Browsing by Subject "corticosterone"
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(2024)Cranial windows are commonly used in neuroscience for direct brain access, but they require skull removal which can lead to neuroinflammation, potentially affecting experiment outcomes. As the nature of the window varies from experiment to experiment along with parallel treatments, it is of particular interest to map the quality and extent of the resulting brain inflammation on a case-by-case basis to have a better understanding of inflammation-related confounding factors in future experiments. As the focus of our future experiments is on finding electrophysiological biomarkers of depression employing state-of-the-art in vivo electrophysiological tools through a cranial window, we would like to characterise the extent of inflammation linked to the cranial window of interest in a mouse model of depression. To achieve this, we implanted mice with a soft cranial window and afterwards, treated them with corticosterone for a month. The animals were sacrificed and astrocytic glial fibrillary acidic protein (GFAP) and microglial ionized calcium-binding adapter molecule 1 (IBA) were labelled on coronal brain sections and imaged using a confocal microscope. We quantified the percentage of GFAP+ and IBA+ pixels on brain slices as measures of neuroinflammation using an automatic global thresholding-based approach and a semi-automatised machine-learning-based approach of the QUINT workflow. Our thresholding-based analysis revealed a significant elevation in GFAP-positive pixels, indicative of astrogliosis, in mice subjected to both cranial window implantation and corticosterone treatment compared to controls. However, no significant changes in microglial reactivity were observed under similar conditions. Importantly, it appears that the cranial window alone did not evoke long-lasting brain inflammation and corticosterone only slightly affected astrocytic reactivity. And despite results using the QUINT workflow presented some confounds, our results provide important considerations for future experiments employing a combination of soft cranial window and chronic corticosterone treatment, but more research is needed to enhance the generalisability of our findings.
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(2020)While weeks of continuous treatment is required for conventional antidepressant drugs (e.g. fluoxetine) to bring their full therapeutic effects, a subanesthetic dose of ketamine alleviates the core symptoms of depression (anhedonia, depressed mood) and suicidal thinking within just few hours and the effects may last for days. Nitrous oxide (N2O, “laughing gas”), another NMDAR antagonist, has recently been shown to have similar rapid antidepressant effects in treatment-resistant depressed patients (Nagele et al. 2015). We previously found using naïve mice ketamine and N2O treatment to upregulate five mRNAs related to the MAPK pathway and synaptic plasticity, both implicated as being important in the action of rapid-acting antidepressants. In the current study, these shared mechanisms were further investigated in C57BL/6JHsd mice, using behavioral test batteries to study depressive-like behaviour and RT-qPCR for biochemical analyses. We first aimed to demonstrate behavioral differences between naïve mice and a chronic corticosterone-induced animal model of depression, and to use this model to investigate antidepressant-like effects of ketamine and N2O. According to the results, chronic corticosterone produced some behaviors typical of a depressive-like phenotype, namely significant worsening of coat state and decreased saccharin consumption in the saccharin preference test. Both ketamine and N2O exhibited antidepressant-like effects by reverting decreased saccharin preference. We then aimed to elucidate the effects of ketamine and N2O on five previously found shared mRNAs: Arc, Dusp1, Dusp5, Dusp6 and Nr4a1. N2O significantly upregulated all targets in the vmPFC, except Dusp5, two hours after beginning of N2O treatment. Neither ketamine nor sole chronic corticosterone produced any significant changes. The results of this study suggest that N2O is a potential candidate for rapid alleviation of depressive symptoms. We suggest that the action of rapid-acting antidepressants, more specifically N2O, is based on a homeostatic response of the brain to a presented challenge. Here this challenge would be cortical excitation previously been shown to be caused by N2O, which leads to activation of pathways such as MAPK and subsequent Arc, Dusp and Nr4a1 signaling. The level of expression of these markers would then depend on which phase this response is in and hence, the differences in time between treatment and brain sample dissection could be a reason for conflicting results to previous research. Future studies would benefit from detailed investigation of the chronic corticosterone-induced model due to its potential in controlling for behavioral variability, thus reducing the number of animals needed for preclinical research. Overall the preliminary findings of this study could be one of the first steps in the search for the mechanisms underlying the potential antidepressant effect of N2O, how these molecular markers are related to its action and how it differs from the action of ketamine.
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