Authors: Feng Yi, Shu-Su Liu, Fei Luo, Xue-Han Zhang, Bao-Ming Li
Published: May 23, 2013, 9:52 am
Abstract: Stimulation of α2A-adrenoceptors (ARs) in the prefrontal cortex (PFC) produces a beneficial effect on cognitive functions such as working memory. A previous study in our laboratory showed that α2A-AR stimulation suppresses excitatory synaptic transmission in layer V-VI pyramidal cells of the rat medial PFC (mPFC). However, the intracellular mechanism underlying the α2A-AR suppression remains unclear. In the present study, we recorded evoked excitatory postsynaptic current (eEPSC) in layer V-VI pyramidal cells of the mPFC, using whole-cell patch-clamp recording. We found that the α2A-AR agonist guanfacine significantly suppresses eEPSC in mPFC pyramidal cells. The α2A-AR inhibition is mediated by the Gi-cAMP-PKA-PP1-CaMKII-AMPAR signaling pathway, as such inhibition no longer exists when each step of this pathway is blocked with NF023, Rp-cAMP, PKI5–24 or H89, tautomycin, and KN-62 or KN-93, respectively.
Activation of α2A-adrenergic receptors suppresses excitatory synaptic transmission by postsynaptic mechanism. The inhibitory effect of α2A-adrenergic receptors activation is mediated mainly via Gi-cAMP-PKA-PP1-CaMKII-AMPAR pathway. This finding provides important information on acute neuromodulation of neocortical circuits, which may play roles in regulating cortical function.
Authors: Lukasz Piszczek, Kevin Schlax, Anna Wyrzykowska, Agnieszka Piszczek, Enrica Audero, Cornelius Thilo Gross
Published: May 23, 2013, 3:30 am
Abstract: The neurotransmitter serotonin plays an important role in modulating diverse behavioral traits. Mice lacking the serotonin 1A receptor (Htr1a) show elevated avoidance of novel open spaces, suggesting that it has a role in modulating anxiety behavior. Htr1a is a Gαi-coupled G-protein-coupled receptor expressed on serotonin neurons (auto-receptor), where it mediates negative feedback of serotonin neuron firing. Htr1a is also expressed on non-serotonin neurons (hetero-receptor) in diverse brain regions, where it mediates an inhibitory effect of serotonin on neuronal activity. Debate exists about which of these receptor populations is responsible for the modulatory effects of Htr1a on anxiety. Studies using tissue-specific transgenic expression have suggested that forebrain Htr1a hetero-receptors are sufficient to restore normal anxiety behavior to Htr1a knockout mice. At the same time, experiments using tissue-specific transgenic suppression of Htr1a expression have demonstrated that Htr1a auto-receptors, but not forebrain hetero-receptors, are necessary for normal anxiety behavior. One interpretation of these data is that multiple Htr1a receptor populations are involved in modulating anxiety. Here, we aimed to test this hypothesis by determining whether Htr1a auto-receptors are sufficient to restore normal anxiety to Htr1a knockout animals. Transgenic mice expressing Htr1a under the control of the tryptophan hydroxylase 2 (Tph2) promoter showed restored Htr1a-mediated serotonin negative feedback and hypothermia, but anxiety behavior indistinguishable from that of knockout mice. These data show that, in the absence of Htr1a hetero-receptors, auto-receptors are unable to have an impact on anxiety. When combined with previous data, these findings support the hypothesis that Htr1a auto-receptors are necessary, but not sufficient, to modulate anxiety.
Mice lacking the serotonin 1A receptor (Htr1a) show elevated avoidance of novel open spaces, suggesting that this receptor plays a role in modulating anxiety behavior. Here we show that mice carrying a transgene rescuing receptor expression exclusively in serotonin neurons (Htr1aRR mice) were not able to restore wild-type anxiety behavior. These findings can be reconciled if Htr1a autoreceptors and heteroreceptors modulate anxiety in a manner that depends on each other.
Authors: Kazuhiro Wada, Shin Hayase, Raimu Imai, Chihiro Mori, Masahiko Kobayashi, Wan-chun Liu, Miki Takahasi, Kazuo Okanoya
Published: May 23, 2013, 2:25 am
Abstract: In songbirds, a specialized neural system, the song system, is responsible for acquisition and expression of species-specific vocal patterns. We report evidence for differential gene expression between wild and domesticated strains having different learned vocal phenotypes. A domesticated strain of the wild white-rumped munia, the Bengalese finch, has a distinct song pattern with a more complicated syntax than the wild strain. We identified differential androgen receptor (AR) expression in basal ganglia nucleus Area X GABAergic neurons between the two strains, and within different domesticated populations. Differences in AR expression were correlated with the mean coefficient of variation of the inter-syllable duration in the two strains. Differential AR expression in Area X was observed before the initiation of singing, suggesting that inherited and/or early developmental mechanisms may affect expression within and between strains. However, there were no distinct differences in regions upstream of the AR start codon among all the birds in the study. In contrast, an epigenetic modification, DNA methylation state in regions upstream of AR in Area X, was observed to differ between strains and within domesticated populations. These results provide insight into the molecular basis of behavioral evolution through the regulation of hormone-related genes and demonstrate the potential association between epigenetic modifications and behavioral phenotype regulation.
AR was differentially expressed in striatum Area X GABAergic neurons between wild and domesticated songbird strains having different learned vocal phenotypes. Differences in AR expression were correlated with a song feature related to inter-syllable duration. DNA methylation in AR also differed between strains and within domesticated populations. These results provide insight into the molecular basis of behavioral evolution through the regulation of epigenetic modification.
Authors: Lior Botzer, Amir Karniel
Published: May 23, 2013, 1:11 am
Abstract: It has been suggested that the brain and in particular the cerebellum and motor cortex adapt to represent the environment during reaching movements under various visuomotor perturbations. It is well known that significant delay is present in neural conductance and processing; however, the possible representation of delay and adaptation to delayed visual feedback has been largely overlooked. Here we investigated the control of reaching movements in human subjects during an imposed visuomotor delay in a virtual reality environment. In the first experiment, when visual feedback was unexpectedly delayed, the hand movement overshot the end-point target, indicating a vision-based feedback control. Over the ensuing trials, movements gradually adapted and became accurate. When the delay was removed unexpectedly, movements systematically undershot the target, demonstrating that adaptation occurred within the vision-based feedback control mechanism. In a second experiment designed to broaden our understanding of the underlying mechanisms, we revealed similar after-effects for rhythmic reversal (out-and-back) movements. We present a computational model accounting for these results based on two adapted forward models, each tuned for a specific modality delay (proprioception or vision), and a third feedforward controller. The computational model, along with the experimental results, refutes delay representation in a pure forward vision-based predictor and suggests that adaptation occurred in the forward vision-based predictor, and concurrently in the state-based feedforward controller. Understanding how the brain compensates for conductance and processing delays is essential for understanding certain impairments concerning these neural delays as well as for the development of brain–machine interfaces.
We investigated the control of reaching movements during an imposed visuomotor delay. In a series of two experiments, subjects learned to reach and to perform rhythmic movements using a visual feedback cue to a spatial target. Our findings show that subjects can adapt to visual delay, and our computational model and simulations explain these results based on two adapted forward models and a third feedforward controller, while refuting delay representation in a pure forward vision-based predictor.
Authors: Sara Ailane, Philip Long, Peter Jenner, Sarah Rose
Published: May 22, 2013, 9:30 am
Abstract: The multifunctional protein osteopontin (OPN) is expressed in the substantia nigra (SN) and protects nigral dopaminergic neurones against toxic insult in animal models of Parkinson's disease, although the mechanisms involved are uncertain. In the periphery, OPN regulates inflammatory processes by interacting with integrin and CD44 receptors but the presence and distribution of these sites in SN is unknown. We investigated the expression of integrin receptor subunits and CD44 receptors in the normal SN and after induction of inflammation by lipopolysaccharide (LPS), and their interaction with OPN. In normal rat SN, integrin αv, β3 and β1, and CD44, receptors were expressed on neurones including TH-positive cells but not on glia. LPS administration induced a loss of TH-positive neurones in SN and increased expression of glial cells as shown by GFAP, OX-6 and ED-1 immunoreactivity. In LPS-lesioned SN, there was up-regulation of the expression of integrin β3 and CD44 receptors. Co-localisation studies showed that this related to their increased expression on OX-6-, ED-1- and GFAP-positive cells. Furthermore, OPN interacted with integrin and CD44 receptors in the normal rat SN as demonstrated by co-immunoprecipitation and pull-down techniques. These data show that integrin and CD44 receptors are present on neurones in normal rat SN and that they are up-regulated on glial cells following LPS-mediated inflammation in SN, suggesting that they are functionally important in the inflammatory process. The interaction of OPN with these receptors suggests a role in the neuroprotective effect of this protein in the LPS model of Parkinson's disease.
Integrin and CD44 receptors, that mediate actions of the potential neuroprotective protein OPN in the periphery, are expressed on dopaminergic neurons of the SN and interact with OPN in the brain. Following inflammation, the expression of these receptors is up-regulated and they are expressed on inflammatory cells implicating a role in regulating the inflammatory process in the SN and thus a potential target for neuroprotection in PD.