Neurobiology of disease
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Neurobiology of disease · Jan 2015
Characterisation of immune cell function in fragment and full-length Huntington's disease mouse models.
Inflammation is a growing area of research in neurodegeneration. In Huntington's disease (HD), a fatal inherited neurodegenerative disease caused by a CAG-repeat expansion in the gene encoding huntingtin, patients have increased plasma levels of inflammatory cytokines and circulating monocytes that are hyper-responsive to immune stimuli. Several mouse models of HD also show elevated plasma levels of inflammatory cytokines. ⋯ However, bone marrow CD11b(+) cells did not show the same hyper-responsive phenotype as spleen and blood cells. Furthermore, macrophages isolated from R6/2 mice show increased levels of phagocytosis, similar to findings in HD patients. Taken together, these results show significant promise for these mouse models to be used to study targeting innate immune pathways identified in human cells, thereby helping to understand the role the peripheral immune system plays in HD progression.
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Neurobiology of disease · Jan 2015
Role of CSPG receptor LAR phosphatase in restricting axon regeneration after CNS injury.
Extracellular matrix molecule chondroitin sulfate proteoglycans (CSPGs) are highly upregulated in scar tissues and form a potent chemical barrier for CNS axon regeneration. Recent studies support that the receptor protein tyrosine phosphatase σ (PTPσ) and its subfamily member leukocyte common antigen related phosphatase (LAR) act as transmembrane receptors to mediate CSPG inhibition. PTPσ deficiency increased regrowth of ascending axons into scar tissues and descending corticospinal tract (CST) axons into the caudal spinal cord after spinal cord injury (SCI). ⋯ LAR protein was upregulated days to weeks after injury and co-localized to serotonergic and CST axons. Moreover, LAR deletion improved functional recovery by increasing BMS locomotor scores and stride length and reducing grid walk errors. This is the first transgenic study that demonstrates the crucial role of LAR in restricting regrowth of injured CNS axons.
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Neurobiology of disease · Jan 2015
Diet, age, and prior injury status differentially alter behavioral outcomes following concussion in rats.
Mild traumatic brain injury (mTBI) or concussion affects a large portion of the population and although many of these individuals recover completely, a small subset of people experience lingering symptomology and poor outcomes. Little is known about the factors that affect individual susceptibility or resilience to poor outcomes after mTBI and there are currently no biomarkers to delineate mTBI diagnosis or prognosis. Based upon the growing literature associated with caloric intake and altered neurological aging and the ambiguous link between repetitive mTBI and progressive neurodegeneration, the current study was designed to examine the effect of a high fat diet (HFD), developmental age, and repetitive mTBI on behavioral outcomes following a mTBI. ⋯ Exposure to the high fat diet exacerbated many of the behavioral deficits associated with concussion. Finally, telomere length was shortened following mTBI and was influenced by the animal's dietary intake. Diet, age at the time of injury, and the number of prior concussion incidents differentially contribute to behavioral deficits and may help explain individual variations in susceptibility and resilience to poor outcomes following an mTBI.
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Neurobiology of disease · Jan 2015
Dynamic cortical gray matter volume changes after botulinum toxin in cervical dystonia.
Previous electrophysiological and functional imaging studies in focal dystonia have reported on cerebral reorganization after botulinum toxin (BoNT) injections. With the exception of microstructural changes, alterations in gray matter volume after BoNT have not been explored. In this study, we sought to determine whether BoNT influences gray matter volume in a group of cervical dystonia (CD) patients. ⋯ We have identified structural, yet dynamic gray matter volume changes in CD. There were specific gray matter volume changes related to BoNT injections, illustrating indirect central consequences of modified peripheral sensory input. As differences were exclusively seen in higher order motor areas relevant to motor planning and spatial cognition, these observations support the hypothesis that deficits in these cognitive processes are crucial in the pathophysiology of CD.
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Neurobiology of disease · Jan 2015
BDNF contributes to the development of neuropathic pain by induction of spinal long-term potentiation via SHP2 associated GluN2B-containing NMDA receptors activation in rats with spinal nerve ligation.
The pathogenic mechanisms underlying neuropathic pain still remain largely unknown. In this study, we investigated whether spinal BDNF contributes to dorsal horn LTP induction and neuropathic pain development by activation of GluN2B-NMDA receptors via Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) phosphorylation in rats following spinal nerve ligation (SNL). We first demonstrated that spinal BDNF participates in the development of long-lasting hyperexcitability of dorsal horn WDR neurons (i.e. central sensitization) as well as pain allodynia in both intact and SNL rats. ⋯ Finally, we validated that BDNF-evoked SHP2 phosphorylation is required for subsequent GluN2B-NMDA receptors up-regulation and spinal LTP induction, and also for pain allodynia development. Blockade of SHP2 phosphorylation in the spinal dorsal horn using a potent SHP2 protein tyrosine phosphatase inhibitor NSC-87877, or knockdown of spinal SHP2 by intrathecal delivery of SHP2 siRNA, not only prevents BDNF-mediated GluN2B-NMDA receptors activation as well as spinal LTP induction and pain allodynia elicitation in intact rats, but also reduces the SNL-evoked GluN2B-NMDA receptors up-regulation and spinal LTP occlusion, and ultimately alleviates pain allodynia in neuropathic rats. Taken together, these results suggest that the BDNF/SHP2/GluN2B-NMDA signaling cascade plays a vital role in the development of central sensitization and neuropathic pain after peripheral nerve injury.