Neuroscience
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Regrowth inhibitory molecules prevent axon regeneration in the adult mammalian central nervous system (CNS). RhoA, a small GTPase in the Rho family, is a key intracellular switch that mediates the effects of these extracellular regrowth inhibitors. The bacterial enzyme C3-ADP ribosyltransferase (C3) selectively and irreversibly inhibits the activation of RhoA and stimulates axon outgrowth and regeneration. ⋯ Our vectors deliver C3 in a cell-autonomous (endogenous) or a cell-nonautonomous (secretable/permeable) fashion and promote in vitro process outgrowth on inhibitory chondroitin sulfate proteoglycan substrate. Further conditional control of our vectors was achieved via the addition of a Tet-On system, which allows for transcriptional control with doxycycline administration. These vectors will be crucial tools for promoting continued axonal regeneration after CNS injuries or neurodegenerative diseases.
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Transcriptomic and proteomic approaches have separately proven effective at identifying novel mechanisms affecting addiction-related behavior; however, it is difficult to prioritize the many promising leads from each approach. A convergent secondary analysis of proteomic and transcriptomic results can glean additional information to help prioritize promising leads. The current study is a secondary analysis of the convergence of recently published separate transcriptomic and proteomic analyses of nucleus accumbens (NAc) tissue from rats subjected to environmental enrichment vs. isolation and cocaine self-administration vs. saline. ⋯ Overall environmental enrichment produced better correspondence than cocaine self-administration. The individual targets contributing to mRNA and protein effects were largely not overlapping. As a whole, these results confirm that robust transcriptomic and proteomic data sets can provide similar results at the gene/protein set level even when there is little correspondence at the individual target level and little overlap in the targets contributing to the effects.
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Orofacial pain conditions including temporomandibular disorder (TMD) and migraine are characterized by peripheral and central sensitization of trigeminal nociceptive neurons. The goal of this study was to investigate the role of calcitonin gene-related peptide (CGRP) in promoting bidirectional signaling within the trigeminal system to mediate sensitization of primary nociceptive neurons. Adult male Sprague-Dawley rats were injected intercisternally with CGRP or co-injected with the receptor antagonist CGRP8-37 or KT 5720, a protein kinase A (PKA) inhibitor. ⋯ Seven days post injection, Fast Blue was observed in ganglion neurons and satellite glial cells. Our results demonstrate that elevated levels of CGRP in the upper spinal cord promote sensitization of primary nociceptive neurons via a mechanism that involves activation of PKA centrally and P-ERK in ganglion neurons. Our findings provide evidence of bidirectional signaling within the trigeminal system that facilitate increased neuron-glia communication within the ganglion associated with trigeminal sensitization.
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Epidemiological studies report that infarct size is decreased and stroke outcomes are improved in young females when compared to males. However, mechanistic insight is lacking. We posit that sex-specific differences in glial cell functions occurring immediately after ischemic stroke are a source of dichotomous outcomes. ⋯ When compared to sham, only male mice exhibited an increase in CD11b immunoreactivity after MCA occlusion (P=0.006). We posit that a sex difference in the presence of constitutive CD11b has a role in determining male and female microglia phagocytic responses to ischemia. Taken together, these findings are critical to understanding potential sex differences in glial physiology as well as stroke pathobiology which are foundational for the development of future sex-specific stroke therapies.
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Coordinated activity in different sets of widely-projecting neurochemical systems characterize waking (W) and sleep (S). How and when this coordination is achieved during development is not known. We used embryos and newborns of a precocial bird species (chickens) to assess developmental activation in different neurochemical systems using cFos expression, which has been extensively employed to examine cellular activation during S and W in adult mammals. ⋯ Unexpectedly, a strong activation was seen at E16 in H/O neurons. The highest activation of Ch-LDT/PT (also S-active) and MCH neurons was seen at E20. These data suggest that maturation of arousal systems is achieved soon after hatching, while S-control networks are active in late chick embryos.