Neuroscience
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Transient receptor potential melastatin 8 (TRPM8) is a nonselective cation channel that primarily detects the innocuous cold. In pathological conditions, TRPM8 plays a role in the development of cold hyperalgesia/allodynia. Nerve growth factor (NGF) is an important mediator involved in various pain disorders. ⋯ It was inferred that LAMP-2 was involved in the vesicular transport of TRPM8. Pharmacological blockade of the proteasome with MG132 led to a further increase in NGF-induced TRPM8 expression, indicating that the proteasome system played a pivotal role in the degradation of TRPM8. Our findings provide novel insight into the signaling pathways involved in NGF-mediated TRPM8 upregulation and its reversion to the normal state.
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Pseudorabies virus (PRV), a neurovirulent α-herpesvirus, spreads between neurons at synaptic connections. PRV-infected neurons have been shown to exhibit functional deficits with the attenuated PRV152 Bartha strain negatively influencing neuronal functioning in in vitro model systems. However, the impact of this attenuated PRV152 Bartha strain on the native central nervous system has not been fully explored. ⋯ The minor changes in the approximated passive membrane parameters induced by the infection cannot explain the full loss in excitability, indicating that channel densities and properties have changed. This impact on neuronal functioning might contribute to the lethal neurovirulent effects of PRV viruses as vital neuronal circuits might cease activity. Since the detrimental effects of the attenuated PRV152 Bartha strain are reduced compared to wild-type strains, it comprises an excellent tool to study the neuropathological mechanisms of viral infections.
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Hypertension is a major risk factor for stroke, which is one of the leading global causes of death. In the search for new and effective therapeutic targets in stroke research, we need to understand the influence of hypertension in the vasculature following stroke. We used Affymetrix whole-transcriptome expression profiling as a tool to address gene expression differences between the occluded and non-occluded middle cerebral arteries (MCAs) from spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto (WKY) rats after transient middle cerebral artery occlusion (tMCAO), to provide clues about the pathological mechanisms set in play after stroke. ⋯ Thus these data suggest that Ccl2, Edn1, Tgfβ2, Olr1 and Serpine1 may be possible mediators of the vascular changes in the occluded MCAs from both SHRs and WKY rats after tMCAO. The aforementioned genes possess biological functions that are consistent with early stroke injuries. In conclusion, these genes may be potential targets in future strategies for acute stroke treatments that can be used in patients with and without hypertension.
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Although recent studies have reported that gamma-aminobutyric acid (GABA) neurons in the parafacial zone (PZ) of the rostral medulla are needed for the induction of slow-wave sleep (SWS) and that the PZ is a medullary SWS-promoting center, it remains unknown whether the PZ contains SWS-active or sleep-promoting neurons. In the present study, a total of 125 neurons were recorded, for the first time, in non-anesthetized, head-restrained mice during the complete wake-sleep cycle throughout the PZ of the rostral medulla. The vast majority (87.2%) of the neurons displayed increased activity during both wakefulness (W) and paradoxical (or rapid eye movement) sleep (PS) compared to during SWS (W/PS-active neurons) and a few (8.0%) discharged phasically and selectively during PS (PS-active neurons), but none discharged maximally during SWS (SWS-active neurons) or displayed a higher rate of spontaneous discharge during both SWS and PS than during W (SWS/PS-active neurons). These findings do not support the view that the GABAergic PZ is a medullary SWS-promoting center.
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In brainstem motor networks, hypoglossal motoneurons (HMs) play the physiological role of driving tongue contraction, an activity critical for inspiration, phonation, chewing and swallowing. HMs are an early target of neurodegenerative diseases like amyotrophic lateral sclerosis that, in its bulbar form, is manifested with initial dysphagia and dysarthria. One important pathogenetic component of this disease is the high level of extracellular glutamate due to uptake block that generates excitotoxicity. ⋯ Two hours later, propofol prevented the rise in reactive oxygen species (ROS) and, at 4 hours, it inhibited intracellular release of apoptosis-inducing factor (AIF) and prevented concomitant cell loss. Midazolam did not contrast ROS and AIF release. The present work provides experimental evidence for the neuroprotective action of a general anesthetic like propofol, which, in this case, may be achieved through a combination of boosted GABAergic inhibition and reduced ROS production.