Neuroscience
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Glycogen synthase kinase 3β (GSK3β) is known to control neuroinflammation, however the status of GSK3β in multiple sclerosis, the most common inflammatory demyelinating disease of the CNS, and its animal model EAE, is unknown. In this study, we investigated the expression of phosphorylated GSK3β, the inactive form of GSK3β, in the spinal cords of EAE mice. We demonstrate that while the expression of phosphorylated GSK3β was present in radial astrocytes and neurons of the control mice that received only complete Freund's adjuvant, it was absent in radial astrocytes and significantly lower in neurons of EAE animals. ⋯ This disturbance in the expression of inactive GSK3β was recovered in neurons, but not in the radial glia, after treatment of EAE mice with adipose-derived mesenchymal stem cells capable of inducing a Th2 shift. Collectively, our results suggest a link between inactive GSK3β and modulation of the immune responses during EAE. Thus, we propose that maintenance of GSK3β in its inactive status may play a role in preserving the normal physiology of the spinal cord and amelioration of EAE following stem cell therapy.
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Synaptic alterations in the nucleus accumbens (NAc) are crucial for the aberrant reward-associated learning that forms the foundation of drug dependence. Altered glutamatergic synaptic plasticity, in particular, is thought to be a vital component of the neurobiological underpinnings of addictive behavior. The development of bacterial artificial chromosome-eGFP (enhanced green fluorescent protein) transgenic mice that express eGFP driven by endogenous D1 dopamine receptor (D1R) promoters has now allowed investigation of the cell type-specific synaptic modifications in the NAc in response to drugs of abuse. ⋯ Complete recovery of the baseline plasticity phenotype in both cell types required a full 2 weeks of withdrawal from CIE vapor exposure. Thus, we observed a cell type specificity of synaptic plasticity in the NAc shell, as well as, a gradual recovery of the pre-ethanol exposure plasticity state following extended withdrawal. These changes highlight the adaptability of NAc shell MSNs to the effects of ethanol exposure and may represent critical neuroadaptations underlying the development of ethanol dependence.
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Spiral ganglion neurons (SGNs), the target cells of the cochlear implant, undergo gradual degeneration following loss of the sensory epithelium in deafness. The preservation of a viable population of SGNs in deafness can be achieved in animal models with exogenous application of neurotrophins such as brain-derived neurotrophic factor (BDNF) and neurotrophin-3. For translation into clinical application, a suitable delivery strategy that provides ongoing neurotrophic support and promotes long-term SGN survival is required. ⋯ We found that fibroblasts that were nucleofected to express BDNF provided the most sustained neurotrophin expression, with ongoing BDNF expression for at least 30 weeks. In addition, the secreted neurotrophin was biologically active and elicited survival effects on SGNs in vitro. Nucleofected fibroblasts may therefore represent a method for safe, long-term delivery of neurotrophins to the deafened cochlea to support SGN survival in deafness.
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In a previous study, we have shown that the small organic compound tegaserod, a drug approved for clinical application in an unrelated condition, is a mimic of the regeneration-beneficial glycan polysialic acid (PSA) in a mouse model of femoral nerve injury. Several independent observations have shown positive effects of PSA and its mimetic peptides in different paradigms of injury of the central and peripheral mammalian nervous systems. Since small organic compounds generally have advantages over metabolically rapidly degraded glycans and the proteolytically vulnerable mimetic peptides, a screen for a small PSA mimetic compound was successfully carried out, and the identified molecule proved to be beneficial in neurite outgrowth in vitro, independent of its originally described function as a 5-HT4 receptor agonist. ⋯ Immunohistology of the spinal cord rostral and caudal to the lesion site showed increased numbers of neurons, and a reduced area and intensity of glial fibrillary acidic protein immunoreactivity. Quantification of regrowth/sprouting of axons immunoreactive for tyrosine hydroxylase and serotonin showed increased axonal density rostral and caudal to the injury site in the ventral horns of mice treated with tegaserod. The combined observations suggest that tegaserod has the potential for treatment of spinal cord injuries in higher vertebrates.
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Fat, ethanol, and nicotine share a number of properties, including their ability to reinforce behavior and produce overconsumption. To test whether these substances act similarly on the same neuronal populations in specific brain areas mediating these behaviors, we administered the substances short-term, using the same methods and within the same experiment, and measured their effects, in areas of the hypothalamus (HYPO), amygdala (AMYG), and nucleus accumbens (NAc), on mRNA levels of the opioid peptide, enkephalin (ENK), using in situ hybridization and on c-Fos immunoreactivity (ir) to indicate neuronal activity, using immunofluorescence histochemistry. In addition, we examined for comparison another reinforcing substance, sucrose, and also took measurements of stress-related behaviors and circulating corticosterone (CORT) and triglycerides (TG), to determine if they contribute to these substances' behavioral and physiological effects. ⋯ Fat, ethanol, and nicotine, but not sucrose, increased the single- and double-labeling of ENK and c-Fos-ir in precisely the same brain areas, the middle parvocellular but not lateral area of the paraventricular nucleus, central but not basolateral nucleus of the AMYG, and core but not shell of the NAc. While having little effect on stress-related behaviors or CORT levels, fat, ethanol, and nicotine all increased circulating levels of TG. These findings suggest that the overconsumption of these three substances and their potential for abuse are mediated by the same populations of ENK-expressing neurons in specific nuclei of the hypothalamus and limbic system.