RESUMEN
Previous studies on paternal epigenetic inheritance have shown that sperm RNAs play a role in this type of inheritance. The microinjection of sperm small noncoding RNAs into fertilised mouse oocytes induces reprogramming of the early embryo, which is thought to be responsible for the differences observed in adult phenotype. While sperm long noncoding RNAs (lncRNAs) have also been investigated in a previous study, their microinjection into fertilised oocytes did not yield conclusive results regarding their role in modulating brain development and adult behavioural phenotypes. Therefore, in the current study we sought to investigate this further. We used our previously established paternal corticosterone (stress hormone) model to assess sperm lncRNA expression using CaptureSeq, a sequencing technique that is more sensitive than the ones used in other studies in the field. Paternal corticosterone exposure led to dysregulation of sperm long noncoding RNA expression, which encompassed lncRNAs, circular RNAs and transposable element transcripts. Although they have limited functional annotation, bioinformatic approaches indicated the potential of these lncRNAs in regulating brain development and function. We then separated and isolated the sperm lncRNAs and performed microinjections into fertilised oocytes, to generate embryos with modulated lncRNA populations. We observed that the resulting adult offspring had lower body weight and altered anxiety and affective behavioural responses, demonstrating roles for lncRNAs in modulating development and brain function. This study provides novel insights into the roles of lncRNAs in epigenetic inheritance, including impacts on brain development and behaviours of relevance to affective disorders.
Asunto(s)
Corticosterona , Microinyecciones , ARN Largo no Codificante , Espermatozoides , Animales , Masculino , ARN Largo no Codificante/metabolismo , ARN Largo no Codificante/genética , Ratones , Corticosterona/farmacología , Espermatozoides/metabolismo , Microinyecciones/métodos , Femenino , Epigénesis Genética , Ratones Endogámicos C57BL , Ansiedad/metabolismo , Ansiedad/genética , Oocitos/metabolismo , Conducta Animal/fisiología , Estrés Psicológico/metabolismo , Encéfalo/metabolismoRESUMEN
Attention deficits are frequently reported within the clinical autism population. Despite not being a core diagnostic feature, some aetiological theories place atypical attention at the centre of autism development. Drugs used to treat attention dysfunction are therefore increasingly prescribed to autistic patients, though currently off-label with uncertain efficacy. We utilised a rodent-translated touchscreen test of sustained attention in mice carrying an autism-associated R451C mutation in the neuroligin-3 gene (Nlgn3R451C). In doing so, we replicated their cautious but accurate response profile and probed it using two widely prescribed attention-modulating drugs: methylphenidate (MPH) and atomoxetine (ATO). In wild-type mice, acute administration of MPH (3 mg/kg) promoted impulsive responding at the expense of accuracy, while ATO (3 mg/kg) broadly reduced impulsive responding. These drug effects were absent in Nlgn3R451C mice, other than a small reduction in blank touches to the screen following ATO administration. The absence of drug effects in Nlgn3R451C mice likely arises from their altered behavioural baseline and underlying neurobiology, highlighting caveats to the use of classic attention-modulating drugs across disorders and autism subsets. It further suggests that altered dopaminergic and/or norepinephrinergic systems may drive behavioural differences in the Nlgn3R451C mouse model of autism, supporting further targeted investigation.
RESUMEN
Autism spectrum disorder (ASD) is a neurodevelopmental disorder typified by impaired social communication and restrictive and repetitive behaviors. Mice serve as an ideal candidate organism for studying the neural mechanisms that subserve these symptoms. The Neuroligin-3 (NL3) mouse, expressing a R451C mutation discovered in two Swedish brothers with ASD, exhibits impaired social interactions and heightened aggressive behavior towards male mice. Social interactions with female mice have not been characterized and in the present study were assessed in male NL3R451C and WT mice. Mice were housed in social and isolation conditions to test for isolation-induced increases in social interaction. Tests were repeated to investigate potential differences in interaction in naïve and experienced mice. We identified heightened interest in mating and atypical aggressive behavior in NL3R451C mice. NL3R451C mice exhibited normal social interaction with WT females, indicating that abnormal aggressive behavior towards females is not due to altered motivation to engage. Social isolation rearing heightened interest in social behavior in all mice. Isolation housing selectively modulated the response to female pheromones in NL3R451C mice. This study is the first to show altered mating behavior in the NL3R451C mouse and has provided new insights into the aggressive phenotype in this model.
Asunto(s)
Agresión/fisiología , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/psicología , Moléculas de Adhesión Celular Neuronal/genética , Proteínas de la Membrana/genética , Proteínas del Tejido Nervioso/genética , Conducta Sexual Animal/fisiología , Aislamiento Social , Animales , Conducta Animal , Modelos Animales de Enfermedad , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Mutación , Conducta SocialRESUMEN
Environmental enrichment (EE) increases levels of novelty and complexity, inducing enhanced sensory, cognitive and motor stimulation. In wild-type rodents, EE has been found to have a range of effects, such as enhancing experience-dependent cellular plasticity and cognitive performance, relative to standard-housed controls. Whilst environmental enrichment is of course a relative term, dependent on the nature of control environmental conditions, epidemiological studies suggest that EE has direct clinical relevance to a range of neurological and psychiatric disorders. EE has been demonstrated to induce beneficial effects in animal models of a wide variety of brain disorders. The first evidence of beneficial effects of EE in a genetically targeted animal model was generated using Huntington's disease transgenic mice. Subsequent studies found that EE was also therapeutic in mouse models of Alzheimer's disease, consistent with epidemiological studies of relevant environmental modifiers. EE has also been found to ameliorate behavioural, cellular and molecular deficits in animal models of various neurological and psychiatric disorders, including Parkinson's disease, stroke, traumatic brain injury, epilepsy, multiple sclerosis, depression, schizophrenia and autism spectrum disorders. This review will focus on the effects of EE observed in animal models of neurodegenerative brain diseases, at molecular, cellular and behavioural levels. The proposal that EE may act synergistically with other approaches, such as drug and cell therapies, to facilitate brain repair will be discussed. I will also discuss the therapeutic potential of 'enviromimetics', drugs which mimic or enhance the therapeutic effects of cognitive activity and physical exercise, for both neuroprotection and brain repair.
Asunto(s)
Ambiente , Enfermedades Neurodegenerativas/terapia , Animales , Cognición , Modelos Animales de Enfermedad , Ratones , Plasticidad Neuronal/fisiología , Condicionamiento Físico Animal , RatasRESUMEN
Atypical attention orienting has been found to be impaired in many neuropsychological disorders, but the underlying neural mechanism remains unclear. Attention can be oriented exogenously (i.e., driven by salient stimuli) or endogenously (i.e., driven by one's goals or intentions). Genetic mouse models are useful tools to investigate the neurobiology of cognition, but a well-established assessment of attention orienting in mice is missing. This study aimed to adapt the Posner task, a widely used attention orienting task in humans, for use in mice using touchscreen technology and to test the effects of two attention-modulating drugs, methylphenidate (MPH) and atomoxetine (ATX), on the performance of mice during this task. In accordance with human performance, mice responded more quickly and more accurately to validly cued targets compared to invalidly cued targets, thus supporting mice as a valid animal model to study the neural mechanisms of attention orienting. This is the first evidence that mice can be trained to voluntarily maintain their nose-poke on a touchscreen and to complete attention orienting tasks using exogenous peripheral cues and endogenous symbolic cues. The results also showed no significant effects of MPH and ATX on attention orienting, although MPH improved overall response times in mice during the exogenous orienting task. In summary, the current study provides a critical translational task for assessing attention orienting in mice and to investigate the effects of attention-modulating drugs on attention orienting.
Asunto(s)
Atención , Señales (Psicología) , Animales , Ratones , Tiempo de ReacciónRESUMEN
Brain-derived neurotrophic factor (BDNF) is an essential neurotrophin and regulation of its expression is complex due to multiple 5' untranslated exons which are separately spliced to a common coding exon to form unique mRNA transcripts. Disruption of BDNF gene expression is a key to the development of symptoms in Huntington's disease (HD), a fatal neurodegenerative condition. Abnormal epigenetic modifications are associated with reduced gene expression in late-stage HD but such regulation of BDNF gene expression has yet to be investigated. We hypothesized that BDNF gene expression is altered in the HD hippocampus of pre-motor symptomatic R6/1 transgenic HD mice, correlating with a change in the DNA methylation profile. The effects of wheel-running and environmental enrichment on wild-type mice, in association with a proposed environment-mediated correction of BDNF gene expression deficits in HD mice, were also investigated. Using real-time PCR, levels of total BDNF mRNA were found to be reduced in the hippocampus of both male and female HD mice. Wheel-running significantly increased total BDNF gene expression in all groups of mice except male HD mice. In contrast, environmental enrichment significantly increased expression only in male wild-type animals. Further quantification of BDNF exon-specific transcripts revealed sex-specific changes in relation to the effect of the HD mutation and differential effects on gene expression by wheel-running and environmental enrichment. The HD-associated reduction of BDNF gene expression was not due to increased methylation of the gene sequence. Furthermore, environment-induced changes in BDNF gene expression in the wild-type hippocampus were independent of the extent of DNA methylation. Overall, the results of this study provide new insight into the role of BDNF in HD pathogenesis in addition to the mechanisms regulating normal BDNF gene expression.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Ambiente , Regulación de la Expresión Génica/fisiología , Hipocampo/metabolismo , Enfermedad de Huntington/rehabilitación , Esfuerzo Físico/fisiología , Caracteres Sexuales , Análisis de Varianza , Animales , Factor Neurotrófico Derivado del Encéfalo/genética , Inmunoprecipitación de Cromatina , Modelos Animales de Enfermedad , Exones/genética , Exones/fisiología , Femenino , Regulación de la Expresión Génica/genética , Proteína Huntingtina , Enfermedad de Huntington/genética , Enfermedad de Huntington/metabolismo , Enfermedad de Huntington/patología , Masculino , Ratones , Ratones Transgénicos , Mutación/genética , Proteínas del Tejido Nervioso/genética , Proteínas Nucleares/genética , ARN Mensajero/metabolismo , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodosRESUMEN
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterised by impairments in social communication and the presence of restrictive and repetitive behaviours. A mouse model expressing an autism-associated R451C mutation in the gene encoding the synaptic adhesion protein neuroligin-3 (NL3) has been extensively characterised and shows altered behaviour relevant to core traits observed in ASD. Reported impairments in social behaviours in NL3R451C mice however remain controversial due to inconsistent findings in various assays across different laboratories. Such inconsistencies could plausibly be explained by an increased susceptibility of the NL3R451C mouse social phenotype to environmental modulation. To address this, NL3R451C mice were housed in standard or enriched housing from 4 weeks of age prior to behavioural testing. Enrichment rearing enhanced direct interactions with the stranger mouse in all mice in the three-chamber social interaction test however, NL3R451C mice did not show impairment in social interaction in the three-chamber test, in contrast with previous reports. Environmental enrichment enhanced aggressive behaviour in all mice, and did not specifically alter the heightened aggressive phenotype previously described in NL3R451C mice. Specific genotype effects of enrichment included reduced anxiety-like behaviour in WT mice, and lower locomotor activity levels in NL3 mice. While genotype-specific effects of enrichment were not seen on social behaviour, the general increase in affiliative social interaction and aggression seen in all mice, indicates that these behaviours, are vulnerable to change based on housing condition. Mouse models expressing ASD-associated mutations have great utility in elucidating the neurobiology underling development of core traits and it is crucial that efforts are focussed on those models exhibiting robust phenotypes. In light of the findings in the present study, we suggest approaches to improve replicability and reproducibility in mouse models of ASD.
Asunto(s)
Agresión/psicología , Trastorno del Espectro Autista/psicología , Moléculas de Adhesión Celular Neuronal/genética , Vivienda para Animales , Proteínas de la Membrana/genética , Mutación , Proteínas del Tejido Nervioso/genética , Condicionamiento Físico Animal/psicología , Interacción Social , Animales , Ansiedad , Conducta Animal , Peso Corporal , Modelos Animales de Enfermedad , Femenino , Locomoción , Masculino , Aprendizaje por Laberinto , Ratones , Ratones Endogámicos C57BLRESUMEN
Independent studies have observed that a paternal history of stress or trauma is associated with his children having a greater likelihood of developing psychopathologies such as anxiety disorders. This father-to-child effect is reproduced in several mouse models of stress, which have been crucial in developing a greater understanding of intergenerational epigenetic inheritance. We previously reported that treatment of C57Bl/6J male breeders with low-dose corticosterone (CORT) for 28 days prior to mating yielded increased anxiety-related behaviours in their male F1 offspring. The present study aimed to determine whether subchronic 7-day CORT treatment of male mice just prior to mating would be sufficient to induce intergenerational modifications of anxiety-related behaviours in offspring. We report that subchronic CORT treatment of male breeders reduced their week-on-week body weight gain and altered NR3C1 and CRH gene expression in the hypothalamus. There were no effects on sperm count and glucocorticoid receptor protein levels within the epididymal tissue of male breeders. Regarding the F1 offspring, screening for anxiety-related behaviours using the elevated-plus maze, light-dark box, and novelty-suppressed feeding test revealed no differences between the offspring of CORT-treated breeders compared to controls. Thus, it is crucial that future studies take into consideration the duration of exposure when assessing the intergenerational impacts of paternal health.
Asunto(s)
Ansiedad/etiología , Ansiedad/metabolismo , Herencia Paterna/genética , Animales , Trastornos de Ansiedad/etiología , Trastornos de Ansiedad/genética , Conducta Animal/efectos de los fármacos , Corticosterona/metabolismo , Corticosterona/farmacología , Hormona Liberadora de Corticotropina/efectos de los fármacos , Hormona Liberadora de Corticotropina/genética , Epigénesis Genética/efectos de los fármacos , Padre , Masculino , Ratones , Ratones Endogámicos C57BL , Receptores de Glucocorticoides/efectos de los fármacos , Receptores de Glucocorticoides/genética , Estrés Psicológico/metabolismoRESUMEN
Phospholipase C-beta1 (PLC-beta1) is a rate-limiting enzyme implicated in postnatal-cortical development and neuronal plasticity. PLC-beta1 transduces intracellular signals from specific muscarinic, glutamate and serotonin receptors, all of which have been implicated in the pathogenesis of schizophrenia. Here, we present data to show that PLC-beta1 knockout mice display locomotor hyperactivity, sensorimotor gating deficits as well as cognitive impairment. These changes in behavior are regarded as endophenotypes homologous to schizophrenia-like symptoms in rodents. Importantly, the locomotor hyperactivity and sensorimotor gating deficits in PLC-beta1 knockout mice are subject to beneficial modulation by environmental enrichment. Furthermore, clozapine but not haloperidol (atypical and typical antipsychotics, respectively) rescues the sensorimotor gating deficit in these animals, suggesting selective predictive validity. We also demonstrate a relationship between the beneficial effects of environmental enrichment and levels of M1/M4 muscarinic acetylcholine receptor binding in the neocortex and hippocampus. Thus we have demonstrated a novel mouse model, displaying disruption of multiple postsynaptic signals implicated in the pathogenesis of schizophrenia, a relevant behavioral phenotype and associated gene-environment interactions.
Asunto(s)
Clozapina/uso terapéutico , Fosfolipasa C beta/deficiencia , Esquizofrenia/genética , Esquizofrenia/rehabilitación , Animales , Antipsicóticos/uso terapéutico , Modelos Animales de Enfermedad , Ambiente , Hipocampo/fisiopatología , Ratones , Ratones Noqueados , Actividad Motora , Neocórtex/fisiopatología , Fenotipo , Receptores Muscarínicos/fisiología , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/enzimología , Psicología del EsquizofrénicoRESUMEN
During development of the cerebral cortex, the invasion of thalamic axons and subsequent differentiation of cortical neurons are tightly coordinated. Here we provide evidence that glutamate neurotransmission triggers a critical signaling mechanism involving the activation of phospholipase C-beta1 (PLC-beta1) by metabotropic glutamate receptors (mGluRs). Homozygous null mutation of either PLC-beta1 or mGluR5 dramatically disrupts the cytoarchitectural differentiation of 'barrels' in the mouse somatosensory cortex, despite segregation in the pattern of thalamic innervation. Furthermore, group 1 mGluR-stimulated phosphoinositide hydrolysis is dramatically reduced in PLC-beta1-/- mice during barrel development. Our data indicate that PLC-beta1 activation via mGluR5 is critical for the coordinated development of the neocortex, and that presynaptic and postsynaptic components of cortical differentiation can be genetically dissociated.
Asunto(s)
Diferenciación Celular/fisiología , Cicloleucina/análogos & derivados , Ácido Glutámico/metabolismo , Isoenzimas/deficiencia , Receptores de Glutamato Metabotrópico/metabolismo , Corteza Somatosensorial/crecimiento & desarrollo , Corteza Somatosensorial/metabolismo , Transmisión Sináptica/fisiología , Fosfolipasas de Tipo C/deficiencia , Animales , Axones/metabolismo , Axones/ultraestructura , Carbacol/farmacología , Cicloleucina/farmacología , Inositol 1,4,5-Trifosfato/metabolismo , Isoenzimas/genética , Ratones , Ratones Noqueados , Fármacos Neuroprotectores/farmacología , Fosfatidilinositoles/metabolismo , Fosfolipasa C beta , Receptor del Glutamato Metabotropico 5 , Receptores de Glutamato Metabotrópico/deficiencia , Receptores de Glutamato Metabotrópico/efectos de los fármacos , Receptores de Glutamato Metabotrópico/genética , Receptores Muscarínicos/efectos de los fármacos , Receptores Muscarínicos/metabolismo , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismo , Fosfolipasas de Tipo C/genéticaRESUMEN
There is growing evidence that the preconceptual lifestyle and other environmental exposures of a father can significantly alter the physiological and behavioral phenotypes of their children. We and others have shown that paternal preconception stress, regardless of whether the stress was experienced during early-life or adulthood, results in offspring with altered anxiety and depression-related behaviors, attributed to hypothalamic-pituitary-adrenal axis dysregulation. The transgenerational response to paternal preconceptual stress is believed to be mediated by sperm-borne small noncoding RNAs, specifically microRNAs. As physical activity confers physical and mental health benefits for the individual, we used a model of voluntary wheel-running and investigated the transgenerational response to paternal exercise. We found that male offspring of runners had suppressed reinstatement of juvenile fear memory, and reduced anxiety in the light-dark apparatus during adulthood. No changes in these affective behaviors were observed in female offspring. We were surprised to find that running had a limited impact on sperm-borne microRNAs. The levels of three unique microRNAs (miR-19b, miR-455 and miR-133a) were found to be altered in the sperm of runners. In addition, we discovered that the levels of two species of tRNA-derived RNAs (tDRs)-tRNA-Gly and tRNA-Pro-were also altered by running. Taken together, we believe this is the first evidence that paternal exercise is associated with an anxiolytic behavioral phenotype of male offspring and altered levels of small noncoding RNAs in sperm. These small noncoding RNAs are known to have an impact on post-transcriptional gene regulation and can thus change the developmental trajectory of offspring brains and associated affective behaviors.
Asunto(s)
Ansiedad/genética , Miedo/psicología , Transmisión Vertical de Enfermedad Infecciosa/veterinaria , MicroARNs/genética , Condicionamiento Físico Animal/efectos adversos , Espermatozoides/metabolismo , Animales , Ansiedad/psicología , Depresión/genética , Depresión/psicología , Exposición a Riesgos Ambientales/efectos adversos , Femenino , Regulación de la Expresión Génica , Sistema Hipotálamo-Hipofisario/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Fenotipo , Sistema Hipófiso-Suprarrenal/fisiopatología , ARN Pequeño no TraducidoRESUMEN
Our previous study demonstrated that phospholipase C beta 1 mRNA was down-regulated in Brodmann's area 46 from subjects with schizophrenia. However, phospholipase C beta 1 protein has also been shown to be lower in Brodmann's area 8 and 9 from teenage suicide subjects, creating a potential confound in interpreting the findings in schizophrenia due to the high suicide rate associated with this disorder. To begin to reconcile and consolidate these findings, in this study, we measured mRNA and protein levels of phospholipase C beta 1 variants a and b in Brodmann's area 46 and Brodmann's area 9 from subjects with schizophrenia, many of whom were suicide completers, and determined the diagnostic specificity of observed findings. Consistent with our previous study, levels of phospholipase C beta 1 a and b mRNA, but not protein, were lower in Brodmann's area 46 from subjects with schizophrenia. In Brodmann's area 9, phospholipase C beta 1a protein levels were lower in subjects with schizophrenia, while phospholipase C beta 1b mRNA was higher and protein was lower in those that had died of suicide. Altered protein levels in Brodmann's area 9 appeared to be diagnostically specific, as we did not detect these changes in subjects with bipolar disorder, major depressive disorder or suicide completers with no diagnosis of mental illness. We further assessed the relationship between phospholipase C beta 1 and levels of muscarinic receptors (CHRMs) that signal through this protein, in both human and Chrm knockout mouse central nervous system tissue, and found no strong relationship between the two. Understanding central nervous system differences in downstream effector pathways in schizophrenia may lead to improved treatment strategies and help to identify those at risk of suicide.
RESUMEN
Huntington's disease is a fatal neurodegenerative disorder caused by a mutation of the huntingtin gene and involves progressive motor abnormalities (including chorea), cognitive deficits (dementia) as well as psychiatric symptoms. We have previously demonstrated that environmental enrichment slows the onset and progression of Huntington's disease in transgenic mice. Here, we investigated the effects of enhanced physical exercise on disease progression and brain-derived neurotrophic factor expression. Standard-housed Huntington's disease mice developed phenotypic rear-paw clasping by 16 weeks of age, displayed abnormal rearing behavior, deficits in motor co-ordination and of spatial working memory. Huntington's disease mice with access to running wheels exhibited delayed onset of rear-paw clasping, normalized levels of rearing behavior and amelioration of the cognitive deficits. However, in contrast to our previous environmental enrichment studies, there was no rescue of motor coordination deficits in wheel-running Huntington's disease mice. An abnormal accumulation of brain-derived neurotrophic factor protein in the frontal cortex of Huntington's disease mice was unaffected by running. Striatal and hippocampal brain-derived neurotrophic factor protein levels were unchanged. Brain-derived neurotrophic factor mRNA levels were reduced in the anterior cortex, striatum and hippocampus of Huntington's disease mice, and only striatal deficits were ameliorated by running. Overall, we show that voluntary physical exercise delays the onset of Huntington's disease and the decline in cognitive ability. In addition, our results reveal that some aspects of hippocampal dependent memory are not entirely reliant on sustained hippocampal brain-derived neurotrophic factor expression.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/deficiencia , Enfermedad de Huntington/metabolismo , Enfermedad de Huntington/rehabilitación , Condicionamiento Físico Animal/métodos , Factores de Edad , Análisis de Varianza , Animales , Conducta Animal , Factor Neurotrófico Derivado del Encéfalo/genética , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Conducta Exploratoria/fisiología , Lóbulo Frontal/metabolismo , Regulación de la Expresión Génica/genética , Proteína Huntingtina , Enfermedad de Huntington/genética , Enfermedad de Huntington/fisiopatología , Masculino , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Transgénicos , Proteínas del Tejido Nervioso/genética , Proteínas Nucleares/genética , Desempeño Psicomotor/fisiología , ARN Mensajero/metabolismo , Tiempo de Reacción/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Carrera/fisiología , Factores de TiempoRESUMEN
Cognitive dysfunction appears as a core feature of dementia, which includes its most prevalent form, Alzheimer's disease (AD), as well as vascular dementia, frontotemporal dementia, and other brain disorders. AD alone affects more than 45 million people worldwide, with growing prevalence in aging populations. There is no cure, and therapeutic options remain limited. Gene-edited and transgenic animal models, expressing disease-specific gene mutations, illuminate pathogenic mechanisms leading to cognitive decline in AD and other forms of dementia. To date, cognitive tests in AD mouse models have not been directly relevant to the clinical presentation of AD, providing challenges for translation of findings to the clinic. Touchscreen testing in mice has enabled the assessment of specific cognitive domains in mice that are directly relevant to impairments described in human AD patients. In this review, we provide context for how cognitive decline is measured in the clinic, describe traditional methods for assessing cognition in mice, and outline novel approaches, including the use of the touchscreen platform for cognitive testing. We highlight the limitations of traditional memory-testing paradigms in mice, particularly their capacity for direct translation into cognitive testing of patients. While it is not possible to expect direct translation in testing methodologies, we can aim to develop tests that engage similar neural substrates in both humans and mice. Ultimately, that would enable us to better predict efficacy across species and therefore improve the chances that a treatment that works in mice will also work in the clinic.
Asunto(s)
Enfermedad de Alzheimer/fisiopatología , Cognición , Pruebas Neuropsicológicas , Investigación Biomédica Traslacional/métodos , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Animales , Modelos Animales de Enfermedad , Humanos , Memoria , RatonesRESUMEN
Clinical evidence indicates that serotonin-1A receptor (5-HT1AR) gene polymorphisms are associated with anxiety disorders and deficits in cognition. In animal models, exercise (Ex) and environmental enrichment (EE) can change emotionality-related behaviours, as well as enhance some aspects of cognition and hippocampal neurogenesis. We investigated the effects of Ex and EE (which does not include running wheels) on cognition and anxiety-like behaviours in wild-type (WT) and 5-HT1AR knock-out (KO) mice. Using an algorithm-based classification of search strategies in the Morris water maze, we report for we believe the first time that Ex increased the odds for mice to select more hippocampal-dependent strategies. In the retention probe test, Ex (but not EE) corrected long-term spatial memory deficits displayed by KO mice. In agreement with these findings, only Ex increased hippocampal cell survival and BDNF protein levels. However, only EE (but not Ex) modified anxiety-like behaviours, demonstrating dissociation between improvements in cognition and innate anxiety. EE enhanced hippocampal cell proliferation in WT mice only, suggesting a crucial role for intact serotonergic signalling in mediating this effect. Together, these results demonstrate differential effects of Ex vs EE in a mouse model of anxiety with cognitive impairment. Overall, the 5-HT1AR does not seem to be critical for those behavioural effects to occur. These findings will have implications for our understanding of how Ex and EE enhance experience-dependent plasticity, as well as their differential impacts on anxiety and cognition.
Asunto(s)
Ansiedad/fisiopatología , Conducta Animal/fisiología , Disfunción Cognitiva/fisiopatología , Ambiente , Condicionamiento Físico Animal , Animales , Western Blotting , Modelos Animales de Enfermedad , Hipocampo/fisiopatología , Aprendizaje por Laberinto/fisiología , Memoria a Largo Plazo/fisiología , Ratones , Ratones Noqueados , Reacción en Cadena de la PolimerasaRESUMEN
Recent studies have suggested that physiological and behavioral traits may be transgenerationally inherited through the paternal lineage, possibly via non-genomic signals derived from the sperm. To investigate how paternal stress might influence offspring behavioral phenotypes, a model of hypothalamic-pituitary-adrenal (HPA) axis dysregulation was used. Male breeders were administered water supplemented with corticosterone (CORT) for 4 weeks before mating with untreated female mice. Female, but not male, F1 offspring of CORT-treated fathers displayed altered fear extinction at 2 weeks of age. Only male F1 offspring exhibited altered patterns of ultrasonic vocalization at postnatal day 3 and, as adults, showed decreased time in open on the elevated-plus maze and time in light on the light-dark apparatus, suggesting a hyperanxiety-like behavioral phenotype due to paternal CORT treatment. Interestingly, expression of the paternally imprinted gene Igf2 was increased in the hippocampus of F1 male offspring but downregulated in female offspring. Male and female F2 offspring displayed increased time spent in the open arm of the elevated-plus maze, suggesting lower levels of anxiety compared with control animals. Only male F2 offspring showed increased immobility time on the forced-swim test and increased latency to feed on the novelty-supressed feeding test, suggesting a depression-like phenotype in these animals. Collectively, these data provide evidence that paternal CORT treatment alters anxiety and depression-related behaviors across multiple generations. Analysis of the small RNA profile in sperm from CORT-treated males revealed marked effects on the expression of small noncoding RNAs. Sperm from CORT-treated males contained elevated levels of three microRNAs, miR-98, miR-144 and miR-190b, which are predicted to interact with multiple growth factors, including Igf2 and Bdnf. Sustained elevation of glucocorticoids is therefore involved in the transmission of paternal stress-induced traits across generations in a process involving small noncoding RNA signals transmitted by the male germline.
Asunto(s)
Ansiedad/genética , Corticosterona/farmacología , Depresión/genética , Sistema Hipotálamo-Hipofisario/fisiopatología , Exposición Paterna , Fenotipo , Sistema Hipófiso-Suprarrenal/fisiopatología , ARN Pequeño no Traducido/genética , Espermatozoides/efectos de los fármacos , Espermatozoides/metabolismo , Animales , Ansiedad/fisiopatología , Factor Neurotrófico Derivado del Encéfalo/genética , Depresión/fisiopatología , Exones , Miedo/efectos de los fármacos , Miedo/fisiología , Femenino , Expresión Génica/genética , Expresión Génica/fisiología , Factor II del Crecimiento Similar a la Insulina/genética , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Ratones Endogámicos C57BL , MicroARNs/genética , Embarazo , Factores SexualesRESUMEN
Huntington's disease (HD) is an autosomal dominant, neurodegenerative disease caused by a CAG tandem repeat mutation encoding a polyglutamine tract expansion in the huntingtin protein. Depression is among the most common affective symptoms in HD but the pathophysiology is unclear. We have previously discovered sexually dimorphic depressive-like behaviours in the R6/1 transgenic mouse model of HD at a pre-motor symptomatic age. Interestingly, only female R6/1 mice display this phenotype. Sexual dimorphism has not been explored in the human HD population despite the well-established knowledge that the clinical depression rate in females is almost twice that of males. Female susceptibility suggests a role of sex hormones, which have been shown to modulate stress response. There is evidence suggesting that the gonads are adversely affected in HD patients, which could alter sex hormone levels. The present study examined the role sex hormones play on stress response in the R6/1 mouse model of HD, in particular, its modulatory effect on the hypothalamic-pituitary-adrenal (HPA) axis and depression-like behaviour. We found that the gonads of female R6/1 mice show atrophy at an early age. Expression levels of gonadotropin-releasing hormone (GnRH) were decreased in the hypothalamus of female HD mice, relative to wild-type female littermates, as were serum testosterone levels. Female serum estradiol levels were not significantly changed. Gonadectomy surgery reduced HPA-axis activity in female mice but had no effect on behavioural phenotypes. Furthermore, expression of the oestrogen receptor (ER) α gene was found to be higher in the adrenal cells of female HD mice. Finally, administration of an ERß agonist diarylpropionitrile (DPN) rescued depressive-like behaviour in the female HD mice. Our findings provide new insight into the pathogenesis of sexually dimorphic neuroendocrine, physiological and behavioural endophenotypes in HD, and suggest a new avenue for therapeutic intervention.
Asunto(s)
Depresión/fisiopatología , Enfermedad de Huntington/fisiopatología , Sistema Hipotálamo-Hipofisario/fisiopatología , Sistema Hipófiso-Suprarrenal/fisiopatología , Animales , Conducta Animal/fisiología , Depresión/etiología , Modelos Animales de Enfermedad , Femenino , Enfermedad de Huntington/psicología , Ratones , Ratones Transgénicos , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Caracteres SexualesRESUMEN
Huntington's disease (HD) is a neurodegenerative disorder, involving psychiatric, cognitive and motor symptoms, caused by a CAG-repeat expansion encoding an extended polyglutamine tract in the huntingtin protein. Oxidative stress and excitotoxicity have previously been implicated in the pathogenesis of HD. We hypothesized that N-acetylcysteine (NAC) may reduce both excitotoxicity and oxidative stress through its actions on glutamate reuptake and antioxidant capacity. The R6/1 transgenic mouse model of HD was used to investigate the effects of NAC on HD pathology. It was found that chronic NAC administration delayed the onset and progression of motor deficits in R6/1 mice, while having an antidepressant-like effect on both R6/1 and wild-type mice. A deficit in the astrocytic glutamate transporter protein, GLT-1, was found in R6/1 mice. However, this deficit was not ameliorated by NAC, implying that the therapeutic effect of NAC is not due to rescue of the GLT-1 deficit and associated glutamate-induced excitotoxicity. Assessment of mitochondrial function in the striatum and cortex revealed that R6/1 mice show reduced mitochondrial respiratory capacity specific to the striatum. This deficit was rescued by chronic treatment with NAC. There was a selective increase in markers of oxidative damage in mitochondria, which was rescued by NAC. In conclusion, NAC is able to delay the onset of motor deficits in the R6/1 model of Huntington's disease and it may do so by ameliorating mitochondrial dysfunction. Thus, NAC shows promise as a potential therapeutic agent in HD. Furthermore, our data suggest that NAC may also have broader antidepressant efficacy.
Asunto(s)
Acetilcisteína/farmacología , Conducta Animal/efectos de los fármacos , Depuradores de Radicales Libres/farmacología , Enfermedad de Huntington/metabolismo , Mitocondrias/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Animales , Encéfalo/efectos de los fármacos , Encéfalo/patología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Transportador 2 de Aminoácidos Excitadores/efectos de los fármacos , Transportador 2 de Aminoácidos Excitadores/metabolismo , Marcha/efectos de los fármacos , Ratones , Ratones Transgénicos , Mitocondrias/metabolismo , Actividad Motora/efectos de los fármacos , Tamaño de los ÓrganosRESUMEN
Receptor-mediated signal transduction is thought to play an important role in neuronal differentiation and the modification of synaptic connections during brain development. The intracellular signalling molecule phospholipase C-beta1 (PLC-beta1), which is activated via specific neurotransmitter receptors, has recently been implicated in activity-dependent plasticity in the cat visual cortex. PLC-beta1 has been shown to be concentrated in an intermediate compartment-like organelle, the botrysome, which is present in 5-week-old, but not adult, cat cortical neurons. We have characterized the spatial and temporal regulation of PLC-beta1 expression in the developing rat cerebral cortex. PLC-beta1-positive botrysome-like organelles are observed during early postnatal cortical development, but not at postnatal day 14 or later stages. In the postnatal somatosensory cortex, there is also striking spatial variation in diffuse neuropilar immunoreactivity of layer IV and above, in a pattern corresponding to the thalamocortical recipient zones known as barrels. This expression pattern is specific to the developing barrel field and is most distinct at postnatal days 4-7, when cellular components of barrels are capable of activity-dependent modification. During later stages of cortical maturation, stained botrysomes disappear, expression of PLC-beta1 is down-regulated and only diffuse immunoreactivity remains in dendritic processes. Our results are consistent with a role for PLC-beta1 in activity-dependent, receptor-mediated neuronal plasticity during development of the somatosensory cortex.
Asunto(s)
Isoenzimas/biosíntesis , Plasticidad Neuronal/fisiología , Neuronas/enzimología , Corteza Somatosensorial/anatomía & histología , Corteza Somatosensorial/enzimología , Sinapsis/enzimología , Fosfolipasas de Tipo C/biosíntesis , Animales , Encéfalo/enzimología , Encéfalo/crecimiento & desarrollo , Diferenciación Celular/fisiología , Dendritas/química , Dendritas/enzimología , Regulación hacia Abajo/fisiología , Embrión de Mamíferos , Inmunohistoquímica , Isoenzimas/análisis , Neuronas/química , Neuronas/citología , Orgánulos/metabolismo , Fosfolipasa C beta , Ratas , Ratas Sprague-Dawley , Corteza Somatosensorial/química , Sinapsis/metabolismo , Fosfolipasas de Tipo C/análisisRESUMEN
The differentiation of neurons involves the establishment of distinct molecular compartments which regulate neuronal shape and function. This requires targeting of specific gene products to growth-associated regions of the neuron. We have investigated the temporal and spatial regulation of SCG10 gene expression during neuronal differentiation. There are two SCG10 messenger RNAs, 1 and 2 kg in length, which encode the same growth-associated protein. These messenger RNAs were found to be differentially regulated during the onset of neurite outgrowth in early rat cerebellum development. In PC12 cells, the two SCG10 messenger RNAs were shown to be differentially induced by nerve growth factor. Regulation of the 2 kb messenger RNA, but not the 1 kb messenger RNA, is dependent on the differentiation of PC12 cells, indicating that post-transcriptional regulation of SCG10 expression during neurite outgrowth. Spatial regulation of the 2 kb SCG10 messenger RNA distribution during brain development was examined by in situ hybridization. The 2 kb messenger RNA was found to be localized to the neuronal pole where outgrowth was occurring, within differentiating neurons in vivo. Intracellular localization of SCG10 messenger RNA was also observed in differentiating primary cultured neurons, with the 2 kb messenger RNA transported into growing neurites during the development of neuronal polarity. In neurons which had developed polarity, the 2 kb SCG10 messenger RNA was consistently found in the cell body and axon. This study demonstrates both temporal and spatial post-transcriptional regulation of SCG10 expression which is associated with neurite outgrowth. The directed transport and positional translation of SCG10 messenger RNA provide a potential mechanism for protein targeting and the creation of molecular compartments during neuronal differentiation.