Neuroscience
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Early-life stress (ELS) is associated with later onset of depression. Early cannabis use may be a risk factor that interacts with environmental factors to increase the risk of psychopathologies. We aimed to examine the long-term effects of ELS on depression- and anxiety-like behavior, and examine whether chronic fatty acid amide hydrolase (FAAH) inhibition during mid-adolescence could ameliorate or exacerbate ELS effects on behavior. ⋯ Moreover, in males, ELS and URB597 decreased CB1r levels in the prefrontal cortex (PFC) and CA1 and GRs in the PFC and basolateral amygdala (BLA). In females, ELS and URB decreased CB1r in the BLA and GRs in the CA1 and BLA. The findings suggest that mid-adolescence, as opposed to late-adolescence, may not be a potential developmental period for chronic treatment with FAAH inhibitors and that sex-dependent alterations in CB1r and GRs expression in the BLA-PFC-CA1 circuit may contribute to the depressive behavioral phenotype.
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The proto-oncogene pleomorphic adenoma gene 1 (Plag1) encodes a zinc finger transcription factor. PLAG1 is part of the high motility group AT hook-2 (HGMA2)-PLAG1-insulin-like growth factor 2 (IGF2) pathway that, when disrupted, leads to Silver-Russell syndrome, a severe form of intrauterine growth restriction. With little known about PLAG1's role in normal physiology, this study is the first to characterise the behavioural phenotype of PLAG1-deficient mice. ⋯ Overall, the behavioural phenotype of the Plag1 knock-out (KO) mice was mild: no significant differences were seen in circadian activity levels, locomotion, object recognition, spatial memory or sociability compared to wild-type mice. However, the cued test of fear conditioning, prepulse inhibition of the startle response and Preyer's reflex test suggest that Plag1 KO mice may have a hearing impairment. This implies that PLAG1 plays an important role in proper functioning and/or development of the neural circuitry behind the auditory processes or interacts with genes involved in those processes.
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Gallic acid (GA) is a polyphenolic compound that has attracted significant interest due to its antioxidant action through free radical elimination and metal chelation. Ethanol is a highly soluble psychoactive substance, and its toxicity is associated with oxidative stress. In this context, the purpose of the present study was to investigate the effect of GA on neurochemical changes in zebrafish brains exposed to ethanol. ⋯ Treatment with GA at 5 and 10 mg/L reversed impairment of choline acetyltransferase activity and the damage to TBA-RS levels, DCFH oxidation, and superoxide dismutase activity induced by ethanol. Results of the present study suggest that GA treatment (20 mg/L) appeared to disrupt oxidative parameters in the zebrafish brain. GA treatment at 5 and 10 mg/L reversed alterations to the cholinergic system induced by prolonged exposure to ethanol in the zebrafish brain, probably through an antioxidant mechanism.
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Postural and movement components must be coordinated without significant disturbance to balance when reaching from a standing position. Traditional theories propose that muscle activity prior to movement onset create the mechanics to counteract the internal torques generated by the future limb movement, reducing possible instability via centre of mass (CoM) displacement. However, during goal-directed reach movements executed on a fixed base of support (BoS), preparatory postural adjustments (or pPAs) promote movement of the CoM within the BoS. ⋯ Participants executed beyond-arm reaching movements in four different postural configurations that altered the quality of the BoS. Quantification of these changes to stability did not drastically alter the tuning or timing of preparatory muscle activity despite modifications to arm and CoM trajectories necessary to complete the reaching movement. In contrast to traditional views, preparatory postural muscle activity is not always tuned for balance maintenance or even as a calculation of upcoming instability but may reflect a requirement of voluntary movement towards a pre-defined location.
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The analgesic effect of alpha-2 adrenergic receptor (α2AR) agonists, which relieve chronic neuropathic pain, is highly variable among individuals. Here, we used a mouse model of spared nerve injury (SNI) to show that treatment time after the establishment of neuropathic pain was important for the variability in the analgesic efficacy of α2AR agonists, which was related to the activity of regulator of G-protein signaling protein 4 (RGS4). Intrathecal treatment with α2AR agonists, clonidine (0.1-1 nmol) or dexmedetomidine (0.3-1 nmol), relieved mechanical allodynia and thermal hyperalgesia on postoperative day (POD) 14, but their efficacy was weaker on POD28 and absent on POD56. ⋯ Whereas, the coadministration of CCG50014 with clonidine (1 nmol) or dexmedetomidine (1 nmol) did not cause side effects. These findings demonstrated that SNI-induced increase in plasma membrane RGS4 expression was associated with low efficacy of α2AR agonists in a model of persistent, chronic neuropathic pain. Furthermore, α2AR agonist administration together with RGS4-targeted intervention represents a novel strategy for the treatment of neuropathic pain to overcome dose-limiting side effects.