Florey Department of Neuroscience and Mental Health - Research Publications
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ItemEvaluation of attention in APP/PS1 mice shows impulsive and compulsive behaviours(WILEY, 2021-01)While Alzheimer's disease (AD) is traditionally associated with deficits in episodic memory, early changes in other cognitive domains, such as attention, have been gaining interest. In line with clinical observations, some animal models of AD have been shown to develop attentional deficits, but this is not consistent across all models. The APPswe/PS1ΔE9 (APP/PS1) mouse is one of the most commonly used AD models and attention has not yet been scrutinised in this model. We set out to assess attention using the 5-choice serial reaction time task (5CSRTT) early in the progression of cognitive symptoms in APP/PS1 mice, using clinically translatable touchscreen chambers. APP/PS1 mice showed no attentional changes across 5CSRTT training or any probes from 9 to 11 months of age. Interestingly, APP/PS1 mice showed increased impulsive and compulsive responding when task difficulty was high. This suggests that while the APP/PS1 mouse model may not be a good model of attentional changes in AD, it may be useful to study the early changes in impulsive and compulsive behaviour that have been identified in patient studies. As these changes have not previously been reported without attentional deficits in the clinic, the APP/PS1 mouse model may provide a unique opportunity to study these specific behavioural changes seen in AD, including their mechanistic underpinnings and therapeutic implications.
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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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ItemBrain Zinc Deficiency Exacerbates Cognitive Decline in the R6/1 Model of Huntington's Disease.(Springer Nature, 2020-01)There is currently no disease-modifying treatment for Huntington's disease (HD), which is characterized by chorea motor impairment and cognitive decline. The zinc ionophore, PBT2, was previously shown to improve the phenotype of a HD mouse model and reported efficacy in certain cognitive tests in a phase II clinical trial in HD. Here we report that zinc deficiency is a feature of the hippocampus and cortex in the R6/1 mouse model of HD. Low cortical zinc has been shown to induce cognitive impairment, and indeed, dietary restriction of zinc in R6/1 mice was associated with cognitive impairment in the Y-maze, an exacerbated hippocampal long-term potentiation (LTP) deficit and reduction of AMPA receptors (and not other glutamatergic receptors). These data reveal the importance of zinc in maintaining brain function in HD.