Search

Epilepsy is a chronic neurological disorder characterized by recurrent seizures that affects over 70 million people worldwide. Although many antiepileptic drugs that block seizures are available, they have little effect on preventing and curing epilepsy, and their side effects sometimes lead to serious morbidity. Therefore, prophylactic agents with anticonvulsant properties and no adverse effects need to be identified. Recent studies on probiotic administration have reported a variety of beneficial effects on the central nervous system via the microbiota–gut–brain axis. In this study, we investigated the effects of the oral administration of Bifidobacterium breve strain A1 [MCC1274] (B. breve A1) on tonic–clonic seizure in a pentylenetetrazole (PTZ)-induced kindling mouse (KD mouse) model. We found that the oral administration of B. breve A1 every other day for 15 days significantly reduced the seizure score, which gradually increased with repetitive injections of PTZ in KD mice. The administration of B. breve A1, but not saline, to KD mice significantly increased the level of Akt Ser473 phosphorylation (p-Akt) in the hippocampus; this increase was maintained for a minimum of 24 h after PTZ administration. Treatment of B. breve A1-administered KD mice with the selective inhibitor of integrin-linked kinase (ILK) Cpd22 significantly increased the seizure score and blocked the antiepileptic effect of B. breve A1. Moreover, Cpd22 blocked the B. breve A1-induced increase in hippocampal p-Akt levels. These results suggest that the ILK-induced phosphorylation of Akt Ser473 in the hippocampus might be involved in the antiepileptic effect of B. breve A1. [ABSTRACT FROM AUTHOR]

Simple Summary: The mechanism of adipose browning in mammals has not been clarified completely. This study examined the influence of isoproterenol, a catecholamine preparation, on dedifferentiated fat (DFAT) cells from pig fat primary culture lacking functional uncoupling protein (UCP) 1. The DFAT was redifferentiated to adipocytes and used in this study. The adipocytes were examined for the expression of genes related to the browning and fragmentation of droplets after the administration of isoproterenol. PGC-1α, UCP3, and COX family expressions increased following administration of 1 µM isoproterenol. Exposure to 1 µM isoproterenol significantly decreased the size of lipid droplets in the adipocytes of pigs. Furthermore, the promoter assay indicated that the UCP3 promoter was activated by PPARγ and PGC-1α, similar to mouse UCP1. In summary, this study demonstrated that catecholamine preparation may induce adipose browning with an upregulation of UCP3 in pig fat primary culture without UCP1. This study indicates the functional similarity between UCP1 and UCP3 and that UCP3 may contribute to adipose browning in mammals. Adipose tissue plays an important role in regulating body temperature and metabolism, with white adipocytes serving as storage units for energy. Recent research focused on the browning of white adipocytes (beige adipocytes), causing thermogenesis and lipolysis. The process of browning is linked to the activation of uncoupling protein (UCP) expression, which can be mediated by the β3 adrenergic receptor pathway. Transcriptional factors, such as peroxisome proliferator activated receptor γ (PPARγ) and PPARγ coactivator 1 alpha, play vital roles in cell fate determination for fat cells. Beige adipocytes have metabolic therapeutic potential to combat diseases such as obesity, diabetes mellitus, and dyslipidemia, owing to their significant impact on metabolic functions. However, the molecular mechanisms that cause the induction of browning are unclear. Therefore, research using animal models and primary culture is essential to provide an understanding of browning for further application in human metabolic studies. Pigs have physiological similarities to humans; hence, they are valuable models for research on adipose tissue. This study demonstrates the browning potential of pig white adipocytes through primary culture experiments. The results show that upregulation of UCP3 gene expression and fragmentation of lipid droplets into smaller particles occur due to isoproterenol stimulation, which activates beta-adrenergic receptor signaling. Furthermore, PPARγ and PGC-1α were found to activate the UCP3 promoter region, similar to that of UCP1. These findings suggest that pigs undergo metabolic changes that induce browning in white adipocytes, providing a promising approach for metabolic research with potential implications for human health. This study offers valuable insights into the mechanism of adipocyte browning using pig primary culture that can enhance our understanding of human metabolism, leading to cures for commonly occurring diseases. [ABSTRACT FROM AUTHOR]

Glutamatergic signals in the dorsal raphe nucleus (DRN) regulate maternal aggression and care in mice. We examined whether glutamatergic input from the medial prefrontal cortex (mPFC) to the DRN might regulate maternal aggression and care in mice. In the maternal aggression test, each dam was exposed to an identical intruder male twice for 5 min, 60 min apart. During the latter trial (opt trial), the terminals of glutamatergic neurons from the mPFC to the DRN were manipulated using optogenetic techniques. Compared to the former trial (pre-opt trial), the inhibition of glutamatergic input in the opt trial decreased bite frequency and prevented the shortening of biting latency. In contrast, the activation of glutamatergic input at 5 Hz increased the biting frequency. Meanwhile, the activation of glutamatergic input at 1, 10, and 20 Hz prevented the shortening of biting latency without affecting biting frequency. In the maternal care test, activation of glutamatergic input at 5 Hz did not affect maternal care. Our results suggest that glutamatergic neurons from the mPFC to the DRN differently regulate maternal aggression, depending on temporal patterns of their activation, and that the glutamatergic signals that enhance maternal aggression are not involved in the regulation of maternal care. • Inhibition of the mPFC glutamatergic input into the DRN suppresses biting behavior. • Optogenetic activation of the glutamatergic inputs at 5 Hz enhances biting behavior. • The mPFC glutamatergic input into the DRN does not affect maternal care. [ABSTRACT FROM AUTHOR]

The cerebellar lesions of bovine spongiform encephalopathy (BSE)‐infected guinea pigs were characterized as severe atrophy of the cerebellar cortex associated with the loss of granule cells, decrease in the width of the molecular layer, and intense protease‐resistant prion protein (PrPSc) accumulations that are similar to cerebellar lesions in kuru and the VV2 type of sporadic Creutzfeldt‐Jakob disease. The aim of this study is to assess the relationships between the distribution and localization of PrPSc and synapses expressing neurotransmitter transporters in order to reveal the pathogenesis of the disease. We used cell‐type‐specific immunohistochemical makers recognizing glutamatergic and γ‐aminobutylic acid (GABA)ergic terminals to identify terminals impaired with PrPSc accumulations. The distribution of PrPSc accumulations and immunoreactivity of synaptic vesicles were studied throughout the neuroanatomical pathways in cerebellar lesions. Time course study demonstrated that PrPSc accumulation showed a tendency to spread from granular layer to molecular layer. The immunoreactivity of vesicular glutamate transporter 1 (VGluT1) was localized in axon terminals of cerebellar granule cells, and decreased in association with the severity of PrPSc accumulations and loss of granule cells. Immunoreactivities of vesicular glutamate transporter 2 (VGluT2) and vesicular GABA transporter (VGAT) that exist in axon terminals of inferior olivary neurons and GABAergic synapses of Purkinje cells, respectively, were preserved well in these lesions. In brainstem, VGluT1 immunoreactivity decreased selectively in pontine nuclei that are a component of the pontocerebellar pathway, although other neurotransmitter immunoreactivities were preserved well. Our findings suggest that the selective loss of VGluT1‐immunoreactive synapses subsequent to PrPSc accumulations can contribute to the pathogenesis of cerebellar lesions of BSE‐infected guinea pigs. [ABSTRACT FROM AUTHOR]

Abstract Lactating female mice nurture their pups and attack intruders in their territory. When an intruder invades a dam's territory, she needs to switch her behavior from care to aggression to protect her pups and territory. Although the neuronal mechanisms underlying each distinct behavior have been studied, it is unclear how these behaviors are displayed alternatively. The dorsal raphe nucleus (DRN) regulates both nurturing and aggressive behaviors. In the present study, we examined whether the DRN is involved in regulating alternative display of maternal care and aggression. We first examined neuronal activity in the medial prefrontal cortex (mPFC) and lateral habenula (LHb), which send glutamatergic input to the DRN, in dams by injecting Fluorogold, a retrograde tracer, into the DRN. The number of c-Fos- and Fluorogold-positive neurons in the mPFC and LHb increased in the dams that displayed biting behavior in response to an intruder, but remained unchanged in the dams that displayed nurturing behavior. Injections of N-methyl- d -aspartic acid (NMDA) receptor antagonists or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor antagonists into the DRN inhibited biting behavior but not nurturing behavior. In contrast, injections of NMDA or AMPA into the DRN inhibited nurturing behavior. These results suggest that glutamatergic signals in the DRN, which may originate from the mPFC and/or LHb, regulate the preferential display of biting behavior over nurturing behavior in dams. [ABSTRACT FROM AUTHOR]

Drinking behavior is regulated by endogenous factors such as the hydration condition of animals and exogenous factors such as the taste of ingested fluids. These factors have been suggested to interact with each other via serotonergic (5-HT) signaling to regulate drinking behavior. In the present study, we examined how dehydration affects the intake of bitter water, which suppresses drinking behavior, via 5-HT signaling. Water deprivation increased water intake for 1 h, depending on the duration of water deprivation. The intake of 1 mM quinine, which is a bitter tastant, was lower than that of water in mice deprived of water for 24 h but not 48 h. We next examined the involvement of the dorsal raphe nucleus (DRN) and median raphe nucleus (MRN), which contain a large population of 5-HT neurons, in changing tolerance for quinine intake after water deprivation. The intake of quinine following water deprivation for 24 h, but not 48 h, increased the number of tryptophan hydroxylase-positive neurons expressing c-Fos in the DRN, but not in the MRN. Moreover, administration of paroxetine, a selective serotonin reuptake inhibitor, decreased the intake of quinine solution, but not water, in mice deprived of water for 48 h, indicating that paroxetine treatment restored the aversion to quinine. These results suggest that unresponsiveness of 5-HT neurons in the DRN may be involved in the dehydration-induced increase in tolerance for bitter water. [ABSTRACT FROM AUTHOR]

Lysophospholipids are important signaling molecules in animals and metazoan cells. They are widely distributed among marine invertebrates, where their physiological roles are unknown. Sea cucumbers produce unique lysophospholipids. In this study, two lysophospholipids were detected in Holothuria atra for the first time, lyso-platelet activating factor and lysophosphatidylcholine, with nuclear magnetic resonance and liquid chromatography–time-of-flight mass spectrometric analyses. The lipid fraction of H. atra contained lyso-platelet activating factor and lysophosphatidylcholine, and inhibited H2O2-induced apoptosis in the macrophage cell line J774A.1. The antioxidant activity of the lysophospholipid-containing lipid fraction of H. atra was confirmed with the oxygen radical absorbance capacity method. Our results suggest that the lysophospholipids from H. atra are potential therapeutic agents for the inflammation induced by oxidative stress. [ABSTRACT FROM AUTHOR]

Maternal care is indispensable for the survival of mammalian offspring. Although virgin female mice avoid pups, they actively display maternal behavior after parturition. To determine which brain regions are involved in the qualitative differences observed in the responses of virgin and lactating females to pups, we compared the expression of c-Fos, which is a marker of neuronal activation, in brain regions involved in regulating maternal behavior. Pup presentation increased the number of c-Fos-positive cells in both the ventrotegmental area (VTA) and nucleus accumbens to a greater extent in lactating females than in virgin females. The bed nucleus of striaterminalis (BNST), which innervates VTA neurons to regulate both aversive and rewarding responses, showed increased number of c-Fos-positive cells following pup presentation in virgin females, butnotin lactating females. On the other hand, the number of c-Fos-positive cells in the medial preoptic area (MPOA) increased in both virgin and lactating females. The number of c-Fos-positive cells in lactating females not presented with pups was high and similar to that in virgin females presented with pups. Moreover, c-Fos-positive GABAergicneurons projecting from the MPOA to the BNST was confirmed using a retrograde tracer Fluorogold in lactating females. Our results indicate that constitutive GABAergic modulation projecting from the MPOA may suppress the activity of BNST neurons and prevent avoidance responses to pups in lactating females. [ABSTRACT FROM AUTHOR]

Botulinum neurotoxin serotype A (BoNT/A) inhibits acetylcholine release at the neuromuscular junction in isolated muscles, and ouabain can partially block its effect. However, it is not clear whether ouabain attenuates BoNT/A-induced neuromuscular paralysis in vivo. In this work, we investigated the effects of ouabain on BoNT/A-induced neuromuscular paralysis in mice. Ouabain was administered to mice intraperitoneally immediately after a single injection of BoNT/A into skeletal muscle. The effects of ouabain on BoNT/A-induced muscle paralysis were assessed by quantitative monitoring of muscle tension and digit abduction via the digit abduction scoring (DAS) assay. A single administration of ouabain significantly prolonged BoNT/A-induced neuromuscular paralysis. Moreover, consecutive daily injection of ouabain exacerbated BoNT/A-induced neuromuscular paralysis, and led to a significant decrease in both twitch and tetanic forces as assayed in isolated BoNT/A-injected muscles. We next looked at the effects of ouabain on BoNT/A-induced muscle atrophy. Administration of ouabain led to a decrease in the myofibrillar cross-sectional area (CSAs) by 14 post-BoNT/A injection. In addition, repeated administration of ouabain increased mRNA expression levels of ubiquitin ligases, which are markers of muscle atrophy, in BoNT/A-injected muscle. These results suggest that ouabain exacerbates BoNT/A-induced neuromuscular paralysis via a marked progression of BoNT/A-induced muscle atrophy. [ABSTRACT FROM AUTHOR]

The innate immune system plays an important role in protecting organs that are continuous with the outer surface of the body from bacterial infection. The antibacterial factors involved in this system have been sought in exocrine glands, particularly in the mammary glands. Because milk produced in the mammary glands is enriched in various nutrients, supporting the proliferation of bacteria, mammary glands appear to be at the greatest risk of bacterial infection and proliferation. Here, we show that mouse milk contains L-amino acid oxidase (LAO), a lactating mammary gland-specific protein that displays antibacterial activity in vitro through the production of hydrogen peroxide from free amino acids. We produced LAO-disrupted mouse lines to define the physiological properties and importance of the protein in vivo. The LAO-knockout mice were healthy and had normal mammary gland development; however, the antibacterial activity normally observed in milk from wild-type mice was absent from the milk of knockout mice. The content of free amino acids targeted by LAO was very low in wild-type milk, whereas these amino acids were abundant in LAO-knockout milk. Knockout mice exhibited weak resistance to an intramammary bacterial challenge compared to their wild-type counterparts. Further, preadministration of wild-type milk whey reduced the severity of bacterial infection in LAO-knockout mice. These results demonstrate that milk LAO protects the mammary gland against bacterial infection, and this antibacterial effect may be due to the generation of hydrogen peroxide by using free amino acids abundantly present in milk. [ABSTRACT FROM AUTHOR]

Abstract: Olfaction plays an important role in animal communication. We hypothesized that males recognize the attractive volatile odors attributed to female reproductive ability. We measured the period during which a male mouse spent sniffing volatile odors from a sham-operated female mouse or an ovariectomized mouse without visual or tactile contact. Intact male mice spent more time sniffing volatile odors from proestrous, estrous or metestrous females than from ovariectomized females. There was no difference in castrated male mice. To investigate the involvement of sexual hormone in this behavior, castrated male mice were treated with 17 α-estradiol (E), dihydrotestosterone (DHT), or both. E-treatment did not affect sniffing behavior. Regardless of the estrous stages, DHT-treated castrated males spent less time sniffing the volatile odors from sham-operated than from ovariectomized female mice. Both E- and DHT-treated castrated males spent less time sniffing the volatile odors from proestrous or estrous females than from ovariectomized females. These results suggest that neither androgen nor estrogen is sufficient for reproducing male attraction to volatile female mouse odors, and that androgen signaling has a competitive effect against the attraction. [Copyright &y& Elsevier]

• Juvenile mice, over the age of 14-days, can induce biting behavior in dams. • Consumption of food pellets does not affect the induction of biting behavior. • The frequency of biting behavior depends on the strain of the dams and intruders. • Body hair around the proximal tail contains the aggression-inducible chemical cues. Maternal care and aggression are representative of maternal behavior among lactating female mice. Even neonates and juveniles, who are not biological offspring, can induce maternal care and aggression in dams. Here, we investigated the factors that induce maternal aggression through exposure to juvenile mice. We first addressed the role of intruder age on the induction of maternal aggression in dams. BALB/c dams displayed attacking behavior towards 14-day-old C57BL/6J male intruders. Consumption of food pellets during the weaning period was unlikely to affect the induction of attacking behavior, as the intruders reared by breastfeeding, without food pellets, induced intensive attacking behavior in dams. Next, we compared the intruder-mediated induction of attacking behavior through different mouse strains. Specifically, BALB/c intruders induced a lower level of attacking behavior in BALB/c or ICR dams, compared to the other strains tested. However, BALB/c intruders induced intense attacking behavior in C57BL/6N dams, indicating that the occurrence of attacking behavior is dependent on the strains of dams as well as intruders. A cross-fostering experiment highlighted that the rearing by an original mother was required for C57BL/6J juveniles to induce attacking behavior. In contrast, BALB/c intruders may emit an inhibitory factor that limits attacking behavior. We finally explored which parts of the body emit these aggression-inducible signals. Removal of body hair around the proximal tail of the intruders significantly decreased the attacking behavior of dams, demonstrating that chemical cues, namely pheromones, attached to the body hair around the proximal tail may be essential for inducing attacking behavior in dams. [ABSTRACT FROM AUTHOR]

Previously, we found that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) model mice (PD mice) showed facilitation of hippocampal memory extinction via reduced cyclic adenosine monophosphate (cAMP)/cAMP-dependent response element-binding protein (CREB) signaling, which may cause cognitive impairment in PD. Serotonergic neurons in the median raphe nucleus (MnRN) project to the hippocampus, and functional abnormalities have been reported. In the present study, we investigated the effects of the serotonin 5-HT4 receptor (5-HT4R) agonists prucalopride and velusetrag on the facilitation of memory extinction observed in PD mice. Both 5-HT4R agonists restored facilitation of contextual fear extinction in PD mice by stimulating the cAMP/CREB pathway in the dentate gyrus of the hippocampus. A retrograde fluorogold-tracer study showed that γ-aminobutyric acid-ergic (GABAergic) neurons in the reticular part of the substantia nigra (SNr), but not dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc), projected to serotonergic neurons in the MnRN, which are known to project their nerve terminals to the hippocampus. It is possible that the degeneration of the SNpc DAergic neurons in PD mice affects the SNr GABAergic neurons, and thereafter, the serotonergic neurons in the MnRN, resulting in hippocampal dysfunction. These findings suggest that 5HT4R agonists could be potentially useful as therapeutic drugs for treating cognitive deficits in PD. [ABSTRACT FROM AUTHOR]

Neospora caninum is a protozoan parasite that causes neurological disorders in dogs and cattle. It can cause nonsuppurative meningoencephalitis and a variety of neuronal symptoms are observed, particularly in dogs. However, the pathogenic mechanism, including the relationship between the parasite distribution and the clinical signs, is unclear. In this study, to understand the pathogenic mechanism of neosporosis, parasite distribution and lesions were assessed in the brain of mice infected with N. caninum (strain Nc-1). Host gene expression was also analyzed with RNA sequencing (RNA-Seq). The histopathological lesions in the frontal lobe and the medulla oblongata were significantly more severe in symptomatic mice than in asymptomatic mice, although no association between the severity of the lesions and parasite numbers was found. In infected mice, the expression of 772 mouse brain genes was upregulated. A GOstat analysis predicted that the upregulated genes were involved in the host immune response. Genes whose expression correlated positively and negatively with parasite numbers were involved in the host immune response, and neuronal morphogenesis and lipid metabolic processes, respectively. These results suggest that changes in the gene expression profile associated with neuronal functions as well as immune responses can contribute to the pathogenesis in N. caninum-infected animals. [ABSTRACT FROM AUTHOR]

ERVWE1 (SYNCYTIN-1), a membrane protein originating from the envelope gene of human endogenous retrovirus-W (HERV-W), mediates the fusion of mononucleated cytotrophoblasts into multinucleated syncytiotrophoblast. Though ERVWE1 has been characterized since its discovery, regulatory mechanisms associated with ERVWE1 expression have not been firmly established. We hypothesized that membrane protein CD9, involved in cell-cell fusion of fertilization and myogenesis, could be involved in the regulation of ERVWE1 gene expression. In this study, regulatory mechanisms of ERVWE1 expression were studied using human choriocarcinoma BeWo cells. Forskolin is an activator of adenylate cyclase, which increased CD9 and ERVWE1 expression. The increase in CD9 expression was inhibited by a protein kinase A (PKA) inhibitor, Rp-cAMPS. These results indicate that CD9 expression is regulated by the cAMP/PKA signaling pathway. Overexpression of CD9 increased expression levels of ERVWE1 as well as GCM1 (hGCMa), which is a transcription factor known to activate ERVWE1 gene transcription. However, high ERVWE1 expression induced by CD9 overexpression did not result in the increase in chorionic gonadotropin, beta polypeptide production. Moreover, CD9-induced increase in ERVWE1 and GCM1 expressions were inhibited by Rp-cAMPS. These results suggest that CD9 increases GCM1 expression via the cAMP/PKA signaling pathway, resulting in the increase in ERVWE1 expression. [ABSTRACT FROM AUTHOR]

Integrin-linked kinase (ILK) is a focal adhesion serine/ threonine protein kinase with an important role in integrin and growth factor signaling pathways. Recently, we demonstrated that ILK is expressed in N1E-115 neuroblastoma cells and controls integrin-dependent neurite outgrowth in serum-starved cells grown on laminin (Ishii, T., Satoh, E., and Nishimura, M. (2001) J. Biol. Chem. 276, 42994-43003). Here we report that ILK controls tau phosphorylation via regulation of glycogen synthase kinase-3β (GSK-3β) activity in N1E-115 cells. Stable transfection of a kinase-deficient ILK mutant (DN-ILK) resulted in aberrant tau phosphorylation in N1E-115 cells at sites recognized by the Tau-1 antibody that are identical to some of the phosphorylation sites in paired helical filaments, PHF-tau, in brains of patients with Alzheimer's disease. The tau phosphorylation levels in the DN-ILK-expressing cells are constant under normal and differentiating conditions. On the other hand, aberrant tau phosphorylation was not observed in the parental control cells. ILK inactivation resulted in an increase in the active form but a decrease in the inactive form of GSK-3β, which is a candidate kinase involved in PHF-tau formation. Moreover, inhibition of GSK-3β with lithium prevented aberrant tau phosphorylation in the DN-ILK-expressing cells. These results suggest that ILK inactivation results in aberrant tau phosphorylation via sustained activation of GSK-3β in N1E-115 Cells. ILK directly phosphorylates GSK-3β and inhibits its activity. Therefore, endogenous ILK protects against GSK-3β-induced aberrant tau phosphorylation via inhibition of GSK-3β activity in N1E-115 cells. [ABSTRACT FROM AUTHOR]

Highlights: [•] Cattle were immunized with M3-NcGRA7. [•] M3-NcGRA7 induced antigen-specific antibody and IFN-γ production from the PBMC. [•] M3-NcGRA7 vaccination reduced parasite load in the brain. [•] M3-NcGRA7 (50μg antigen) vaccination induced protective immune responses in cattle. [Copyright &y& Elsevier]

Abstract: Previously, we have found that post-weaning mice fed exclusively milk display low-frequency exploratory behavior compared to mice fed a food pellet diet (). Because cognitive functions play a key role in animal exploration, in the present study we examined the effect of an exclusively milk formula diet on spatial learning and memory in a water maze and also on induction of long-term potentiation (LTP) and long-term depression (LTD) at the Schaffer collateral-CA1 synapse in the hippocampus. Exclusively milk-fed mice exhibited slower learning and memory deficits in hidden water maze tests as compared with pellet-fed mice. Moreover, milk-fed mice showed a significant inhibition of LTD but a normal induction of LTP. Despite these functional deficits, adult neurogenesis in the dentate gyrus of the hippocampus, which has been proposed to have a causal relationship to spatial memory, was stimulated in milk-fed mice. These result suggest that an exclusively milk formula diet after weaning leads to a stimulation of hippocampal neurogenesis but causes deficits in the induction of LTD in the CA1 hippocampal region and impairment of spatial learning and memory. [Copyright &y& Elsevier]

Abstract: The mesencephalic trigeminal sensory nucleus (Me5), which receives signals originating from oral proprioceptors, becomes active at weaning and contributes to the acquisition of active exploratory behavior [Ishii, T., Furuoka, H., Kitamura, N., Muroi, Y., and Nishimura, M. (2006) Brain Res. 1111, 153–161]. Because cognitive functions play a key role in animal exploration, in the present study we assessed the role of Me5 in spatial learning and memory in the water maze. Mice with bilateral Me5 lesions exhibited severe deficits in both a reversal learning and a reversal probe test compared with sham-operated mice. In spite of these reversal tests, Me5 lesions had no effect on a hidden platform test. These results suggest that Me5-lesioned mice show a perseveration of the previously learned spatial strategy rather than an inability to learn a new strategy, resulting in reduced spatial memory resetting. Moreover, adult neurogenesis in the dentate gyrus of the hippocampus, which has been proposed to have a causal relationship to spatial memory, was stimulated in Me5-lesioned mice. Thus, a stimulation of hippocampal neurogenesis observed after Me5 lesions may lead to a rigidity and perseverance of the previously learned strategy because of inferential overuse of past memories in a novel situation. These results suggest that Me5 contributes to spatial memory resetting by controlling the rate of hippocampal neurogenesis through an ascending neuronal pathway to the hippocampus. [Copyright &y& Elsevier]

Abstract: Post-weaning mice fed exclusively milk display low-frequency exploratory behavior [Ishii, T., Itou, T., and Nishimura, M. (2005) Life Sci. 78, 174–179] compared to mice fed a food pellet diet. This low-frequency exploratory behavior switched to high-frequency exploration after a switch from exclusively milk formula to a food pellet diet. Acquisition of the high-frequency exploratory behavior was irreversible. Recently, we demonstrated that the mesencephalic trigeminal nucleus (Me5) is involved in the control of feeding and exploratory behavior in mice without modulating the emotional state [Ishii, T., Furuoka, H., Itou, T., Kitamura, N., and Nishimura, M. (2005) Brain Res. 1048, 80–86]. We therefore investigated whether the Me5 is involved in acquisition of high-frequency exploratory behavior induced by the switch in diet from an exclusively milk formula to food pellets. Mouse feeding and exploratory behaviors were analyzed using a food search compulsion apparatus, which was designed to distinguish between the two behaviors under standard living conditions. Immunohistochemical analysis of immediate early genes indicated that the Me5, which receives signals from oral proprioceptors, is transiently activated after the diet change. The change from low-frequency to high-frequency exploratory behavior was prevented in milk-fed mice by bilateral lesion of the Me5. These results suggest that the Me5 is activated by signals associated with mastication-induced proprioception and contributes to the acquisition of active exploratory behavior. [Copyright &y& Elsevier]

Sequences of retroviral origin occupy approximately 10% of mammalian genomes. Various infectious endogenous retroviruses (ERVs) and functional retroviral elements have been reported for several mammals but not cattle. Here, we identified two proviruses, designated bovine endogenous retrovirus K1 (BERV-K1) and BERV-K2, containing full-length envelope (env) genes in the bovine genome. Phylogenetic analysis revealed that they belong to the genus Betaretrovirus. By reverse transcription (RT)-PCR, both BERV-K1 and -K2 env mRNAs were detected in the placenta and cultured bovine trophoblast cells. Real-time RT-PCR analysis using RNAs isolated from various bovine tissues revealed that BERV-K1 env mRNA was preferentially expressed in the placenta. Moreover, we also found the expression of doubly spliced transcripts, named the REBK1 and REBK2 genes. Both the REBK1 and REBK2 proteins have motifs for a putative nuclear localization signal and a nuclear export signal. REBK1 and REBK2 fused with green fluorescent proteins were localized mainly in the nuclei when they were expressed in bovine and porcine cells. In the env and 3' long terminal repeats of BERV-K1 and -K2, we found regulatory elements responsible for the splicing and transport of viral RNAs and/or translation of the env genes. Although we have not identified the expressed Env proteins in bovine tissues, these data suggest that both BERV-K1 and BERV-K2 express Env proteins and that these proteins may have physiological functions in vivo. [ABSTRACT FROM AUTHOR]

We previously reported that the dorsal raphe nucleus (DRN) was involved in the regulation of maternal care in lactating female mice. The DRN receives multiple innervations from a variety of the brain regions. Corticotropin-releasing factor (CRF) Type 1 and Type 2 receptors are distributed in the DRN. Both receptors have been implicated in regulating negative aspects including stress, fear, and anxiety. However, it remains unknown how CRF receptors in the DRN regulate maternal care. In the present study, we investigated how CRF receptors in the DRN is involved in regulating maternal care in lactating female mice. Injection of antalarmin or antisauvagine-30, which is an antagonist of CRF Type 1 or Type 2 receptor, respectively, into the DRN increased the latency to retrieving pups into the nest and to crouching over pups, and decreased the duration of crouching over pups, indicating that blockage of CRF receptor signaling in the DRN decreased maternal care. Each treatment did not affect anxiety-related behaviors, which were assayed using the hole-board test. These results suggest that CRF receptor signaling in the DRN positively regulates maternal care in lactating female mice. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Previously, we found that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) model mice (PD mice) showed facilitation of hippocampal memory extinction via reduced cyclic adenosine monophosphate (cAMP)/cAMP-dependent response element-binding protein (CREB) signaling, which may cause cognitive impairment in PD. Serotonergic neurons in the median raphe nucleus (MnRN) project to the hippocampus, and functional abnormalities have been reported. In the present study, we investigated the effects of the serotonin 5-HT 4 receptor (5-HT 4 R) agonists prucalopride and velusetrag on the facilitation of memory extinction observed in PD mice. Both 5-HT 4 R agonists restored facilitation of contextual fear extinction in PD mice by stimulating the cAMP/CREB pathway in the dentate gyrus of the hippocampus. A retrograde fluorogold-tracer study showed that γ-aminobutyric acid-ergic (GABAergic) neurons in the reticular part of the substantia nigra (SNr), but not dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc), projected to serotonergic neurons in the MnRN, which are known to project their nerve terminals to the hippocampus. It is possible that the degeneration of the SNpc DAergic neurons in PD mice affects the SNr GABAergic neurons, and thereafter, the serotonergic neurons in the MnRN, resulting in hippocampal dysfunction. These findings suggest that 5HT4R agonists could be potentially useful as therapeutic drugs for treating cognitive deficits in PD.

Chronic infection with Toxoplasma gondii becomes established in tissues of the central nervous system, where parasites may directly or indirectly modulate neuronal function. Epidemiological studies have revealed that chronic infection in humans is a risk factor for developing mental diseases. However, the mechanisms underlying parasite-induced neuronal dysfunction in the brain remain unclear. Here, we examined memory associated with conditioned fear in mice and found that T. gondii infection impairs consolidation of conditioned fear memory. To examine the brain pathology induced by T. gondii infection, we analyzed the parasite load and histopathological changes. T. gondii infects all brain areas, yet the cortex exhibits more severe tissue damage than other regions. We measured neurotransmitter levels in the cortex and amygdala because these regions are involved in fear memory expression. The levels of dopamine metabolites but not those of dopamine were increased in the cortex of infected mice compared with those in the cortex of uninfected mice. In contrast, serotonin levels were decreased in the amygdala and norepinephrine levels were decreased in the cortex and amygdala of infected mice. The levels of cortical dopamine metabolites were associated with the time spent freezing in the fear-conditioning test. These results suggest that T. gondii infection affects fear memory through dysfunction of the cortex and amygdala. Our findings provide insight into the mechanisms underlying the neurological changes seen during T. gondii infection., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Histopathology and quantitative PCR (qPCR) were used to determine the tissue distribution of Neospora caninum in calves at 80 days postinfection. Our findings revealed that the most appropriate brain areas for researching N. caninum pathogenesis were the amygdala and hippocampus for qPCR and the corpus striatum and diencephalon for histopathology.

Expression of interferon-tau (IFNT), necessary for pregnancy establishment in ruminant ungulates, is regulated in a temporal and spatial manner. However, molecular mechanisms by which IFNT gene transcription is regulated in this manner have not been firmly established. In this study, DNA microarray/RT-PCR analysis between bovine trophoblast CT-1 and Mardin-Darby bovine kidney (MDBK) cells was initially performed, finding that transcription factors GATA2, GATA3, and GATA6 mRNAs were specific to CT-1 cells. These mRNAs were also found in Days 17, 20, and 22 (Day 0 = day of estrus) bovine conceptuses. In examining other bovine cell lines, ovary cumulus granulosa (oCG) and ear fibroblast (EF) cells, GATA2 and GATA3, but not GATA6, were found specific to the bovine trophoblast cells. In transient transfection analyses using the upstream region (-631 to +59 bp) of bovine IFNT gene (bIFNT, IFN-tau-c1), over-expression of GATA2/GATA3 did not affect the transcription of bIFNT-reporter construct in human choriocarcinoma JEG3 cells. Transfection of GATA2, GATA3, ETS2, and/or CDX2, however, was effective in the up-regulation of the bIFNT construct transfected into bovine oCG and EF cells. One Point mutation studies revealed that among six potential GATA binding sites located on the upstream region of the bIFNT gene, the one next to ETS2 site exhibited reduced luciferase activity. In CT-1 cells, endogenous bIFNT gene transcription was up-regulated by over-expression of GATA2 or GATA3, but down-regulated by siRNA specific to GATA2 mRNA. These data suggest that GATA2/3 is involved in trophoblast-specific regulation of bIFNT gene transcription.