ABSTRACT
Appropriate animal models are necessary to determine the molecular and cellular mechanisms underlying attention-deficit/hyperactivity disorder (ADHD). This study used a battery of behavioral tests to compare Lister hooded rats (LHRs), an old outbred strain frequently used for autistic epilepsy research, with Wistar rats and spontaneously hypertensive rats (SHRs), a commonly used ADHD model. The open field, elevated plus maze, light/dark box, and drop tests demonstrated that LHRs were the most hyperactive animals and displayed the most inattentive- and impulsive-like behaviors, which are characteristics of ADHD. The radial arm maze, social interaction, and Morris water maze tests showed that LHRs did not display deficits characteristic of autism or intellectual disability. Although LHRs did not show different monoamine contents, the mRNA expression levels of various genes linked to ADHD (Cdh13, Drd5, Foxp2, Maoa, Sema6d, Slc9a9, and St3gal3) and tyrosine hydroxylase protein expression levels were lower in the prefrontal cortex of LHRs compared with that of Wistar rats or SHRs. c-Fos, synapsin I, and tau protein expression levels in the prelimbic region of the medial prefrontal cortex were also increased in LHRs compared with Wistar rats. Atomoxetine and guanfacine, commonly used non-stimulant treatments for ADHD, ameliorated ADHD-like behaviors in LHRs. These results suggest that LHRs can serve as a better ADHD model to develop novel pharmacological interventions.
Subject(s)
Attention Deficit Disorder with Hyperactivity/genetics , Attention Deficit Disorder with Hyperactivity/psychology , Animals , Atomoxetine Hydrochloride/therapeutic use , Attention , Attention Deficit Disorder with Hyperactivity/drug therapy , Disease Models, Animal , Gene Expression Regulation , Guanfacine/therapeutic use , Impulsive Behavior , Male , Maze Learning , Prefrontal Cortex/metabolism , Rats , Rats, Inbred SHR , Rats, Inbred Strains , Rats, Wistar , Social Interaction , Species SpecificityABSTRACT
Levels of high mobility group box 1 (HMGB1), an important inflammatory mediator, are high in the serum of febrile seizure (FS) patients. However, its roles in FS and secondary epilepsy after prolonged FS are poorly understood. We demonstrate HMGB1's role in the pathogenesis of hyperthermia-induced seizures (HS) and secondary epilepsy after prolonged hyperthermia-induced seizures (pHS). In the first experiment, 14-15-day-old male rats were divided into four groups: high-dose HMGB1 (100 µg), moderate-dose (10 µg), low-dose (1 µg), and control. Each rat was administered HMGB1 intranasally 1 h before inducing HS. Temperature was measured at seizure onset with electroencephalography (EEG). In the second experiment, 10-11-day-old rats were divided into four groups: pHS + HMGB1 (10 µg), pHS, HMGB1, and control. HMGB1 was administered 24 h after pHS. Video-EEGs were recorded for 24 h at 90 and 120 days old; histological analysis was performed at 150 days old. In the first experiment, the temperature at seizure onset was significantly lower in the high- and moderate-dose HMGB1 groups than in the control group. In the second experiment, the incidence of spontaneous epileptic seizure was significantly higher in the pHS + HMGB1 group than in the other groups. Comparison between pHS + HMGB1 groups with and without epilepsy revealed that epileptic rats had significantly enhanced astrocytosis in the hippocampus and corpus callosum. In developing rats, HMGB1 enhanced HS and secondary epilepsy after pHS. Our findings suggest that HMGB1 contributes to FS pathogenesis and plays an important role in the acquired epileptogenesis of secondary epilepsy associated with prolonged FS.
Subject(s)
Fever/complications , HMGB1 Protein/administration & dosage , Seizures, Febrile/etiology , Seizures/etiology , Animals , Avoidance Learning/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Electroencephalography , Male , Rats , Rats, Sprague-DawleyABSTRACT
Activating transcription factor 5 (ATF5) is a stress response transcription factor of the cAMP-responsive element-binding/ATF family. Earlier, we reported that ATF5 expression is up-regulated in response to stress, such as amino acid limitation or arsenite exposure. Although ATF5 is widely expressed in the brain and the olfactory epithelium, the role of ATF5 is not fully understood. Here, the olfactory bulbs (OBs) of ATF5-deficient mice are smaller than those of wild-type mice. Histological analysis reveals the disturbed laminar structure of the OB, showing the thinner olfactory nerve layer, and a reduced number of interneurons. This is mainly due to the reduced number of bromodeoxyuridine-positive proliferating cells in the subventricular zone, where the interneuron progenitors are formed and migrate to the OBs. Moreover, the olfaction-related aggressive behavior of ATF5-deficient mice is reduced compared to wild-type mice. Our data suggest that ATF5 plays a crucial role in mouse OB development via interneuron.
Subject(s)
Activating Transcription Factors/metabolism , Interneurons/physiology , Olfactory Bulb/growth & development , Activating Transcription Factors/genetics , Aggression , Animals , Animals, Newborn , Behavior, Animal , Female , Interneurons/pathology , Male , Mice, Inbred C57BL , Mice, Knockout , Olfactory Bulb/embryology , Olfactory Bulb/pathology , Olfactory Nerve/embryology , Olfactory Nerve/pathologyABSTRACT
Blood circulation and the route of nutritional supply both change dramatically in the immediate neonatal period. These systemic shifts lead to adjustment of metabolic patterns in the neonate, with alterations in the spectrum of metabolites in body fluids. We have investigated whether (1)H-NMR-based metabolic profiling (NMR-MP) with principal component analysis (PCA) can be used to evaluate metabolite profiles in highly-diluted samples of individual neonatal mouse urine. We report that a 60-fold dilution of urine gave a reproducible NMR-MP analysis. Here the NMR spectral patterns and PCA score plot clearly delineated the developmental changes in urine metabolites in the immediate neonatal period. These results suggest that NMR-MP may offer a powerful method for assessing the physiology and toxicity of chemicals in neonatal periods of experimental animals.
Subject(s)
Animals, Newborn/metabolism , Magnetic Resonance Spectroscopy/methods , Animals , Animals, Newborn/growth & development , Male , Metabolomics , Mice , Mice, Inbred C57BL , Principal Component Analysis , Reproducibility of Results , UrinalysisABSTRACT
AIMS: Food deprivation (fasting) is commonly encountered in the lives of animals and humans. In mammals, adaptive responses predominantly include the induction of hepatic gluconeogenesis, but the regulatory mechanisms remain unclear. Atf5 (activating transcription factor 5) is a transcription factor of the ATF/cAMP response element-binding protein family and is expressed abundantly in human liver. Atf5 has been associated with stress responses, cell differentiation, proliferation, and survival. However, its role in the liver response to in vivo food deprivation has not yet been investigated. MAIN METHODS: Adult mice were food-deprived for 48 h and the expression of two Atf5 mRNA subtypes (Atf5-R1 and Atf-R2) and gluconeogenic factors was investigated. Using in vitro cell culture, Pgc-1alpha (peroxisome proliferator-activated receptor-gamma coactivator-1alpha) promoter activities after ectopic expression of Atf5 and Cebpg (CCAAT/enhancer-binding protein gamma) proteins were measured. KEY FINDINGS: The Atf5-R1 transcript was found to be abundant in liver and other energy metabolism-related organs; Atf5-R2 was prominent in the testis. Fasting resulted in elevation of the expression of both Atf5-R1 and R2 in the liver. Interestingly, up-regulation of Atf5 was accompanied by increased expression of Cebpg and Pgc-1alpha. In human hepatoma cells (HepG2), but not in human cervical carcinoma cells (HeLa), forced expression of Atf5 and Cebpg cooperatively stimulated Pgc-1alpha promoter activity, suggesting that hepatic Pgc-1alpha could be induced by Atf5 and Cebpg in cooperation with other hepatic factors. SIGNIFICANCE: Hepatic Atf5 might be potentially involved in the induction of gluconeogenetic factors during in vivo fasting stress.
Subject(s)
Activating Transcription Factors/genetics , Embryo, Mammalian/metabolism , Fasting , Liver/metabolism , Activating Transcription Factors/metabolism , Animals , Base Sequence , CCAAT-Enhancer-Binding Proteins/genetics , CCAAT-Enhancer-Binding Proteins/metabolism , Cell Line, Tumor , Embryo, Mammalian/embryology , Female , Humans , Liver/ultrastructure , Male , Mice , Mice, Inbred C57BL , Pregnancy , Promoter Regions, Genetic , RNA, Messenger/analysis , RNA, Messenger/genetics , Transcription Factors/genetics , Transcription Factors/metabolism , Transfection , Up-RegulationABSTRACT
ATF5 is a transcription factor in the cAMP response element (CRE)-binding protein/activating transcription factor (CREB/ATF) family. We studied the effect of amino acid limitation on ATF5 mRNA levels in a mammalian cell line. Northern-blot analysis demonstrated that limitation of a single amino acid, glutamine, methionine, or leucine, resulted in increased ATF5 mRNA levels in HeLaS3 cells. This resulted, at least in part, from increased half-life of the ATF5 mRNA transcript. Cycloheximide inhibited the increase in ATF5 mRNA expression induced by glutamine limitation, indicating that it was dependent on de novo protein synthesis. Moreover, rapamycin had no effect on basal ATF5 mRNA expression or on increased expression induced by glutamine limitation. These results indicate that amino acid limitation regulates ATF5 mRNA expression during post-transcription in a rapamycin-independent manner. The potential role for ATF5 in protecting cells from amino acid-limitation is of considerable interest.
