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 2007
Hypertension and dysregulated proinflammatory cytokine production in receptor activity-modifying protein 1-deficient mice.
Calcitonin gene-related peptide (CGRP) is thought to be a prominent neuropeptide in cardiovascular regulation and neuroimmune modulation. There are two isoforms of CGRP (alphaCGRP and betaCGRP), and the main CGRP receptors are probably composed of a calcitonin receptor-like receptor (CLR) and a receptor activity-modifying protein (RAMP)1. However, the physiological functions of CGRP that are mediated through the CLR/RAMP1 receptors remain to be clarified. ⋯ The LPS-induced inflammatory responses of the RAMP1(-/-) mice revealed a transient and significant increase in the serum CGRP levels and high serum levels of proinflammatory cytokines compared with the RAMP1(+/+) mice. alphaCGRP and betaCGRP equally suppressed the production of TNF-alpha and IL-12 in bone marrow-derived dendritic cells stimulated with lipopolysaccharide. Their inhibitory effects were not observed in the bone marrow-derived dendritic cells of the RAMP1(-/-) mice. These results indicate that CGRP signaling through CLR/RAMP1 receptors plays a crucial role in the regulation of both blood pressure by vascular relaxation and proinflammatory cytokine production from dendritic cells.
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Proc. Natl. Acad. Sci. U.S.A. · Oct 2007
Case ReportsImpaired familiarity with preserved recollection after anterior temporal-lobe resection that spares the hippocampus.
It is well established that the medial-temporal lobe (MTL) is critical for recognition memory. The MTL is known to be composed of distinct structures that are organized in a hierarchical manner. At present, it remains controversial whether lower structures in this hierarchy, such as perirhinal cortex, support memory functions that are distinct from those of higher structures, in particular the hippocampus. ⋯ Her resection included a large portion of perirhinal cortex but spared the hippocampus. The results of four experiments based on three different experimental procedures (remember-know paradigm, receiver operating characteristics, and response-deadline procedure) indicate that NB exhibits impaired familiarity with preserved recollection. The present findings thus provide a crucial missing piece of support for functional specialization in the MTL.
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Proc. Natl. Acad. Sci. U.S.A. · Oct 2007
Dissociating speech perception and comprehension at reduced levels of awareness.
We used functional MRI and the anesthetic agent propofol to assess the relationship among neural responses to speech, successful comprehension, and conscious awareness. Volunteers were scanned while listening to sentences containing ambiguous words, matched sentences without ambiguous words, and signal-correlated noise (SCN). During three scanning sessions, participants were nonsedated (awake), lightly sedated (a slowed response to conversation), and deeply sedated (no conversational response, rousable by loud command). ⋯ A significant decline in postscan recognition memory for sentences also suggests that sedation impaired encoding of sentences into memory, with left inferior frontal and temporal lobe responses during light sedation predicting subsequent recognition memory. These findings suggest a graded degradation of cognitive function in response to sedation such that "higher-level" semantic and mnemonic processes can be impaired at relatively low levels of sedation, whereas perceptual processing of speech remains resilient even during deep sedation. These results have important implications for understanding the relationship between speech comprehension and awareness in the healthy brain in patients receiving sedation and in patients with disorders of consciousness.
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Proc. Natl. Acad. Sci. U.S.A. · Oct 2007
Hypomorphic CEP290/NPHP6 mutations result in anosmia caused by the selective loss of G proteins in cilia of olfactory sensory neurons.
Cilia regulate diverse functions such as motility, fluid balance, and sensory perception. The cilia of olfactory sensory neurons (OSNs) compartmentalize the signaling proteins necessary for odor detection; however, little is known regarding the mechanisms of protein sorting/entry into olfactory cilia. Nephrocystins are a family of ciliary proteins likely involved in cargo sorting during transport from the basal body to the ciliary axoneme. ⋯ Interestingly, we observed defective ciliary localization of G(olf) and Ggamma(13) but not of G protein-coupled odorant receptors or other components of the odorant signaling pathway in the rd16 OSNs. Our data implicate distinct mechanisms for ciliary transport of olfactory signaling proteins, with CEP290 being a key mediator involved in G protein trafficking. The assessment of olfactory function can, therefore, serve as a useful diagnostic tool for genetic screening of certain syndromic ciliary diseases.