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    ABSTRACT: Information concerning the roles of different brain regions in recognition memory processes is reviewed. The review concentrates on findings from spontaneous recognition memory tasks performed by rats, including memory for single objects, locations, object-location associations and temporal order. Particular emphasis is given to the potential roles of different regions in the circuit of interacting structures involving the perirhinal cortex, hippocampus, medial prefrontal cortex and medial dorsal thalamus in recognition memory for the association of objects and places. It is concluded that while all structures in this circuit play roles critical to such memory, these roles can potentially be differentiated and differences in the underlying synaptic and biochemical processes involved in each region are beginning to be uncovered.
    Behavioural Brain Research 10/2014; 285. DOI:10.1016/j.bbr.2014.09.050
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    ABSTRACT: Platelets store and secrete the chemokine stromal cell-derived factor (SDF)-1α upon platelet activation, but the ability of platelet-derived SDF-1α to signal in an autocrine/paracrine manner mediating functional platelet responses relevant to thrombosis and haemostasis is unknown. We sought to explore the role of platelet-derived SDF-1α and its receptors, CXCR4 and CXCR7 in facilitating platelet activation and determine the mechanism facilitating SDF-1α-mediated regulation of platelet function. Using human washed platelets, CXCR4 inhibition, but not CXCR7 blockade significantly abrogated collagen-mediated platelet aggregation, dense granule secretion and thromboxane (Tx) A2 production. Time-dependent release of SDF-1α from collagen-activated platelets supports a functional role for SDF-1α in this regard. Using an in vitro whole blood perfusion assay, collagen-induced thrombus formation was substantially reduced with CXCR4 inhibition. In washed platelets, recombinant SDF-1α in the range of 20-100ng/mL(-1) could significantly enhance platelet aggregation responses to a threshold concentration of collagen. These enhancements were completely dependent on CXCR4, but not CXCR7, which triggered TxA2 production and dense granule secretion. Rises in cAMP were significantly blunted by SDF-1α, which could also enhance collagen-mediated Ca(2+) mobilisation, both of which were mediated by CXCR4. This potentiating effect of SDF-1α primarily required TxA2 signalling acting upstream of dense granule secretion, whereas blockade of ADP signalling could only partially attenuate SDF-1α-induced platelet activation. Therefore, this study supports a potentially novel autocrine/paracrine role for platelet-derived SDF-1α during thrombosis and haemostasis, through a predominantly TxA2-dependent and ADP-independent pathway.
    Cellular Signalling 10/2014; 27(1). DOI:10.1016/j.cellsig.2014.09.021
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    ABSTRACT: Calcium (Ca2+) and Calmodulin (CaM)-dependent serine/threonine kinase II (CaMKII) plays a central role in synaptic plasticity and memory due to its ability to phosphorylate itself and regulate its own kinase activity. Autophosphorylation at threonine 287 (T287) switches CaMKII to a Ca2+ independent and constitutively active state replicated by overexpression of a phosphomimetic CaMKII-T287D transgene or blocked by expression of a T287A transgene. A second pair of sites, T306 T307 in the CaM binding region once autophosphorylated, prevents CaM binding and inactivates the kinase during synaptic plasticity and memory, and can be blocked by a TT306/7AA transgene. Recently the synaptic scaffolding molecule called CASK (Ca2+/CaM-associated serine kinase) has been shown to control both sets of CaMKII autophosphorylation events during neuronal growth, Ca2+ signaling and memory in Drosophila. Deletion of either full length CASK or just its CaMK-like and L27 domains removed middle-term memory (MTM) and long-term memory (LTM), with CASK function in the α′/ß′ mushroom body neurons being required for memory. In a similar manner directly changing the levels of CaMKII autophosphorylation (T287D, T287A, or TT306/7AA) in the α′/ß′ neurons also removed MTM and LTM. In the CASK null mutant expression of either the Drosophila or human CASK transgene in the α′/ß′ neurons was found to completely rescue memory, confirming that CASK signaling in α′/β′ neurons is necessary and sufficient for Drosophila memory formation and that the neuronal function of CASK is conserved between Drosophila and human. Expression of human CASK in Drosophila also rescued the effect of CASK deletion on the activity state of CaMKII, suggesting that human CASK may also regulate CaMKII autophosphorylation. Mutations in human CASK have recently been shown to result in intellectual disability and neurological defects suggesting a role in plasticity and learning possibly via regulation of CaMKII autophosphorylation.
    Frontiers in Neuroscience 06/2014; 8:178. DOI:10.3389/fnins.2014.00178
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    ABSTRACT: Experiences with a high degree of emotional salience are better remembered than events that have little emotional context and the amygdala is thought to play an important role in this enhancement of memory. Visual recognition memory relies on synaptic plasticity in the perirhinal cortex but little is known about the mechanisms that may underlie emotional enhancement of this form of memory. There is good evidence that noradrenaline acting via β-adrenoceptors can enhance memory consolidation. In the present study we examine the role of β-adrenoceptors in synaptic plasticity at the amygdala-perirhinal pathway (LA-PRh) and compare this to mechanisms of intra-perirhinal (PRh-PRh) synaptic plasticity. We demonstrate that activity-dependent PRh-PRh LTP does not rely on β1- or β2-adrenoceptors and that LA-PRh LTP relies on β1-adrenoceptors but not β2-adrenoceptors. We further demonstrate that application of the β-adrenoceptor agonist isoprenaline produces lasting PRh-PRh potentiation but only transient potentiation at the LA-PRh input. However, at the LA-PRh input, combining stimulation that is subthreshold for LTP induction with isoprenaline results in long-lasting potentiation. Isoprenaline-induced and isoprenaline plus subthreshold stimulation-induced potentiation in the PRh-PRh and LA-PRh inputs, respectively were both dependent on activation of NMDARs, voltage gated calcium channels and PKA. Understanding the mechanisms of amygdala-perirhinal cortex plasticity will allow a greater understanding of how emotionally-charged events are remembered.
    Neuroscience 05/2014; 273(100). DOI:10.1016/j.neuroscience.2014.04.070
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    ABSTRACT: Defective epithelial ion transport is the hallmark of the life-limiting genetic disease cystic fibrosis (CF). This abnormality is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), the ATP-binding cassette transporter that functions as a ligand-gated anion channel. Since the identification of the CFTR gene, almost 2,000 disease-causing mutations associated with a spectrum of clinical phenotypes have been reported, but the majority remain poorly characterised.Studiesof a small number of mutations including the most common, F508del-CFTR, have identified six general mechanisms of CFTR dysfunction. Here, we review selectively progress to understand how CF mutations disrupt CFTR processing, stability and function. We explore CFTR structure and function to explain the molecular mechanisms of CFTR dysfunction and highlight new knowledge of disease pathophysiology emerging from large animal models of CF. Understanding CFTR dysfunction is crucial to the development of transformational therapies for CF patients.
    The international journal of biochemistry & cell biology 04/2014; 52. DOI:10.1016/j.biocel.2014.04.001
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    ABSTRACT: Although recent neuroanatomical evidence has demonstrated closed-loop connectivity between prefrontal cortex and the cerebellum, the physiology of cerebello-cerebral circuits and the extent to which cerebellar output modulates neuronal activity in neocortex during behavior remain relatively unexplored. We show that electrical stimulation of the contralateral cerebellar fastigial nucleus (FN) in awake, behaving rats evokes distinct local field potential (LFP) responses (onset latency ~13 ms) in the prelimbic (PrL) subdivision of the medial prefrontal cortex. Trains of FN stimulation evoke heterogeneous patterns of response in putative pyramidal cells in frontal and prefrontal regions in both urethane-anesthetized and awake, behaving rats. However, the majority of cells showed decreased firing rates during stimulation and subsequent rebound increases; more than 90% of cells showed significant changes in response. Simultaneous recording of on-going LFP activity from FN and PrL while rats were at rest or actively exploring an open field arena revealed significant network coherence restricted to the theta frequency range (5-10 Hz). Granger causality analysis indicated that this coherence was significantly directed from cerebellum to PrL during active locomotion. Our results demonstrate the presence of a cerebello-prefrontal pathway in rat and reveal behaviorally dependent coordinated network activity between the two structures, which could facilitate transfer of sensorimotor information into ongoing neocortical processing during goal directed behaviors.
    Frontiers in Systems Neuroscience 02/2014; 8:4. DOI:10.3389/fnsys.2014.00004
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    ABSTRACT: Myocardial damage during ischaemia-reperfusion is partly mediated by the accelerated production of reactive oxygen species (ROS). Under physiological conditions, antioxidants, such as catalase, regulate ROS levels. The capacity for elevated catalase levels to offer cardio-protective benefits to hearts exposed to ischaemia-reperfusion has been demonstrated previously. However, no studies thus far have selectively inhibited catalase in isolated cardiomyocytes, This study investigated the importance of endogenous catalase in regulating ROS generation basally and during oxidative stress by using the catalase inhibitor, 3-amino-1,2,4-triazole (3-AT). Cardiomyocytes were isolated from adult rat hearts. Cells were loaded with 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate acetyl ester (CM-H2DCFDA) in the presence or absence of different concentrations of 3-AT (0-40 mM). The ROS production rate in quiescent cardiomyocytes was estimated by measuring the fluorescence signal emitted by 5-(and 6)-chloromethyl-2',7'-dichlorofluorescein, using a fluorescence plate reader. Incubation with 3-AT did not affect the ROS generation rate under basal conditions. However, upon addition of 10 mM H2O2, 3-AT administration resulted in a dose-dependent increase in the ROS generation rate (P < 0.0001). This increase plateaued with 20 mM 3-AT, which resulted in a near-tripling of the mean ROS generation rate compared to 0 mM 3-AT (P < 0.01). This study demonstrates that endogenous catalase has a limited contribution to the regulation of ROS levels in resting, unstressed cardiomyocytes. However, its activity appears important in reducing the ROS generation rate when intracellular H2O2 levels are elevated. We conclude that, despite the low levels of endogenous catalase present in cardiomyocytes, its regulation of ROS generation is very important during conditions of significant oxidative stress.
    Heart (British Cardiac Society) 01/2014; 100(Suppl_1):A3. DOI:10.1136/heartjnl-2013-305297.5
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    ABSTRACT: L-type Ca channels (LTCC), which play a key role in cardiac excitation-contraction coupling, are located predominantly at the transverse (t-) tubules in ventricular myocytes. Caveolae and the protein caveolin-3 (Cav-3) are also present at the t-tubules and have been implicated in localizing a number of signaling molecules, including protein kinase A (PKA) and β2-adrenoreceptors. The present study investigated whether disruption of Cav-3 binding to its endogenous binding partners influenced LTCC activity. Ventricular myocytes were isolated from male Wistar rats and LTCC current (ICa) recorded using the whole-cell patch-clamp technique. Incubation of myocytes with a membrane-permeable peptide representing the scaffolding domain of Cav-3 (C3SD) reduced basal ICa amplitude in intact, but not detubulated, myocytes, and attenuated the stimulatory effects of the β2-adrenergic agonist zinterol on ICa. The PKA inhibitor H-89 also reduced basal ICa; however, the inhibitory effects of C3SD and H-89 on basal ICa amplitude were not summative. Under control conditions, myocytes stained with antibody against phosphorylated LTCC (pLTCC) displayed a striated pattern, presumably reflecting localization at the t-tubules. Both C3SD and H-89 reduced pLTCC staining at the z-lines but did not affect staining of total LTCC or Cav-3. These data are consistent with the idea that the effects of C3SD and H-89 share a common pathway, which involves PKA and is maximally inhibited by H-89, and suggest that Cav-3 plays an important role in mediating stimulation of ICa via PKA-induced phosphorylation under basal conditions, and in response to β2-adrenoceptor stimulation.
    Journal of Molecular and Cellular Cardiology 01/2014; 68(100). DOI:10.1016/j.yjmcc.2013.12.026
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    ABSTRACT: The 8-15 Hz thalamocortical oscillations known as sleep spindles are a universal feature of mammalian non-REM sleep, during which they are presumed to shape activity-dependent plasticity in neocortical networks. The cortex is hypothesized to contribute to initiation and termination of spindles, but the mechanisms by which it implements these roles are unknown. We used dual-site local field potential and multiple single-unit recordings in the thalamic reticular nucleus (TRN) and medial prefrontal cortex (mPFC) of freely behaving rats at rest to investigate thalamocortical network dynamics during natural sleep spindles. During each spindle epoch, oscillatory activity in mPFC and TRN increased in frequency from onset to offset, accompanied by a consistent phase precession of TRN spike times relative to the cortical oscillation. In mPFC, the firing probability of putative pyramidal cells was highest at spindle initiation and termination times. We thus identified "early" and "late" cell subpopulations and found that they had distinct properties: early cells generally fired in synchrony with TRN spikes, whereas late cells fired in antiphase to TRN activity and also had higher firing rates than early cells. The accelerating and highly structured temporal pattern of thalamocortical network activity over the course of spindles therefore reflects the engagement of distinct subnetworks at specific times across spindle epochs. We propose that early cortical cells serve a synchronizing role in the initiation and propagation of spindle activity, whereas the subsequent recruitment of late cells actively antagonizes the thalamic spindle generator by providing asynchronous feedback.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 11/2013; 33(47):18469-18480. DOI:10.1523/JNEUROSCI.2197-13.2013
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    ABSTRACT: Somatostatin (SRIF), by acting mainly through sst2 and sst5 receptors, is a potent inhibitor of hormonal secretion by human anterior pituitary. However the pattern of protein expression of these SRIF receptors remains unknown during pituitary development. To get further insights into the physiological role of SRIF receptor in human development and pituitary function, the present study examined the developmental expression of the sst2 and sst5 receptors in the individual cell types of the anterior human pituitary. Thirteen fetal human pituitaries between 13 to 38 weeks of gestation (WG) were investigated by double-labeling immunofluorescence with antibodies raised against sst2 or sst5 receptors and GH, LH, FSH, TSH or Pro-opiomelanocortin (POMC) proteins. SRIF immunoreactivity in hypothalamus and median eminence was investigated at the same developmental ages. Immunoreactivity for the sst2 receptor was evident as early as 13-15 WG and onward mainly in TSH, LH and FSH expressing cells, whereas sst5 immunoreactivity was apparent at the late development stages (35-38 WG). GH expressing cells mainly expressed sst5 immunoreactivity. SRIF positive fibers and cells were detected as soon as 13-16 GW in the hypothalamus and median eminence and their densities increased with gestational age. Early appearance of hypothalamic SRIF cells and fibers suggests a physiological link between SRIF and its receptors during pituitary development. While sst2 receptors might play a primary role on the differentiation and regulation of TSH, LH and FSH cells, sst5 receptors appear to be mainly involved in GH regulation from birth onward.
    Endocrinology 11/2013; 155(1). DOI:10.1210/en.2013-1683
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