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  • 1
    Online Resource
    Online Resource
    A common haplotype in the complement regulatory gene factor H ( HF1/CFH ) predisposes individuals to age-related macular degeneration
    Proceedings of the National Academy of Sciences ; 2005
    In:  Proceedings of the National Academy of Sciences Vol. 102, No. 20 ( 2005-05-17), p. 7227-7232
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 102, No. 20 ( 2005-05-17), p. 7227-7232
    Abstract: Age-related macular degeneration (AMD) is the most frequent cause of irreversible blindness in the elderly in developed countries. Our previous studies implicated activation of complement in the formation of drusen, the hallmark lesion of AMD. Here, we show that factor H (HF1), the major inhibitor of the alternative complement pathway, accumulates within drusen and is synthesized by the retinal pigmented epithelium. Because previous linkage analyses identified chromosome 1q25-32, which harbors the factor H gene ( HF1 / CFH ), as an AMD susceptibility locus, we analyzed HF1 for genetic variation in two independent cohorts comprised of ≈900 AMD cases and 400 matched controls. We found association of eight common HF1 SNPs with AMD; two common missense variants exhibit highly significant associations (I62V, χ 2 = 26.1 and P = 3.2 × 10 -7 and Y402H, χ 2 = 54.4 and P = 1.6 × 10 -13 ). Haplotype analysis reveals that multiple HF1 variants confer elevated or reduced risk of AMD. One common at-risk haplotype is present at a frequency of 50% in AMD cases and 29% in controls [odds ratio (OR) = 2.46, 95% confidence interval (1.95-3.11)]. Homozygotes for this haplotype account for 24% of cases and 8% of controls [OR = 3.51, 95% confidence interval (2.13-5.78)] . Several protective haplotypes are also identified (OR = 0.44-0.55), further implicating HF1 function in the pathogenetic mechanisms underlying AMD. We propose that genetic variation in a regulator of the alternative complement pathway, when combined with a triggering event, such as infection, underlie a major proportion of AMD in the human population.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0501536102
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2005
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    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 2
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    Online Resource
    Group I Metabotropic Glutamate Receptors Control Metaplasticity of Spinal Cord Learning through a Protein Kinase C-Dependent Mechanism
    Society for Neuroscience ; 2008
    In:  The Journal of Neuroscience Vol. 28, No. 46 ( 2008-11-12), p. 11939-11949
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 28, No. 46 ( 2008-11-12), p. 11939-11949
    Abstract: Neurons within the spinal cord can support several forms of plasticity, including response–outcome (instrumental) learning. After a complete spinal transection, experimental subjects are capable of learning to hold the hindlimb in a flexed position (response) if shock (outcome) is delivered to the tibialis anterior muscle when the limb is extended. This response-contingent shock produces a robust learning that is mediated by ionotropic glutamate receptors (iGluRs). Exposure to nociceptive stimuli that are independent of limb position (e.g., uncontrollable shock; peripheral inflammation) produces a long-term ( 〉 24 h) inhibition of spinal learning. This inhibition of plasticity in spinal learning is itself a form of plasticity that requires iGluR activation and protein synthesis. Plasticity of plasticity (metaplasticity) in the CNS has been linked to group I metabotropic glutamate receptors (subtypes mGluR1 and mGluR5) and activation of protein kinase C (PKC). The present study explores the role of mGluRs and PKC in the metaplastic inhibition of spinal cord learning using a combination of behavioral, pharmacological, and biochemical techniques. Activation of group I mGluRs was found to be both necessary and sufficient for metaplastic inhibition of spinal learning. PKC was activated by stimuli that inhibit spinal learning, and inhibiting PKC activity restored the capacity for spinal learning. Finally, a PKC inhibitor blocked the metaplastic inhibition of spinal learning produced by a group I mGluR agonist. The data strongly suggest that group I mGluRs control metaplasticity of spinal learning through a PKC-dependent mechanism, providing a potential therapeutic target for promoting use-dependent plasticity after spinal cord injury.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.3098-08.2008
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2008
    detail.hit.zdb_id: 1475274-8
    SSG: 12
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  • 3
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    Online Resource
    Triangulating a Cognitive Control Network Using Diffusion-Weighted Magnetic Resonance Imaging (MRI) and Functional MRI
    Society for Neuroscience ; 2007
    In:  The Journal of Neuroscience Vol. 27, No. 14 ( 2007-04-04), p. 3743-3752
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 27, No. 14 ( 2007-04-04), p. 3743-3752
    Abstract: The ability to stop motor responses depends critically on the right inferior frontal cortex (IFC) and also engages a midbrain region consistent with the subthalamic nucleus (STN). Here we used diffusion-weighted imaging (DWI) tractography to show that the IFC and the STN region are connected via a white matter tract, which could underlie a “hyperdirect” pathway for basal ganglia control. Using a novel method of “triangulation” analysis of tractography data, we also found that both the IFC and the STN region are connected with the presupplementary motor area (preSMA). We hypothesized that the preSMA could play a conflict detection/resolution role within a network between the preSMA, the IFC, and the STN region. A second experiment tested this idea with functional magnetic resonance imaging (fMRI) using a conditional stop-signal paradigm, enabling examination of behavioral and neural signatures of conflict-induced slowing. The preSMA, IFC, and STN region were significantly activated the greater the conflict-induced slowing. Activation corresponded strongly with spatial foci predicted by the DWI tract analysis, as well as with foci activated by complete response inhibition. The results illustrate how tractography can reveal connections that are verifiable with fMRI. The results also demonstrate a three-way functional–anatomical network in the right hemisphere that could either brake or completely stop responses.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.0519-07.2007
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2007
    detail.hit.zdb_id: 1475274-8
    SSG: 12
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  • 4
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    Online Resource
    Effects of Lorazepam and Citalopram on Human Defensive Reactions: Ethopharmacological Differentiation of Fear and Anxiety
    Society for Neuroscience ; 2009
    In:  The Journal of Neuroscience Vol. 29, No. 40 ( 2009-10-07), p. 12617-12624
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 29, No. 40 ( 2009-10-07), p. 12617-12624
    Abstract: Drugs that are clinically effective against generalized anxiety disorder preferentially alter rodent risk assessment behavior, whereas drugs that are clinically effective against panic disorder preferentially alter rodent flight behavior. The theoretical principle of “defensive direction” explains the pattern of associations between emotion and defensive behavior in terms of the differing functional demands arising from cautious approach to threat (anxiety) versus departure from threat (fear), offering the prospect that clinically important emotions may be explained using a single rubric of defense. We used a within-subjects, placebo-controlled, design to test this theory, measuring the effects of citalopram and lorazepam on the defensive behavior of 30 healthy adult male humans. We indexed human defensive behavior with a translation of an active avoidance task used to measure rodent defense and found that lorazepam significantly reduced the intensity of defensive behavior during approach to threat (hypothetically anxiety-related) but not departure from threat (hypothetically fear-related). Contrary to prediction, citalopram did not affect either form of defensive reaction. Since lorazepam is a drug with well established anxiety reducing properties, these data support the hypothesis that anxiety is an emotion elicited by threat stimuli that require approach. These data also contribute to the validation of a novel human analog of an established experimental model of rodent fear and anxiety.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.2696-09.2009
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2009
    detail.hit.zdb_id: 1475274-8
    SSG: 12
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