Neuroscience
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Every spring, deer cast their old antlers and initiate a regeneration process, which yields a new set of antlers of up to 1m in length. Over the course of three months, branches of the trigeminal nerve, originating from the frontal skull, innervate velvet, a modified skin that covers the regenerating antler. The rate of growth of these axons reaches up to 2cm per day making them the fastest regenerating axons in adult mammals. ⋯ Our proteomic analyses identified several axon growth promoters in the velvet-conditioned medium (VCM), including soluble proteins such as nerve growth factor (NGF) and apolipoprotein A-1, as well as matrix extracellular proteins, such as periostin and SPARC. Additional in vitro analyses allowed us to determine that a synergic relationship between periostin and NGF may contribute to neurite growth-promoting effects of velvet secretome. A combinatorial approach using these factors may promote regeneration at high speeds in patients with peripheral neuropathies.
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The interaction of early life stress (ELS) and the serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR) has been associated with increased risk to develop depression in later life. We have used the maternal separation paradigm as a model for ELS exposure in homozygous and heterozygous 5-HTT knockout rats and measured urocortin 1 (Ucn1) mRNA and/or protein levels, Ucn1 DNA methylation, as well as 5-HT innervation in the centrally projecting Edinger-Westphal (EWcp) and dorsal raphe (DR) nuclei, both implicated in the regulation of stress response. We found that ELS and 5-HTT genotype increased the number of 5-HT neurons in specific DR subdivisions, and that 5-HTT knockout rats showed decreased 5-HT innervation of EWcp-Ucn1 neurons. ⋯ In contrast, 5-HTT deficiency was associated with site-specific alterations in DNA methylation of the Ucn1 promoter, and heterozygous 5-HTT knockout rats showed decreased expression of CRF receptor 1 in the EWcp. Together, our findings extend the existing literature on the relationship between EWcp-Ucn1 and DR-5-HT neurons. These observations will further our understanding on their potential contribution to mediate affect as a function of ELS interacting with 5-HTTLPR.
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Deregulation of glutamate homeostasis is associated with degenerative neurological disorders. Glutamate dehydrogenase (GDH) is important for glutamate metabolism and plays a central role in expanding the pool of tricarboxylic acid (TCA) cycle intermediate alpha-ketoglutarate (α-KG), which improves overall bioenergetics. Under high energy demand, maintenance of ATP production results in functionally active mitochondria. ⋯ We also found that beta-lapachone increased glutamate utilization, accompanied by a reduction in extracellular glutamate. Thus, our hypothesis that mitochondrial GDH activators increase α-KG production as an alternative energy source for use in the TCA cycle under energy-depleted conditions was confirmed. Our results suggest that increasing GDH-mediated glutamate oxidation represents a new therapeutic intervention for neurodegenerative disorders, including stoke.
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Parkinson's disease (PD) is one of the progressive neurodegenerative diseases of whose condition is characterized by dopaminergic neuronal cell loss and dysfunction in the substantia nigra pars compacta (SNpc) and the striatum. Recent studies have demonstrated that the nuclear receptor-related 1 protein (Nurr1) is critical of dopaminergic phenotype induction in mesencephalic dopaminergic neurons. Further, Nurr1 engages in synthesizing and storing dopamine through regulating levels of tyrosine hydroxylase (TH), dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2). ⋯ To evaluate the effects of MABH on Nurr1 expression, we measured the protein levels of Nurr1 and its regulating factors using Western blot analysis in PC12 cells. MABH treatment induced the phosphorylation of extracellular signal-regulated kinase protein via increasing the protein expression levels of Nurr1 and ultimately the levels of TH, VMAT2, and DAT. These results indicate that MABH has protective effects on dopaminergic neurons in a mouse model of PD by regulating Nurr1.
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Recent evidence indicates the involvement of inflammatory factors and mitochondrial dysfunction in the etiology of psychiatric disorders such as anxiety and depression. To investigate the possible role of mitochondrial-induced sterile inflammation in the co-occurrence of anxiety and depression, in this study, we treated adult male mice with the intracerebroventricular (i.c.v.) infusion of a single low dose of streptozotocin (STZ, 0.2mg/mouse). Using valid and qualified behavioral tests for the assessment of depressive and anxiety-like behaviors, we showed that STZ-treated mice exhibited behaviors relevant to anxiety and depression 24h following STZ treatment. ⋯ Results of this study revealed that behavioral abnormalities provoked by STZ, as a cytotoxic agent that targets mitochondria and energy metabolism, are associated with abnormal mitochondrial activity and, consequently the initiation of innate-inflammatory responses in the hippocampus. Our findings highlight the role of mitochondria and innate immunity in the formation of sterile inflammation and behaviors relevant to anxiety and depression. Also, we have shown that STZ injection (i.c.v.) might be an animal model for depression and anxiety disorders based on sterile inflammation.