Neuroscience
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The state of protein folding in the endoplasmic reticulum (ER), via the unfolded protein response (UPR), regulates a pro- or anti-apoptotic cell fate. Hypoxic preconditioning (HPC) is a potent anti-apoptotic stimulus, wherein ischemic neural injury is averted by a non-damaging exposure to hypoxia. We tested if UPR modulation contributes to the pro-survival/anti-apoptotic phenotype in neurons preconditioned with hypoxia, using organotypic cultures of rat hippocampus as a model system. ⋯ Ischemia-like conditions (oxygen/glucose deprivation, OGD) caused extensive neuron cell damage and involved some of the same UPR protein signals as HPC. In distinction to HPC and tunicamycin, OGD caused widespread suppression of UPR genes: 55 of 84 UPR gene mRNAs were numerically downregulated. We conclude that although HPC and ischemic cell death in hippocampal neurons involve protein-based signaling in all 3 UPR pathways, these processes co-opt only a subset of the genomic response elicited by agents known to cause protein misfolding, possibly because of persistent transcription/translation arrest induced by hypoxia and especially OGD.
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Brain-derived neurotrophic factor (BDNF) is abundantly expressed by both developing and adult rat visceral sensory neurons from the nodose ganglion (NG) in vivo and in vitro. We have previously shown that BDNF is released from neonatal NG neurons by activity and regulates dendritic development in their postsynaptic targets in the brainstem. The current study was carried out to examine the cellular and molecular mechanisms of activity-dependent BDNF expression in neonatal rat NG neurons, using our established in vitro model of neuronal activation by electrical field stimulation with patterns that mimic neuronal activity in vivo. ⋯ Electrical stimulation-evoked BDNF expression was inhibited by pretreating neurons with the blocker of voltage-gated sodium channels tetrodotoxin and by removing extracellular calcium. Moreover, our data show that repetitive stimulation-evoked BDNF expression requires calcium influx through N-, but not L-type, channels. Together, our study reveals novel mechanisms through which electrical activity stimulates de novo synthesis of BDNF in sensory neurons, and points to the role of N-type calcium channels in regulating BDNF expression in sensory neurons in response to repetitive stimulation.
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The possible role that response processes play in Inhibition of Return (IOR), traditionally associated with reduced or inhibited attentional processing of spatially cued target stimuli presented at cue-target intervals longer than 300ms, is still under debate. Previous psychophysiological studies on response-related Electroencephalographic (EEG) activity and IOR have found divergent results. Considering that the ability to optimize our behavior not only resides in our capacity to inhibit the focus of attention from irrelevant information but also to inhibit or reduce motor activation associated with responses to that information, it is conceivable that response processes are also affected by IOR. ⋯ In the lower visual field spatial IOR was related to a synchronization in the pre-movement mu band at bilateral precentral and central electrodes, and in the post-movement beta band at contralateral precentral and central electrodes, which may be associated with an attention-driven reduction of somatomotor processing prior to the execution of responses to relevant stimuli presented at previously cued locations followed by a post-movement deactivation of motor areas. In the upper visual field, spatial IOR was associated with a decrease in desynchronization around response execution in the beta band at contralateral postcentral electrodes that might indicate a late (last moment) reduction of motor activation when responding to spatially cued targets. The present results suggest that different response processes are affected by spatial IOR depending on the visual field where the target is presented.
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Phoenixin (PNX) is a 14-amino acid amidated peptide (PNX-14) or an N-terminal extended 20-residue amidated peptide (PNX-20) recently identified in neural and non-neural tissue. Mass spectrometry analysis identified a major peak corresponding to PNX-14, with negligible PNX-20, in mouse spinal cord extracts. Using a previously characterized antiserum that recognized both PNX-14 and PNX-20, PNX-immunoreactivity (irPNX) was detected in a population of dorsal root ganglion (DRG) cells and in cell processes densely distributed to the superficial layers of the dorsal horn; irPNX cell processes were also detected in the skin. ⋯ The number of scratching bouts varied from 16 to 95 in 30 min, commencing within 5 min post-injection and lasted 10-15 min. Pretreatment of mice at -20 min with nalfurafine (20 μg/kg, s.c.), the kappa opioid receptor agonist, significantly reduced the number of bouts induced by PNX-14 (4 mg/kg) compared with that of saline-pretreated mice. Our results suggest that the peptide, PNX-14, serves as one of the endogenous signal molecules transducing itch sensation in the mouse.
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Transient receptor potential cation channel, subfamily A, member 1 (TRPA1) is expressed in muscle afferents and direct activation of these receptors induces acute mechanical hypersensitivity. However, the functional role of TRPA1 under pathological muscle pain conditions and mechanisms by which TRPA1 mediate muscle pain and hyperalgesia are not clearly understood. Two rodent behavioral models validated to assess craniofacial muscle pain conditions were used to study ATP- and N-Methyl-D-aspartate (NMDA)-induced acute mechanical hypersensitivity and complete Freund's adjuvant (CFA)-induced persistent mechanical hypersensitivity. ⋯ Our findings showed that TRPA1 in muscle afferents plays an important role in the development of acute mechanical hypersensitivity and in the maintenance of persistent muscle pain and hypersensitivity. Our data suggested that TRPA1 may serve as a downstream target of pro-nociceptive ion channels, such as P2X3 and NMDA receptors in masseter afferents, and that increased TRPA1 expression under inflammatory conditions may contribute to the maintenance of persistent muscle pain and mechanical hyperalgesia. Mechanistic studies elucidating transcriptional or post-translational regulation of TRPA1 expression under pathological pain conditions should provide important basic information to further advance the treatment of craniofacial muscle pain conditions.