensis Georgi, is known as a protective agent against delayed neuronal cell death after ischemia/reperfusion. To investigate the neuroprotective mechanism of baicalin, the present study was conducted to explore whether the alterations of GABAergic signaling, heat shock protein 70 (HSP70) and mitogen-activated protein kinases (MAPKs) were involved in its neuroprotection on gerbils global ischemia. The bilateral carotid arteries were occluded by 5 min and baicalin at the dose of 200 mg/kg was intraperitoneally injected into the gerbils immediately after cerebral ischemia. Seven days after reperfusion, neurological deficit was scored and changes in hippocampal neuronal cell death were assessed by Nissl staining as well as NeuN immunohistochemistry. The mRNA and protein expressions of GABAergic signal molecules (GABA(A)R α1, GABA(A)R γ2, KCC2 and NKCC1) were determined in ischemic hippocampus by real-time RT-PCR and Western blot, respectively. In addition, HSP70 and MAPKs cascades (ERK, JNK and p38) were also detected using western blot assay. Our results illustrated that baicalin treatment significantly facilitated neurological function, suppressed the ischemia-induced neuronal damage. Besides, administration of baicalin also caused a striking increase of GABA(A)R α1, GABA(A)R γ2 and KCC2 together with the decrease of NKCC1 at mRNA and protein levels in gerbils hippocampus following an ischemic insult. Furthermore, the protein expressions of HSP70 and phosphorylated ERK (p-ERK) were evidently augmented while the phosphorylated JNK (p-JNK) and phosphorylated p38 (p-p38) were strikingly diminished in ischemic gerbils with baicalin treatment. These findings suggest that baicalin activates GABAergic signaling, HSP70 and MAPKs cascades in global ischemia, which may be a mechanism underlying the baicalin's neuroprotection., (Copyright © 2012 Elsevier Inc. All rights reserved.)

A salient feature of the developing brain is that spontaneous oscillations (SOs) and waves may influence the emergence of synaptic connections. While GABA produces depolarization and may support SOs in the neurons of developing rodents, it elicits hyperpolarization and diminishes SOs in developing gerbil auditory cortex (ACx). Therefore, we asked whether SOs exist in developing gerbil ACx in vivo and if GABAergic involvement can be manipulated. In vivo extracellular recordings in P3-5 ACx revealed SOs with longer burst durations and shorter inter-event intervals compared to ACx SOs in slices. ACx was then validated by gross anatomical features and lesions created at the in vivo recording site that corresponded with the electrophysiological coordinates of thalamorecipient ACx in slices. Further, NeuroVue Red, a lipophilic dye loaded at the in vivo recording sites, stained anatomically identifiable fiber tracks between the ACx and the auditory thalamus, medial geniculate body (MG). Separately, to chronically perturb GABAergic role in SOs, P2-5 pups were administered daily with GABA(A) receptor blocker, bicuculline (BIC). We then recorded from P14-17 ACx neurons in slices generated after hearing onset. ACx neurons from BIC-administered pups exhibited spontaneous action potentials in contrast to subthreshold synaptic potentials in neurons from sham-injected animals. Finally, to elucidate whether the gap junction blocker mefloquine (MFQ) previously shown to dampen ACx SOs in slices affected GABAergic transmission, MFQ was acutely applied in P3-5 slices while spontaneous inhibitory postsynaptic currents (sIPSCs) were recorded. Whereas MFQ increased the amplitude and frequency of sIPSCs in ACx neurons, the broad-spectrum gap junction blocker carbenoxolone decreased sIPSC amplitudes only. Together, we show that P2-5 gerbil ACx can endogenously generate SOs in vivo. Persistence of activity in ACx in P14-17 slices from pups administered with BIC at P2-5 implies that inhibitory GABAergic activity linked with gap-junction participates in the maturation of ACx., (Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.)

The underlying mechanisms and involved brain areas in sensory gating of repetitive auditory stimuli remain unclear. Especially, the influence of the auditory cortex and the role of temporal precision are under debate. Our first objective was to analyze gating dynamics of local field potentials in the primary auditory cortex and the ventral striatum in an animal experiment, particularly, assessing the influence of the cortex. The second aim was to follow the hypothesis that auditory gating results from phase de-synchronization of evoked potentials in response to the second auditory stimulus. Local field potentials were recorded simultaneously in the auditory cortex and ventral striatum of awake Mongolian gerbils (n=15) during stimulation with trains of frequency-modulated tones. Gating was analyzed by amplitude ratios of the auditory potentials evoked by the first two stimuli in a train, as well as by time-frequency analyses and between-area phase coupling. The strength of auditory gating in the striatum was found to exceed that in the primary auditory cortex by more than 50%. While total-signal-power was comparable between areas, energy in the striatum was primarily expressed in the non-phase-locked fraction. At the same time, energy in the auditory cortex remained phase-locked to the stimuli. Furthermore, we also observed a between-area phase unlocking during sound presentations. Phase de-synchronization appears to be the candidate mechanism behind attenuation of responses to identical repetitive stimuli in the ventral striatum. We conclude that a direct inhibitory response suppression by the auditory cortex plays a minor role in this process., (Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.)

The tympanic membrane transfers sound waves in the ear canal to mechanical vibrations in the middle ear and cochlea. Good estimates of the mechanical properties of the tympanic membrane are important to obtain realistic models. Up till now, only limited resources about tympanic membrane viscoelastic properties are available in the literature. This study aimed to quantify the viscoelastic properties of gerbil tympanic membrane. Step indentations were applied with a custom indenter on four fresh, intact tympanic membranes and the resulting force relaxation was measured. The reduced relaxation functions were then fitted with two viscoelastic model representations: a 5-parameter Maxwell model and a model with a continuous relaxation spectrum. The average relaxation function is described by an initial rapid decrease of 6.5% with characteristic time 0.77 s, followed by a long term decrease with characteristic time 46 s that gradually tends stable till a total relaxation of 15%. The relaxation curves in the time domain were transformed to complex moduli in the frequency domain. It was found that these transformations yield information on strain-rate dependence only from quasi-static to the very lowest acoustic frequencies. Finally, relaxation and hysteresis were simulated in a finite element model with viscoelastic material properties., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Helicobacter pylori encodes a single iron-cofactored superoxide dismutase (SodB), which is regulated by the ferric uptake regulator (Fur). Ferrous ion (Fe(2+)) is necessary for the activation of SodB. The activity of SodB is an important determinant of the capability of H. pylori for long-term colonization of the stomach and of the development of metronidazole (Mtz) resistance of the bacterium. This study is conducted to characterize the Fe(2+)-supply mechanisms for the activation of SodB in H. pylori, which, as mentioned above, is associated with the host-colonization ability and Mtz resistance of H. pylori. In this study, we demonstrate that fecA1, a Fe(3+)-dicitrate transporter homolog, is an essential gene for SodB activation, but not for the biogenic activity of H. pylori. H. pylori with SodB inactivation by fecA1 deletion showed reduced resistance to H(2)O(2), reduced gastric mucosal-colonization ability in Mongolian gerbils, and also reduced resistance to Mtz. Our experiment demonstrated that FecA1 is an important determinant of the host-colonization ability and Mtz resistance of H. pylori through Fe(2+) supply to SodB, suggesting that FecA1 may be a possible target for the development of a novel bactericidal drug., (Copyright © 2011 Elsevier Inc. All rights reserved.)