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39.10 Metabotropic glutamate receptor mediated long term depression involves AMPA receptor redistribution triggered by protein tyrosine phosphatases Gladding C M, Fitzjohn S M, Bashir Z I, Collingridge G L, Molnar E Medical Research Council Centre for Synaptic Plasticity; Department of Anatomy, University of Bristol, School of Medical Sciences, Bristol, BS8 1TD, United Kingdom Long-term depression (LTD) can be induced at hippocampal CA1 synapses, by activation of either N-methyl-D-aspartate receptors (NMDARs) or metabotropic glutamate receptors (mGluRs). Although NMDAR-LTD has been relatively well characterised, the molecular mechanisms underlying mGluR-LTD are still unknown. However, these can be investigated by bath application of the group 1 mGluR agonist (RS)-3,5-dihydroxyphenylglycine (DHPG). Previous studies have indicated that DHPG-LTD is calcium independent and does not require activation of CaMKII, protein kinases A or C or serine/threonine phosphatases. It does however require protein tyrosine phosphatases (PTPs), GƒÑq activation and involve internalisation of AMPA receptors (AMPARs) and NMDARs. In this study, 400 μm thick acute hippocampal slices were obtained from female Wistar rats (10-12 weeks of age), and incubated in 100 μM DHPG for 10 minutes, followed by immunoprecipitation of AMPARs and quantitative immunoblot analysis using an anti-phosphotyrosine antibody at different time-points. We have established that DHPG-LTD involves a transient tyrosine dephosphorylation of the GluR2 AMPAR subunit, and that this is blocked by prior application of the PTP inhibitor, orthovanadate. The total AMPAR content in the slices is unaffected in DHPG-LTD. AMPAR phosphotyrosine levels do not change significantly upon activation of NMDARs implying that the mechanism is specific to mGluR-LTD. The combination of cell surface biotin-labelling and immunoprecipitation revealed that tyrosine dephosphorylation is required for the trafficking of AMPARs away from the synapse. This study has therefore established that AMPAR tyrosine dephosphorylation by PTPs is an important postsynaptic component of mGluR-LTD which does not seem to be involved in NMDAR-LTD. 39.11 Learning-specific changes in long-term depression in rat perirhinal cortex. Massey P V, Pythian D, Narduzzo K E, Warburton E C, Brown M W, Bashir Z I MRC Centre for Synaptic Plasticity, Dept of Anatomy, University of Bristol, BS8 1TD, UK. Learning is widely believed to involve mechanisms of synaptic plasticity but their precise relationship remains poorly understood. The perirhinal cortex is required for both single exposure learning of recognition memory (familiarity discrimination) and multi-trial perceptual and reinforcement learning. We exploited the involvement of rat perirhinal cortex in these different forms of learning to compare within the same brain their effects on synaptic plasticity. Every effort was made to minimise pain and discomfort in accordance with the Animals (Scientific Procedures) Act 1986. A paired viewing apparatus allowed novel pictures to be presented to the monocular field of one eye, and familiar pictures to the other under the same behavioural conditions. Picture presentations were accompanied by a juice reward. 60 min after the last session perirhinal slices were prepared from ‘novel’ and ‘familiar’ hemispheres and extracellular field potential recording used to assess synaptic plasticity. Repeated exposure to familiar pictures, but not many novel pictures, occluded, in a muscarinic-dependent manner, subsequent induction of both depotentiation and de novo LTD in perirhinal cortex in vitro whilst having no effect on LTP. The contrast in the effects of the two types of learning on LTD indicates that the change cannot be due to synapse-specific plastic changes registering precise details of the individual learned associations. Instead, we conclude that the occlusions of LTD arise from a learning-related generalised change in plasticity gain. The existence of this additional mechanism has important implications for interpretations of how plasticity relates to learning. Supported by Wellcome Trust. 40.01 Effects of melatonin on neuronal activity in the rat suprachiasmatic nuclei (SCN) in vitro. Scott F, Brown T, Delagrange P, Piggins H (1,2,4) University of Manchester, UK, (3) Institut de Recherches Internationales Servier (IRIS), France The suprachiasmatic nuclei (SCN) act as the master circadian pacemaker in mammals, controlling daily rhythms in many aspects of physiology, including secretion of the pineal gland hormone melatonin. Melatonin levels peak during the early night and exogenous application of melatonin during the evening alters the activity of rodent SCN neurons and the timing of rodent behavioural rhythms via high affinity G protein-coupled receptors. Using a novel recording technique, we investigated the acute and long-term effects of exogenous melatonin on single and multiple unit (SUA and MUA) SCN cellular activity in vitro. We used suction electrodes to record SCN MUA from coronal, 400µm thick rat SCN slices maintained in an interface-style tissue chamber. SUA firing patterns were discriminated from these MUA recordings offline using Spike2 software (CED, UK). For acute studies, melatonin (10fM to 1μM) was applied via the perfusion line for at least 10min between zeitgeber times (ZT) 3 and ZT 8.5 where ZT12=projected lights-off. Consistent with previous reports, melatonin evoked activations or suppressions in SCN SUA, but contrasting with these earlier studies, we found that melatonin-induced predominantly activational effects on both MUA and SUA firing rates. Late day application (ZT 10-11) of 1pM melatonin also produced a phase advance in the timing of peak firing in a subset of single SCN neurons. These findings indicate heterogeneity in the responses of individual SCN neurons, in vitro, to exogenous melatonin. 40.02 Scheduled exercise stabilises behavioural rhythms of mice with deficient neuropeptide signalling Power A, Hughes A T, Namvar S, Brown T M, Piggins H D Faculty of Life Sciences, University of Manchester, Manchester, UK The principal mammalian circadian pacemaker, located within the hypothalamic suprachiasmatic nuclei (SCN), is reset by both light (photic) and arousal-promoting non-photic cues (eg.scheduled exercise). Vasoactive intestinal polypeptide and its VPAC2 receptor are abundant within the SCN. Mice lacking the VPAC2 receptor (Vipr2-/-) exhibit altered behavioural and neuronal rhythms and lack normal responses to photic stimuli, suggesting a completely dysfunctional SCN pacemaker. It is unknown if Vipr2-/- mice show resynchronisation to non-photic stimuli. Here we assessed the effects of scheduled exercise on locomotor and drinking rhythms in wild-type (WT) and Vipr2-/- mice. Mice were individually housed in running wheel equipped cages under a light-dark cycle and then released into constant darkness (DD). After 14 days (DD1), access to the running wheel was restricted to 6h a day. This scheduled exercise continued for 21 days, during which both genotypes showed apparent entrainment of drinking rhythms. Subsequently mice freely exercised for a further 21-35 days (DD2). In DD1, all WT mice were strongly rhythmic (period=23.54±0.05h;n=20), 23/26 Vipr2-/- animals exhibited very weak rhythms (period=22.91±0.29h) and 3 were arrhythmic. In DD2, all WT mice were rhythmic (period=23.55±0.08h) while 25/26 Vipr2-/- mice were rhythmic (period=24.01±0.19h). Two previously arrhythmic Vipr2-/- mice now expressed robust ~24h behavioural rhythms. These results show that, unlike light, scheduled exercise, can stabilise behavioural rhythmicity in Vipr2-/- mice and reveal surprising plasticity in the circadian system to reorganise to a non-photic stimulus. Page 60/101 - 10/05/2013 - 11:11:03
40.03 Live imaging of Per1 driven GFP expression in mice lacking VPAC2 receptors. Hughes A T L 1, Lennox L 1, McMahon D G 2, Piggins H D 1 1 Faculty of Life Sciences, University of Manchester, UK ;, , 2 Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee, USA Vasoactive intestinal polypeptide and its receptor, VPAC2, play important roles in the functioning of the mammalian circadian clock located in the hypothalamic suprachiasmatic nuclei (SCN). Mice lacking VPAC2 receptors (Vipr2-/-) show altered circadian rhythms in locomotor behaviour, neuronal firing rate and clock gene expression, however the nature of molecular oscillations at the individual cell level are unclear. In this study we used real-time confocal imaging of a destabilised green fluorescent protein (dGFP) reporter to track the expression profile of the core clock gene Per1 in live SCN-containing brain slices taken from wildtype (WT) and Vipr2-/- mice. Significantly more dGFP expressing cells were visible in WT slices than in Vipr2-/- slices. Rhythmic oscillations in Per1-driven dGFP were detected in both WT and Vipr2-/- cells, though a significantly greater proportion of cells imaged in WT slices expressed detectable rhythms. WT cells expressed a mean period of ~24h and Vipr2-/- cells expressed a mean period of ~22.5h. Vipr2-/- cells expressed significantly lower amplitude oscillations than WT cells, with significantly lower average and peak fluorescence. Within each slice, the phases of WT cells were synchronised whereas cells in Vipr2-/- slices where poorly synchronised. These data demonstrate that intercellular communication via the VPAC2 receptor is important for SCN neurones to sustain robust, synchronous oscillations in clock gene expression. Supported by the BBSRC. 40.04 Uncertainty coding neurons in the primate orbitofrontal cortex O`Neill M, Schultz W Physiology, Development and Neuroscience,, University of Cambridge,, Downing Street,, Cambridge,, CB2 3DY The orbitofrontal cortex plays an important role in decision-making under conditions of uncertainty. Human patients and orbitofrontal-lesioned animals show alterations in tasks involving uncertainty, including loss of risk sensitivity, increased risk-seeking, and increased risk aversion. However, there has been no clear evidence of the involvement of orbitofrontal neurons in uncertainty processing. We recorded single unit neuronal activity from the orbitofrontal cortex from 2 rhesus macaques presented with cues with varying degrees of reward uncertainty. Reward uncertainty was defined by the variance of a high or low equiprobable (p=0.5) reward following cue presentation. Preliminary results show that 15% (29/196) of orbitofrontal neurons that responded to a task event selectively responded to the degree of reward uncertainty represented by the visual cues. We identified neurons that were selective for high (18/29) or low (6/29) reward uncertainty and neurons with activity that reflected a gradient of uncertainty (low, medium, high: 5/29). These findings suggest that neurons in the orbitofrontal cortex are involved in encoding the degree of reward uncertainty signalled by visual cues and this coding may be involved in decision making under conditions of uncertainty. 40.05 Deficits in emotional and social behaviours in the complexin 2 knockout mouse Glynn D, Morton A J Department of Pharmacology, University of Cambridge, Cambridge, CB2 1PD Complexins are presynaptic proteins that bind to the SNARE complex and modulate neurotransmitter release. Complexin II levels are reduced in neurodegenerative diseases such as Huntington’s disease (HD) as well as in schizophrenia and depression. All of these are diseases in which motor, cognitive and psychiatric disturbances coexist. Previously, we showed that adult complexin 2 knockout (Cplx2-/-) mice exhibit progressive deficits of motor and cognitive function (Glynn et al., 2003). We wondered whether or not Cplx2-/- mice might also show abnormalities in emotional and social behaviour, since these are prominent in patients with HD, schizophrenia and depression. We used a battery of tests to investigate information processing (prepulse inhibition of acoustic startle) anxiety-type behaviour (the zero-maze), depression (Porsolt forced swim test) and social behaviour (a resident-intruder test, a social recognition task and a test of sociability and preference for social novelty). Both the acoustic startle response and prepulse inhibition of startle were decreased in Cplx2-/- mice. Further, Cplx2-/- mice exhibited early deficits in other emotional and social behaviours. In particular, they showed deficits in social recognition and social memory, sociability and preference for social novelty. Our results show that in addition to the motor and cognitive deficits we have already described, Cplx2-/- mice have abnormalities in information processing and emotional-type behaviour. Since all of the disorders in which complexin II levels are decreased include deficits in socialisation and cognition, Cplx2-/- mice potentially provide a model in which to study these aspects of those disorders. 40.06 Object-centred neglect in rats with unilateral 6-hydroxydopamine lesions of the medial forebrain bundle Annett L E, Lord K L, Watt C A, Thiemann G, Hasenöhrl R U School of Psychology, University of Hertfordshire, College Lane, Hatfield, Hertfordshire, AL10 9AB, UK Neglect of contralateral stimuli is well documented in animals with unilateral dopamine loss, for example responses are slow or absent to stimuli presented on the side contralateral to a unilateral 6-hydroxydopamine (6OHDA) lesion and ipsilateral biases are evident when food is retrieved from different spatial locations. Neglect in humans can result from right parietal cortex damage and a mild form of neglect has been reported in people with asymmetric symptoms of Parkinson’s disease1. One interesting feature of neglect in humans is that it may be object-centred, i.e. the contralateral side of an object is ignored irrespective of the location of that object in space. The present study used a ‘line bisection’ task devised for rats to investigate whether the neglect produced by unilateral 6-OHDA lesions of the medial forebrain bundle includes an object-centred component. The experiment was conducted in accordance with the UK Animals (Scientific Procedures) Act 1986. The lesions were confirmed at the end of the study by tyrosine-hydroxylase immunohistochemistry. Rats were trained to retrieve a single coco pop (chocolate flavoured cereal) hidden in sawdust from the exact centre of a rectangular tray. Following a unilateral 6OHDA lesion, rats showed neglect in that their initial head response over the tray was displaced ipsilaterally. As the tray width increased (6, 10, 14, 18 and 22 cm) the extent of the ipsilateral displacement also increased, an indication of object-centred neglect. 1Lee AC et al. (2001) Vision Research 41:2677-2686 The support of the Parkinson’s Disease Society, UK, is gratefully acknowledged. Page 61/101 - 10/05/2013 - 11:11:03
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1.0 Paths to recovery: Modulating P
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3.07 Congenital hypothyroidism alte
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4.01 The effect of hippocampal slic
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Page 31 and 32: 18.03 Finding cells for replacement
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