Neuroscience
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Humans are more vulnerable to addiction in comparison to all other mammals, including nonhuman primates, yet there is a lack of research addressing this. This paper reviews the field of comparative addiction neuroscience, highlighting the significant inter-species variation in the mesocortical dopaminergic and other neuromodulatory systems involved in addiction. Artificial selection gives rise to significant changes in neuroanatomy, neurophysiology and behaviour as shown in certain rodent strains and other domesticated animals. ⋯ During the course of human evolution, traits crucial to our survival, expansion and domination (traits such as the ability to innovate, adapt to different environments and thrive in a civilization) have been positively selected for, yet also predispose humans to addiction. This is evident in our unique neurochemistry and receptor-drug activation potencies. Examples of these are provided as possible targets for precision medicine.
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The dorsolateral prefrontal cortex (DLPFC) is a crucial brain region for inhibitory control, an executive function essential for behavioral self-regulation. Recently, inhibitory control has been shown to be important for endurance performance. Improvement in inhibitory control was found following transcranial direct current stimulation (tDCS) applied over the left DLPFC (L-DLPFC). ⋯ Stroop task performance was improved after Real-tDCS as demonstrated by a lower number of errors for incongruent stimuli (p=0.012). TTE was significantly longer following Real-tDCS compared to Sham-tDCS (p=0.029, 17±8 vs 15±8min), with significantly lower HR (p=0.002) and RPE (p<0.001), while no significant difference was found for PAIN (p>0.224). ∆B[La-] was significantly higher at exhaustion in Real-tDCS (p=0.040). Our findings provide preliminary evidence that tDCS with the anodal electrode over the L-DLPFC can improve both inhibitory control and endurance cycling performance in healthy individuals.
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Synaptic vesicle protein 2A (SV2A), which plays an important role in the pathophysiology of epilepsy, is a unique vesicular protein recognized as a pharmacological target of anticonvulsant drugs. Furthermore, SV2A is a potential synaptic density marker, as it is ubiquitously expressed throughout the brain in all nerve terminals independently of their neurotransmitter content. Due to the growing interest in this protein, we thoroughly analyzed SV2A levels, expression patterns and colocalization in both excitatory and inhibitory synapses among different brain structures in healthy rats. ⋯ In addition, immunohistochemistry demonstrated slight but consistent asymmetrical SV2A levels in different laminated structures, and SV2A expression was increased by up to 40% in some specific layers compared to that in others. Finally, triple immunofluorescence revealed strong SV2A colocalization with GABAergic terminals, mainly around the principal cells, suggesting that SV2A primarily participates in this inhibitory system in different rat brain structures. Although the SV2A protein is considered a good candidate marker of synaptic density, our data show that changes in its expression in pathological processes must be viewed as not only increased or decreased synapse numbers but also in light of the type of neurotransmission being affected.
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Disrupted neuronal intracellular trafficking is often related with protein aggregates present in the brain during neurodegenerative diseases such as Alzheimer's. Impairment of intracellular transport may be related to Rab proteins, a class of small GTPases responsible for trafficking of organelles and vesicles. Deficit in trafficking between the endoplasmic reticulum (ER) and Golgi apparatus mediated by Rab1 and 6 may lead to increased unfolded protein response (UPR) and ER stress and remodeling. ⋯ Rab1 levels and cell viability decreased, whereas Rab6, UPR proteins and ER remodeling increased during protein aggregation, which were restored to normal levels after exogenous expression of Rab1. These results suggest that decrease of Rab1 levels contributes to ER stress and remodeling, while maintaining the elevated expression of Rab1 prevented impairment of cell viability during protein aggregation. In conclusion, Rab1 is a significant player to maintain intracellular homeostasis and its expression may mitigate ER dysfunction in the context of neurodegeneration-related protein inclusions.
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The activation of inflammatory cytokines following stroke leads to neuron apoptosis and microglial activation, both of which are involved in ischemic brain damages. The ubiquitin-specific protease 18 (USP18) negatively regulated the expression of inflammatory cytokines and suppresses microglial activation. This study aims to determine whether USP18 expression protects against brain damage in ischemic models of stroke. ⋯ Additionally, microglial activation was inhibited, including the suppression of the JAK/STAT pathway and the proinflammatory cytokines expression. In vitro experiments demonstrated that USP18 inhibited BV2 microglial activity and reduced the mRNA and protein levels of NF-κB, JAK1, p-JAK1, STAT1, and p-STAT1 in BV2 microglial cells. USP18 overexpression decreased ischemic brain injury through the suppression of microglial activation by negatively regulating the release of proinflammatory cytokines.