Neuroscience
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Gene therapy for rare monogenetic neurological disorders is reaching clinics and offering hope to families affected by these diseases. There is also potential for gene therapy to offer new and effective treatments for common, non-genetic disorders. Treatments for Parkinson's Disease are in clinical trials, and treatments for refractory epilepsies are due to enter first-in-human clinical trials in 2022. ⋯ Several lines of research are aimed at developing gene therapy approaches that allow for the treatment to be turned on and off, including: using proteins activated by exogenous ligands, and promoters turned on by activators. We review these approaches and propose an overall de-risking strategy for gene therapy for common neurological and psychiatric diseases. This approach is based on using a temporary mRNA-based treatment to initially assess efficacy and safety of the planned manipulation, and only following with permanent, virally-delivered treatment if the approach appears safe and effective.
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Physiological movement develops on the basis of sensorimotor integration through synchronisation between the copy of signals sent to the effector muscles and the incoming flow of sensory information. Our aim is to study corticomuscular coherence (CMC), the most widely used measure of synchronization between brain and muscle electrical activities, in dependence on the level of visual feedback and the executing body side. We analysed CMC in 18 healthy volunteers while performing a weak isometric handgrip of an air bulb with either the right or the left hand, in either the presence or absence of visual feedback on the exerted pressure. ⋯ The lack of dependence of CMC on the controlled hand involved in the movement can be considered in agreement with small hemispheric asymmetries of hand representations in primary sensorimotor cortices. Modulation of visual information changed corticomuscular synchronizations and cortical involvement, reflecting the crucial role of gaze in human behaviour. Given the fundamental role of sensory integration in motor execution, the availability of a simple index sensitive to modulations of perceptual afferents may prove useful in determining the use or the monitoring of the effects of sensory enrichments in personalized rehabilitation.
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Early-life stress (ELS) has long-term consequences, including an increased risk for drug abuse and psychiatric disorders later in life, which is higher in women than in men. The consequences of ELS include heightened sensitivity to stressful events. Here, we hypothesized that ELS changes the stress sensitivity of dopaminergic (DAergic) neurons in the ventral tegmental area (VTA) and orexin (OXA) neurons in the lateral hypothalamus (LH), that are crucial for the control of motivated behaviors. ⋯ Furthermore, an increase in spine head diameter of VTA neurons and a concurrent decrease in dendritic spine density in dorsal VTA were observed. We also showed that MS changed the stress sensitivity of OXA neurons selectively in the dorsomedial hypothalamus (DMH), which is implicated in arousal and the stress response. These findings show the long-lasting consequences of ELS and indicate the selective, regional sensitivity of structures involved in the control of arousal, motivational behaviors and the stress response to ELS.
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Fear of falling increases conscious control of balance and postural threat warrants accurate anticipatory motor commands for keeping a safe body posture. This study examines the anticipatory (APAs) and compensatory (CPAs) postural adjustments generated in response to an external perturbation while individuals are positioned at two different altitudes (2 cm and 80 cm) from the floor level. The main result indicates that due to the perceived emotional threat, different agonist and antagonist muscles synergies (R and C-Indexes) are manifested, particularly during the anticipatory phase. ⋯ Interestingly, the APAs strategies were modified under different postural threats by controlling the agonist-antagonist muscles at different joints of lower extremity. For CPAs the reciprocal activation was less applied compared to muscles co-activation to unsure larger margin for compensatory adjustments as needed and re-establish the postural stability. The results indicate that when facing to a postural threat, the CNS modulates the anticipatory and compensatory phases of postural adjustments to minimize the risk of falling.
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Proteinase-activated receptor-1 (PAR1) antagonist plays a protective effect in brain injury. We investigated the potential function and mechanisms of PAR1 antagonist in ICH-induced brain injury. Results showed that PAR1 antagonist protected against neurobehavior deficits, brain edema and blood-brain barrier integrity in ICH mice via the JNK/ERK/p38 MAPK signaling pathway at 24 h after ICH. ⋯ Moreover, the protective effect of PAR1 antagonist on ICH-induced brain injury was blocked by FGL2 or TLR4 overexpression, and the levels of p-JNK, p-ERK and p-p38 MAPK were increased. Furthermore, PAR1 antagonist combined with TLR4 antagonist markedly alleviated brain injury after ICH at 72 h. Overall, PAR1 antagonist protected against short-term brain injury, and the effect of PAR1 antagonist on ICH-induced brain injury was mediated by FGL2 or TLR4.