Neuroscience
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Mutation of TAR DNA-binding protein-43 (TDP-43) is detected in familial and sporadic amyotrophic lateral sclerosis (FALS and SALS). TDP-43-positive cytoplasmic inclusions are present in both neuron and glia of ALS, although not in mutant Cu/Zn-superoxide dismutase (mSOD1)-related or RNA binding protein Fused in sarcoma (FUS)-related ALS. Previous studies have established that cortical hyper-excitability is common to both FALS and SALS patients. ⋯ Other studies suggest that Nav channel activity can be increased directly by different oxidative species and, we have shown previously that oxidative stress and mitochondrial dysfunction occurs simultaneously in the cellular model of mutant TDP-43 and can be ameliorated by dimethoxy curcumin (DMC), a safe and effective antioxidant. In the present study we found that the abnormities of APs and Nav channels were significantly ameliorated when treated with DMC (15μM) for 24h, suggesting a dropping-excitability state. Taken together, mutant Q331K TDP-43 induces high excitability in a motoneuron-like cellular model, and this abnormal state is rescued by DMC which may act through alleviation of oxidative stress and mitochondrial dysfunction.
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The endogenous neuroactive steroid allopregnanolone (ALLO) has previously been shown to induce reinstatement of ethanol seeking in rodents. ALLO is a positive allosteric modulator at both synaptic and extrasynaptic GABAA receptors. The contribution of each class of GABAA receptors in mediating reinstatement of ethanol seeking is unknown. ⋯ The results of this study suggest that direct activation of extrasynaptic GABAA receptors at the GABA site is not sufficient to induce ethanol seeking in the reinstatement procedure. Future studies are necessary to elucidate the mechanisms and brain areas by which differences in the pharmacological activity of GAN and THIP at the GABAA receptor contribute to the dissimilarity in their effect on the reinstatement of ethanol seeking. Nonetheless, based on the increased use of these drugs in clinical trials across multiple disease states, the effects of GAN or THIP on alcohol seeking may be an important consideration if these drugs are to be used clinically in a population with a co-occurring alcohol use disorder.
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Sex and reproductive status affect hippocampal neurogenesis and dentate gyrus (DG) size in rodents. Relatively few studies, however, address these two effects simultaneously and even fewer studies address this issue in wild populations. Here, we examined seasonal and sex differences in neurogenesis and DG size in a wild, polygynous and social rodent, Richardson's ground squirrel (Uriocitellus richardsonii). ⋯ Using unbiased stereology and doublecortin (DCX) immunohistochemistry, we found that brain volume, DG size and number of DCX cells varied significantly between breeding and non-breeding seasons, but only brain volume and the number of DCX labeled cells differed between the sexes. Both sex and seasonal differences likely reflect circulating hormone levels, but the extent to which these differences relate to space use in this species is unclear. Based on the degree of seasonal differences in neurogenesis and the DG, we suggest that ground squirrels could be considered model species in which to examine hippocampal plasticity in an ecologically valid context.
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Successful regeneration after injury requires either the direct reformation of the circuit or the formation of a bridge circuit to provide partial functional return through a more indirect route. Presently, little is known about the specificity of how regenerating axons reconnect or reconstruct functional circuits. We have established an in vivo Dorsal root entry zone (DREZ) model, which in the presence of Nerve Growth Factor (NGF), shows very robust regeneration of peptidergic nociceptive axons, but not other sensory axons. ⋯ NGF-induced sprouting of calcitonin gene-related peptide (CGRP) axons resulted in a significant redistribution of synapses and cFos expression into the deeper dorsal horn. Regeneration of only the CGRP axons showed a general reduction in synapses and cFos expression within laminae I and II; however, inflammation of the hindpaw induced peripheral sensitization. These data show that although NGF-induced sprouting of peptidergic axons induces robust chronic pain and cFos expression throughout the entire dorsal horn, regeneration of the same axons resulted in normal protective pain with a synaptic and cFos distribution similar, albeit significantly less than that shown by the sprouting of CGRP axons.
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Light has profound effects on mood, as exemplified by seasonal affective disorder (SAD) and the beneficial effects of bright light therapy. However, the underlying neural pathways through which light regulates mood are not well understood. Our previous work has developed the diurnal grass rat, Arvicanthis niloticus, as an animal model of SAD (Leach et al., 2013a,b). ⋯ Results revealed a reduction in the number of OXA-ir neurons in the hypothalamus and attenuated OXA-ir fiber density in the dorsal raphe nucleus of animals in the DLD compared to those in the BLD group. Then, the animals in BLD were treated systemically with SB-334867, a selective orexin 1 receptor (OX1R) antagonist, which led to a depressive phenotype characterized by increased immobility in the FST and a decrease in SSP compared to vehicle-treated controls. Results suggest that attenuated orexinergic signaling is associated with increased depression-like behaviors in grass rats, and support the hypothesis that the orexinergic system mediates the effects of light on mood.