Florey Department of Neuroscience and Mental Health - Research Publications
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ItemPostnatal developmental trajectory of dopamine receptor 1 and 2 expression in cortical and striatal brain regions(WILEY, 2019-04-15)Healthy brain function requires a balance between the activity of dopamine receptor 1 (D1) and dopamine receptor 2 (D2). Alterations in this balance increase the risk for numerous developmental brain disorders. Indeed, D1 and D2 expression fluctuates throughout maturation, although there is conflicting evidence regarding the precise changes that occur. Here, we used stereology to investigate the developmental changes in the number of D1- or D2-expressing neurons in the prelimbic cortex, infralimbic cortex (IL), insula cortex, dorsal striatum, and ventral striatum of female and male mice with green fluorescent protein-tagged D1 or D2. Postnatal day 17, 25, 35, 49, and 70 were examined to cover juvenility to adulthood. In all regions, analysis of D1 density compared to D2 density within each sex seldom detected effects or interactions involving age. However, D1:D2 density ratio changed across age depending on sex. In the IL, D1:D2 density ratio increased in females from adolescence, whereas it was stable in males. In the insula cortex, D1:D2 ratio initially increased in males but decreased in females from juvenility to preadolescence. The ratio then increased in males and females from adolescence to adulthood, with males showing a more dramatic increase. In both the dorsal and ventral striatum, the ratio increased from adolescence. In all regions, females had a higher ratio compared to males throughout maturation except in the insula cortex at P25. These comprehensive observations are novel, and highlight how the maturational changes in the expression of these receptors may contribute to developmental disorders.
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ItemCognition and Related Neural Findings on Methamphetamine Use Disorder: Insights and Treatment Implications From Schizophrenia Research(FRONTIERS MEDIA SA, 2019-12-17)Despite the prevalence of methamphetamine (meth) use disorder, research on meth is disproportionately scarce compared to research on other illicit drugs. Existing evidence highlights cognitive deficits as an impediment against daily function and treatment of chronic meth use. Similar deficits are also observed in schizophrenia, and this review therefore draws on schizophrenia research by examining similarities and differences between the two disorders on cognition and related neural findings. While meth use disorder and schizophrenia are two distinct disorders, they are highly co-morbid and share impairments in similar cognitive domains and altered brain structure/function. This narrative review specifically identifies overlapping features such as deficits in learning and memory, social cognition, working memory and inhibitory/impulse control. We report that while working memory deficits are a core feature of schizophrenia, such deficits are inconsistently observed following chronic meth use. Similar structural and functional abnormalities are also observed in cortical and limbic regions between the two disorders, except for cingulate activity where differences are observed. There is growing evidence that targeting cognitive symptoms may improve functional outcome in schizophrenia, with evidence of normalized abnormal brain activity in regions associated with cognition. Considering the overlap between meth use disorder and schizophrenia, targeting cognitive symptoms in people with meth use disorder may also improve treatment outcome and daily function.
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ItemChronic voluntary alcohol consumption causes persistent cognitive deficits and cortical cell loss in a rodent model(NATURE PORTFOLIO, 2019-12-09)Chronic alcohol use is associated with cognitive decline that impedes behavioral change during rehabilitation. Despite this, addiction therapy does not address cognitive deficits, and there is poor understanding regarding the mechanisms that underlie this decline. We established a rodent model of chronic voluntary alcohol use to measure ensuing cognitive effects and underlying pathology. Rats had intermittent access to alcohol or an isocaloric solution in their home cage under voluntary 2-bottle choice conditions. In Experiments 1 and 2 cognition was assessed using operant touchscreen chambers. We examined performance in a visual discrimination and reversal task (Experiment 1), and a 5-choice serial reaction time task (Experiment 2). For Experiment 3, rats were perfused immediately after cessation of alcohol access period, and volume, cell density and microglial populations were assessed in the prefrontal cortex and striatum. Volume was assessed using the Cavalieri probe, while cell and microglial counts were estimated using unbiased stereology with an optical fractionator. Alcohol-exposed and control rats showed comparable acquisition of pairwise discrimination; however, performance was impaired when contingencies were reversed indicating reduced behavioral flexibility. When tested in a 5-choice serial reaction time task alcohol-exposed rats showed increased compulsivity and increased attentional bias towards a reward associated cue. Consistent with these changes, we observed decreased cell density in the prefrontal cortex. These findings confirm a detrimental effect of chronic alcohol and establish a model of alcohol-induced cognitive decline following long-term voluntary intake that may be used for future intervention studies.