RESUMO
We found that CS mice exhibit an extremely low immobility time (almost no immobility) in both the tail suspension test (TST) and forced swimming test (FST). In these tests, animals are subjected to the short-term, inescapable stress of being suspended by their tail or being forced to swim in a water-filled cylinder. In such situations, the animals rapidly adopt a characteristic immobile posture that has been named "behavioral despair" on the assumption that the animals have given up hope of escaping. These tests have been widely used for assessing antidepressant activity and depression-like behavior. Quantitative trait locus (QTL) mapping using CS and C57BL/6J mice revealed significant QTLs on chromosomes (Chrs) 4 (FST) and 5 (TST and FST). To identify the quantitative trait gene on Chr 5, we narrowed the QTL interval to 0.5 Mb using several congenic and subcongenic strains. Ubiquitin-specific peptidase 46 (Usp46) with a lysine codon deletion was located in this region. This deletion affected nest-building, muscimol-induced righting reflex and anti-immobility effects of imipramine. The muscimol-induced current in the hippocampal CA1 pyramidal neurons and hippocampal expression of the 67-kDa isoform of glutamic acid decarboxylase significantly decreased in the Usp46 mutant mice compared to control mice. All these phenotypes were rescued in transgenic mice with bacterial artificial chromosomes containing wild-type Usp46. Thus, Usp46 affects "behavioral despair" and it is implicated in the regulation of GABA action.
Assuntos
Depressão/genética , Animais , Antidepressivos/farmacologia , Modelos Animais de Doenças , Camundongos , Camundongos EndogâmicosRESUMO
The tail suspension test (TST) and forced swimming test (FST) are widely used for assessing antidepressant activity and depression-like behavior. We found that CS mice show negligible immobility in inescapable situations. Quantitative trait locus (QTL) mapping using CS and C57BL/6J mice revealed significant QTLs on chromosomes 4 (FST) and 5 (TST and FST). To identify the quantitative trait gene on chromosome 5, we narrowed the QTL interval to 0.5 Mb using several congenic and subcongenic strains. Ubiquitin-specific peptidase 46 (Usp46) with a lysine codon deletion was located in this region. This deletion affected nest building, muscimol-induced righting reflex and anti-immobility effects of imipramine. The muscimol-induced current in the hippocampal CA1 pyramidal neurons and hippocampal expression of the 67-kDa isoform of glutamic acid decarboxylase were significantly decreased in the Usp46 mutant mice compared to control mice. These phenotypes were rescued in transgenic mice with bacterial artificial chromosomes containing wild-type Usp46. Thus, Usp46 affects the immobility in the TST and FST, and it is implicated in the regulation of GABA action.
Assuntos
Locos de Características Quantitativas/genética , Cauda/fisiologia , Animais , Mapeamento Cromossômico , Códon/genética , Endopeptidases/genética , Estudos de Associação Genética/métodos , Glutamato Descarboxilase/genética , Imobilização , Camundongos , Camundongos Endogâmicos C57BL/genética , Camundongos Endogâmicos/genética , Deleção de Sequência , Cauda/anatomia & histologia , Ácido gama-AminobutíricoRESUMO
A new circadian variant was isolated by screening the intercross offspring of wild-caught mice (Mus musculus castaneus). This variant was characterized by an initial maintenance of damped oscillations and subsequent loss of rhythmicity after being transferred from light-dark (LD) cycles to constant darkness (DD). To map the genes responsible for the persistence of rhythmicity (circadian ratio) and the length of free-running period (tau), quantitative trait locus (QTL) analysis was performed using F(2) mice obtained from an F(1) cross between the circadian variant and C57BL/6J mice. As a result, a significant QTL with a main effect for circadian ratio (Arrhythmicity; Arrh-1) was mapped on Chromosome (Chr) 8. For tau, four significant QTLs, Short free-running period (Sfp-1) (Chr 1), Sfp-2 (Chr 6), Sfp-3 (Chr 8), Sfp-4 (Chr 11) were determined. An epistatic interaction was detected between Chr 3 (Arrh-2) and Chr 5 (Arrh-3). An in situ hybridization study of clock genes and mouse Period1::luciferase (mPer1::luc) real-time monitoring analysis in the suprachiasmatic nucleus (SCN) suggested that arrhythmicity in this variant might not be attributed to core circadian mechanisms in the SCN neurons. Our strategy using wild-derived variant mice may provide a novel opportunity to evaluate circadian and its related disorders in human that arise from the interaction between multiple variant genes.
Assuntos
Animais Selvagens/genética , Animais Selvagens/fisiologia , Comportamento Animal/fisiologia , Ritmo Circadiano/genética , Substituição de Aminoácidos , Animais , Proteínas CLOCK , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Cromossomos de Mamíferos/genética , Ritmo Circadiano/fisiologia , Cruzamentos Genéticos , Escuridão , Epistasia Genética , Feminino , Regulação da Expressão Gênica , Escore Lod , Medições Luminescentes , Masculino , Camundongos , Mutação/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Circadianas Period , Locos de Características Quantitativas/genética , Análise de Sequência de DNA , Núcleo Supraquiasmático/metabolismo , Transativadores/genética , Transativadores/metabolismoRESUMO
CS mice show unique properties of circadian rhythms: unstable free-running periods and distinct bimodal rhythms (similar to rhythm splitting, but hereafter referred to as bimodal rhythms) under constant darkness. In the present study, we compared clock-related gene expression (mPer1, mBmal1 and Dbp) in the SCN and peripheral tissues (liver, adrenal gland and heart) between CS and C57BL/6J mice. In spite of normal robust oscillation in the SCN of both mice, behavioral rhythms and peripheral rhythms of clock-related genes were significantly different between these mice. However, when daytime restricted feeding was given, no essential differences between the two strains were observed. These results indicate that unusual circadian behaviors and peripheral gene expression in CS mice do not depend on the SCN but rather mechanisms outside of the SCN.
