Neuroscience
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Dopamine neurons in the periaqueductal gray (PAG)/dorsal raphe are key modulators of antinociception with known supraspinal targets. However, no study has directly tested whether these neurons contribute to descending pain inhibition. We hypothesized that PAG dopamine neurons contribute to the analgesic effect of D-amphetamine via a mechanism that involves descending modulation via the rostral ventral medulla (RVM). ⋯ This hyperalgesia was transiently restored by intra-PAG injection of eticlopride, as well as RVM microinjection of muscimol. We conclude that D-amphetamine analgesia is partially mediated by descending inhibition and that D2 receptors in the PAG are responsible for this effect via modulating neurons that project to the RVM. These results further our understanding of the antinociceptive effects of dopamine and elucidate a mechanism by which clinically available dopamine modulators produce analgesia.
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Opioid use by women during pregnancy has risen dramatically since 2004, accompanied by a striking increase in the prevalence of neonatal opioid withdrawal syndrome (NOWS) and other long-term neurological deficits. However, the mechanisms underlying the impact of prenatal opioid exposure on fetal neurodevelopment are largely unknown. To translate from the clinical presentation, we developed a novel mouse model to study the neurodevelopmental consequences of maternal opioid use and management. ⋯ However, adolescent offspring exposed to maternal opioid use during pregnancy exhibited hyperactivity in late adolescence. Remarkably, we also show increased generation of dopaminergic neurons within the ventral tegmental area (VTA) of mice exposed to prenatal opioids. These data provide critical evidence of teratogenic effects of opioid use during pregnancy and suggest a causal relationship between maternal opioid use and neurodevelopmental/behavioral anomalies in adolescence.
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Beta-secretase (BACE1) and gamma-secretase activating protein (GSAP) are pivotal enzymes in the cleavage of amyloid precursor protein (APP). Beta-amyloid (Aß) formation is considered one of the main reasons for Alzheimer's disease (AD) pathology. In our preliminary study, a series of microRNAs (miRs) with possible interaction with BACE1 and/or GSAP was selected using computational analysis. ⋯ Also, western blotting and immunocytochemistry confirmed the regulatory role of miR-4422-5p mimic on BACE1 and GSAP genes. miR-4422-5p mimic significantly decreased BACE1 and GSAP protein expression in SH-SY5Y and A549 cells, respectively. Moreover, miR-4422-5p-inhibitor reversed the expression processes in both cell lines. Our data suggest that miR-4422-5p may be an important regulator of both BACE1 and GSAP genes and can represent a novel potential biomarker or therapeutic target in AD.
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Human behaviour amazes with extraordinary flexibility and the underlying neural mechanisms have often been studied using task switching. Despite extensive research, the relative importance of "cognitive" and "motor" aspects during switching is unclear. In the current study we examine this question combining EEG analysis techniques and source localization to examine whether the selection of the response, or processes during the execution of the response, contribute most to switching effects. ⋯ On a functional neuroanatomical level, these modulations in motor processes showed a clear temporal sequence in that motor codes are processed primarily in superior parietal regions (Brodman area 7) and only then in premotor regions (Brodman area 6). The observed modulations may reflect motor reprogramming processes. The study shows how EEG signal analysis in combination with brain mapping methods can inform debates on theories of human cognitive flexibility.
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Estrogen produces a beneficial role in animal models of multiple sclerosis (MS). The effect of 17β-estradiol therapy on microglia polarization and neuroinflammation in the corpus callosum of the cuprizone-induced demyelination model has not been elucidated. In this study, mice were given 0.2% cuprizone (CPZ) for 5 weeks to induce demyelination during which they received 50 ng of 17β-estradiol (EST), injected subcutaneously in the neck region, twice weekly. ⋯ Moreover, administration of 17β-estradiol resulted in a significant reduction (∼3-fold) in transcript levels of NLRP3 inflammasome and its downstream product IL-18, compared to controls. In summary, this study demonstrated for the first time that exogenous 17β-estradiol therapy robustly leads to the reduction of M1 phenotype, stimulation of polarized M2 microglia, and repression of NLRP3 inflammasome in the corpus callosum of CPZ demyelination model of MS. The positive effects of 17β-estradiol on microglia and inflammasome seems to facilitate and accelerate the remyelination process.