Neuroscience
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Steroid hormones secreted by the gonads (sex steroids) and adrenal glands (glucocorticoids, GC) are known to influence brain structure and function. While levels of sex steroids wane in late adulthood, corticosteroid levels tend to rise in many individuals due to age-related impairments in their feedback on central mechanisms regulating adrenal function. These fluctuations in sex and adrenal steroid secretion may be relevant to age-related neurodegenerative disorders such as Alzheimer's disease (AD) in which hyperphosphorylation of Tau protein is a key pathological event. ⋯ Interestingly, we observed that the changes in Tau induced by manipulation of the GC milieu of male rats were exacerbated by testosterone depletion (by orchiectomy). While this finding supports previous suggestions of a neuroprotective role of male sex hormones, this is the first study to address interactions between adrenal and sex steroids on Tau hyperphosphorylation and accumulation that are known to endanger neuronal function and plasticity. These results are particularly important for understanding the mechanisms that can precipitate AD because, besides being modulated by age, GC are elevated by stress, a phenomenon now established as a trigger of deficits in neural plasticity and survival, cognitive behaviour and AD-like Tau pathology.
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Depression is a chronic disease that affects nearly twice as many women as men, and symptoms can differ by sex. Preclinical models disproportionately use male subjects and test a single behavioral endpoint immediately at the cessation of stress. We conducted variable stress in male and female mice for 6, 28, and 56 days, and measured behavior with a battery chosen to match research domain criteria. ⋯ These studies confirm that behavioral sex differences are detected in response to variable stress, and reveal information about individual differences. Use of a test battery that measures varying endophenotypes can be combined into a single stress susceptibility score as a tool similar to the scales/inventories used for the study of depression in humans. We present these data with the goal of furthering the field's understanding sex differences and how they shape the biology of mood disorders.
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Cannabidiol (CBD) is a non-addictive ingredient of cannabis with antipsychotic potential, while ketamine (KET), an uncompetitive NMDA receptor inhibitor, has been extensively used as a psychotomimetic. Only few studies have focused on the role of CBD on the KET-induced motor profile, while no study has investigated the impact of CBD on KET-induced alterations in NMDA receptor subunit expression and ERK phosphorylation state, in brain regions related to the neurobiology and treatment of schizophrenia. Therefore, the aim of the present study is to evaluate the role of CBD on KET-induced motor response and relevant glutamatergic signaling in the prefrontal cortex, the nucleus accumbens, the dorsal and ventral hippocampus. ⋯ Interestingly, in the nucleus accumbens KET per se reduced NR2B and p-ERK levels, while the CBD/KET combination increased NR2B and p-ERK levels, as compared to control. This study is the first to show that CBD prolongs KET-induced motor stimulation and restores KET-induced effects on glutamatergic signaling and neuroplasticity-related markers. These findings contribute to the understanding of CBD effects on the behavioral and neurobiological profiles of psychotogenic KET.
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Cognitive deficits and alterations in emotional behaviour are typical features of Alzheimer's disease (AD). Moreover, exposure to stress or adversity during the early life period has been associated with an acceleration of cognitive deficits and increased AD pathology in transgenic AD mouse models. Whether and how early life adversity affects fear memory in AD mice remains elusive. ⋯ We conclude that in APPswe/PS1dE9 mice, ELS increases fear memory in the conditioning context as well as a novel context, which is accompanied by aberrant hippocampal synaptic potentiation. These results may help to understand how individual differences in the vulnerability to develop AD arise and emphasise the importance of the early postnatal time window in these differences. This article is part of Special Issue entitled: Lifestyle and Brain Metaplasticity.