Neuroscience
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Previous studies demonstrated that exendin-4 (Ex-4) may possess neurotrophic and neuroprotective functions in ischemia insults, but its mechanism remained unknown. Here, by using real-time PCR and ELISA, we identified the distribution of active GLP-1Rs in the rat primary cortical neurons. After establishment of an in vitro ischemia model by oxygen/glucose deprivation (OGD), neurons were treated with various dosages of Ex-4. ⋯ Our study also revealed that, compared with the Ex-4 group, inhibition of the PKA signaling pathway significantly decreased the survival rate of neurons, down-regulated the expression of B-cell lymphoma 2 (Bcl-2) and up-regulated the Bax expression 3h after ODG (P<0.05, P<0.01, respectively), while neither PI3K nor MAPK inhibition exerted such effects. Furthermore, Western blotting exhibited that PKA expression was elevated in the presence or absence of OGD insults (P<0.05). This study indicated that Ex-4 protected neurons against OGD by modulating the unfolded protein response (UPR) through the PKA pathway and may serve as a novel therapeutic agent for stroke.
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The development of tolerance to the antinociceptive effects of morphine has been associated with networks within ventrolateral periaqueductal gray (vlPAG) and separately, nitric oxide signaling. Furthermore, it is known that the mechanisms that underlie tolerance differ with age. In this study, we used a rat model of antinociceptive tolerance to morphine at two ages, postnatal day (PD) 7 and adult, to determine if changes in the vlPAG related to nitric oxide signaling produced by chronic morphine exposure were age-dependent. ⋯ In contrast, changes in the gene expression of PD7 rats suggested superoxide and peroxide metabolisms may be engaged. These data indicate that there is supraspinal neuroplasticity following morphine administration as early as PD7. Furthermore, oxidative stress pathways associated with chronic morphine exposure appear age-specific.
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Overexpression of pruritogens and their precursors may contribute to the sensitization of histamine-dependent and -independent itch-signaling pathways in chronic itch. We presently investigated self- and cross-sensitization of scratching behavior elicited by various pruritogens, and their effects on primary sensory neurons. The MrgprC11 agonist BAM8-22 exhibited self- and reciprocal cross-sensitization of scratching evoked by the protease-activated receptor-2 (PAR-2) agonist SLIGRL. ⋯ SLIGRL unilaterally cross-sensitized responses of DRG cells to chloroquine and BAM8-22, consistent with the behavioral data. These results indicate that unidirectional cross-sensitization of histamine-independent itch-signaling pathways might occur at a peripheral site through PAR-2. PAR-2 expressed in pruriceptive nerve endings is a potential target to reduce sensitization associated with chronic itch.
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Glycogen synthase kinase 3 (GSK3) is a serine/threonine kinase that has been implicated in psychiatric diseases, neurodevelopment, and circadian regulation. Both GSK3 isoforms, α and β, exhibit a 24-h variation of inhibitory phosphorylation within the suprachiasmatic nucleus (SCN), the primary circadian pacemaker. We examined the hypothesis that rhythmic GSK3 activity is critical for robust circadian rhythmicity using GSK3α(21A/21A)/β(9A/9A) knock-in mice with serine-alanine substitutions at the inhibitory phosphorylation sites, making both forms constitutively active. ⋯ These results suggest that constitutive activation of GSK3 results in the loss of the typical day/night variation of SCN neuronal activity. Together, these results implicate GSK3 activity as a critical regulator of circadian behavior and neurophysiological rhythms. Because GSK3 has been implicated in numerous pathologies, understanding how GSK3 modulates circadian rhythms and neurophysiological activity may lead to novel therapeutics for pathological disorders and circadian rhythm dysfunction.
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The amygdala has a fundamental role in driving affective behaviors in response to sensory cues. To accomplish this, neurons of the lateral nucleus (LAT) must integrate a large number of synaptic inputs. A wide range of factors influence synaptic integration, including membrane potential, voltage-gated ion channels and GABAergic inhibition. ⋯ In combination with intracellular delivery of pharmacological agents, it was found that the voltage-dependent suppression of PSP clusters was sensitive to tetraethylammonium (TEA), but not cesium or a blocker of fast GABAergic inhibition. These findings indicate that integration of PSPs in LAT neurons in vivo is strongly modified by somatic membrane potential, likely through voltage-dependent TEA-sensitive potassium channels. Conditions that lead to a shift in membrane potential, or a modulation of the number or function of these ion channels will lead to a more uniform capacity for integration across voltages, and perhaps greatly facilitate amygdala-dependent behaviors.