Long-term corticosterone exposure decreases insulin sensitivity and induces depressive-like behaviour in the C57BL/6NCrl mouse.

Chronic stress or long-term administration of glucocorticoids disrupts the hypothalamus-pituitary-adrenal system leading to continuous high levels of glucocorticoids and insulin resistance (IR). This pre-diabetic state can eventually develop into type 2 diabetes mellitus and has been associated with a higher risk to develop depressive disorders. The mechanisms underlying the link between chronic stress, IR and depression remains unclear. The present study aimed to establish a stress-depression model in mice to further study the effects of stress-induced changes upon insulin sensitivity and behavioural consequences. A pilot study was conducted to establish the optimal administration route and a pragmatic measurement of IR. Subsequently, 6-month-old C57BL/6NCrl mice were exposed to long-term oral corticosterone treatment via the drinking water. To evaluate insulin sensitivity changes, blood glucose and plasma insulin levels were measured at different time-points throughout treatment and mice were behaviourally assessed in the elevated zero maze (EZM), forced swimming test (FST) and open field test to reveal behavioural changes. Long-term corticosterone treatment increased body weight and decreased insulin sensitivity. The latter was revealed by a higher IR index and increased insulin in the plasma, whereas blood glucose levels remained unchanged. Corticosterone treatment induced longer immobility times in the FST, reflecting depressive-like behaviour. No effects were observed upon anxiety as measured in the EZM. The effect of the higher body weight of the CORT treated animals at time of testing did not influence behaviour in the EZM or FST, as no differences were found in general locomotor activity. Long-term corticosterone treatment via the drinking water reduces insulin sensitivity and induces depressive-like behaviour in the C57BL/6 mouse. This mouse model could thus be used to further explore the underlying mechanisms of chronic stress-induced T2DM and its association with increased prevalence of major depressive disorder on the short-term and other behavioural adaptations on the longer term

Chronic phosphodiesterase type 2 inhibition improves memory in the APPswe/PS1dE9 mouse model of Alzheimer's disease

Alzheimer's disease (AD) is characterized by progressive cognitive deficits and synaptic dysfunction. Over the last decade phosphodiesterase inhibitors (PDEIs) have received increasing attention as putative cognition enhancers and have been suggested as a novel treatment strategy for AD. Given their ability to prevent hydrolysis of cAMP and/or cGMP, they can stimulate the cAMP/protein kinase A (PKA)/cAMP element-binding protein (CREB) and cGMP/PKG/CREB pathway to enhance synaptic transmission by increasing CREB phosphorylation (pCREB) and brain-derived neurotrophic factor (BDNF) transcription. Based on previous research, we hypothesized that chronic PDE2I treatment would improve AD-related cognitive deficits, by decreasing amyloid-beta (A beta) plaque load, enhancing pCREB and BDNF levels and increasing synaptic density in the hippocampus of 8-month-old APPswe/PS1dE9 mice. Results indicated that chronic PDE2I treatment could indeed improve memory performance in APPswe/PS1dE9 mice, without affecting anxiety, depressive-like behavior or hypothalamus pituitary adrenal axis regulation. However, no treatment effects were observed on A beta plaque load, pCREB or BDNF concentrations, or presynaptic density in the hippocampus, suggesting that other signaling pathways and/or effector molecules might be responsible for its cognition-enhancing effects. Presynaptic density in the stratum lucidum of the CA3 subregion was significantly higher in APPswe/PS1dE9 mice compared to WT controls. possibly reflecting a compensatory mechanism. In conclusion, PDEs in general, and PDE2 specifically, could be considered as promising therapeutic targets for cognition enhancement in AD, although the underlying mechanism of action remains to be elucidated. This article is part of a Special Issue entitled 'Cognitive Enhancers'

Effects of prenatal stress exposure on soluble A beta and brain-derived neurotrophic factor signaling in male and female APPswe/PS1dE9 mice

Chronic stress and stress-related disorders, such as major depression (MD), have been shown to increase the risk for developing Alzheimer's disease (AD). Brain-derived neurotrophic factor (BDNF) has been postulated as a neurophysiological link between these illnesses. Our previous research has indicated that exposing the APPswe/PS1dE9 mouse model of AD to prenatal maternal stress (PS) induced a depressive-like phenotype, specifically in female mice. Considering the role of BDNF in depressive-like behavior and its interactions with amyloid-beta (A beta), our aim was to explore whether these mice would also exhibit alterations in soluble A beta, mature BDNF (mBDNF), proBDNF, and the receptors TrkB and p75(NTR) in comparison to non-stressed animals. Our results demonstrate that female APPswe/PS1dE9 mice have higher levels of hippocampal proBDNF and soluble A beta as compared to their male littermates. Additionally, a tendency was observed for PS to lower mBDNF protein levels in the hippocampus, but only in female mice, while receptor levels remained unaltered by sex or PS exposure. Given that female mice both have higher proBDNF and A beta levels, these findings suggest an underlying role for BDNF signaling and A beta production in the selective vulnerability of women for MD and AD development

Plasma glucose levels (mean % change from baseline+S.E.M.) after acute glucose challenge in fasted animals receiving corticosterone (CORT) or vehicle either orally via the drinking water or by daily s.c. injection as measured by oral glucose tolerance tests (OGGT).

<p>Within each OGTT, plasma glucose levels are measured at baseline (0) and 15, 30, 60 and 120 min after an oral administration of glucose. Treatment effects upon glucose tolerance were measured at 3 time-points throughout the experiment, namely directly after 4 weeks treatment (OGTT1) and 1 and 2 weeks after treatment cessation (OGTT2, OGTT3, respectively). (*) <i>trend</i>; <i>P</i> = 0.094.</p

Effects of corticosterone (CORT) administration via the drinking water upon water intake (mean % change+S.E.M.) during the 12 week treatment period.

<p>Significant increased amounts of water intake in the CORT group are denoted with *(<i>P</i><0.01).</p

Experimental overview of the pilot study.

<p>CORT: corticosterone; OGTT: oral glucose tolerance test.</p

Effects of CORT treatment orally via the drinking water or by daily s.c. injection upon body weight (mean % change compared to body weight prior to start of treatment+S.E.M.) during the 4 week treatment period and 1 and 2 weeks after treatment cessation (week 5 and 6).

<p>The figure shows significant increased body weights in the group receiving CORT via the drinking water compared to the vehicle drinking water group (^#) or CORT injection group (*). ^#/*<i>P</i><0.05.</p

Effect of corticosterone (CORT) administration via the drinking water (mean+S.E.M.) upon total distance moved, body weight at time of testing and total immobility time in the forced swim test (FST).

<p>*Significant difference between CORT and vehicle treatment (<i>P</i><0.01).</p