Florey Department of Neuroscience and Mental Health - Research Publications
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ItemElevated paternal glucocorticoid exposure modifies memory retention in female offspring(PERGAMON-ELSEVIER SCIENCE LTD, 2017-09)Recent studies have demonstrated that behavioral traits are subject to transgenerational modification by paternal environmental factors. We previously reported on the transgenerational influences of increased paternal stress hormone levels on offspring anxiety and depression-related behaviors. Here, we investigated whether offspring sociability and cognition are also influenced by paternal stress. Adult C57BL/6J male mice were treated with corticosterone (CORT; 25mg/L) for four weeks prior to paired-matings to generate F1 offspring. Paternal CORT treatment was associated with decreased body weights of female offspring and a marked reduction of the male offspring. There were no differences in social behavior of adult F1 offspring in the three-chamber social interaction test. Despite male offspring of CORT-treated fathers displaying hyperactivity in the Y-maze, there was no observable difference in short-term spatial working memory. Spatial learning and memory testing in the Morris water maze revealed that female, but not male, F1 offspring of CORT-treated fathers had impaired memory retention. We used our recently developed methodology to analyze the spatial search strategy of the mice during the learning trials and determined that the impairment could not be attributed to underlying differences in search strategy. These results provide evidence for the impact of paternal corticosterone administration on offspring cognition and complement the cumulative knowledge of transgenerational epigenetic inheritance of acquired traits in rodents and humans.
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ItemThe influence of the HPG axis on stress response and depressive-like behaviour in a transgenic mouse model of Huntington's disease(ACADEMIC PRESS INC ELSEVIER SCIENCE, 2015-01)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 ERβ 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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ItemParadoxical effects of exercise on hippocampal plasticity and cognition in mice with a heterozygous null mutation in the serotonin transporter gene(WILEY, 2019-09)BACKGROUND AND PURPOSE: Exercise is known to improve cognitive function, but the exact synaptic and cellular mechanisms remain unclear. We investigated the potential role of the serotonin (5-HT) transporter (SERT) in mediating these effects. EXPERIMENTAL APPROACH: Hippocampal long-term potentiation (LTP) and neurogenesis were measured in standard-housed and exercising (wheel running) wild-type (WT) and SERT heterozygous (HET) mice. We also assessed hippocampal-dependent cognition using the Morris water maze (MWM) and a spatial pattern separation touchscreen task. KEY RESULTS: SERT HET mice had impaired hippocampal LTP regardless of the housing conditions. Exercise increased hippocampal neurogenesis in WT mice. However, this was not observed in SERT HET animals, even though both genotypes used the running wheels to a similar extent. We also found that standard-housed SERT HET mice displayed altered cognitive flexibility than WT littermate controls in the MWM reversal learning task. However, SERT HET mice no longer exhibited this phenotype after exercise. Cognitive changes, specific to SERT HET mice in the exercise condition, were also revealed on the touchscreen spatial pattern separation task, especially when the cognitive pattern separation load was at its highest. CONCLUSIONS AND IMPLICATIONS: Our study is the first evidence of reduced hippocampal LTP in SERT HET mice. We also show that functional SERT is required for exercise-induced increase in adult neurogenesis. Paradoxically, exercise had a negative impact on hippocampal-dependent cognitive tasks, especially in SERT HET mice. Taken together, our results suggest unique complex interactions between exercise and altered 5-HT homeostasis.
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ItemHypersensitivity to sertraline in the absence of hippocampal 5-HT1AR and 5-HTT gene expression changes following paternal corticosterone treatment(OXFORD UNIV PRESS, 2018-04)The male germ line is capable of transmitting a legacy of stress exposure to the next generation of offspring. This transgenerational process manifests by altering offspring affective behaviours, cognition and metabolism. Paternal early life trauma causes hippocampal serotonergic dysregulation in male offspring. We previously showed a transgenerational modification to male offspring anxiety-like behaviours by treatment of adult male breeders with corticosterone (CORT) prior to mating. In the present study, we used offspring from our paternal CORT model and characterised offspring serotonergic function by examining their responses to the 5HT1AR agonist, 8-OH-DPAT, and the selective serotonin reuptake inhibitor, sertraline. We also examined whether post-weaning environmental enrichment, a paradigm well-known to modulate serotonergic signalling in the brain, had the capacity to normalise the anxiety phenotype of male offspring. Finally, we assessed gene expression levels of 5HT1AR and serotonin transporter in the offspring hippocampus to determine whether deficits in gene transcription contributed to the male-only anxiety phenotype. We report that male and female offspring of CORT-treated fathers are hypersensitive to sertraline but have normal hypothermic responses to 8-OH-DPAT. No deficits in htr1a and sert were found in association with paternal CORT treatment, and environmental enrichment did not rescue the anxiety phenotype of male offspring on the elevated-plus maze. These findings indicate that varying forms of paternal stress exert different effects on offspring brain serotonergic function.
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ItemPositive environmental modification of depressive phenotype and abnormal hypothalamic-pituitary-adrenal axis activity in female C57BL/6J mice during abstinence from chronic ethanol consumption(FRONTIERS MEDIA SA, 2013)Depression is a commonly reported co-morbidity during rehabilitation from alcohol use disorders and its presence is associated with an increased likelihood of relapse. Interventions which impede the development of depression could be of potential benefit if incorporated into treatment programs. We previously demonstrated an ameliorative effect of physical exercise on depressive behaviors in a mouse model of alcohol abstinence. Here, we show that environmental enrichment (cognitive and social stimulation) has a similar beneficial effect. The hypothalamic-pituitary-adrenal (HPA) axis is a key physiological system regulating stress responses and its dysregulation has been separably implicated in the pathophysiology of depression and addiction disorders. We performed a series of dexamethasone challenges and found that mice undergoing 2 weeks of alcohol abstinence had significantly greater corticosterone and ACTH levels following a DEX-CRH challenge compared to water controls. Environmental enrichment during alcohol abstinence corrected the abnormal DEX-CRH corticosterone response despite a further elevation of ACTH levels. Examination of gene expression revealed abstinence-associated alterations in glucocorticoid receptor (Gr), corticotrophin releasing hormone (Crh) and pro-opiomelanocortin (Pomc1) mRNA levels which were differentially modulated by environmental enrichment. Overall, our study demonstrates a benefit of environmental enrichment on alcohol abstinence-associated depressive behaviors and HPA axis dysregulation.
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ItemSexually Dimorphic Serotonergic Dysfunction in a Mouse Model of Huntington's Disease and Depression(PUBLIC LIBRARY SCIENCE, 2011-07-08)Depression is the most common psychiatric disorder in Huntington's disease (HD) patients. In the general population, women are more prone to develop depression and such susceptibility might be related to serotonergic dysregulation. There is yet to be a study of sexual dimorphism in the development and presentation of depression in HD patients. We investigated whether 8-week-old male and female R6/1 transgenic HD mice display depressive-like endophenotypes associated with serotonergic impairments. We also studied the behavioral effects of acute treatment with sertraline. We found that only female HD mice exhibited a decreased preference for saccharin as well as impaired emotionality-related behaviors when assessed on the novelty-suppressed feeding test (NSFT) and the forced-swimming test (FST). The exaggerated immobility time displayed by female HD in the FST was reduced by acute administration of sertraline. We also report an increased response to the 5-HT(1A) receptor agonist 8-OH-DPAT in inducing hypothermia and a decreased 5-HT(2A) receptor function in HD animals. While tissue levels of serotonin were reduced in both male and female HD mice, we found that serotonin concentration and hydroxylase-2 (TPH2) mRNA levels were higher in the hippocampus of males compared to female animals. Finally, the antidepressant-like effects of sertraline in the FST were blunted in male HD animals. This study reveals sex-specific depressive-related behaviors during an early stage of HD prior to any cognitive and motor deficits. Our data suggest a crucial role for disrupted serotonin signaling in mediating the sexually dimorphic depression-like phenotype in HD mice.
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ItemHippocampal Neurogenesis, Cognitive Deficits and Affective Disorder in Huntington's Disease(HINDAWI LTD, 2012)Huntington's disease (HD) is a neurodegenerative disorder caused by a tandem repeat expansion encoding a polyglutamine tract in the huntingtin protein. HD involves progressive psychiatric, cognitive, and motor symptoms, the selective pathogenesis of which remains to be mechanistically elucidated. There are a range of different brain regions, including the cerebral cortex and striatum, known to be affected in HD, with evidence for hippocampal dysfunction accumulating in recent years. In this review we will focus on hippocampal abnormalities, in particular, deficits of adult neurogenesis. We will discuss potential molecular mechanisms mediating disrupted hippocampal neurogenesis, and how this deficit of cellular plasticity may in turn contribute to specific cognitive and affective symptoms that are prominent in HD. The generation of transgenic animal models of HD has greatly facilitated our understanding of disease mechanisms at molecular, cellular, and systems levels. Transgenic HD mice have been found to show progressive behavioral changes, including affective, cognitive, and motor abnormalities. The discovery, in multiple transgenic lines of HD mice, that adult hippocampal neurogenesis and synaptic plasticity is disrupted, may help explain specific aspects of cognitive and affective dysfunction. Furthermore, these mouse models have provided insight into potential molecular mediators of adult neurogenesis deficits, such as disrupted serotonergic and neurotrophin signaling. Finally, a number of environmental and pharmacological interventions which are known to enhance adult hippocampal neurogenesis have been found to have beneficial affective and cognitive effects in mouse models, suggesting common molecular targets which may have therapeutic utility for HD and related diseases.
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ItemEnvironmental enrichment rescues female-specific hyperactivity of the hypothalamic-pituitary-adrenal axis in a model of Huntington's disease(NATURE PUBLISHING GROUP, 2012-07)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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ItemShort-Term Environmental Stimulation Spatiotemporally Modulates Specific Serotonin Receptor Gene Expression and Behavioral Pharmacology in a Sexually Dimorphic Manner in Huntington's Disease Transgenic Mice(FRONTIERS MEDIA SA, 2018-12-10)Huntington's disease (HD) is a neurodegenerative disorder caused by a tandem repeat mutation encoding an expanded polyglutamine tract in the huntingtin protein, which leads to cognitive, psychiatric and motor dysfunction. Exposure to environmental enrichment (EE), which enhances levels of cognitive stimulation and physical activity, has therapeutic effects on cognitive, affective and motor function of transgenic HD mice. The present study investigated gene expression changes and behavioral pharmacology in male and female R6/1 transgenic HD mice at an early time-point in HD progression associated with onset of cognitive and affective abnormalities, following EE and exercise (wheel running) interventions. We have demonstrated changes in expression levels of the serotonin (5-HT) receptor Htr1a, Htr1b, Htr2a and Htr2c genes (encoding the 5-HT1A, 5-HT1B, 5-HT2A and 5-HT2C receptors, respectively) in HD brains at 8 weeks of age, using quantitative real-time PCR. In contrast, expression of the serotonin transporter (SerT, also known as 5-HTT or Slc6a4) was not altered in these brains. Furthermore, we identified region-specific, sex-specific and environmentally regulated (comparing EE, exercise and standard housing conditions) impacts on gene expression of particular 5-HT receptors, as well as SerT. For example, SerT gene expression was upregulated by exercise (wheel running from 6 to 8 weeks of age) in the hippocampus. Interestingly, when EE was introduced from 6 to 8 weeks of age, Htr2a gene expression was upregulated in the cortex, striatum and hippocampus of male mice. EE also rescued the functional activity of 5-HT2 receptors as observed in the head-twitch test, reflecting sexually dimorphic effects of environmental stimulation. These findings demonstrate that disruption of the serotonergic system occurs early in HD pathogenesis and, together with previous findings, show that the timing and duration of environmental interventions are critical in terms of their ability to modify gene expression. This study is the first to show that EE is able to selectively enhance both gene expression of a neurotransmitter receptor and the functional consequences on behavioral pharmacology, and links this molecular modulation to the therapeutic effects of environmental stimulation in this neurodegenerative disease.
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ItemTouchscreen testing reveals clinically relevant cognitive abnormalities in a mouse model of schizophrenia lacking metabotropic glutamate receptor 5(NATURE PORTFOLIO, 2018-11-06)Metabotropic glutamate receptor 5 (mGlu5) has been implicated in certain forms of synaptic plasticity and cognitive function. mGlu5 knockout (KO) mice and mGlu5 antagonists have been previously used to study the pathophysiology of schizophrenia as they have been shown respectively to display or induce endophenotypes relevant to schizophrenia. While schizophrenia presents with generalized cognitive impairments, the cognitive phenotype of mice lacking mGlu5 has so far only been explored using largely hippocampal-dependent spatial and contextual memory tasks. To address this, we used a touchscreen system to assess mGlu5 KO mice for pairwise visual discrimination, reversal learning, and extinction of an instrumental response requiring no discrimination. Furthermore, we tested the role of mGlu5 in working memory using the Trial-Unique Non-Matching to Location (TUNL) task utilizing pharmacological ablation. mGlu5 KO mice were impaired on discrimination learning, taking longer to reach criterion and requiring more correction learning trials. Performance on reversal learning was also impaired, with mGlu5 KO mice demonstrating a perseverative phenotype. The mGlu5 KO mice responded at a higher rate during extinction, consistent with this perseverative profile. In contrast, wildtype mice treated acutely with an mGlu5 antagonist (MTEP) showed no deficits in a touchscreen task assessing working memory. The present study demonstrates learning and memory deficits as well as an increased perseverative phenotype following constitutive loss of mGlu5 in this mouse model of schizophrenia. These findings will inform translational approaches using this preclinical model and the pursuit of mGlu5 as therapeutic target for schizophrenia and other brain disorders.