Proceedings of the National Academy of Sciences of the United States of America
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Proc. Natl. Acad. Sci. U.S.A. · Aug 2012
Comparative StudyVariation in neural development as a result of exposure to institutionalization early in childhood.
We used structural MRI and EEG to examine brain structure and function in typically developing children in Romania (n = 20), children exposed to institutional rearing (n = 29), and children previously exposed to institutional rearing but then randomized to a high-quality foster care intervention (n = 25). In so doing, we provide a unique evaluation of whether placement in an improved environment mitigates the effects of institutional rearing on neural structure, using data from the only existing randomized controlled trial of foster care for institutionalized children. Children enrolled in the Bucharest Early Intervention Project underwent a T1-weighted MRI protocol. ⋯ We were also able to explain previously reported reductions in EEG α-power among institutionally reared children compared with children raised in families using these MRI data. As hypothesized, the association between institutionalization and EEG α-power was partially mediated by cortical white matter volume for children not randomized to foster care. The increase in white matter among children randomized to an improved rearing environment relative to children who remained in institutional care suggests the potential for developmental "catch up" in white matter growth, even following extreme environmental deprivation.
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Proc. Natl. Acad. Sci. U.S.A. · Jul 2012
Comparative Study Clinical TrialPeripheral inflammatory disease associated with centrally activated IL-1 system in humans and mice.
During peripheral immune activation caused by an infection or an inflammatory condition, the innate immune response signals to the brain and causes an up-regulation of central nervous system (CNS) cytokine production. Central actions of proinflammatory cytokines, in particular IL-1β, are pivotal for the induction of fever and fatigue. In the present study, the influence of peripheral chronic joint inflammatory disease in rheumatoid arthritis (RA) on CNS inflammation was investigated. ⋯ Next, spinal inflammation in experimental arthritis was investigated. A marked increase of IL-1β, IL-18, and tumor necrosis factor, but not IL-6 mRNA production, in the spinal cord was observed, coinciding with increased arthritis scores in the KBxN serum transfer model. These data provide evidence that peripheral inflammation such as arthritis is associated with an immunological activation in the CNS in both humans and mice, suggesting a possible therapeutic target for centrally affecting conditions as fatigue in chronic inflammatory diseases, for which to date there are no specific treatments.
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Proc. Natl. Acad. Sci. U.S.A. · Jul 2012
Circadian clock protein cryptochrome regulates the expression of proinflammatory cytokines.
Chronic sleep deprivation perturbs the circadian clock and increases susceptibility to diseases such as diabetes, obesity, and cancer. Increased inflammation is one of the common underlying mechanisms of these diseases, thus raising a hypothesis that circadian-oscillator components may regulate immune response. Here we show that absence of the core clock component protein cryptochrome (CRY) leads to constitutive elevation of proinflammatory cytokines in a cell-autonomous manner. ⋯ In addition, we report that CRY1 binds to adenylyl cyclase and limits cAMP production. Based on these data, we propose that absence of CRY protein(s) might release its (their) inhibition on cAMP production, resulting in elevated cAMP and increased PKA activation, subsequently leading to NF-κB activation through phosphorylation of p65 at S276. These results offer a mechanistic framework for understanding the link between circadian rhythm disruption and increased susceptibility to chronic inflammatory diseases.
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Proc. Natl. Acad. Sci. U.S.A. · Jul 2012
C-fiber activity-dependent maturation of glycinergic inhibition in the spinal dorsal horn of the postnatal rat.
Sensory circuits are shaped by experience in early postnatal life and in many brain areas late maturation of inhibition drives activity-dependent development. In the newborn spinal dorsal horn, activity is dominated by inputs from low threshold A fibers, whereas nociceptive C-fiber inputs mature gradually over the first postnatal weeks. How this changing afferent input influences the maturation of dorsal horn inhibition is not known. ⋯ We further show that the onset of glycinergic inhibition depends upon the maturation of C-fiber inputs to the dorsal horn: selective block of afferent C fibers in postnatal week 2, using perisciatic injections of the cationic anesthetic QX-314, lidocaine, and capsaicin, delays the maturation of both GlyR subunits and glycinergic inhibition, maintaining dorsal neurons in a neonatal state, where tactile responses are facilitated, rather than inhibited, by glycinergic network activity. Thus, glycine may serve to facilitate tactile A-fiber-mediated information and enhance activity-dependent synaptic strengthening in the immature dorsal horn. This period ceases in the second postnatal week with the maturation of C-fiber spinal input, which triggers postsynaptic changes leading to glycinergic inhibition and only then is balanced excitation and inhibition achieved in dorsal horn sensory circuits.
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Proc. Natl. Acad. Sci. U.S.A. · Jul 2012
Transient opening of the perineurial barrier for analgesic drug delivery.
Selective targeting of sensory or nociceptive neurons in peripheral nerves remains a clinically desirable goal. Delivery of promising analgesic drugs is often impeded by the perineurium, which functions as a diffusion barrier attributable to tight junctions. We used perineurial injection of hypertonic saline as a tool to open the perineurial barrier transiently in rats and elucidated the molecular action principle in mechanistic detail: Hypertonic saline acts via metalloproteinase 9 (MMP9). ⋯ Perisciatic injection of any component of this pathway, including MMP9 hemopexin domain or claudin-1 siRNA, enables an opioid peptide ([D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin) and a selective sodium channel (NaV1.7)-blocking toxin (ProToxin-II) to exert antinociceptive effects without motor impairment. The latter, as well as the classic TTX, blocked compound action potentials in isolated nerves only after disruption of the perineurial barrier, which, in return, allowed endoneurally released calcitonin gene-related peptide to pass through the nerve sheaths. Our data establish the function and regulation of claudin-1 in the perineurium as the major sealing component, which could be modulated to facilitate drug delivery or, potentially, reseal the barrier under pathological conditions.