The Journal of neuroscience : the official journal of the Society for Neuroscience
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Circadian rhythmicity in the primary mammalian circadian pacemaker, the suprachiasmatic nucleus (SCN) of the hypothalamus, is maintained by transcriptional and translational feedback loops among circadian clock genes. Photic resetting of the SCN pacemaker involves induction of the clock genes Period1 (Per1) and Period2 (Per2) and communication among distinct cell populations. Gastrin-releasing peptide (GRP) is localized to the SCN ventral retinorecipient zone, from where it may communicate photic resetting signals within the SCN network. ⋯ Blocking endogenous Per1 with antisense oligodeoxynucleotides inhibited GRP-induced increases in spike frequency. Furthermore, inhibition of CREB-mediated gene activation with decoy oligonucleotides blocked GRP-induced phase shifts of PER2::luciferase rhythms in SCN slices. Altogether, these results indicate that GRP communicates phase resetting signals within the SCN network via both spike-dependent and spike-independent mechanisms, and that activation of the CREB pathway and Per1 are key steps in mediating downstream events in GRP resetting of SCN neurons.
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Randomized Controlled Trial Clinical Trial
Opioid-mediated placebo responses boost pain endurance and physical performance: is it doping in sport competitions?
The neurobiological investigation of the placebo effect has shown that placebos can activate the endogenous opioid systems in some conditions. So far, the impact of this finding has been within the context of the clinical setting. Here we present an experiment that simulates a sport competition, a situation in which opioids are considered to be illegal drugs. ⋯ These long time intervals indicate that the pharmacological conditioning procedure has long-lasting effects and that opioid-mediated placebo responses may have practical implications and applications. For example, in the context of the present sport simulation, athletes can be preconditioned with morphine and then a placebo can be given just before competition, thus avoiding administration of the illegal drug on the competition day. However, these morphine-like effects of placebos raise the important question whether opioid-mediated placebo responses are ethically acceptable in sport competitions or whether they have to be considered a doping procedure in all respects.
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We often generate movements without any external event that immediately triggers them. How the brain decides the timing of self-initiated movements remains unclear. Previous studies suggest that the basal ganglia-thalamocortical pathways play this role, but the subcortical signals that determine movement timing have not been identified. ⋯ When monkeys made a saccade in response to the fixation point (FP) offset in the traditional memory saccade task, neurons in the ventrolateral and the ventroanterior nuclei of the thalamus exhibited a gradual buildup of activity that peaked around the most probable time of the FP offset; however, neither the timing nor the magnitude of neuronal activity correlated with saccade latencies, suggesting that the brain is unlikely to have used this information to decide the times of saccades in the traditional memory saccade task. In contrast, when monkeys were required to make a self-timed saccade within a fixed time interval after an external cue, the same neurons again exhibited a strong buildup of activity that preceded saccades by several hundred milliseconds, showing a close correlation between the times of neuronal activity and the times of self-initiated saccades. The results suggest that neurons in the motor thalamus carry subjective time information, which is used by cortical networks to determine the timing of self-initiated saccades.
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Different phases of motor skill learning appear to involve different physiological processes, with long-term potentiation (LTP) occurring at existing synapses in early and cortical reorganization involving synaptogenesis in later phases. Here, we test the evolution of skill learning-dependent changes in motor plasticity and excitability in six subjects trained to perform rapid thumb abductions over 5 d. Plasticity was examined using paired-associative stimulation (PAS) of the median nerve and motor cortex to induce LTP-like "PAS given with an interstimulus interval of 25 ms (PAS25)" or long-term depression (LTD)-like "PAS given with an interstimulus interval of 10 ms (PAS10)" plasticity. ⋯ The interference with PAS-induced plasticity suggests that the initial performance improvement relies on increasing the efficacy of existing synaptic connections. However, the long-lasting changes in the IO curve, SICI curve, and SMO suggest that continued practice enhances performance by changing Motor cortical organization. We hypothesize that new synaptic connections might have formed that allow LTP/LTD-susceptibility to be restored without reducing synaptic strength and performance skill.
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The neuropeptide substance P (SP) is expressed in unmyelinated primary sensory neurons and represents the best known "pain" neurotransmitter. It is generally believed that SP regulates pain transmission and sensitization by acting on neurokinin-1 receptor (NK-1), which is expressed in postsynaptic dorsal horn neurons. However, the expression and role of NK-1 in primary sensory neurons are not clearly characterized. ⋯ Sar-SP also induced membrane translocation of PKCepsilon in a portion of small DRG neurons. These results reveal a novel mechanism of NK-1 in primary sensory neurons via a possible autocrine and paracrine action of SP. Activation of NK-1 in these neurons induces heat hyperalgesia via PKCepsilon-mediated potentiation of TRPV1.