Neuroscience
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Ketamine is a promising therapeutic for treatment-resistant depression (TRD) but is associated with an array of short-term psychomimetic side-effects. These disparate drug effects may be elicited through the modulation of neural circuit activity. The purpose of this study was to therefore delineate dose- and time-dependent changes in ketamine-induced neural oscillatory patterns in regions of the brain implicated in depression. ⋯ These low dose ketamine-induced oscillatory alterations were accompanied by a reduction in immobility time in the forced swim test. These results show that ketamine induces time-dependent effects on neural oscillations at specific frequencies. These drug-induced changes may differentially contribute to the psychomimetic and therapeutic effects of the drug.
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Sodium tanshinone IIA sulfonate (STS) can protect against brain damage induced by stroke. However, the neural protection mechanism of STS remains unclear. We investigated whether STS performs its protective function by suppressing autophagy and inflammatory activity during brain injury. ⋯ STS treatment reduced neuroinflammation, as assessed by the infiltration of macrophages and neutrophils, corresponding with reduced numbers of macrophages, T cells, and B cells in ischemia/reperfusion (I/R) brains. In addition, STS treatment also attenuated the upregulation of autophagy associated proteins, such as LC3-II, Beclin-1 and Sirt 6, which was induced by MCAO. These results demonstrated that STS can provide remarkable protection against ischemic stroke, possibly via the inhibition of autophagy and inflammatory activity.
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Chemokine signaling has been implicated in the pathogenesis of diabetic neuropathy; however, the role of chemokine CC motif receptor 4 (CCR4) remains unknown. The goal was to examine the function of CCR4 in hypersensitivity development and opioid effectiveness in diabetic neuropathy. Streptozotocin (STZ; 200 mg/kg, intraperitoneally administered)-induced mouse model of diabetic neuropathy were used. ⋯ Importantly, our results provide the first evidence that in a mouse model of diabetic neuropathy, single intrathecal and intraperitoneal injections of C021 diminished neuropathic pain-related behavior in a dose-dependent manner and improved motor functions. Moreover, both single intrathecal and intraperitoneal injections of C021 enhanced morphine and buprenorphine effectiveness. These results reveal that pharmacological modulation of CCR4 may be a good potential therapeutic target for the treatment of diabetic neuropathy and may enhance the effectiveness of opioids.
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Schizophrenia in humans typically develops during and after adolescence; however, the biological underpinning for the specificity of this onset time window remains to be determined. In the present study, we investigated this knowledge gap using our own animal model for schizophrenia. Rodents and monkeys challenged with a cytokine, epidermal growth factor (EGF), as neonates are known to exhibit various behavioral and cognitive abnormalities at the post-pubertal stage. ⋯ The increase in burst firing was accompanied by a decline in Ca2+-activated K+ (ISK) currents, which influence the firing pattern of dopamine neurons. In vivo local application of the SK channel blocker apamin (80 μM) to the substantia nigra was less effective at increasing burst firing in the EGF model than in control mice, suggesting the pathologic role of the ISK decrease in this model. Thus, these results suggest that the aberrant post-pubertal hyperactivity of midbrain dopaminergic neurons is associated with the temporal specificity of the behavioral deficit of this model, and support the hypothesis that this dopaminergic aberration could be implicated in the adolescent onset of schizophrenia.
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Photoreceptors are light-sensitive cells in the retina converting visual stimuli into electrochemical signals. These signals are evaluated and interpreted in the visual pathway, a process referred to as visual processing. Phosphodiesterase type 5 and 6 (PDE5 and 6) are abundant enzymes in retinal vessels and notably photoreceptors where PDE6 is exclusively present. ⋯ The effects of sildenafil were dependent on the wavelength condition in both assays. Our results support the observation that while PDE6 is a key player in phototransduction, near full inhibition of PDE6 is not enough to abolish the complex process of visual processing. Taken together, VEPs and SSVEPs are effective in demonstrating progressive effects of drug-induced changes in visual processing in rats and as the same paradigms may be applied in humans, representing a promising tool for translational research.