Neuroscience
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Although mild traumatic brain injury is associated with behavioral dysfunction and histopathological alterations, few studies have assessed the temporal pattern of regional apoptosis following mild brain injury. Anesthetized rats were subjected to mild lateral fluid-percussion brain injury (1.1-1.3 atm), and brains were evaluated for the presence of in situ DNA fragmentation (terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling, TUNEL) and morphologic characteristics of apoptotic cell death (nuclear and cytoplasmic condensation, presence of apoptotic bodies). Significant numbers of apoptotic TUNEL(+) cells were observed in the injured parietal cortex and underlying white matter up to 72 h post-injury (P<0.05 compared to sham-injured-injured), with maximal numbers present at 24 h. ⋯ However, selective neuronal loss was evident in the CA3 region at 24 h post-injury, that was preceded by an overt loss of neuronal Bcl-2 immunoreactivity at 6 h. No changes in either cellular Bcl-2 or Bax expression were observed in the thalamus or white matter at any time post-injury. Taken together from these data, we suggest that apoptosis contributes to cell death in both gray and white matter, and that decreases in cellular Bcl-2 may, in part, be associated with both apoptotic and non-apoptotic cell death following mild brain trauma.
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In the present study we investigated the effects of spinal morphine on the electrically and naturally evoked responses of gracile nuclei neurones in a rat model of neuropathy, induced by the tight ligation of lumbar L5/6 spinal nerves. Two weeks after surgery, animals were prepared for electrophysiological recordings and neuronal responses were characterised to a range of controlled natural (brush, low- and high-intensity von Frey filaments, heat 45 degrees C) and peripheral electrical stimuli. Morphine (0.1, 0.25, 1 and 5 microg) was applied spinally and its effect was compared to that in sham-operated or naive animals. ⋯ In complete contrast, morphine produced a marked inhibition of the low-intensity punctate mechanical evoked responses (von Freys 2 and 9 g) after nerve injury, an effect that was totally lacking in the sham-operated or naive animal groups. This dramatic shift was selective for the low-intensity punctate mechanical stimuli and such an effect was not seen with the noxious mechanical punctate stimulus (von Frey 75 g) where there was a modest inhibition in all groups. Our results suggest that there is plasticity in the opioid modulation of dorsal column projection pathways following spinal nerve ligation and these alterations appear to interact with sensory pathways conveying low-threshold punctate stimuli.
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We investigated the roles of bare morphogenetic protein (BMP), sonic hedgehog (SHH) and fibroblast growth factor (FGF)-expressing signaling centers in regulating the patterned outgrowth of the telencephalic and optic vesicles. Implantation of BMP4 beads in the anterior neuropore of stage 10 chicken embryos repressed FGF8 and SHH expression. Similarly, loss of SHH expression in Shh mutant mice leads to increased BMP signaling and loss of Fgf8 expression in the prosencephalon. ⋯ We suggest that the juxtaposition of Fgf8, Bmp4 and Shh expression domains generate patterning centers that coordinate the growth of the telencephalic and optic vesicles, similar to how Fgf8, Bmp4 and Shh regulate growth of the limb bud. Furthermore, these patterning centers regulate regional specification within the forebrain and eye, as exemplified by the regulation of Emx2 expression by different levels of BMP signaling. In summary, we present evidence that there is cross-regulation between BMP-, FGF- and SHH-expressing signaling centers in the prosencephalon which regulate morphogenesis of, and regional specification within, the telencephalic and optic vesicles.
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Nitric oxide synthase is expressed abundantly in the spinal cord, and nitric oxide (NO) has been shown to play important roles in the central mechanism of inflammatory hyperalgesia. However, the expression and function of the NO receptor, soluble guanylate cyclase, is not fully understood in this processing at the spinal cord level. In the present study, we report that the soluble guanylate cyclase alpha(1) subunit but not the beta(1) subunit was expressed in rat spinal cord, particularly in the dorsal horn. ⋯ During formalin-induced long-lasting inflammation, we found that the expression of the alpha(1) subunit of soluble guanylate cyclase was dramatically increased in the lumbar spinal cord on the second and fourth days after formalin injection into the dorsal side of a hind paw. Intraperitoneal pretreatment with an N-methyl-D-aspartate (NMDA) receptor antagonist, dizocilpine maleate (MK-801), and a neuronal NO synthase inhibitor, 7-nitroindazole, not only significantly blocked formalin-induced secondary thermal hyperalgesia but also suppressed formalin-produced increase in the alpha(1) subunit of soluble guanylate cyclase in the spinal cord. The present results indicate that peripheral inflammation not only initially activates but also later up-regulates soluble guanylate cyclase expression via the NMDA receptor-NO signaling pathway, suggesting that soluble guanylate cyclase might be involved in the central mechanism of formalin-induced inflammatory hyperalgesia in the spinal cord.
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Dopaminergic projections to the forebrain arising from the mesencephalic ventral tegmentum modulate information processing in cortical and limbic sites. The lateral hypothalamus is crucial for the coordination of behavioral responses to interoceptive cues. The presence of a hypothalamic input to the ventral tegmental area has been known for some time, but the organization of this pathway has received little attention. ⋯ Moreover, axons that were anterogradely labeled from the lateral hypothalamus were seen throughout the ventral tegmental area, and were often in close proximity to the dendrites and somata of dopamine neurons. Dopamine and orexin fibers were found to codistribute in the medial prefrontal cortex; orexin fibers were present in lower density in the medial shell of the nucleus accumbens, and the central and posterior basolateral nuclei of the amygdala. We conclude that the lateral hypothalamic/perifornical projection represents an anatomical substrate by which interoceptive-related signals may influence forebrain dopamine function.