RESUMEN
Catalepsy is a behavioral condition that is associated with severe psychopathologies, including schizophrenia, depression, and Parkinson's disease. In some mouse strains, catalepsy can be induced by pinching the skin at the scruff of the neck. The main locus of hereditary catalepsy in mice has recently been linked to the 105-115 Mb fragment of mouse chromosome 13 by QTL analysis. We performed whole-genome sequencing of catalepsy-resistant and catalepsy-prone mouse strains in order to pinpoint the putative candidate genes related to hereditary catalepsy in mice. We remapped the previously described main locus for hereditary catalepsy in mice to the chromosome region 103.92-106.16 Mb. A homologous human region on chromosome 5 includes genetic and epigenetic variants associated with schizophrenia. Furthermore, we identified a missense variant in catalepsy-prone strains within the Nln gene. Nln encodes neurolysin, which degrades neurotensin, a peptide reported to induce catalepsy in mice. Our data suggest that Nln is the most probable candidate for the role of major gene of hereditary, pinch-induced catalepsy in mice and point to a shared molecular pathway between catalepsy in mice and human neuropsychiatric disorders.
RESUMEN
A decrease in the light in autumn and winter causes depression like seasonal affective disorders (SAD) in sensitive patients, in which the serotonin (5-HT) and dopamine (DA) brain mediator systems are involved. We studied the interaction of the 5-HT and DA brain systems in an experimental SAD model in sexually mature male mice of the congenic B6-1473C and B6-1473G lines with high and low activity of tryptophan hydroxylase 2, a key enzyme of 5-HT synthesis in the brain. Mice of each line (divided into two groups of eight individuals) were kept for 30 days in standard (14 h light/10 h dark) and short (4 h light/20 h dark) daylight. The presence of the C1473G variant in the tryptophan hydroxylase 2 gene did not affect the expression of key genes of DA system: Drd1, Drd2, Scl6a3, Th, and Comt, that encode the D1 and D2 receptors, dopamine transporter, tyrosine hydroxylase, and catechol-o-methyltransferase, respectively. A decrease in the level of DA in the midbrain, as well as of its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum, was detected in B6-1473G mice. Keeping mice in short daylight did not affect expression of the Drd1 gene in all brain structures nor the expression of the Slc6a3 and Th genes in the midbrain. Drd2 expression increased in the midbrain and decreased in the hippocampus, where Comt expression increased. An increase in DA level in the midbrain and DOPAC in the striatum was detected in mice kept in short daylight. This indicates the involvement of the brain's DA system in the reaction to a decrease in daylight duration. No statistically significant effect of the interaction between the presence of the C1473G variant and daylight length on indicators of the activity of DA system was detected. No reasons were found to assert that this polymorphism determines the observed reaction of the brain DA system in keeping of animals under short daylight conditions.
Asunto(s)
Encéfalo/metabolismo , Dopamina/metabolismo , Fotoperiodo , Polimorfismo Genético , Triptófano Hidroxilasa/genética , Animales , Encéfalo/enzimología , Masculino , Ratones , Triptófano Hidroxilasa/metabolismoRESUMEN
We compared the effect of a new potential antidepressant 8-trifluoromethyl 1,2,3,4,5-benzopentathiepine-6-amine hydrochloride (TC-2153) and classical antidepressant fluoxetine in a dose of 0.25 mg/liter on the behavior of Danio rerio in the "novel tank" test and content of biogenic amines and their metabolites in the brain. Fluoxetine alone and TC-2153 alone significantly increased the time spent in the upper part of the tank and insignificantly reduced motor activity. Combined exposure of fishes in the solution containing potential and classical antidepressants potentiated their effects on both parameters. The compounds did not affect brain contents of serotonin, dopamine, and norepinephrine. At the same time, fluoxetine, but not TC-2153, reduced brain content of the main serotonin metabolite 5-hydroxyindole acetic acid.
Asunto(s)
Antidepresivos/farmacología , Benzotiepinas/farmacología , Aminas Biogénicas/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Fluoxetina/farmacología , Animales , Conducta Animal/efectos de los fármacos , Dopamina/metabolismo , Norepinefrina/metabolismo , Serotonina/metabolismo , Pez CebraRESUMEN
The study of spaceflight effects on the brain is technically complex concern; complicated by the problem of applying an adequate ground model. The most-widely used experimental model to study the effect of microgravity is the tail-suspension hindlimb unloading model; however, its compliance with the effect of actual spaceflight on the brain is still unclear. We evaluated the effect of one month hindlimb unloading on the expression of genes related to the brain neuroplasticity-brain neutotrophic factors (Gdnf, Cdnf), apoptotic factors (Bcl-xl, Bax), serotonin- and dopaminergic systems (5-HT2A, Maoa, Maob, Th, D1r, Comt), and compared the results with the data obtained on mice that spent one month in spaceflight on Russian biosatellite Bion-M1. No effect of hindlimb unloading was observed on the expression of most genes, which were considered as risk neurogenes for long-term actual spaceflight. The opposite effect of hindlimb unloading and spaceflight was found on the level of mRNA of D1 dopamine receptor and catechol-O-methyltransferase in the striatum. At the same time, the expression of Maob in the midbrain decreased, and the expression of Bcl-xl genes increased in the hippocampus, which corresponds to the effect of spaceflight. However, the hindlimb unloading model failed to reproduce the majority of effects of long-term spaceflight on serotonin-, dopaminergic systems and some apoptotic factors.
Asunto(s)
Apoptosis , Encéfalo/metabolismo , Dopamina/metabolismo , Serotonina/metabolismo , Ingravidez , Animales , Dopamina/genética , Suspensión Trasera , Masculino , Ratones Endogámicos C57BL , Monoaminooxidasa/metabolismo , Receptor de Serotonina 5-HT2A/metabolismo , Serotonina/genética , Vuelo Espacial , Factores de TiempoRESUMEN
Mice of C57BL/6J strain were exposed to 1-month spaceflight on Russian biosatellite Bion-M1 to determine the effect of long-term actual spaceflight on the expression of genes involved in the processes of neurogenesis and apoptosis. Specifically, we focused on the genes encoding proapoptotic factor BAX, antiapoptotic factor BCL-XL, brain-derived neurotrophic factor (BDNF) and BDNF receptors TrkB and p75. Spaceflight reduced the expression of the antiapoptotic BCL-XL gene in the striatum and hypothalamus, but increased it in the hippocampus. To estimate environmental stress contribution into spaceflight effects we analyzed spaceflight-responsive genes in mice housed for 1 month on Earth in the same shuttle cabins that were used for spaceflight, and in mice of the laboratory control group. It was shown that 1-month shuttle cabin housing decreased BCL-XL gene expression in the striatum but failed to alter BCL-XL mRNA levels in the hippocampus or hypothalamus. Spaceflight failed to alter the expression of the proapoptotic BAX gene in all investigated brain structures, although the insignificant increase of the BAX mRNA level in the hippocampus of spaceflight mice was found. At the same time, shuttle cabin housing produced insignificant decrease in BAX gene expression in the hippocampus. In contrast to the BCL-XL gene, genes encoding BAX, BDNF as well as TrkB and p75 receptors did not respond to 30-day spaceflight. Thus, long-term spaceflight (1) did not affect the expression of genes encoding BDNF as well as TrkB and p75 receptors, (2) produced dysregulation in genetic control of the neuronal apoptosis, (3) implicated BCL-XL as the risk factor for spaceflight-induced behavioral abnormalities.
Asunto(s)
Encéfalo/metabolismo , Vuelo Espacial , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Expresión Génica , Vivienda para Animales , Masculino , Ratones Endogámicos C57BL , ARN Mensajero/metabolismo , Receptor trkB/metabolismo , Receptores de Factor de Crecimiento Nervioso/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Estrés Fisiológico/fisiología , Proteína X Asociada a bcl-2/metabolismo , Proteína bcl-X/metabolismoRESUMEN
Mice were exposed to 1 month of spaceflight on Russian biosatellite BION-M1 to determine its effect on the expression of key genes in the brain dopamine (DA) and serotonin (5-HT) systems. Spaceflight decreased the expression of crucial genes involved in DA synthesis and degradation, as well as the D1 receptor. However, spaceflight failed to alter the expression of tryptophan hydroxylase-2, 5-HT transporter, 5-HT1A, and 5-HT3 receptor genes, though it reduced 5-HT2A receptor gene expression in the hypothalamus. We revealed risk DA and 5-HT neurogenes for long-term spaceflight for the first time, as well as microgravity-responsive genes (tyrosine hydroxylase, catechol-O-methyltransferase, and D1 receptor in the nigrostriatal system; D1 and 5-HT2A receptors in the hypothalamus; and monoamine oxidase A (MAO A) in the frontal cortex). Decreased genetic control of the DA system may contribute to the spaceflight-induced locomotor impairment and dyskinesia described for both humans and rats.
Asunto(s)
Conducta Animal/fisiología , Encéfalo/metabolismo , Dopamina/metabolismo , Serotonina/metabolismo , Vuelo Espacial , Animales , Regulación de la Expresión Génica/fisiología , Humanos , Masculino , Ratones Endogámicos C57BL , Receptor de Serotonina 5-HT2A/metabolismo , TiempoRESUMEN
We studied the effect of IL-6 on the open-field behavior and degree of cataleptic freezing in male AKR/J mice and AKR.CBA-D13Mit76 congenic animals (differing from CBA/Lac mice in the chromosome 13 fragment of 111.35-116.14 Mbp). IL-6 in both doses significantly increased the time of cataleptic freezing. IL-6 in a dose of 3 µg/kg had a strong inhibitory effect on locomotor activity of AKR.CBA-D13Mit76 males in the open-field test. However, IL-6 in both doses did not modulate locomotor activity and severity of catalepsy in AKR/J males. Our results indicate that the distal fragment of chromosome 13 is involved in the effect of IL-6 on the locomotor activity of mice.
Asunto(s)
Cromosomas de los Mamíferos/fisiología , Interleucina-6/fisiología , Animales , Femenino , Reacción Cataléptica de Congelación , Masculino , Ratones Endogámicos AKR , Ratones Endogámicos CBA , Actividad MotoraRESUMEN
Catalepsy usually is caused by imbalance of dopamine (DA) and serotonin (5-HT) systems of brain. The aim of our work was to verify if this imbalance plays an important role in the mechanism of hereditary catalepsy in mice. Maintenance of DA, 5-HT and their main metabolites--5-hydroxyindoleacetic acid, 3,4-dihydroxyphenylacetic acid, homovanilic acid was determined in cortex, hypothalamus, hippocampus, striatum, substantia nigra and nuclei raphes in catalepsy-resistant AKR/J mice strain and catalepsy-prone CBA/LacJ mice strain and recombinant mice AKR/J.CBA-D13Mit76 (D13) strain. The latest strain was selected by transferring of a fragment of the chromosome 13 from CBA/LacJ carrying the main gene of hereditary catalepsy to AKR/J genome. There were no interstrain differences in concentration of biogenic amines and their metabolites in all brain regions. As a result of our work the hypothesis about the important role of 5-HT and/or DA systems of brain in the mechanism of hereditary catalepsy in mice was denied.
Asunto(s)
Ácido 3,4-Dihidroxifenilacético/metabolismo , Catalepsia/metabolismo , Dopamina/metabolismo , Ácido Homovanílico/metabolismo , Ácido Hidroxiindolacético/metabolismo , Serotonina/metabolismo , Animales , Catalepsia/genética , Catalepsia/fisiopatología , Corteza Cerebral/metabolismo , Corteza Cerebral/fisiopatología , Cuerpo Estriado/metabolismo , Cuerpo Estriado/fisiopatología , Cruzamientos Genéticos , Predisposición Genética a la Enfermedad , Hipocampo/metabolismo , Hipocampo/fisiopatología , Hipotálamo/metabolismo , Hipotálamo/fisiopatología , Masculino , Ratones Endogámicos AKR , Ratones Endogámicos CBA , Núcleo Accumbens/metabolismo , Núcleo Accumbens/fisiopatología , Núcleo Magno del Rafe/metabolismo , Núcleo Magno del Rafe/fisiopatología , Sustancia Negra/metabolismo , Sustancia Negra/fisiopatologíaRESUMEN
Glycoprotein gp130 is involved in the interleukin-6 (IL-6) and related cytokines' signaling. Linkage between the gp130 coding gene and freezing reaction (catalepsy) was shown. Here, we compared the expression and function of the gp130 in male mice of catalepsy-resistant AKR/J strain and catalepsy-prone congenic AKR.CBA-D13Mit76 strain created by transferring the gp130 gene allele from catalepsy-prone CBA/Lac to the genome of AKR/J strain. No difference in the gp130 expression in the frontal cortex, hippocampus and midbrain between AKR and AKR.CBA-D13Mit76 mice was found. However, AKR.CBA-D13Mit76 mice were more sensitive to bacterial lipopolysaccharide (LPS). The administration of LPS (50 µg/kg, ip) significantly increased mRNA level of the gene coding IL-6-regulated glial fibrillary acidic protein (GFAP) in the midbrain, induced catalepsy and decreased locomotion in the open field and social investigation tests in AKR.CBA-D13Mit76, but not in AKR mice. The result indicates (1) the association between gp130 and hereditary catalepsy, (2) increased functional activity rather than expression of gp130 in AKR.CBA-D13Mit76 mice and (3) the involvement of gp130 in the mechanism of LPS-induced alteration of behavior.