RESUMO
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.
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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.
Assuntos
Corticosterona , Microinjeções , RNA Longo não Codificante , Espermatozoides , Animais , Masculino , RNA Longo não Codificante/metabolismo , RNA Longo não Codificante/genética , Camundongos , Corticosterona/farmacologia , Espermatozoides/metabolismo , Microinjeções/métodos , Feminino , Epigênese Genética , Camundongos Endogâmicos C57BL , Ansiedade/metabolismo , Ansiedade/genética , Oócitos/metabolismo , Comportamento Animal/fisiologia , Estresse Psicológico/metabolismo , Encéfalo/metabolismoRESUMO
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.
Assuntos
Atenção , Sinais (Psicologia) , Animais , Camundongos , Tempo de ReaçãoRESUMO
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.
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Ansiedade/etiologia , Ansiedade/metabolismo , Herança Paterna/genética , Animais , Transtornos de Ansiedade/etiologia , Transtornos de Ansiedade/genética , Comportamento Animal/efeitos dos fármacos , Corticosterona/metabolismo , Corticosterona/farmacologia , Hormônio Liberador da Corticotropina/efeitos dos fármacos , Hormônio Liberador da Corticotropina/genética , Epigênese Genética/efeitos dos fármacos , Pai , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Glucocorticoides/efeitos dos fármacos , Receptores de Glucocorticoides/genética , Estresse Psicológico/metabolismoRESUMO
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.
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Agressão/psicologia , Transtorno do Espectro Autista/psicologia , Moléculas de Adesão Celular Neuronais/genética , Abrigo para Animais , Proteínas de Membrana/genética , Mutação , Proteínas do Tecido Nervoso/genética , Condicionamento Físico Animal/psicologia , Interação Social , Animais , Ansiedade , Comportamento Animal , Peso Corporal , Modelos Animais de Doenças , Feminino , Locomoção , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BLRESUMO
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.
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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.
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Ansiedade/genética , Medo/psicologia , Transmissão Vertical de Doenças Infecciosas/veterinária , MicroRNAs/genética , Condicionamento Físico Animal/efeitos adversos , Espermatozoides/metabolismo , Animais , Ansiedade/psicologia , Depressão/genética , Depressão/psicologia , Exposição Ambiental/efeitos adversos , Feminino , Regulação da Expressão Gênica , Sistema Hipotálamo-Hipofisário/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fenótipo , Sistema Hipófise-Suprarrenal/fisiopatologia , Pequeno RNA não TraduzidoRESUMO
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.
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Agressão/fisiologia , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/psicologia , Moléculas de Adesão Celular Neuronais/genética , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Comportamento Sexual Animal/fisiologia , Isolamento Social , Animais , Comportamento Animal , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação , Comportamento SocialRESUMO
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.
Assuntos
Doença de Alzheimer/fisiopatologia , Cognição , Testes Neuropsicológicos , Pesquisa Translacional Biomédica/métodos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Modelos Animais de Doenças , Humanos , Memória , CamundongosRESUMO
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.
Assuntos
Ansiedade/genética , Corticosterona/farmacologia , Depressão/genética , Sistema Hipotálamo-Hipofisário/fisiopatologia , Exposição Paterna , Fenótipo , Sistema Hipófise-Suprarrenal/fisiopatologia , Pequeno RNA não Traduzido/genética , Espermatozoides/efeitos dos fármacos , Espermatozoides/metabolismo , Animais , Ansiedade/fisiopatologia , Fator Neurotrófico Derivado do Encéfalo/genética , Depressão/fisiopatologia , Éxons , Medo/efeitos dos fármacos , Medo/fisiologia , Feminino , Expressão Gênica/genética , Expressão Gênica/fisiologia , Fator de Crescimento Insulin-Like II/genética , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Gravidez , Fatores SexuaisRESUMO
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.
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Ansiedade/fisiopatologia , Comportamento Animal/fisiologia , Disfunção Cognitiva/fisiopatologia , Meio Ambiente , Condicionamento Físico Animal , Animais , Western Blotting , Modelos Animais de Doenças , Hipocampo/fisiopatologia , Aprendizagem em Labirinto/fisiologia , Memória de Longo Prazo/fisiologia , Camundongos , Camundongos Knockout , Reação em Cadeia da PolimeraseRESUMO
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.
Assuntos
Acetilcisteína/farmacologia , Comportamento Animal/efeitos dos fármacos , Sequestradores de Radicais Livres/farmacologia , Doença de Huntington/metabolismo , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Modelos Animais de Doenças , Progressão da Doença , Transportador 2 de Aminoácido Excitatório/efeitos dos fármacos , Transportador 2 de Aminoácido Excitatório/metabolismo , Marcha/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Mitocôndrias/metabolismo , Atividade Motora/efeitos dos fármacos , Tamanho do ÓrgãoRESUMO
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.
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Depressão/fisiopatologia , Doença de Huntington/fisiopatologia , Sistema Hipotálamo-Hipofisário/fisiopatologia , Sistema Hipófise-Suprarrenal/fisiopatologia , Animais , Comportamento Animal/fisiologia , Depressão/etiologia , Modelos Animais de Doenças , Feminino , Doença de Huntington/psicologia , Camundongos , Camundongos Transgênicos , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Caracteres SexuaisRESUMO
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.
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Meio Ambiente , Doenças Neurodegenerativas/terapia , Animais , Cognição , Modelos Animais de Doenças , Camundongos , Plasticidade Neuronal/fisiologia , Condicionamento Físico Animal , RatosRESUMO
Huntington's disease (HD) is an autosomal dominant tandem repeat expansion disorder involving cognitive, psychiatric and motor symptoms. The expanded trinucleotide (CAG) repeat leads to an extended polyglutamine tract in the huntingtin protein and a subsequent cascade of molecular and cellular pathogenesis. One of the key features of neuropathology, which has been shown to precede the eventual loss of neurons in the cerebral cortex, striatum and other areas, are changes to synapses, including the dendritic protrusions known as spines. In this review we will focus on synapse and spine pathology in HD, including molecular and experience-dependent aspects of pathogenesis. Dendritic spine pathology has been found in both the human HD brain at post mortem as well as various transgenic and knock-in animal models. These changes may help explain the symptoms in HD, and synaptopathy within the cerebral cortex may be particularly important in mediating the psychiatric and cognitive manifestations of this disease. The earliest stages of synaptic dysfunction in HD, as assayed in various mouse models, appears to involve changes in synaptic proteins and associated physiological abnormalities such as synaptic plasticity deficits. In mouse models, synaptic and cortical plasticity deficits have been directly correlated with the onset of cognitive deficits, implying a causal link. Furthermore, following the discovery that environmental enrichment can delay onset of affective, cognitive and motor deficits in HD transgenic mice, specific synaptic molecules shown to be dysregulated by the polyglutamine-induced toxicity were also found to be beneficially modulated by environmental stimulation. This identifies potential molecular targets for future therapeutic developments to treat this devastating disease.
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Encéfalo/patologia , Espinhas Dendríticas/patologia , Doença de Huntington/patologia , Proteínas de Membrana/metabolismo , Plasticidade Neuronal , Sinapses/patologia , Animais , Cognição , Modelos Animais de Doenças , Humanos , Doença de Huntington/psicologia , CamundongosRESUMO
Huntington's disease (HD) has long been regarded as a disease of the central nervous system, partly due to typical disease symptoms that include loss of motor control, cognitive deficits and neuropsychiatric disturbances. However, the huntingtin gene is ubiquitously expressed throughout the body. We had previously reported a female-specific depression-related behavioural phenotype in the R6/1 transgenic mouse model of HD. One hypothesis suggests that pathology of the hypothalamic-pituitary-adrenal (HPA) axis, the key physiological stress-response system that links central and peripheral organs, is a cause of depression. There is evidence of HPA axis pathology in HD, but whether it contributes to the female R6/1 behavioural phenotype is unclear. We have examined HPA axis response of R6/1 mice following acute stress and found evidence of a female-specific dysregulation of the HPA axis in R6/1 mice, which we further isolated to a hyper-response of adrenal cortical cells to stimulation by adrenocorticotrophin hormone. Interestingly, the adrenal pathophysiology was not detected in mice that had been housed in environmentally enriching conditions, an effect of enrichment that was also reproduced in vitro. This constitutes the first evidence that environmental enrichment can in fact exert a lasting influence on peripheral organ function. Cognitive stimulation may therefore not only have benefits for mental function, but also for overall physiological wellbeing.
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Hormônio Adrenocorticotrópico/sangue , Corticosterona/sangue , Doença de Huntington/genética , Sistema Hipotálamo-Hipofisário/fisiopatologia , Sistema Hipófise-Suprarrenal/fisiopatologia , Estresse Fisiológico/fisiologia , Glândulas Suprarrenais/fisiopatologia , Análise de Variância , Animais , Dexametasona/farmacologia , Modelos Animais de Doenças , Meio Ambiente , Feminino , Perfilação da Expressão Gênica/métodos , Doença de Huntington/fisiopatologia , Masculino , Camundongos , Camundongos Transgênicos , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Glucocorticoides/genética , Fatores SexuaisRESUMO
In recent years metabotropic glutamate receptors have emerged as key targets for the design of new antipsychotic medications for schizophrenia, in particular mGluR5 and mGluR2/3. These receptors exhibit diverse interactions with other neurotransmitter receptors and critical elements of intracellular signalling cascades known to be important to the pharmacotherapy of schizophrenia. In addition, mGluR5 and mGluR2/3 are intimately involved in behavioural domains related to the symptoms of this disorder. Both animal and clinical studies using novel drugs targeting these receptors have provided encouraging results. The number of patents registered for drugs targeting metabotropic glutamate receptors has grown dramatically, and positive allosteric modulators for both receptors show particular promise.
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Antipsicóticos/uso terapêutico , Receptores de Glutamato Metabotrópico/fisiologia , Esquizofrenia/tratamento farmacológico , Animais , HumanosRESUMO
Despite the well established central pathophysiology of Huntington's disease (HD), less is known about systemic impairments that are emerging as significant contributors to the morbidity of this neurodegenerative condition. Given the evidence of neuroendocrine dysfunction in HD patients and the pro-neural properties of sex-hormones, we explored the therapeutic potential of hormone therapy in the HD R6/1 mouse model (HD mice). HD mice over-express exon-1 of the defective human HD gene and replicate many of the clinical behavioural, biochemical and physiological impairments. Seven-week-old HD and wild-type littermate mice had either saline (control) or testosterone (treatment; 160µg/day over 90days) pellets implanted s.c. and were subsequently subjected to behavioural, molecular and cellular analysis. Separate mice were used to establish a decrease in serum testosterone concentrations in HD mice at 12weeks of age. Baseline serum testosterone was significantly reduced in control 19-week-old HD mice, whereas treatment significantly raised serum testosterone in both wild-type and HD mice. Testosterone treatment had a limited effect on the development of rotarod deficiencies in HD mice and no effect on progressive body weight loss or the development of central mutant huntingtin-containing aggregates. Testosterone treatment induced hypo-locomotion in both genotypes. Deficits in hippocampal-dependent cognition and neurogenesis were not rescued in testosterone-treated HD mice. By contrast, wild-type-treatment mice experienced significantly increased neuronal survival and differentiation. Testosterone treatment in HD mice did rescue androgen receptor levels in the hippocampus and testes, significantly improved severe testicular atrophy and restored spermatogenesis. We conclude that chronic testosterone provides systemic efficacy in treating spermatogenesis deficits and testicular atrophy but not central cellular and behavioural pathologies in R6/1 HD mice.
Assuntos
Doença de Huntington/tratamento farmacológico , Infertilidade Masculina/tratamento farmacológico , Neurogênese/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , Testosterona/administração & dosagem , Animais , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Esquema de Medicação , Humanos , Proteína Huntingtina , Doença de Huntington/complicações , Doença de Huntington/genética , Doença de Huntington/fisiopatologia , Infertilidade Masculina/etiologia , Infertilidade Masculina/genética , Infertilidade Masculina/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Transgênicos , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/genética , Neurogênese/genética , Neurogênese/fisiologia , Proteínas Nucleares/química , Proteínas Nucleares/genética , Espermatogênese/genética , Espermatogênese/fisiologia , Resultado do TratamentoRESUMO
Waddington's original description of canalization refers to the ability of an organism to maintain phenotypic fidelity in the face of environmental and/or genetic perturbation. Development of the human brain requires exposure to a 'wild-type' environment-one that supports the optimal set of instructions for development. Recently derived brain structures in our species, such as the expanded neocortex, may be more vulnerable to decanalization because there has been insufficient time to evolve buffering capacity. On the basis of modern notions of decanalization, we provide perspectives on selected environmental and genetic risk factors for schizophrenia, and we discuss strengths and weaknesses of this conceptual framework. We argue that if we are to build a solid foundation for translational psychiatry, we must explore models that attempt to capture the complexity of the interaction between genetic and non-genetic risk factors in mediating and modulating brain development.
Assuntos
Encéfalo/crescimento & desenvolvimento , Esquizofrenia/etiologia , Animais , Encéfalo/metabolismo , Epigenômica/métodos , Interação Gene-Ambiente , Humanos , Modelos Genéticos , Fenótipo , Fatores de Risco , Esquizofrenia/genéticaRESUMO
Early loss of CB1 receptors is a hallmark of human Huntington's disease. Data from rodent studies suggest that preservation and activation of CB1 receptors may be protective against disease progression. R6/1 transgenic mice are considered to be a model of early pathogenic changes in Huntington's disease. We have shown previously that levels of CB1 in R6/1 mice prior to the onset of motor symptoms (12 weeks of age) remain high enough to justify commencement of cannabinoid drug treatment. Eight weeks of daily treatment with the cannabinoid agonists HU210 (0.01 mg/kg) and Delta(9)-tetrahydrocannabinol (THC, 10.00 mg/kg), or the inhibitor of endocannabinoid metabolism URB597 (0.30 mg/kg), did not alter the progressive deterioration of performance observed in motor behavioural testing. HU210-treated R6/1 mice experienced a significant increase in seizure events suggesting that this therapy may lower the seizure threshold and cautioning against highly efficacious agonists as potential therapy in this disease. Molecular characterisation of brains at the end of the study showed that there were no significant effects of HU210 or THC treatment on the ligand binding of cannabinoid CB1, dopamine D1, D2, serotonin 5HT2A or GABA(A) receptors, nor CB1 or fatty acid amide hydrolase (FAAH) mRNA expression in R6/1 mice. Intriguingly, a significant increase in the number of ubiquitinated aggregates was observed in the striatum with HU210 treatment, indicating an influence of CB1 on the disease process. Chronic URB597 treatment preserved CB1 receptors in the R6/1 striatum, suggesting that the manipulation of endocannabinoid levels warrants further exploration.