Neuroscience
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Glutamate receptors have been proposed to mediate the apoptotic actions of glucocorticoids in hippocampal cells. To further analyze the role of glutamate receptors in this process, we pretreated primary hippocampal cells from neonatal (postnatal day 4) rats with antagonists of ionotropic glutamate receptor (iGluR) and metabotropic glutamate receptor (mGluR) antagonists before exposure to the specific glucocorticoid receptor agonist dexamethasone (DEX) at a dose of 1 microM. Dizocilpine (MK801; a general N-methyl-D-aspartic acid [NMDA] receptor antagonist, NMDAR antagonist) and ifenprodil (a specific ligand of the NMDAR 2B subunit, NR2B), were used to block iGluR; (RS)-alpha-ethyl-4-carboxyphenylglycine (E4CPG) and (RS)-alpha-cyclopropyl-4-phosphonophenyl-glycine (CPPG) were employed as I/II (E4CPG) and II/III (CPPG) mGluR antagonists. ⋯ Further, dose-response studies with NMDA revealed that whereas high (10 microM) doses of NMDA themselves elicit cytotoxic responses, low (1-5 microM) concentrations of NMDA can effectively oppose DEX-induced cell death. Interestingly, the neuroprotective actions of low dose NMDA stimulation were abolished when either synaptic or extrasynaptic NMDA receptors were blocked with MK801 in combination with the GABA receptor antagonist bicuculline (synaptic) or ifenprodil (extrasynaptic). In summary, the present data show that both iGluR and mGluR mediate the neurotoxic effects of glucocorticoids on hippocampal cells and that pre-treatment with low doses of NMDA, by acting on synaptic and extrasynaptic receptors, render hippocampal cells less vulnerable to glucocorticoid insults.
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Cell surface glycoconjugates are thought to mediate cell-cell recognition and to play roles in neuronal development and functions. We demonstrated here that exposure of neuronal cells to nanomolar levels of glyco-chains with an N-acetylgalactosamine (GalNAc) residue at the non-reducing termini (GalNAc-S) such as GalNAcbeta4(Neu5Acalpha3)Galbeta4GlcCer (GM2) ganglioside, its oligosaccharide portion, GalNAcbeta4Galbeta4GlcCer (Gg(3)) Cer, GalNAcalpha3GalNAcbeta3Galalpha4Galbeta4GlcCer (Gb(5)) Cer (Forssman hapten) and alpha1-4 linked oligomers of GalNAc, induced a rapid and transient activation of cAMP-dependent protein kinase (PKA) in subplasmalemma. The treatment was accompanied by peripheral actin polymerization and filopodia formation in NG108-15 cells and primary cultured hippocampal neurons, but not in glial cells. ⋯ These results suggest that extracellular GalNAc-S serve as potential regulators of the filopodia formation in neuronal cells by triggering the activation of PKA followed by cdc42 up-regulation via a cell surface receptor-like component. Filopodia formation induced by GalNAc-S may have a physiological relevance because long-term exposure to GalNAc-S enhanced F-actin-rich dendrite generation of primary cultured hippocampal neurons, and PKA-dependent dendritic outgrowth and branch formation of primary cultured cerebellar Purkinje neurons, in which actin isoforms were localized to motile structures in dendrites. These findings provide evidence for a novel GalNAc/PKA-signaling cascade in regulating some neuronal maturation.
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The mitogen-activated protein kinase/extracellular-signal regulated kinase (MAPK/ERK) cascade is an important contributor to synaptic plasticity that underlies learning and memory. ERK activation by the MAPK/ERK kinase (MEK) leading to cyclic-AMP response element binding protein (CREB) phosphorylation is implicated in the formation of long-term memory. We have demonstrated that CREB phosphorylation in the olfactory bulb (OB) is important for aversive olfactory learning in young rats, yet whether MAPK/ERK functions as an upstream regulator are necessary for this olfactory learning remains to be determined. ⋯ Phosphorylated ERKs (P-ERKs) 1 and 2 were significantly increased for 60 min after the training without changes in total ERKs 1 and 2. By contrast, intrabulbar infusion of PD98059 during the training significantly reduced P-ERKs 1 and 2 as well as phosphorylated CREB without any effects on the total ERKs or CREB. Taken together with the previous findings, these results indicate that the MAPK/ERK-CREB pathway is required for the long-term, but not the short-term, facilitation process of aversive olfactory learning in young rats.
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Texture information is an elementary feature utilized by the human visual system to automatically, or pre-attentively, segment the visual scene. The neural substrate underlying human texture processing as well as the basic computational mechanisms remains largely unknown up to now. We propose a neural model of texture processing which integrates the data obtained by a variety of methods into a common computational framework. ⋯ The model allows to link human performance in texture segmentation with model cell activation patterns, in turn permitting to trace back fundamental psychophysical results on texture processing to their putative neural origins. Most importantly, it enables us to identify and evaluate the functional role of feedback connections between cortical areas in the context of texture processing, namely the suppression of ambiguous cell activities leading to a sharply localized detection of texture boundaries. One of the likely neural origins of modulatory effects on V1 cell activation levels, as observed in electrophysiological studies using single- and multi-unit recordings, can be resolved.
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Comparative Study
Combined intrastriatal dopamine D1 and serotonin 5-HT2 receptor stimulation reveals a mechanism for hyperlocomotion in 6-hydroxydopamine-lesioned rats.
Loss of dopaminergic innervation to the striatum increases the sensitivity of dopamine (DA) D1 and serotonin (5-HT) 5-HT2 receptor signaling. Previous work from our laboratory has shown that systemic co-administration of D1 and 5-HT2 receptor agonists leads to the synergistic overexpression of striatal preprotachykinin mRNA levels in the DA-depleted, but not intact animals. In the present study, we examined this mechanism as related to locomotor behavior. ⋯ Combined administration of subthreshold SKF82958 and DOI doses (0.1 microg+0.1 microg) synergistically increased locomotor behavior only in 6-OHDA-lesioned rats. These effects were blocked by either the D1 antagonist SCH23390 3-methyl-1-phenyl-2,3,4,5-tetrahydro-7-chloro-8-hydroxy-(1H)-3-benzazepine or the 5-HT2 antagonist ritanserin (each 1.0 microg in 0.8 microl/side). The results of this study suggest that the behavioral synergy induced by local co-stimulation of D1 and 5-HT2 receptors within the 6-OHDA-lesioned striatum may lead to hyperkinesias that can occur with continued pharmacological treatment of Parkinson's disease.