The Journal of neuroscience : the official journal of the Society for Neuroscience
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There is compelling evidence that oligodendrocyte apoptosis, in response to CNS inflammation, contributes significantly to the development of the demyelinating disorder multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). Therefore, approaches designed to protect oligodendrocytes would likely have therapeutic value. Activation of pancreatic endoplasmic reticulum kinase (PERK) signaling in response to endoplasmic reticulum (ER) stress increases cell survival under various cytotoxic conditions. ⋯ Importantly, we found that enhanced activation of PERK signaling specifically in oligodendrocytes significantly attenuated EAE disease severity, which was associated with reduced oligodendrocyte apoptosis, demyelination, and axonal degeneration. This effect was not the result of an altered degree of the inflammatory response in EAE mice. Our results provide direct evidence that activation of PERK signaling in oligodendrocytes is cytoprotective, protecting mice against EAE.
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Intrathecal application of morphine is among the most powerful methods used to treat severe chronic pain. However, this approach commonly produces itch sufficiently severe that patients are forced to choose between relief of pain or itch. The neuronal populations responsible for processing and transmitting information underlying itch caused by intrathecal application of morphine have not been identified and characterized. ⋯ In addition, intrathecal application of morphine increased responses to pruritogens injected into the skin and greatly heightened responses to innocuous mechanical stimuli. In contrast, the ongoing activity and responses to noxious pinches in nociceptive VTT neurons were frequently inhibited by the same dose of morphine. These results reveal that i.t. application of morphine affects specific subpopulations of VTT neurons in ways that may produce itch, hyperknesis, alloknesis, and analgesia.
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Visceral afferents expressing transient receptor potential (TRP) channels TRPV1 and TRPA1 are thought to be required for neurogenic inflammation and development of inflammatory hyperalgesia. Using a mouse model of chronic pancreatitis (CP) produced by repeated episodes (twice weekly) of caerulein-induced AP (AP), we studied the involvement of these TRP channels in pancreatic inflammation and pain-related behaviors. Antagonists of the two TRP channels were administered at different times to block the neurogenic component of AP. ⋯ Continued treatment with TRP antagonists blocked the development of CP and pain behaviors even when mice were challenged with seven more weeks of twice weekly caerulein. When started after week 3, however, treatment with TRP antagonists was ineffective in blocking the transition from AP to CP and the emergence of pain behaviors. These results suggest: (1) an important role for neurogenic inflammation in pancreatitis and pain-related behaviors, (2) that there is a transition from AP to CP, after which TRP channel antagonism is ineffective, and thus (3) that early intervention with TRP channel antagonists may attenuate the transition to and development of CP effectively.
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Traumatic brain injury (TBI) modulates several cell signaling pathways in the hippocampus critical for memory formation. Previous studies have found that the cAMP-protein kinase A signaling pathway is downregulated after TBI and that treatment with a phosphodiesterase (PDE) 4 inhibitor rolipram rescues the decrease in cAMP. In the present study, we examined the effect of rolipram on TBI-induced cognitive impairments. ⋯ This deficit in CREB activation during learning was rescued in TBI animals treated with rolipram. Hippocampal long-term potentiation was reduced in TBI animals, and this was also rescued with rolipram treatment. These results indicate that the PDE4 inhibitor rolipram rescues cognitive impairments after TBI, and this may be mediated through increased CREB activation during learning.
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The motor system is capable of adapting to changed conditions such as amputations or lesions by reorganizing cortical representations of peripheral musculature. To investigate the underlying mechanisms we induced targeted reorganization of motor output effects by establishing an artificial recurrent connection between a forelimb muscle and an unrelated site in the primary motor cortex (M1) of macaques. A head-fixed computer transformed forelimb electromyographic activity into proportional subthreshold intracortical microstimulation (ICMS) during hours of unrestrained volitional behavior. ⋯ The ease of changing the relationship between cortical sites and associated muscle responses suggests that under normal conditions these relations are maintained through physiological feedback loops. These findings demonstrate that motor cortex outputs may be reorganized in a targeted and sustainable manner through artificial afferent feedback triggered from controllable and readily recorded muscle activity. Such cortical reorganization has implications for therapeutic treatment of neurological injuries.