Publication Date: 2010 Mar 17 PMID: 20237287Authors: Kochlamazashvili, G. - Senkov, O. - Grebenyuk, S. - Robinson, C. - Xiao, M. F. - Stummeyer, K. - Gerardy-Schahn, R. - Engel, A. K. - Feig, L. - Semyanov, A. - Suppiramaniam, V. - Schachner, M. - Dityatev, A.Journal: J NeurosciThe neural cell adhesion molecule (NCAM) is the predominant carrier of alpha2,8 polysialic acid (PSA) in the mammalian brain. Abnormalities in PSA and NCAM expression are associated with schizophrenia in humans and cause deficits in hippocampal synaptic plasticity and contextual fear conditioning in mice. Here, we show that PSA inhibits opening of recombinant NMDA receptors composed of GluN1/2B (NR1/NR2B) or GluN1/2A/2B (NR1/NR2A/NR2B) but not of GluN1/2A (NR1/NR2A) subunits. Deficits in NCAM/PSA increase GluN2B-mediated transmission and Ca(2+) transients in the CA1 region of the hippocampus. In line with elevation of GluN2B-mediated transmission, defects in long-term potentiation in the CA1 region and contextual fear memory in NCAM/PSA-deficient mice are abrogated by application of a GluN2B-selective antagonist. Furthermore, treatment with the glutamate scavenger glutamic-pyruvic transaminase, ablation of Ras-GRF1 (a mediator of GluN2B signaling to p38 MAPK), or direct inhibition of hyperactive p38 MAPK can restore impaired synaptic plasticity in brain slices lacking PSA/NCAM. Thus, PSA carried by NCAM regulates plasticity and learning by inhibition of the GluN2B-Ras-GRF1-p38 MAPK signaling pathway. These findings implicate carbohydrates carried by adhesion molecules in modulating NMDA receptor signaling in the brain and demonstrate reversibility of cognitive deficits associated with ablation of a schizophrenia-related adhesion molecule.post to: CiteULike

Publication Date: 2010 Mar 17 PMID: 20237286Authors: Tubing, F. - Vendra, G. - Mikl, M. - Macchi, P. - Thomas, S. - Kiebler, M. A.Journal: J NeurosciLocalization of mRNAs to postsynaptic sites and their subsequent translation is thought to contribute to synapse-specific plasticity. However, the direct visualization of dendritic RNA transport in living neurons remains a major challenge. Here, we analyze the transport of Alexa-labeled RNAs microinjected into mature hippocampal neurons. We show that microinjected MAP2 and CaMKIIalpha RNAs form particles that localize into dendrites as their endogenous counterparts. In contrast, nonlocalizing RNAs or truncated CaMKIIalpha, lacking the dendritic targeting element, remain in the cell body. Furthermore, our microinjection approach allowed us to identify a novel dendritically localized RNA, Septin7. Time-lapse videomicroscopy of neurons injected with CaMKIIalpha and Septin7 RNAs demonstrates fast directional movement along the dendrites of hippocampal neurons, with similar kinetics to Staufen1 ribonucleoprotein particles (RNPs). Coinjection and simultaneous visualization of two RNAs, as well as double detection of the corresponding endogenous RNAs, reveal that neuronal transcripts are differentially sorted in dendritic RNPs.post to: CiteULike

Publication Date: 2010 Mar 17 PMID: 20237285Authors: Liao, F. - Taishi, P. - Churchill, L. - Urza, M. J. - Krueger, J. M.Journal: J NeurosciGrowth hormone-releasing hormone (GHRH) promotes non-rapid eye movement sleep (NREMS), in part via a well characterized hypothalamic sleep-promoting site. However, GHRH may also act in the cortex to influence sleep. Application of GHRH to the surface of the cortex changes electroencephalographic (EEG) delta power. GHRH and the GHRH receptor (GHRHR) mRNAs are detectable in the rat cortex, and the expression of cortical GHRHR is activity dependent. Here, we microinjected a GHRH antagonist or GHRHR small interfering RNA (siGHRHR) onto the somatosensory cortex surface in rats. The unilateral application of the GHRH antagonist ipsilaterally decreased EEG delta wave power during NREMS, but not wakefulness, during the initial 40 min after injection. Similarly, the injection of siGHRHR reduced cortical expression of GHRHR and suppressed NREMS EEG delta wave power during 20-24 h after injection. Using the fura-2 calcium imaging technique, cultured cortical cells responded to GHRH by increasing intracellular calcium. Approximately 18% of the GHRH-responsive cells were GABAergic as illustrated by glutamic acid decarboxylase-67 (GAD67) immunostaining. Double labeling for GAD67 and GHRHR in vitro and in vivo indicated that only a minority of cortical GHRHR-containing cells were GABAergic. Our data suggest that endogenous cortical GHRH activates local cortical cells to affect EEG delta wave power state-specifically. Results are also consistent with the hypothesis that GHRH contributes to local network state regulation.post to: CiteULike

Publication Date: 2010 Mar 17 PMID: 20237284Authors: van Gaal, S. - Ridderinkhof, K. R. - Scholte, H. S. - Lamme, V. A.Journal: J NeurosciCognitive control processes involving prefrontal cortex allow humans to overrule and inhibit habitual responses to optimize performance in new and challenging situations, and traditional views hold that cognitive control is tightly linked with consciousness. We used functional magnetic resonance imaging to investigate to what extent unconscious "no-go" stimuli are capable of reaching cortical areas involved in inhibitory control, particularly the inferior frontal cortex (IFC) and the pre-supplementary motor area (pre-SMA). Participants performed a go/no-go task that included conscious (weakly masked) no-go trials, unconscious (strongly masked) no-go trials, as well as go trials. Replicating typical neuroimaging findings, response inhibition on conscious no-go stimuli was associated with a (mostly right-lateralized) frontoparietal "inhibition network." Here, we demonstrate, however, that an unconscious no-go stimulus also can activate prefrontal control networks, most prominently the IFC and the pre-SMA. Moreover, if it does so, it brings about a substantial slowdown in the speed of responding, as if participants attempted to inhibit their response but just failed to withhold it completely. Interestingly, overall activation in this "unconscious inhibition network" correlated positively with the amount of slowdown triggered by unconscious no-go stimuli. In addition, neural differences between conscious and unconscious control are revealed. These results expand our understanding of the limits and depths of unconscious information processing in the human brain and demonstrate that prefrontal cognitive control functions are not exclusively influenced by conscious information.post to: CiteULike

Publication Date: 2010 Mar 17 PMID: 20237283Authors: Pang, Z. P. - Cao, P. - Xu, W. - Sudhof, T. C.Journal: J NeurosciCalmodulin regulates multifarious cellular processes via a panoply of target interactions. However, the central role, multiple isoforms, and complex target interactions of calmodulin make it difficult to examine its precise functions. Here, we analyzed calmodulin function in neurons using lentivirally delivered short-hairpin RNAs that suppressed expression of all calmodulin isoforms by approximately 70%. Calmodulin knockdown did not significantly alter neuronal survival or synapse formation but depressed spontaneous neuronal network activity. Strikingly, calmodulin knockdown decreased the presynaptic release probability almost twofold, without altering the presynaptic readily-releasable vesicle pool or postsynaptic neurotransmitter reception. In calmodulin knockdown neurons, presynaptic release was restored to wild-type levels by expression of constitutively active calmodulin-dependent kinase-IIalpha (CaMKIIalpha); in contrast, in control neurons, expression of constitutively active CaMKIIalpha had no effect on presynaptic release. Viewed together, these data suggest that calmodulin performs a major function in boosting synaptic strength via direct activation of presynaptic calmodulin-dependent kinase II.post to: CiteULike

Publication Date: 2010 Mar 17 PMID: 20237282Authors: Ozcelik, M. - Cotter, L. - Jacob, C. - Pereira, J. A. - Relvas, J. B. - Suter, U. - Tricaud, N.Journal: J NeurosciDiameter, organization, and length of the myelin sheath are important determinants of the nerve conduction velocity, but the basic molecular mechanisms that control these parameters are only partially understood. Cell polarization is an essential feature of differentiated cells, and relies on a set of evolutionarily conserved cell polarity proteins. We investigated the molecular nature of myelin sheath polarization in connection with the functional role of the cell polarity protein pals1 (Protein Associated with Lin Seven 1) during peripheral nerve myelin sheath extension. We found that, in regard to epithelial polarity, the Schwann cell outer abaxonal domain represents a basolateral-like domain, while the inner adaxonal domain and Schmidt-Lanterman incisures form an apical-like domain. Silencing of pals1 in myelinating Schwann cells in vivo resulted in a severe reduction of myelin sheath thickness and length. Except for some infoldings, the structure of compact myelin was not fundamentally affected, but cells produced less myelin turns. In addition, pals1 is required for the normal polarized localization of the vesicular markers sec8 and syntaxin4, and for the distribution of E-cadherin and myelin proteins PMP22 and MAG at the plasma membrane. Our data show that the polarity protein pals1 plays an essential role in the radial and longitudinal extension of the myelin sheath, likely involving a functional role in membrane protein trafficking. We conclude that regulation of epithelial-like polarization is a critical determinant of myelin sheath structure and function.post to: CiteULike

Publication Date: 2010 Mar 17 PMID: 20237281Authors: Cai, Z. - Feng, G. S. - Zhang, X.Journal: J NeurosciFGF signaling is critical in the development of the vertebrate retina, which differentiates in a wave-like pattern similar to that found in the Drosophila eye. In this study, we investigated the mechanism of FGF signaling in vertebrate eye development by identifying Shp2, a protein tyrosine phosphatase, as a novel factor in orchestrating retinal morphogenesis. Using a series of Shp2 conditional mutants, we have shown that Shp2 is specifically required for the initiation of retinal neurogenesis but not for the maintenance of the retinal differentiation program. By mosaic deletion of Shp2, we further demonstrated that Shp2 ablation did not prevent the spreading of the retinal differentiation wave. Shp2 instead controls the patterning of the optic vesicle by regulating the retinal progenitor factors and cell proliferation. In ex vivo culture models and genetic rescue experiments, we showed that Shp2 acts downstream to FGF signaling in retinal development and that it can be functionally substituted by activated Ras signaling. Together, these results demonstrate that Shp2 mediates FGF-Ras signaling to control retinal progenitor cell fate.post to: CiteULike

Publication Date: 2010 Mar 17 PMID: 20237280Authors: Lindberg, P. G. - Feydy, A. - Maier, M. A.Journal: J NeurosciDiffusion tensor imaging (DTI) can be used to elucidate relations between CNS structure and function. We hypothesized that the degree of spinal white matter organization relates to the accuracy of control of grip force. Healthy subjects of different age were studied using DTI and visuomotor tracking of precision grip force. The latter is a prime component of manual dexterity. A regional analysis of spinal white matter [fractional anisotropy (FA)] across multiple cervical levels (C2-C3, C4-C5, and C6-C7) and in different regions of interest (left and right lateral or medial spinal cord) was performed. FA was highest at the C2-C3 level, higher on the right than the left side, and higher in the lateral than in the medial spinal cord (p < 0.001). FA of whole cervical spinal cord (C2-C7) was lower in subjects with high tracking error (r = -0.56, p = 0.004) and decreased with age (r = -0.63, p = 0.001). A multiple regression analysis revealed an independent contribution of each predictor (semipartial correlations: age, r = -0.55, p < 0.001; tracking error, r = -0.49, p = 0.003). The closest relation between FA and tracking error was found at the C6-C7 level in the lateral spinal cord, in which the corticospinal tract innervates spinal circuitry controlling hand and digit muscles. FA of the medial spinal cord correlated consistently with age across all cervical levels, whereas FA of the lateral spinal cord did not. The results suggest (1) a functionally relevant specialization of lateral spinal cord white matter and (2) an increased sensitivity to age-related decline in medial spinal cord white matter in healthy subjects.post to: CiteULike

Publication Date: 2010 Mar 17 PMID: 20237279Authors: Moult, P. R. - Cross, A. - Santos, S. D. - Carvalho, A. L. - Lindsay, Y. - Connolly, C. N. - Irving, A. J. - Leslie, N. R. - Harvey, J.Journal: J NeurosciThe hormone leptin can cross the blood-brain barrier and influences numerous brain functions (Harvey, 2007). Indeed, recent studies have demonstrated that leptin regulates activity-dependent synaptic plasticity in the CA1 region of the hippocampus (Shanley et al., 2001; Li et al., 2002; Durakoglugil et al., 2005; Moult et al., 2009). It is well documented that trafficking of AMPA receptors is pivotal for hippocampal synaptic plasticity (Collingridge et al., 2004), but there is limited knowledge of how hormonal systems like leptin influence this process. In this study we have examined how leptin influences AMPA receptor trafficking and in turn how this impacts on excitatory synaptic function. Here we show that leptin preferentially increases the cell surface expression of GluR1 and the synaptic density of GluR2-lacking AMPA receptors in adult hippocampal slices. The leptin-induced increase in surface GluR1 required NMDA receptor activation and was associated with an increase in cytoplasmic PtdIns(3,4,5)P(3) levels. In addition, leptin enhanced phosphorylation of the lipid phosphatase PTEN which inhibits PTEN function and elevates PtdIns(3,4,5)P(3) levels. Moreover, inhibition of PTEN mimicked and occluded the effects of leptin on GluR1 trafficking and excitatory synaptic strength. These data indicate that leptin, via a novel pathway involving PTEN inhibition, promotes GluR1 trafficking to hippocampal synapses. This process has important implications for the role of leptin in hippocampal synaptic function in health and disease.post to: CiteULike

Publication Date: 2010 Mar 17 PMID: 20237278Authors: Jongen, J. L. - Pederzani, T. - Koekkoek, S. K. - Shapiro, J. - van der Burg, J. - De Zeeuw, C. I. - Huygen, F. J. - Holstege, J. C.Journal: J NeurosciPain arises from activation of peripheral nociceptors, and strong noxious stimuli may cause an increase in spinal excitability called central sensitization, which is likely involved in many pathological pain states. So far, it has not been achieved to simultaneously visualize in vivo both the temporal and spatial aspects of spinal activity, including central sensitization. Using autofluorescent flavoprotein imaging (AFI), an optical technique suitable for mapping activity in nervous tissue, we demonstrate a close temporal and spatial correlation of electrically evoked nociceptive input with the spinal AFI signal, representing spinal neuronal activity. The AFI signal increases linearly with stimulation intensity. Furthermore, we found that the AFI signal was much larger in intensity and size when the same electrical stimulation was applied after the induction of central sensitization by a subcutaneous capsaicin injection. Finally, innocuous palpation of the hindpaw did not evoke an AFI response in naive animals, but after capsaicin injection a strong response was obtained. This is the first report demonstrating simultaneously the temporal and spatial propagation of spinal nociceptive activity in vivo.post to: CiteULike

Publication Date: 2010 Mar 17 PMID: 20237277Authors: Maglione, V. - Marchi, P. - Di Pardo, A. - Lingrell, S. - Horkey, M. - Tidmarsh, E. - Sipione, S.Journal: J NeurosciHuntington's disease (HD) is a neurodegenerative disorder caused by the expansion of a polyglutamine stretch in the protein huntingtin (Htt). HD neurons are dysfunctional at multiple levels and have increased susceptibility to stress and apoptotic stimuli. We have discovered that synthesis of the ganglioside GM1 is reduced in fibroblasts from HD patients and in cell and animal models of HD, and that decreased GM1 levels contribute to heighten HD cell susceptibility to apoptosis. The apoptotic susceptibility is recapitulated through inhibition of ganglioside synthesis in wild-type striatal cells, suggesting that decreased GM1 levels might be one of the key events leading to HD pathogenesis and progression. Administration of GM1 restores ganglioside levels in HD cells and promotes activation of AKT and phosphorylation of mutant Htt, leading to decreased mutant Htt toxicity and increased survival of HD cells. Our data identify GM1 as a potential treatment for HD.post to: CiteULike

Publication Date: 2010 Mar 17 PMID: 20237276Authors: Yao, M. - Niu, G. - Sheng, Z. - Wang, Z. - Fei, J.Journal: J NeurosciGABAergic dysfunction is implicated in a variety of neurodevelopmental and psychiatric disorders. The mechanisms underlying GABAergic differentiation, however, are not well understood. GABA transporter 1 (Gat1; Slc6a1) is an essential component of the GABAergic system, and its ectopic mRNA expression may be responsible for GABAergic malfunction under different pathological conditions. Thus, monitoring the transcriptional regulation of gat1 may help to elucidate the mechanisms that govern the differentiation of GABAergic neurons. In this study, we identified a promoter region that is sufficient to recapitulate endogenous gat1 expression in transgenic mice. A 46 bp cis-regulator in the promoter sequence was responsible for the stimulation of bone morphogenetic protein-2 (BMP2) on gat1 expression in cortical cortex. Furthermore, our study demonstrated that Smad4 and YY1 are physically bound to the element and mediate both the negative and positive regulatory effects in which BMP2 can affect the balance. In summary, we have identified a Smad4/YY1-based bidirectional regulation model for GABAergic gene transcription and demonstrated a molecular cue important for the differentiation of GABAergic neurons.post to: CiteULike

Publication Date: 2010 Mar 17 PMID: 20237275Authors: Georgi, S. A. - Reh, T. A.Journal: J NeurosciMicroRNAs (miRNAs), small 19-25 nucleotide RNAs that influence gene expression through posttranscriptional regulation of mRNA translation and degradation, have recently emerged as important regulators of neural development. Using conditional knock-out of Dicer, an RNase III enzyme required for miRNA maturation, previous studies have demonstrated an essential role for miRNAs in mouse cortical, inner ear, and olfactory development. However, a previous study (Damiani et al., 2008) using a Chx10cre mouse to delete Dicer in retinal progenitors reported no defects in the retina before the second postnatal week, suggesting that miRNAs are not required for mouse retinal development. In an effort to further study the role of miRNAs during retinal development and resolve this apparent conflict, we conditionally knocked out Dicer using a different (alphaPax6cre) line of transgenic mice. In contrast to the previous study, we demonstrate an essential role for miRNAs during mouse retinal development. In the absence of Dicer in the embryonic retina, production of early generated cell types (ganglion and horizontal cells) is increased, and markers of late progenitors are not expressed. This phenotype persists into postnatal retina, in which we find the Dicer-deficient progenitors fail to generate late-born cell types such as rods and Muller glia but continue to generate ganglion cells. We further characterize the dynamic expression of miRNAs during retinal progenitor differentiation and provide a comprehensive profile of miRNAs expressed during retinal development. We conclude that Dicer is necessary for the developmental change in competence of the retinal progenitor cells.post to: CiteULike

Publication Date: 2010 Mar 17 PMID: 20237274Authors: Burns, S. P. - Xing, D. - Shelley, M. J. - Shapley, R. M.Journal: J NeurosciGamma-band peaks in the power spectrum of local field potentials (LFP) are found in multiple brain regions. It has been theorized that gamma oscillations may serve as a 'clock' signal for the purposes of precise temporal encoding of information and 'binding' of stimulus features across regions of the brain. Neurons in model networks may exhibit periodic spike firing or synchronized membrane potentials that give rise to a gamma-band oscillation that could operate as a 'clock'. The phase of the oscillation in such models is conserved over the length of the stimulus. We define these types of oscillations to be 'autocoherent'. We investigated the hypothesis that autocoherent oscillations are the basis of the experimentally observed gamma-band peaks: the autocoherent oscillator (ACO) hypothesis. To test the ACO hypothesis, we developed a new technique to analyze the autocoherence of a time-varying signal. This analysis used the continuous Gabor transform to examine the time evolution of the phase of each frequency component in the power spectrum. Using this analysis method, we formulated a statistical test to compare the ACO hypothesis with measurements of the LFP in macaque primary visual cortex, V1. The experimental data were not consistent with the ACO hypothesis. Gamma-band activity recorded in V1 did not have the properties of a 'clock' signal during visual stimulation. We propose instead that the source of the gamma-band spectral peak is the resonant V1 network driven by random inputs.post to: CiteULike

Publication Date: 2010 Mar 17 PMID: 20237273Authors: Snyder, A. C. - Foxe, J. J.Journal: J NeurosciRetinotopically specific increases in alpha-band ( approximately 10 Hz) oscillatory power have been strongly implicated in the suppression of processing for irrelevant parts of the visual field during the deployment of visuospatial attention. Here, we asked whether this alpha suppression mechanism also plays a role in the nonspatial anticipatory biasing of feature-based attention. Visual word cues informed subjects what the task-relevant feature of an upcoming visual stimulus (S2) was, while high-density electroencephalographic recordings were acquired. We examined anticipatory oscillatory activity in the Cue-to-S2 interval ( approximately 2 s). Subjects were cued on a trial-by-trial basis to attend to either the color or direction of motion of an upcoming dot field array, and to respond when they detected that a subset of the dots differed from the majority along the target feature dimension. We used the features of color and motion, expressly because they have well known, spatially separated cortical processing areas, to distinguish shifts in alpha power over areas processing each feature. Alpha power from dorsal regions increased when motion was the irrelevant feature (i.e., color was cued), and alpha power from ventral regions increased when color was irrelevant. Thus, alpha-suppression mechanisms appear to operate during feature-based selection in much the same manner as has been shown for space-based attention.post to: CiteULike

Publication Date: 2010 Mar 17 PMID: 20237272Authors: Faedo, A. - Borello, U. - Rubenstein, J. L.Journal: J NeurosciA fundamental question in developmental biology is how signaling pathways establish a transcription factor code that controls cell proliferation, regional fate and cell fate. Morphogenesis of the rostral telencephalon is controlled in part by Fgf signaling from the rostral patterning center. How Fgf signaling is regulated in the telencephalon is critical for understanding cerebral cortex formation. Here we show that mouse Sprouty1 and Sprouty2 (Spry1-2), which encode negative feedback regulators of Fgf signaling, are affecting cortical proliferation, differentiation, and the expression of genes regulating progenitor identity in the ventricular zone. In addition, Spry2 has a later function in regulating the MAPK pathway, proliferation, and gene expression in the cortex at mid-neurogenesis. Finally, we provide evidence that Coup-TFI, a transcription factor that promotes caudal fate, does so through repressing Fgf signaling, in part by promoting Spry expression.post to: CiteULike

Publication Date: 2010 Mar 17 PMID: 20237271Authors: Yabut, O. - Domogauer, J. - D'Arcangelo, G.Journal: J NeurosciDyrk1A is a member of the mammalian Dyrk [dual-specificity tyrosine-(Y)-phosphorylation regulated kinase] family of protein kinases that is expressed at high levels in the brain, but its role in the development and function of this organ is not well understood. The human DYRK1A gene is located on trisomic chromosome 21 in Down syndrome (DS) patients, leading to its overexpression. Dyrk1A is also overexpressed in animal models of DS and in gene-specific transgenic mice that consistently exhibit cognitive impairment. To elucidate the cellular and molecular mechanisms that are affected by increased levels of Dyrk1A in the developing brain, we overexpressed this kinase in the embryonic mouse neocortex using the in utero electroporation technique. We found that Dyrk1A overexpression inhibits neural cell proliferation and promotes premature neuronal differentiation in the developing cerebral cortex without affecting cell fate and layer positioning. These effects are dependent on the Dyrk1A kinase activity and are mediated by the nuclear export and degradation of cyclin D1. This study identifies specific Dyrk1A-induced mechanisms that disrupt the normal process of corticogenesis and possibly contribute to cognitive impairment observed in DS patients and animal models.post to: CiteULike

Publication Date: 2010 Mar 17 PMID: 20237270Authors: Battista, D. - Rutishauser, U.Journal: J NeurosciCells generated in the subventricular zone give rise to neuroblasts that migrate to the olfactory bulb (OB) along the rostral migratory stream (RMS). The polysialylated form of neural cell adhesion molecule (PSA-NCAM) is expressed by these cells, and has been shown to both promote their migration and suppress differentiation induced by NCAM. In the present study, enzymatic removal of PSA from these neuroblasts using PSA-specific endoneuraminidase has been found not only to disrupt the tangential migration and cellular organization of the RMS, but also to cause a massive dispersion of BrdU (5-bromo-2'-deoxyuridine)-labeled neuroblasts into surrounding brain regions, including cortex and striatum. These dispersed cells are capable of differentiation, some into mature neurons, and could potentially be of value in the repair of CNS injury. Although the removal of PSA by genetic deletion of NCAM also results in a smaller OB and a swollen RMS, the cells do not escape the RMS in large numbers. These findings suggest that the presence of NCAM without PSA plays a role in the dispersion process, possibly by inducing a new pattern of migration associated with NCAM-dependent differentiation.post to: CiteULike

Publication Date: 2010 Mar 17 PMID: 20237269Authors: Golden, J. P. - Hoshi, M. - Nassar, M. A. - Enomoto, H. - Wood, J. N. - Milbrandt, J. - Gereau, R. W. 4th - Johnson, E. M. Jr - Jain, S.Journal: J NeurosciSmall unmyelinated sensory neurons classified as nociceptors are divided into two subpopulations based on phenotypic differences, including expression of neurotrophic factor receptors. Approximately half of unmyelinated nociceptors express the NGF receptor TrkA, and half express the GDNF family ligand (GFL) receptor Ret. The function of NGF/TrkA signaling in the TrkA population of nociceptors has been extensively studied, and NGF/TrkA signaling is a well established mediator of pain. The GFLs are analgesic in models of neuropathic pain emphasizing the importance of understanding the physiological function of GFL/Ret signaling in nociceptors. However, perinatal lethality of Ret-null mice has precluded the study of the physiological role of GFL/Ret signaling in the survival, maintenance, and function of nociceptors in viable mice. We deleted Ret exclusively in nociceptors by crossing nociceptor-specific Na(v)1.8 Cre and Ret conditional mice to produce Ret-Na(v)1.8 conditional knock-out (CKO) mice. Loss of Ret exclusively in nociceptors results in a reduction in nociceptor number and size, indicating that Ret signaling is important for the survival and trophic support of these cells. Ret-Na(v)1.8 CKO mice exhibit reduced epidermal innervation but normal central projections. In addition, Ret-Na(v)1.8 CKO mice have increased sensitivity to cold and increased formalin-induced pain, demonstrating that Ret signaling modulates the function of nociceptors in vivo. Enhanced inflammation-induced pain may be mediated by decreased prostatic acid phosphatase (PAP), as PAP levels are markedly reduced in Ret-Na(v)1.8 CKO mice. The results of this study identify the physiological role of endogenous Ret signaling in the survival and function of nociceptors.post to: CiteULike

Publication Date: 2010 Mar 17 PMID: 20237268Authors: Biswas, S. C. - Zhang, Y. - Iyirhiaro, G. - Willett, R. T. - Rodriguez Gonzalez, Y. - Cregan, S. P. - Slack, R. S. - Park, D. S. - Greene, L. A.Journal: J NeurosciDevelopmental and pathological death of neurons requires activation of a defined pathway of cell cycle proteins. However, it is unclear how this pathway is regulated and whether it is relevant in vivo. A screen for transcripts robustly induced in cultured neurons by DNA damage identified Sertad1, a Cdk4 (cyclin-dependent kinase 4) activator. Sertad1 is also induced in neurons by nerve growth factor (NGF) deprivation and Abeta (beta-amyloid). RNA interference-mediated downregulation of Sertad1 protects neurons in all three death models. Studies of NGF withdrawal indicate that Sertad1 is required to initiate the apoptotic cell cycle pathway since its knockdown blocks subsequent pathway events. Finally, we find that Sertad1 expression is required for developmental neuronal death in the cerebral cortex. Sertad1 thus appears to be essential for neuron death in trophic support deprivation in vitro and in vivo and in models of DNA damage and Alzheimer's disease. It may therefore be a suitable target for therapeutic intervention.post to: CiteULike

Publication Date: 2010 Mar 17 PMID: 20237267Authors: van Meer, M. P. - van der Marel, K. - Wang, K. - Otte, W. M. - El Bouazati, S. - Roeling, T. A. - Viergever, M. A. - Berkelbach van der Sprenkel, J. W. - Dijkhuizen, R. M.Journal: J NeurosciDespite the success of functional imaging to map changes in brain activation patterns after stroke, spatiotemporal dynamics of cerebral reorganization in correlation with behavioral recovery remain incompletely characterized. Here, we applied resting-state functional magnetic resonance imaging (rs-fMRI) together with behavioral testing to longitudinally assess functional connectivity within neuronal networks, in relation to changes in associated function after unilateral stroke in rats. Our specific goals were (1) to identify temporal alterations in functional connectivity within the bilateral cortical sensorimotor system and (2) to elucidate the relationship between those alterations and changes in sensorimotor function. Our study revealed considerable loss of functional connectivity between ipsilesional and contralesional primary sensorimotor cortex regions, alongside significant sensorimotor function deficits in the first days after stroke. The interhemispheric functional connectivity restored in the following weeks, but remained significantly reduced up to 10 weeks after stroke in animals with lesions that comprised subcortical and cortical tissue, whereas transcallosal neuroanatomical connections were preserved. Intrahemispheric functional connectivity between primary somatosensory and motor cortex areas was preserved in the lesion border zone and moderately enhanced contralesionally. The temporal pattern of changes in functional connectivity between bilateral primary motor and somatosensory cortices correlated significantly with the evolution of sensorimotor function scores. Our study (1) demonstrates that poststroke loss and recovery of sensorimotor function is associated with acute deterioration and subsequent retrieval of interhemispheric functional connectivity within the sensorimotor system and (2) underscores the potential of rs-fMRI to assess spatiotemporal characteristics of functional brain reorganization that may underlie behavioral recovery after brain injury.post to: CiteULike

Publication Date: 2010 Mar 17 PMID: 20237266Authors: Kroes, M. C. - Strange, B. A. - Dolan, R. J.Journal: J NeurosciMemory enhancement for emotional events is dependent on amygdala activation and noradrenergic modulation during learning. A potential role for noradrenaline (NE) during retrieval of emotional memory is less well understood. Here, we report that administration of the beta-adrenergic receptor antagonist propranolol at retrieval abolishes a declarative memory enhancement for emotional items. Critically, this effect persists at a subsequent 24 h memory test, in the absence of propranolol. Thus, these findings extend our current understanding of the role of NE in emotional memory to encompass effects at retrieval, and provide face validity to clinical interventions using beta-adrenergic antagonists in conjunction with reactivation of unwanted memories in anxiety-related disorders.post to: CiteULike

Publication Date: 2010 Mar 17 PMID: 20237265Authors: Huxtable, A. G. - Zwicker, J. D. - Alvares, T. S. - Ruangkittisakul, A. - Fang, X. - Hahn, L. B. - Posse de Chaves, E. - Baker, G. B. - Ballanyi, K. - Funk, G. D.Journal: J NeurosciGlia modulate neuronal activity by releasing transmitters in a process called gliotransmission. The role of this process in controlling the activity of neuronal networks underlying motor behavior is unknown. ATP features prominently in gliotransmission; it also contributes to the homeostatic ventilatory response evoked by low oxygen through mechanisms that likely include excitation of preBotzinger complex (preBotC) neural networks, brainstem centers critical for breathing. We therefore inhibited glial function in rhythmically active inspiratory networks in vitro to determine whether glia contribute to preBotC ATP sensitivity. Glial toxins markedly reduced preBotC responses to ATP, but not other modulators. Furthermore, since preBotC glia responded to ATP with increased intracellular Ca(2+) and glutamate release, we conclude that glia contribute to the ATP sensitivity of preBotC networks, and possibly the hypoxic ventilatory response. Data reveal a role for glia in signal processing within brainstem motor networks that may be relevant to similar networks throughout the neuraxis.post to: CiteULike

Publication Date: 2010 Mar 17 PMID: 20237264Authors: Kim, H. J. - Lee, J. H. - Kim, S. J. - Oh, G. S. - Moon, H. D. - Kwon, K. B. - Park, C. - Park, B. H. - Lee, H. K. - Chung, S. Y. - Park, R. - So, H. S.Journal: J NeurosciIn our previous study, we clearly demonstrated the roles of pro-inflammatory cytokines, including tumor necrosis factor-alpha, interleukin-1beta (IL-1beta), and IL-6, and subsequent reactive oxygen species (ROS) generation on the pathogenesis of cisplatin ototoxicity in vitro and in vivo. ROS generation in cisplatin-treated HEI-OC1 auditory cells was also correlated with changing mitochondrial membrane potential. However, the roles of NADPH oxidase in cisplatin-induced ROS generation and ototoxicity have not been fully elucidated. Herein, immunohistochemical studies demonstrated that treatment of cisplatin induced the expression of NADPH oxidase isoforms NOX-1 and NOX-4 in HEI-OC1 auditory cells. Expression of mRNA for NOX-1, NOX-4, NOXO1, NOXA1, p47(phox), and p67(phox) was also increased. Inhibition of NADPH oxidase with diphenyleniodonium chloride or apocynin abolished ROS production and the subsequent apoptotic cell death in cisplatin-treated cells. Furthermore, suppression of NOX1 and NOX4 expression by small interfering RNA transfection markedly abolished the cytotoxicity and ROS generation by cisplatin. Together, our data suggest that ROS generated, in part, through the activation of NADPH oxidase plays an essential role in cisplatin ototoxicity.post to: CiteULike

Publication Date: 2010 Mar 17 PMID: 20237263Authors: Kaneko, M. - Koike, H. - Saito, R. - Kitamura, Y. - Okuma, Y. - Nomura, Y.Journal: J NeurosciEndoplasmic reticulum-associated degradation (ERAD) is a system by which proteins accumulated in the endoplasmic reticulum (ER) are retrotranslocated to the cytosol and degraded by the ubiquitin-proteasome pathway. HRD1 is expressed in brain neurons and acts as an ERAD ubiquitin ligase. Amyloid precursor protein (APP) is processed into amyloid-beta peptides (Abetas) that form plaque deposits in the brains of Alzheimer's disease (AD) patients. We found significantly decreased HRD1 protein levels in the cerebral cortex of AD patients. HRD1 colocalized with APP in brain neurons and interacted with APP through the proline-rich region of HRD1. HRD1 promoted APP ubiquitination and degradation, resulting in decreased generation of Abeta. Furthermore, suppression of HRD1 expression induced APP accumulation that led to increased production of Abeta associated with ER stress. Immunohistochemical analysis revealed that suppression of HRD1 expression inhibited APP aggresome formation, resulting in apoptosis. In addition, we found that the ATF6- and XBP1-induced upregulation of ERAD led to APP degradation and reduced Abeta production. These results suggest that the breakdown of HRD1-mediated ERAD causes Abeta generation and ER stress, possibly linked to AD.post to: CiteULike

Publication Date: 2010 Mar 17 PMID: 20237262Authors: Sun, J. - Chu, Z. - Moenter, S. M.Journal: J NeurosciA robust surge of gonadotropin-releasing hormone (GnRH) release triggers the luteinizing hormone surge that induces ovulation. The GnRH surge is attributable to estradiol feedback, but the mechanisms are incompletely understood. Voltage-gated calcium channels (VGCCs) regulate hormone release and neuronal excitability, and may be part of the surge-generating mechanism. We examined VGCCs of GnRH neurons in brain slices from a model exhibiting daily luteinizing hormone surges. Mice were ovariectomized (OVX), and a subset was treated with estradiol implants (OVX+E). OVX+E mice exhibit negative feedback in the A.M. and positive feedback in the P.M. GnRH neurons express prominent high-voltage-activated (HVA) and small low-voltage-activated (LVA) macroscopic (whole-cell) Ca currents (I(Ca)). LVA-mediated currents were not altered by estradiol or time of day. In contrast, in OVX+E mice, HVA-mediated currents varied with time of day; HVA currents in cells from OVX+E mice were lower than those in cells from OVX mice in the A.M. but were higher in the P.M. These changes were attributable to diurnal alternations in L- and N-type components. There were no diurnal changes in any aspect of HVA-mediated I(Ca) in OVX mice. Acute in vitro treatment of cells from OVX and OVX+E mice with estradiol rapidly increased HVA currents primarily through L- and R-type VGCCs by activating estrogen receptor beta and GPR30, respectively. These results suggest multiple mechanisms contribute to the overall feedback regulation of HVA-mediated I(Ca) by estradiol. In combination with changes in synaptic inputs to GnRH neurons, these intrinsic changes in GnRH neurons may play critical roles in estradiol feedback.post to: CiteULike

Publication Date: 2010 Mar 17 PMID: 20237261Authors: Wang, N. - Kwan, C. - Gong, X. - de Chaves, E. P. - Tse, A. - Tse, F. W.Journal: J NeurosciChanges in cellular cholesterol can affect exocytosis, but the influence of cholesterol in fusion pore kinetics is unclear. Using carbon fiber amperometry, we monitored quantal catecholamine release from rat chromaffin cells. To bypass any possible effect of cholesterol perturbation on ion channels or the colocalization of voltage-gated Ca(2+) channels with sites of exocytosis, exocytosis was stimulated via uniform elevation of cytosolic [Ca(2+)] (with whole-cell dialysis of a Ca(2+)-buffered solution). Under this condition, alterations of cellular cholesterol affected neither the mean number of amperometric events triggered per cell nor their quantal size and the kinetics of their main spike (which reflects the rapid release during and after rapid fusion pore dilation). In contrast, the reduction of cellular cholesterol shortened the "prespike foot" signals (which reflect the leakage of catecholamine via a semi-stable fusion pore) and reduced the proportion of "stand-alone foot" signals (which reflect the release via a flickering fusion pore that may close before it dilates significantly), whereas an oversupply of cholesterol had opposite effects. Acute extraction of cholesterol from the cytosol (via whole-cell dialysis of a cholesterol extractor) also shortened the prespike foot signals and reduced the proportion of stand-alone foot signals, but acute extracellular application of cholesterol extractor or "soluble" cholesterol had no effect. Our data raise the possibility that cholesterol molecules, particularly those in the cytoplasmic leaflet, helps to constrain the narrow waistline of a semi-stable fusion pore while it is flickering or before it starts to dilate rapidly.post to: CiteULike

Publication Date: 2010 Mar 17 PMID: 20237260Authors: Skorupski, P. - Chittka, L.Journal: J NeurosciFast detection of visual change can be mediated by visual processes that ignore chromatic aspects of the visual signal, relying on inputs from a single photoreceptor class (or pooled input from similar classes). There is an established link between photoreceptor processing speed (in achromatic vision) and visual ecology. Highly maneuverable flies, for example, have the fastest know photoreceptors, relying on metabolically expensive membrane conductances to boost performance. Less active species forgo this investment and their photoreceptors are correspondingly slower. However, within a species, additional classes of photoreceptors are required to extract chromatic information, and the question therefore arises as to whether there might be within-species differences in processing speed between photoreceptors involved in chromatic processing compared with those feeding into fast achromatic visual systems. We used intracellular recording to compare light-adapted impulse responses in three spectral classes of photoreceptor in the bumblebee. Green-sensitive photoreceptors, which are known to provide achromatic contrast for motion detection, generated the fastest impulse responses (half-width, Deltat = 7.9 +/- 1.1 ms). Blue- and UV-sensitive photoreceptors (which are involved in color vision) were significantly slower (9.8 +/- 1.2 and 12.3 +/- 1.8 ms, respectively). The faster responses of green photoreceptors are in keeping with their role in fast achromatic vision. However, blue and UV photoreceptors are still relatively fast in comparison with many other insect species, as well as vertebrate cones, suggesting a significant investment in photoreceptor processing for color vision in bees. We discuss this finding in relation to bees' requirement for accurate learning of flower color, especially in conditions of variable luminance contrast.post to: CiteULike

Publication Date: 2010 Mar 17 PMID: 20237259Authors: Kawamura, M. Jr - Ruskin, D. N. - Masino, S. A.Journal: J NeurosciMetabolic perturbations that decrease or limit blood glucose-such as fasting or adhering to a ketogenic diet-reduce epileptic seizures significantly. To date, the critical links between altered metabolism and decreased neuronal activity remain unknown. More generally, metabolic changes accompany numerous CNS disorders, and the purines ATP and its core molecule adenosine are poised to translate cell energy into altered neuronal activity. Here we show that nonpathological changes in metabolism induce a purinergic autoregulation of hippocampal CA3 pyramidal neuron excitability. During conditions of sufficient intracellular ATP, reducing extracellular glucose induces pannexin-1 hemichannel-mediated ATP release directly from CA3 neurons. This extracellular ATP is dephosphorylated to adenosine, activates neuronal adenosine A(1) receptors, and, unexpectedly, hyperpolarizes neuronal membrane potential via ATP-sensitive K(+) channels. Together, these data delineate an autocrine regulation of neuronal excitability via ATP and adenosine in a seizure-prone subregion of the hippocampus and offer new mechanistic insight into the relationship between decreased glucose and increased seizure threshold. By establishing neuronal ATP release via pannexin hemichannels, and hippocampal adenosine A(1) receptors coupled to ATP-sensitive K(+) channels, we reveal detailed information regarding the relationship between metabolism and neuronal activity and new strategies for adenosine-based therapies in the CNS.post to: CiteULike

Publication Date: 2010 Mar 17 PMID: 20237258Authors: Sowell, E. R. - Leow, A. D. - Bookheimer, S. Y. - Smith, L. M. - O'Connor, M. J. - Kan, E. - Rosso, C. - Houston, S. - Dinov, I. D. - Thompson, P. M.Journal: J NeurosciHere we investigate the effects of prenatal exposure to methamphetamine (MA) on local brain volume using magnetic resonance imaging. Because many who use MA during pregnancy also use alcohol, a known teratogen, we examined whether local brain volumes differed among 61 children (ages 5-15 years), 21 with prenatal MA exposure, 18 with concomitant prenatal alcohol exposure (the MAA group), 13 with heavy prenatal alcohol but not MA exposure (ALC group), and 27 unexposed controls. Volume reductions were observed in both exposure groups relative to controls in striatal and thalamic regions bilaterally and in right prefrontal and left occipitoparietal cortices. Striatal volume reductions were more severe in the MAA group than in the ALC group, and, within the MAA group, a negative correlation between full-scale intelligence quotient (FSIQ) scores and caudate volume was observed. Limbic structures, including the anterior and posterior cingulate, the inferior frontal gyrus (IFG), and ventral and lateral temporal lobes bilaterally, were increased in volume in both exposure groups. Furthermore, cingulate and right IFG volume increases were more pronounced in the MAA than ALC group. Discriminant function analyses using local volume measurements and FSIQ were used to predict group membership, yielding factor scores that correctly classified 72% of participants in jackknife analyses. These findings suggest that striatal and limbic structures, known to be sites of neurotoxicity in adult MA abusers, may be more vulnerable to prenatal MA exposure than alcohol exposure and that more severe striatal damage is associated with more severe cognitive deficit.post to: CiteULike