Neuroscience
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Low back pain is a common cause of chronic pain and disability. It is modeled in rodents by chronically compressing the lumbar dorsal root ganglia (DRG) with small metal rods, resulting in ipsilateral mechanical and cold hypersensitivity, and hyperexcitability of sensory neurons. Sodium channels are implicated in this hyperexcitability, but the responsible isoforms are unknown. ⋯ The cytokine profiles induced by DRG compression and DRG inflammation were also very similar, with upregulation of several type 1 pro-inflammatory cytokines and downregulation of type 2 anti-inflammatory cytokines. Surprisingly, the cytokine profile was largely unaffected by NaVβ4 knockdown in either model. The NaV1.6 channel, and the NaVβ4 subunit that can regulate NaV1.6 to enhance repetitive firing, play key roles in both models of low back pain; targeting the abnormal spontaneous activity they generate may have therapeutic value.
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Here we report that the low-voltage-dependent T-type calcium (Ca2+) channel Cav3.2, encoded by the CACNA1H gene, regulates neuronal differentiation during early embryonic brain development through activating caspase-3. At the onset of neuronal differentiation, neural progenitor cells exhibited spontaneous Ca2+ activity. This activity strongly correlated with the upregulation of CACNA1H mRNA. ⋯ In contrast, when CACNA1H was overexpressed, increased neurogenesis was detected. Cortical slices from Cacna1h knockout mice showed decreased spontaneous Ca2+ activity, a significantly lower protein level of cleaved caspase-3, and microanatomical abnormalities in the subventricular/ventricular and cortical plate zones when compared to their respective embryonic controls. In summary, we demonstrate a novel relationship between Cav3.2 and caspase-3 signaling that affects neurogenesis in the developing brain.
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Abnormalities of the autophagy-lysosomal pathway (ALP) have been implicated in the pathology of Alzheimer's disease (AD). Activation of TFEB (transcription factor EB), a master regulator of the ALP, leads to ALP facilitation. The present study sought to clarify whether TFEB-mediated ALP facilitation influences the process of amyloid β-protein (Aβ) generation in neurons. ⋯ Inhibition of proteasomes, but not lysosomes, markedly increased β-CTF levels in β-CTF-expressing neurons. These results collectively indicate that TFEB modulates Aβ production not only by increasing α-secretase processing of APP through ADAM10 upregulation but also by augmenting β-CTF levels possibly via altered proteasome-mediated catabolism. Thus, TFEB-mediated ALP enhancement appears to have dual, but opposite, effects on Aβ production in neurons.
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The facial nerve is necessary for our ability to eat, speak, and make facial expressions. Both the axons and cell bodies of the facial nerve undergo a complex embryonic developmental pattern involving migration of the cell bodies caudally and tangentially through rhombomeres, and simultaneously the axons projecting to exit the hindbrain to form the facial nerve. Our goal in this study was to test the functions of the chemorepulsive receptors Robo1 and Robo2 in facial neuron migration and axon projection by analyzing genetically marked motor neurons in double-mutant mouse embryos through the migration time course, E10.0-E13.5. ⋯ Surprisingly, some facial neurons had multiple axons exiting and projecting into the floor plate. At the same time, a subset of mutant facial cell bodies failed to migrate caudally, and instead either streamed dorsally toward the exit point or shifted into the floor plate. We conclude that Robo1 and Robo2 have redundant functions to guide multiple aspects of the complex cell migration of the facial nucleus, as well as regulating axon trajectories and suppressing formation of ectopic axons.
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The growth of many cities has generated an increase in the emission of environmental pollutants. Exposure to these pollutants has been associated with increased mortality worldwide. These pollutants, such as ozone, produce reactive oxygen species (ROS), which cause oxidative stress throughout the body. ⋯ Rats were exposed to ozone or to ozone-free air for a period of 15, 30, 60, or 90 days. The principal results indicate that chronic oxidative stress induced by ozone produces a decrease in the density of dendritic spines, a decrease in thin and mushroom spine ratios, and an increase in stubby spine ratio, as well as a deficit in learning and memory of the object-place recognition task. These results indicate that chronic ozone exposure produces a loss in the inputs of CA1 neurons of the dorsal hippocampus, which may be the source of the cognitive deficits observed in the object-place recognition task, as indicated by the decrease in density of dendritic spines; these alterations are similar to those reported in some neurodegenerative diseases such as Alzheimer's disease.