Neuroscience
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Inflammation plays a key role in the progression and maintenance of chronic pain, which impacts the lives of millions of Americans. Despite growing evidence that chronic pain can be improved by treating underlying inflammation, successful treatments are lacking and pharmaceutical interventions are limited due to drug side effects. Here we are testing whether a 'healthy human' diet (HHD), with or without anti-inflammatory components (HHAID), improves pain-like behaviors in a preclinical model of chronic widespread hypersensitivity induced by neonatal maternal separation (NMS). ⋯ In female mice, HHAID specifically increased measures of metabolic syndrome and inflammation compared to the HHD and control diet groups. Male mice were susceptible to worsening metabolic measures on both the HHAID and HHD. This work highlights important sexual dimorphic outcomes related to early life stress exposure and dietary interventions, as well as a potential disconnect between improvements in pain-like behaviors and metabolic measures.
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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease preferentially affecting motoneurones. Transgenic mouse models have been used to investigate the role of abnormal motoneurone excitability in this disease. Whilst an increased excitability has repeatedly been demonstrated in vitro in neonatal and embryonic preparations from SOD1 mouse models, the results from the only studies to record in vivo from spinal motoneurones in adult SOD1 models have produced conflicting findings. ⋯ No reductions in repetitive firing were observed showing that this is not a common feature across all ALS models. Immunohistochemistry for the Na+ channel Nav1.6 showed that motoneurone AISs increase in length in G127X SOD1 mice at symptom onset. Consistent with this, the rate of rise of AIS components of antidromic action potentials were significantly faster confirming that this increase in length represents an increase in AIS Na+ channels occurring at symptom onset in this model.
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Sensory disturbance in the orofacial region owing to trigeminal nerve injury is caused by dental treatment or accident. Commercially available therapeutics are ineffective for the treatment of sensory disturbance. Additionally, the therapeutic effects of rapamycin, an allosteric inhibitor of mammalian target of rapamycin (mTOR), which negatively regulates autophagy, on the sensory disturbance are not fully investigated. ⋯ Rapamycin administration facilitated axon regeneration after IANX and increased the number of brain-derived neurotrophic factor positive neurons in the trigeminal ganglion. Thus, recovery from sensory disturbance in the lower lip caused by IANX was markedly facilitated by rapamycin. These findings suggest that rapamycin administration is a promising treatment for the sensory disturbance caused by IANX.
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Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is a crucial regulator of neuronal development, neuronal survival, axonal regeneration, and synaptic plasticity. In this study we examined the potential role of PTEN in cognitive function in a mouse model of perioperative neurocognitive disorder (PND). Adult male C57BL/6J mice received intracerebroventricular injections of small interfering RNA (siRNA) against PTEN or control siRNA 3 days prior to exploratory laparotomy (n = 8 per group). ⋯ Surgically treated mice had increased expression of PTEN, AMPK, Bax, IL-1β, and TNF-α, as well as increasing number of activated microglia and apoptosis neurons in the hippocampus. PTEN knockdown significantly attenuated the behavioral deficits in Barnes maze and fear conditioning tests, as well as over-expression of PTEN, AMPK, Bax, IL-1β, and TNF-α induced by surgery. PTEN knockdown could attenuate cognitive deficits induced by trauma, likely through inhibiting the activation of microglia.
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Synucleinopathy disorders are characterized by aggregates of α-synuclein (α-syn), which engage microglia to elicit a neuroinflammatory response. Here, we determined the gene expression and DNA methylation changes in microglia induced by aggregate α-syn. Transgenic murine Thy-1 promoter (mThy1)-Asyn mice overexpressing human α-syn are a model of synucleinopathy. ⋯ Network analysis also showed increased cell mobility and inflammatory functions at 3 months, shifting to cell cycle, immune response, and metabolism changes at 13 months. We observed significant α-syn-induced methylation and gene expression changes in microglia. Our data suggest that α-syn overexpression initiates microglial activation leading to neuroinflammation and cellular metabolic stresses, which is associated with disease progression.