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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ItemPaternal environmental enrichment transgenerationally alters affective behavioral and neuroendocrine phenotypes(PERGAMON-ELSEVIER SCIENCE LTD, 2017-03)Recent studies have demonstrated that paternal stress in rodents can result in modification of offspring behavior. Environmental enrichment, which enhances cognitive stimulation and physical activity, modifies various behaviors and reduces stress responses in adult rodents. We investigated the transgenerational influence of paternal environmental enrichment on offspring behavior and physiological stress response. Adult C57BL/6J male mice (F0) were exposed to either environmental enrichment or standard housing for four weeks and then pair-mated with naïve females. The F2 generation was generated using F1 male offspring. Male and female F1 and F2 offspring were tested for anxiety using the elevated-plus maze and large open field at 8 weeks of age. Depression-related behavior was assessed using the forced-swim test. Hypothalamic-pituitary-adrenal (HPA) axis function was determined by quantification of serum corticosterone and adrenocorticotropic hormone (ACTH) levels at baseline and after forced-swim stress. Paternal environmental enrichment was associated with increased body weights of male F1 and F2 offspring. There was no significant effect on F1 offspring anxiety and depression-related behaviors. There were no changes in anxiety-related behaviors in the F2 offspring, however these mice displayed a reduced latency to immobility in the forced-swim test. Furthermore, F2 females had significantly higher serum corticosterone levels post-stress, but not ACTH. These results show that paternal environmental enrichment exerts a sex-specific transgenerational impact on the behavioral and physiological response to stress. Our findings have implications for the modelling of psychiatric disorders in rodents.
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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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ItemTransgenerational paternal transmission of acquired traits: stress-induced modification of the sperm regulatory transcriptome and offspring phenotypes(ELSEVIER SCIENCE BV, 2017-04)In recent years, it has become evident that pre-conceptual exposure of males to various environmental factors induces epigenetic changes in sperm, which can mediate the transmission of acquired traits in their offspring. The most thoroughly examined paternal exposures involve stress and elevated corticosterone, which have been shown to modulate offspring phenotypes in a manner that is relevant to predisposition to brain disorders, and psychiatric illness in particular. Recent seminal studies have demonstrated that key epigenetic information transmitted via the paternal germline involves small non-coding (snc) RNA transcripts such as microRNAs. Following fertilisation, these sncRNAs appear to regulate development so as to modify the phenotype of the offspring. Understanding the mechanisms involved in such transgenerational effects may facilitate future screening of human sperm for 'epigenetic health' and the tailoring of therapeutic interventions according to genetic and epigenetic contributions to illness.
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ItemNovel approaches to alcohol rehabilitation: Modification of stress-responsive brain regions through environmental enrichment(PERGAMON-ELSEVIER SCIENCE LTD, 2019-02)Relapse remains the most prominent hurdle to successful rehabilitation from alcoholism. The neural mechanisms underlying relapse are complex, but our understanding of the brain regions involved, the anatomical circuitry and the modulation of specific nuclei in the context of stress and cue-induced relapse have improved significantly in recent years. In particular, stress is now recognised as a significant trigger for relapse, adding to the well-established impact of chronic stress to escalate alcohol consumption. It is therefore unsurprising that the stress-responsive regions of the brain have also been implicated in alcohol relapse, such as the nucleus accumbens, amygdala and the hypothalamus. Environmental enrichment is a robust experimental paradigm which provides a non-pharmacological tool to alter stress response and, separately, alcohol-seeking behaviour and symptoms of withdrawal. In this review, we examine and consolidate the preclinical evidence that alcohol seeking behaviour and stress-induced relapse are modulated by environmental enrichment, and these are primarily mediated by modification of neural activity within the key nodes of the addiction circuitry. Finally, we discuss the limited clinical evidence that stress-reducing approaches such as mindfulness could potentially serve as adjunctive therapy in the treatment of alcoholism. This article is part of the Special Issue entitled "Neurobiology of Environmental Enrichment".
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ItemProgressive impairments in executive function in the APP/PS1 model of Alzheimer’s disease as measured by translatable touchscreen testing( 2019-08-21)Executive function deficits in Alzheimer’s disease (AD) occur early in disease progression and may be predictive of cognitive decline. However, no preclinical studies have identified deficits in rewarded executive function in the commonly used APP/PS1 mouse model. To address this, we assessed 12-26 month old APP/PS1 mice on rewarded reversal and/or extinction tasks. 16-month-old, but not 13- or 26-month-old, APP/PS1 mice showed an attenuated rate of extinction. Reversal deficits were seen in 22-month-old, but not 13-month-old APP/PS1 animals. We then confirmed that impairments in reversal were unrelated to previously reported visual impairments in both AD mouse models and humans. Age, but not genotype, had a significant effect on markers of retinal health, indicating the deficits seen in APP/PS1 mice were directly related to cognition. This is the first characterisation of rewarded executive function in APP/PS1 mice, and has great potential to facilitate translation from preclinical models to the clinic.
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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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ItemSex-Dependent Effects of Environmental Enrichment on Spatial Memory and Brain-Derived Neurotrophic Factor (BDNF) Signaling in a Developmental "Two-Hit" Mouse Model Combining BDNF Haploinsufficiency and Chronic Glucocorticoid Stimulation(FRONTIERS MEDIA SA, 2018-10-09)Neurodevelopmental disorders are thought to be caused by a combination of adverse genetic and environmental insults. The "two-hit" hypothesis suggests that an early first "hit" primes the developing brain to be vulnerable to a second "hit" during adolescence which triggers behavioral dysfunction. We have previously modeled this scenario in mice and found that the combined effect of a genetic hapolinsuffuciency in the brain-derived neurotrophic factor (BDNF) gene (1st hit) and chronic corticosterone (CORT) treatment during adolescence (2nd hit), caused spatial memory impairments in adulthood. Environmental enrichment (EE) protocols are designed to stimulate experience-dependent plasticity and have shown therapeutic actions. This study investigated whether EE can reverse these spatial memory impairments. Wild-type (WT) and BDNF heterozygous (HET) mice were treated with corticosterone (CORT) in their drinking water (50 mg/L) from weeks 6 to 8 and exposed to EE from 7 to 9 weeks. Enriched housing included open top cages with additional toys, tunnels, housing, and platforms. Y-maze novel preference testing, to assess short-term spatial memory, was performed at 10 weeks of age. At week 16 dorsal hippocampus tissue was obtained for Western blot analysis of expression levels of BDNF, the BDNF receptor TrkB, and NMDA receptor subunits, GluNR1, 2A and 2B. As in our previous studies, spatial memory was impaired in our two-hit (BDNF HET + CORT) mice. Simultaneous EE prevented these impairments. However, EE appeared to worsen spatial memory performance in WT mice, particularly those exposed to CORT. While BDNF levels were lower in BDNF HET mice as expected, there were no further effects of CORT or EE in males but a close to significant female CORT × EE × genotype interaction which qualitatively corresponded with Y-maze performance. However, EE caused both sex- and genotype-specific effects on phosphorylated TrkB residues and GluNR expression within the dorsal hippocampus, with GluNR2B levels in males changing in parallel with spatial memory performance. In conclusion, beneficial effects of EE on spatial memory emerge only following two developmental disruptions. The mechanisms by which EE exerts its effects are likely via regulation of multiple activity-dependent pathways, including TrkB and NMDA receptor signaling.
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ItemAltered Amygdala Excitation and CB1 Receptor Modulation of Aggressive Behavior in the Neuroligin-3R451C Mouse Model of Autism(FRONTIERS MEDIA SA, 2018-08-03)Understanding neuronal mechanisms underlying aggression in patients with autism spectrum disorder (ASD) could lead to better treatments and prognosis. The Neuroligin-3 (NL3)R451C mouse model of ASD has a heightened aggressive phenotype, however the biological mechanisms underlying this behavior are unknown. It is well established that NL3R451C mice have imbalanced excitatory and inhibitory synaptic activity in the hippocampus and somatosensory cortex. The amygdala plays a role in modulating aggressive behavior, however potential changes in synaptic activity in this region have not previously been assessed in this model. We investigated whether aggressive behavior is robustly present in mice expressing the R451C mutation, following back-crossing onto a congenic background strain. Endocannabinoids influence social interaction and aggressive behavior, therefore we also studied the effects of cannabinoid receptor 1 (CB1) agonist on NL3R451C mice. We report that NL3R451C mice have increased amplitude of miniature excitatory postsynaptic currents (EPSCs) with a concomitant decrease in the amplitude of inhibitory postsynaptic currents (IPSCs) in the basolateral amygdala. Importantly, we demonstrated that NL3R451C mice bred on a C57Bl/6 background strain exhibit an aggressive phenotype. Following non-sedating doses (0.3 and 1.0 mg/kg) of the CB1 receptor agonist WIN55,212-2 (WIN), we observed a significant reduction in aggressive behavior in NL3R451C mice. These findings demonstrate altered synaptic activity in the basolateral amygdala and suggest that the NL3R451C mouse model is a useful preclinical tool to understand the role of CB1 receptor function in aggressive behavior.
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