Book of abstracts - British Neuroscience Association

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44.01 Functional-pharmacological MRI in drug discovery James M F, Pohlmann A, Barjat H, Tilling L, Upton N, Schwarz AJ, Bifone A Neurology & GI and Psychiatry CEDDs, GlaxoSmithKline, Harlow UK, Verona Italy Pharmacological magnetic resonance imaging (phMRI) is used to detect, most commonly, blood oxygenation level dependent (BOLD) or blood volume (CBV) changes in the cerebral vasculature following the administration of a brain-penetrating compound. The compound evokes a metabolic response that is detected in repetitive images as a change from the baseline condition that also differs from the response to control vehicle. The technique builds on 2-deoxyglucose uptake experiments that first localised drug effects in the conscious rat brain (J McCulloch and colleagues). Three elements of the experiment are crucial: 1) expert animal preparation to provide stable physiology – the choice and dose of anaesthetic is very important; 2) sensitive MR imaging to yield contrast changes without motion; 3) sufficiently sensitive statistical techniques – with good understanding of their functionality. From a drug discovery perspective, phMRI is potentially valuable as an in vivo pharmacodynamic marker of central activity; especially for agents whose effects otherwise require complex behavioural assays. The BOLD-phMRI technique is also potentially translatable to humans. However, despite its increasing use, the question of how animal phMRI findings reflect activity in the human brain remains relatively unexplored. In humans, the use of pharmacological challenges with task-based functional MRI (fMRI) has been preferred, particularly for cognition-enhancing agents. Brain perfusion measurement with techniques such as arterial spin labelling in conjunction with fMRI may provide insight into human phMRI responses in future. This talk will use results from methodological studies in GSK to highlight the problems and possibilities of phMRI for drug discovery. 44.02 Probing serotonin and glutamate actions on the brain in vivo: pharmacological challenge fMRI in animal models and human volunteers Williams S, McKie S, Stark J, Davies K, Luckman S, Bill Deakin Imaging Science and Biomedical Engineering, 2Neuroscience and Psychiatry Unit and 3Faculty of Life Sciences; Oxford Rd; University of Manchester; Manchester M13 9PT Functional magnetic resonance imaging (fMRI) is one of the most important techniques used in cognitive neurosciences to relate brain structure to function and to elucidate brain processing networks. Conventionally a task (cognitive or motor) or sensory input (visual, auditory, somatic) is used to stimulate regional brain activity, but in the last few years pharmacological stimuli have also been used. We have used pharmacological-challenge fMRI (pMRI) to investigate the direct effects on the brain of serotinergic and glutamatergic drugs. In both rats and man, we have used the antidepressant m-chlorophenylpiperazine (a 5HT2c agonist) as a challenge and identified brain areas which respond to the drug. We showed that these regions are related to post mortem receptor distribution in man and to c-Fos expression in rats. Combined antagonist challenges were used to tease out the receptor sub-types activated in the rat. Ketamine has been used as a glutamatergic challenge and we have detected de-activations in the limbic system which correlated with subjective ‘dissociative’ effects of ketamine, as reported by the participants. Combining ketamine with pre-dosing by lamotrigine, which blocks glutamate-activated Na+ channels, we were able to distinguish brain areas where ketamine acts by inhibiting NMDA receptors, and where it acts by increasing glutamate release leading to stimulation of AMPA receptors. Most of the effects of ketamine were antagonized by lamotrigine, suggesting that the drug acts mainly by stimulating glutamate release. 44.03 Modulating neuronal and haemodynamic responses: coupling and uncoupling Sibson N Head of Experimental Neuroimaging, Department of Physiology, Anatomy & Genetics, Sherrington Building, Parks Rd, Oxford, OX1 3PT, , , Head of Experimental Neuroimaging, Department of Physiology, Anatomy & Genetics, Sherrington Building, Parks Rd, Oxford, OX1 3PT, We have adapted a model described for somatotopically mapping the hindpaw pathway from the cortex to the brainstem to enable direct cortical stimulation (DCS) of the rodent brain within a high-field magnetic resonance imaging (MRI) system. Unilateral electrical stimulation of the rat hindpaw motor cortex yields BOLD (blood oxygenation level dependent) and CBV (cerebral blood volume) fMRI signal changes not only in the electrically stimulated motor cortex, but also in the functionally connected homotypic contralateral motor cortex, both the ipsilateral and contralateral secondary somatosensory cortices and striatal areas in both hemispheres. Since activation is observed in multiple brain regions with disparate neuronal architecture, the DCS model offers a useful approach for investigating regional differences in drug action. By combining the BOLD and CBV fMRI approaches we can potentially obtain additional information on metabolism, since the BOLD signal is a composite of both haemodynamic and metabolic responses. We have used this approach to determine the effect of a metabotropic glutamate type 5 receptor (mGluR5) antagonist, MPEP, on neuronal and haemodynamic responses to stimulation. MPEP caused significant reductions in both the BOLD and CBV fMRI responses to DCS across all brain regions, although the magnitude of this effect varied between cortical and striatal areas. Electrophysiological recordings demonstrated no effect of MPEP on neuronal responses to DCS, suggesting uncoupling of the haemodynamic response to neuronal activation. We propose that this experimental approach provides a means of dissecting the consequences of drugs on neuronal activity, perfusion and metabolism across multiple brain regions simultaneously. 44.04 Analysis of pMRI data with blind source separation Schiessl I Faculty of Life Sciences, Jacksons Mill, The University of Manchester, Sackville St, Manchester M60 1QD, Most Functional magnetic resonance imaging (fMRI) experiments involve controlled delivery of stimuli (e.g. visual, auditory, somatosensory) or require the subject to undertake specific cognitive tasks. More recently fMRI methods have been used to monitor direct effects of neuroactive substances on the brain, so-called pharmacological challenge fMRI (pMRI). This approach brings the methodology into a more clinical domain with the possibility to characterise effects of drugs, provide biomarkers of effect and help to understand the neurochemical basis of diseases. However, although these methods have considerable potential there is uncertainty as to the most appropriate methods of analysis. The problem in the analysis of pharmacological challenge pMRI arises from the fact that because of the long time it takes to return to baseline often only one trial per session is available for analysis. Standard hypothesis driven analysis methods of fMRI data statistically test the time course of voxels against a model hypothesis. An alternative approach is the exploratory analysis of data Independent Component Analysis (ICA) to find common statistical features. We use an ICA algorithm called Extended Spatial Decorrelation (ESD) to improve the analysis of pMRI data. The ESD algorithm is based on the assumption that (i) the original spatial prototype patterns are mutually uncorrelated but auto correlated, and (ii) that correlations also vanish between sources that are shifted by any non zero vector with respect to each other. Therefore the ESD algorithm exploits the spatial structure within and between the original sources that are underlying the recorded mixture to separate them. Page 68/101 - 10/05/2013 - 11:11:03
45.01 Mutant SOD1-PUMA knockout double mutants in relation to amyotrophic lateral sclerosis Kieran D, Koegel I, Villunger A, Strasser A, Prehn J H M 1Department of Physiology and Medical Physics and RCSI Neuroscience Research Centre, Royal College of Surgeons in Ireland, 123 St. Stephen’s Green, Dublin 2, Ireland. 2 Division of Developmental Immunology, Biocenter, Innsbruck Medical University, A-6020 Innsbruck, Austria. The accumulation of unfolded or misfolded proteins in the endoplasmic reticulum activates evolutionary conserved stress responses which if severe and persistent activate apoptosis. Previously, we reported that activation of the BH3-only protein PUMA is necessary and sufficient for ER-stress induced apoptosis, however PUMA’s role in neurodegeneration in-vivo remained undetermined. Defects in protein processing and transport are implicated in Amyotrophic Lateral Sclerosis, a fatal neurodegenerative condition characterized by motoneuron degeneration and paralysis. Here we show activation of the ER-stress response and PUMA up-regulation in SOD1G93A mice. We also show that genetic deletion of PUMA protects cultured motoneurons against ER-stress, but not excitotoxininduced apoptosis, and delays disease onset in SOD1G93A mice. However, deletion of PUMA failed to prevent disease progression or increase lifespan. Together, these findings show chronic neurodegeneration associated with defects in protein quality control are controlled in-vitro and in-vivo by PUMA, however in later stages of disease other cell death mechanisms can compensate for a loss of PUMA. 45.02 Semaphorin and Plexin mutants as models for disorders of connectivity. Rünker A E, Morris D W, O’Tuathaigh C M P, Dunleavy M, Henshall D, Waddington, J.L, Gill, M, Corvin, A.P., Mitchell, K.J. (1) Smurfit Institute of Genetics and (2) Neuropsychiatric Genetics Research Group, Trinity College Dublin, Ireland, (3) Dept. of Neuroscience and (4) Dept. of Clinical Pharmacology, Royal College of Surgeons in Ireland There is mounting anatomical, physiological and genetic evidence that many psychiatric and neurological disorders have underlying defects in neural connectivity. We have been investigating the functions of a transmembrane semaphorin, Sema6A, and two interacting proteins, Plexin- A2 and -A4, in cell migration and axon guidance in the developing mouse brain. Sema6A mutants display a spectrum of defects in cell migration in the cerebellum, hippocampus and piriform cortex and in axon guidance of the anterior commissure, thalamocortical axons, fornix and corticospinal tract. PlxnA2 and PlxnA4 mutants show overlapping subsets of defects, and complex epistatic interactions with Sema6A. Some of the anatomical regions affected have been implicated in the pathology of schizophrenia (SZ) and we have found that Sema6A mutant mice show a number of behavioural and physiological phenotypes thought to model aspects of schizophrenia, several of which are completely reversible by the antipsychotic clozapine. In addition, we have evidence of an association of variants in the human SEMA6A gene with increased risk of schizophrenia. These mutants may thus provide an excellent model to investigate how neurodevelopmental defects can lead to altered function of circuits and behaviour. 45.03 Dissecting the genetic contribution to psychosis: new evidence from susceptibility gene mutants O’TuathaighCMP, Babovic D, O’Sullivan GJ, O’Meara G, Croke DT, Harvey R, Waddington JL 1Molecular & Cellular Therapeutics, Royal College of Surgeons in Ireland, 123 St. Stephen’s Green, Dublin 2. 2 The Victor Chang Cardiac Research Institute, St. Vincent’s Hospital, 384 Victoria St., Darlinghurst 2010, Australia Neuregulin-1 (NRG1) has been identified as a candidate susceptibility gene for schizophrenia. We have studied the functional role of the NRG1 gene, as it relates to cognitive and social processes known to be disrupted in schizophrenia, in mice with heterozygous deletion of transmembrane (TM)-domain NRG1 in comparison with wildtypes (WT). Social affiliative behaviour was assessed using the sociability and preference for social novelty paradigm, while social dominance and aggressive behaviour was examined in the resident-intruder task. Spatial learning and memory was assessed using the Barnes maze paradigm, while spatial working memory was measured using the continuous variant of the spontaneous alternation task. We also examined the effect of subchronic treatment with the NMDA receptor antagonist phencyclidine (PCP) on the performance of NRG1 mutants in a number of these behavioural paradigms. 45.04 An aneuploid mouse with a human chromosome modelling Down syndrome. Fisher E M C, Doherty A O, Ruf S, Mulligan C, Cooke S, Vanes L, Hernandez D, Sharpe P T, Brandner S, Bliss T V P, Tybulewicz V* Department of Neurodegenerative Disease, Institute of Neurology, Queen Square, London WC1N 3BG: NIMR, London NW7 At least 5% of all human pregnancies are aneuploid, and ~1 in 700 children are born with Down syndrome (DS) which results from having three copies of human chromosome 21 (Hsa21). DS is the most common known genetic cause of mental retardation and also results in increased susceptibility for other disorders, including developmental deficits. It is a complex disorder that involves multiple Hsa21 genes in interaction with the rest of the genome. To gain insight into the biology of DS, we have generated a new type of mouse model in which an almost complete human chromosome, Hsa21, segregates through the germline. We present evidence that this trans-species aneuploid mouse strain, ‘Tc1’, displays phenotypic alterations in behaviour, synaptic plasticity, cerebellar neuronal number and heart development that relate directly to human DS and to other partial trisomy models of DS. Transchromosomic mouse lines such as Tc1 may represent useful genetic tools to dissect other aneuploidies and complex human genetic conditions. Spatial learning and working memory processes appear intact in the NRG1 mutant; any phenotypic changes in performance in these tasks are proposed to be due to elevated baseline activity levels. However, heterozygous deletion of TM-domain NRG1 was associated with disruption to a number of elements of social functioning including social dominance behaviour and response to social novelty. Subchronic administration of PCP was found to significantly alter the NRG1 mutant phenotype. These data inform at a novel phenotypic level on the functional role of this gene in the context of its association with risk for schizophrenia. Page 69/101 - 10/05/2013 - 11:11:03
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Book of abstracts - British Neuroscience Association

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