Neuroscience
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The major outward chloride transporter in neurons is the potassium chloride co-transporter 2 (KCC2), critical for maintaining an inhibitory reversal potential for GABA(A) receptor channels. In a recent study, we showed that Zn(2+) regulates GABA(A) reversal potentials in the hippocampus by enhancing the activity of KCC2 through an increase in its surface expression. Zn(2+) initiates this process by activating the Gq-coupled metabotropic Zn(2+) receptor/G protein-linked receptor 39 (mZnR/GPR39). ⋯ Non-transfected cells, or cells transfected with marker vector alone, showed a Zn(2+)-dependent increase in KCC2 activity. In contrast, KCC2 activity in neurons expressing Botox C1 was unchanged by Zn(2+). These results suggest that SNARE proteins are necessary for the increased activity of KCC2 after Zn(2+) stimulation of mZnR/GPR39.
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Cocaine addiction is characterized by compulsive drug seeking, including relapse after a period of withdrawal. The relapse response requires increased glutamate transmission in the nucleus accumbens (NAc). Consistent with this view, glutamate type 1 transporter (GLT1), the transporter responsible for >90% of glutamate uptake, is downregulated in NAc after several days of withdrawal in rats previously trained to self-administer cocaine under limited access conditions (1-2 h/d). ⋯ We found that although cocaine withdrawal decreases GLT1 expression in both core and shell, only in core is GLT1 downregulation sensitive to both access and withdrawal. In fact, after long withdrawal, GLT1 in core is downregulated more than in shell in either the limited or extended access condition. Thus, glutamate regulation in core appears to be a critical factor in the drug-seeking behavior that follows relatively long periods of cocaine withdrawal.
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γ-Secretase is an important contributing enzyme in Alzheimer's disease and is therefore an important therapeutic target. However, the impact of γ-secretase inhibition is not well studied in acute neuroinflammation induced by systemic infection. In this study the influence of γ-secretase on the expression of some proinflammatory markers was assessed in the acute phase as well as the subsiding phase of neuroinflammation. ⋯ Our results demonstrate that both local and systemic modulation of γ-secretase hyper-activity with DAPT increase the duration of TNF-α, COX-II, and NFκB induction. We consistently found mild augmented apoptosis in animals treated with DAPT as determined by measuring cleaved caspase-3 expression and by TUNEL assay 72 h following LPS injection. These results suggest that γ-secretase modulation interferes with certain immune regulatory pathways which may restrict some inflammatory transcription factors such as NFκB.
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Data from our laboratory indicate that the orexin system is involved in the regulation of both conditioned and unconditioned responding for palatable foods. Anticipation of food rewards activates orexin receptor containing neurons within the paraventricular nucleus of the thalamus (PVT). The PVT regulates mesolimbic dopamine neurochemistry through direct connections with the nucleus accumbens and modulates the processing of cognitive-emotional information, suggesting that the PVT may represent a unique brain region with the capacity to mediate orexinergic effects on brain dopamine and behavior. ⋯ Data from these studies indicate that orexin-A action in the PVT increases dopamine levels in the nucleus accumbens. In addition, endogenous orexin signaling in the PVT mediates locomotor activity and hedonic feeding responses. Together these data highlight the PVT as a critical site capable of mediating orexin action on brain dopamine and reward-based feeding.
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The objective of this study was to explore changes in hyaluronan levels in the cerebrospinal fluid (CSF) in a spinal cord compression model, to investigate whether hyaluronan tetrasaccharide was involved in this process, and to test the effects of hyaluronan tetrasaccharide on neuron and oligodendrocyte repair. We developed a chronic spinal cord compression model with various sizes of polymer sheets (1.5×0.7×0.3 mm(3); 5×1.5×0.7 mm(3)) that were implanted microsurgically underneath the C(5-6) laminae. The rats were divided into three groups: a sham group, a mildly compressed (MC) group, and a widely compressed (WC) group. ⋯ The brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) expression was upregulated in astrocytes at the fourth week post-compression. Hyaluronan tetrasaccharide (HA(4)) induced NF-κB and c-IAP(2) to suppress the H(2)O(2)-induced apoptosis in primary neuronal cultures and increased BDNF and VEGF expression in astrocytic cultures in vitro. These findings suggest that HA(4) in the CSF may associate with behavioral recovery by increasing the levels of NF-κB, c-IAP(2), and neurotrophic factors after chronic spinal cord compression.