Neuroscience
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Experience-dependent synaptic plasticity is an important component of both learning and motivational disturbances found in addicted individuals. Here, we investigated the role of cocaine experience-dependent plasticity at excitatory synapses in the nucleus accumbens shell (NAcSh) in relapse-related behavior in mice with a history of volitional cocaine self-administration. ⋯ Furthermore, we show that these effects are due to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-specific mechanisms that differ depending on the nature and context of the reinstatement-inducing stimuli. Together, our findings identify common themes as well as differential mechanisms that are likely important for the ability of diverse environmental stimuli to drive relapse to addictive-like cocaine-seeking behavior.
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Besides physical insult, spinal cord injury (SCI) can also result from transient ischemia, such as ischemia-reperfusion SCI (I/R SCI) as a postoperative complication. Increasing evidence has suggested that oxidative stress and related reactive aldehyde species are key contributors to cellular injury after SCI. Previous work in spinal cord contusion injury has demonstrated that acrolein, both a key product and an instigator of oxidative stress, contributes to post-traumatic hyperalgesia. ⋯ Taken together, these results support the causal role of acrolein in inducing hyperalgesia after I/R SCI via activation and upregulation of TRPA1 channels. Furthermore, endogenously produced acrolein resulting from metabolic abnormality in the absence of mechanical insults appears to be capable of heightening pain sensitivity after SCI. Our data also further supports the notion of acrolein scavenging as an effective analgesic as well neuroprotective strategy in conditions where oxidative stress and aldehyde toxicity is implicated.
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A disintegrin and metalloprotease protein 23 (ADAM23) is a transmembrane type I glycoprotein involved with the development and maintenance of the nervous system, including neurite outgrowth, neuronal adhesion and differentiation and regulation of synaptic transmission. In addition, ADAM23 seems to participate in immune response and tumor establishment through interaction with different members of integrin receptors. Here, we describe a novel monoclonal antibody (DL11C8) that specifically recognizes the cysteine-rich domain of both pre-protein (100 kDa) and mature (70 kDa) forms of ADAM23 from different species, including human, rodents and avian orthologs. ⋯ Indeed, the mature ADAM2370 kDa partitions between raft and non-raft membrane domains, while the pro-protein ADAM23100 kDa is mainly expressed in non-raft domains. These membranous distributions were observed in both different brain regions homogenates and primary cultured neurons lysates from mouse cortex and cerebellum. Taken together, these findings point out ADAM23 as a lipid raft molecular component.
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Several conditions related to the intrauterine environment are associated with neuropsychiatric conditions in later life. In humans, approximately 2% of infants are exposed to perinatal hypoxia-ischemia or prolonged anoxic insult, a condition to which very low birth weight preterm infants exhibit the highest susceptibility. Analyses of postmortem tissue link some presentations of these conditions to changes in GABA pathway functionality in the brains of affected subjects. ⋯ Finally, changes in guidance molecules in the developing cortex, including increases in hypoxia-inducible factor 1-alpha levels and intracellular distribution, decreases in reelin levels in the cortical plate and altered organization of radial glia, were observed. These changes in the molecular landscape of the immediate environment of the immature neurons may contribute to the observed outcomes in neuronal migration to, and establishment in, the correct cortical layers. We suggest that the interneuron loss may be related to these early events.
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Previous studies have shown that chronic stress and chronic stress hormone treatment induce oxidative damage in rodents. Thioredoxin (Trx) is a small redox protein that plays an important role in regulation of oxidative protein cysteine modification. A Trx reduced state is maintained by thioredoxin reductase (TrxR), and the thioredoxin-interacting protein (Txnip) is an endogenous inhibitor of Trx. ⋯ Using immunocytochemistry we also found that chronic corticosterone treatment increased Txnip in both nucleus and cytosol, while glucocorticoid receptor inhibitor RU486 can block corticosterone-increased Txnip protein levels. Using biotin switch, dimedone conjugation and CRISPR/Cas9 methods we found that chronic corticosterone treatment increased protein nitrosylation and sulfenylation, while knocking out Txnip blocked corticosterone-induced protein nitrosylation and sulfenylation. Since Trx can reduce cysteine oxidative protein modification such as nitrosylation and sulfenylation, our findings suggest that chronic corticosterone treatment may upregulate Txnip by targeting glucocorticoid receptor, subsequently inhibiting Trx activity and enhancing oxidative protein cysteine modification, which contributes to corticosterone-caused oxidative damage.