Neuroscience
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Dual orexinergic antagonists (DORAs) have been recently developed as a pharmacotherapy alternative to established hypnotics. Hypnotics are largely evaluated in preclinical rodent models in the dark/active period yet should be ideally evaluated in the light/inactive period, analogous to when sleep disruption occurs in humans. We describe here the hypnotic efficacy of DORA-22 in rodent models of sleep disturbance produced by cage changes in the light/inactive period. ⋯ EEG measures indicated that all DORA-22 doses largely promoted sleep in the first hour. The lowest dose (1 mg/kg) did not decrease sleep onset latency at the six-hour timepoint, suggesting no residual hypersomnolence. We described here DORA-22 hypnotic efficacy during the normal sleep period of nocturnal rats, and demonstrate that well-chosen (low) hypnotic doses of DORA-22 may be hypnotically effective yet have minimal lingering effects.
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The mitogen-activated protein kinases (MAPK) are major signaling components of intracellular pathways required for memory consolidation. Mitogen- and stress-activated protein kinases 1 and 2 (MSK1 and MSK2) mediate signal transduction downstream of MAPK. MSKs are activated by Extracellular-signal Regulated Kinase 1/2 (ERK1/2) and p38 MAPK. ⋯ Loss of Msk1, but not of Msk2, affected excitatory synaptic transmission at perforant path-to-dentate granule cell synapses, altered short-term presynaptic plasticity, impaired selectively long-term spatial recognition memory, and decreased basal levels of CREB and its activated form. LTP in vivo and LTP-induced CREB phosphorylation and EGR1 expression were unchanged after Msk1 or Msk2 deletion. Our findings demonstrate a dissimilar contribution of MSKs proteins in cognitive processes and suggest that Msk1 loss-of-function only has a deleterious impact on neuronal activity and hippocampal-dependent memory consolidation.
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Because somatosensory PNS neurons, in particular nociceptors, are specially tuned to be able to detect a wide variety of both exogenous and endogenous signals, one might assume that these neurons express a greater variety of receptor genes. This assumption has not been formally tested. Because cells detect such signals via cell surface receptors, we sought to formally test the hypothesis that PNS neurons might express a broader array of cell surface receptors than CNS neurons using existing single cell RNA sequencing resources from mouse. ⋯ Finally, we sought to examine specific ligand-receptor interactions between T cells and PNS and CNS neurons. Again, we noted that most interactions between these cells are shared by CNS and PNS neurons despite the fact that T cells only enter the CNS under rare circumstances. Our findings demonstrate that both PNS and CNS neurons express an astonishing array of cell surface receptors and suggest that most neurons are tuned to receive signals from other cells types, in particular immune cells.
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Ensuring stability of the human vertical posture is a complex task requiring both anticipatory and compensatory postural strategies when a standing person performs fast actions and interacts with the environment, which can include other persons. How people adjust their preparatory and compensatory postural adjustments in situations when they interact with an active partner is still poorly understood. In this study we investigated the postural adjustments while two healthy persons played a traditional childhood game. ⋯ Results showed higher indices of muscle co-activation during EPAs during the game compared to the control conditions. We found that postural preparation strategies defined whether a participant kept or lost balance during the game. Our results highlight the importance of muscle co-activation, the role of anticipation, and the difference in strategies while interacting with an active partner as compared to interactions with passive objects.
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Nociceptive stimulation is predicted to uniformly inhibit motoneurone pools of painful muscles and those producing painful movements. Although reduced motoneurone discharge rate during pain provides some evidence, recent data show evidence of increased excitability of some motoneurones. These observations suggest non-uniform effects of nociception on motoneurone excitability. ⋯ This does not support the hypothesis that nociceptive input induces uniform inhibition of painful muscle. Instead, interpretation of results implies redistribution of activity between motor units, with possible benefit for unloading painful tissues. This finding supports an interpretation that differs from the generally accepted view in pain physiology regarding adaptation to motor function in pain.