Proceedings of the National Academy of Sciences of the United States of America
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Proc. Natl. Acad. Sci. U.S.A. · Oct 2012
Marked difference in saxitoxin and tetrodotoxin affinity for the human nociceptive voltage-gated sodium channel (Nav1.7) [corrected].
Human nociceptive voltage-gated sodium channel (Na(v)1.7), a target of significant interest for the development of antinociceptive agents, is blocked by low nanomolar concentrations of (-)-tetrodotoxin(TTX) but not (+)-saxitoxin (STX) and (+)-gonyautoxin-III (GTX-III). These findings question the long-accepted view that the 1.7 isoform is both tetrodotoxin- and saxitoxin-sensitive and identify the outer pore region of the channel as a possible target for the design of Na(v)1.7-selective inhibitors. Single- and double-point amino acid mutagenesis studies along with whole-cell electrophysiology recordings establish two domain III residues (T1398 and I1399), which occur as methionine and aspartate in other Na(v) isoforms, as critical determinants of STX and gonyautoxin-III binding affinity. An advanced homology model of the Na(v) pore region is used to provide a structural rationalization for these surprising results.
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Proc. Natl. Acad. Sci. U.S.A. · Oct 2012
Neural latencies across auditory cortex of macaque support a dorsal stream supramodal timing advantage in primates.
Sensory systems across the brain are specialized for their input, yet some principles of neural organization are conserved across modalities. The pattern of anatomical connections from the primate auditory cortex to the temporal, parietal, and prefrontal lobes suggests a possible division into dorsal and ventral auditory processing streams, with the dorsal stream originating from more caudal areas of the auditory cortex, and the ventral stream originating from more rostral areas. These streams are hypothesized to be analogous to the well-established dorsal and ventral streams of visual processing. ⋯ Across three varieties of auditory stimuli (clicks, noise, and pure tones), we find that latencies increase with hierarchical level, as predicted by anatomical connectivity. Critically, we also find a pronounced timing differential along the caudal-to-rostral axis within the same hierarchical level, with caudal (dorsal stream) latencies being faster than rostral (ventral stream) latencies. This observed timing differential mirrors that found for the dorsal stream of the visual system, suggestive of a common timing advantage for the dorsal stream across sensory modalities.
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Proc. Natl. Acad. Sci. U.S.A. · Oct 2012
Recruitment of medial prefrontal cortex neurons during alcohol withdrawal predicts cognitive impairment and excessive alcohol drinking.
Chronic intermittent access to alcohol leads to the escalation of alcohol intake, similar to binge drinking in humans. Converging lines of evidence suggest that impairment of medial prefrontal cortex (mPFC) cognitive function and overactivation of the central nucleus of the amygdala (CeA) are key factors that lead to excessive drinking in dependence. However, the role of the mPFC and CeA in the escalation of alcohol intake in rats with a history of binge drinking without dependence is currently unknown. ⋯ The results showed that abstinence from alcohol in rats with a history of escalation of alcohol intake specifically recruited GABA and corticotropin-releasing factor (CRF) neurons in the mPFC and produced working memory impairments associated with excessive alcohol drinking during acute (24-72 h) but not protracted (16 -68 d) abstinence. Moreover, abstinence from alcohol was associated with a functional disconnection of the mPFC and CeA but not mPFC and nucleus accumbens. These results show that recruitment of a subset of GABA and CRF neurons in the mPFC during withdrawal and disconnection of the PFC-CeA pathway may be critical for impaired executive control over motivated behavior, suggesting that dysregulation of mPFC interneurons may be an early index of neuroadaptation in alcohol dependence.
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Proc. Natl. Acad. Sci. U.S.A. · Oct 2012
Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes.
Adaptive features of innate immunity, recently described as "trained immunity," have been documented in plants, invertebrate animals, and mice, but not yet in humans. Here we show that bacille Calmette-Guérin (BCG) vaccination in healthy volunteers led not only to a four- to sevenfold increase in the production of IFN-γ, but also to a twofold enhanced release of monocyte-derived cytokines, such as TNF and IL-1β, in response to unrelated bacterial and fungal pathogens. ⋯ In experimental studies, BCG vaccination induced T- and B-lymphocyte-independent protection of severe combined immunodeficiency SCID mice from disseminated candidiasis (100% survival in BCG-vaccinated mice vs. 30% in control mice). In conclusion, BCG induces trained immunity and nonspecific protection from infections through epigenetic reprogramming of innate immune cells.