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Gene Expression Analysis of Trigeminal Ganglia and Peripheral Blood Mononuclear Cells in a Rat Orofacial Pain Model

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Gene Expression Analysis of Trigeminal Ganglia and Peripheral Blood Mononuclear Cells in a Rat Orofacial Pain Model GENE EXPRESSION ANALYSIS OF TRIGEMINAL GANGLIA AND PERIPHERAL BLOOD MONONUCLEAR CELLS IN A RAT OROFACIAL PAIN MODEL Aczél T1,2, Kun J1,2,3, Szőke É1,2,3, Rauch T4, Bölcskei K1,2, Helyes Zs1,2,3 1Department of Pharmacology and Pharmacotherapy, University of Pécs Medical School, Pécs, Hungary 2Centre for Neuroscience & Szentágothai Research Centre, University of Pécs, University of Pécs, Pécs, Hungary 3MTA-PTE NAP B Chronic Pain Research Group, Hungarian Academy of Sciences, University of Pécs, Pécs, Hungary 4Section of Molecular Medicine, Rush University Medical Center, Chicago, IL, USA Objective: The origin and precise pathomechanism of migraine are still being debated. Trigeminal nociceptor sensitization is proposed to play a role by eliciting hyperalgesia and allodynia. We aimed to investigate gene expression changes in trigeminal ganglia (TRG), central trigeminal nucleus caudalis (TNC) and peripheral blood mononuclear cells (PBMC) evoked by Complete Freund's Adjuvant (CFA) induced peripheral inflammation. Methods: Orofacial inflammation was induced by unilateral s.c. injection of 50 µl CFA into the whisker pad of male Wistar rats (n=8). Transcriptome analysis was performed using cDNA microarray on TRG tissue samples collected after 7 days. Five differentially expressed genes were selected for validation by quantitative PCR (qPCR) on days 1, 3 and 7 of a second experiment (n=12). Three genes were detected as markers of neuronal or glial activation. TRG and TNC tissue samples, and PBMCs comprising of monocytes and lymphocytes were taken. Saline-treated animals and contralateral sides of CFA-injected rats served as controls. Mechanical pain thresholds of the orofacial region were determined with a series of von Frey filaments. Results: 253 differentially expressed genes were found between CFA treated and contralateral TRG samples 7 days after CFA injection. The mRNA expression changes of G-protein coupled receptor 39 (Gpr39), kisspeptin-1 receptor (Kiss1r), Lkaaear1 and Otoraplin were validated. They were most upregulated on day 3 in TRGs of the CFA-treated side. CFA induced significant orofacial mechanical allodynia in one day with a maximum on day 3. This correlated with patterns of neuronal (FosB), glial (Iba1), and astrocyte (GFAP) activation markers in both TRG and TNC, and surprisingly in PBMCs. In TNCs, gene expression changes similar to TRGs were observed but Kiss1r transcripts were not significantly altered while Neurod2 was observed only in TNC. Conclusion: The genes revealed by our study may participate in the cascade of events resulting in the sensitization underlying migraine headache and the accompanying facial allodynia. Expression changes of Lkaaear1, Otoraplin and Neurod2 can be related to the modulation of synaptic plasticity. Gpr39 and Kiss1 receptors have emerging roles in pain but have not been implicated in migraine before thus may become potential targets in treatment. Corresponding mRNA changes in peripheral leukocytes is an intriguing result that might lead to the identification of biomarkers. The present study was supported by National Brain Research Program B (KTIA_NAP_13-2014- 0022), EFOP-3.6.1.-16-2016-0004, KA-2015-20, GINOP 2.3.2-15-2016-00050 „PEPSYS" and StayAlive GINOP (GINOP-2.3.2-15-2016-00048). J. K. was supported by a scholarship from the European Union and the State of Hungary, co-financed by the European Social Fund in the framework of TAMOP-4.2.4.A/2-11/1-2012-0001 'National Excellence Program Apaczai Scholarship'. The role of neuro-inflammation in neurodegeneration: from molecules to clinics, EFOP-3.6.2-16- 2017-00008 THALAMIC DUAL-CONTROL MECHANISM FOR SLEEP AND WAKE Adamantidis AR, Gent TC, Bandarabadi M, Herrera CG University of Bern, Bern, Switzerland Animals alternate between wakefulness and sleep during the circadian cycle which is a vital component of homeostatic control. During wakefulness, neocortical neurone show tonic activity whereas during non-rapid eye movement sleep (NREM) they burst fire with high synchrony across the whole neocortex. However, the circuit mechanism controlling this activity remains unclear. Excitatory drive from the midline thalamus has emerged as an essential hub for control of cortical excitability. Indeed, lesions of the midline thalamus may produce loss of consciousness as well as failure to consolidate NREM. Here we identify excitatory neurones in the centromedial thalamus (CMT) as being phase-advanced to the cortex and sensory thalamus in sleep slow-waves in freely moving mice. Channelrhodopsin-2 transfection of CMT neurones for anatomical mapping, optogenetic activation and optrode recording revealed that monosynaptic projection to the cingulate cortex controls both wakefulness and cortical slow-waves. Furthermore, we show that widespread synchrony of cortical slow-waves is dependent on a relay in the dorsal thalamus (AD) using combined optogenetic activation and inhibition recordings. Finally, intact function of both the CMT and AD are required for sleep recovery following a period of deprivation. Together these results demonstrate CMT dual control of neocortical activity and vigilance state which is dependent on AD and provides a circuit mechanism for cortical synchrony and sleep homeostasis. NEUROSERPIN EXPRESSION IN DEVELOPING HUMAN CORTEX Adorján I1,2, Millar LJ1, Parley K1, Bakó M2, Møllgård K3, Ansorge O4, Shi L5, Hoerder-Suabedissen A1, Molnár Z1 1Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, UK 2Department of Anatomy, Histology and Embryology, Semmelweis University, Budapest, Hungary 3Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark 4Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, UK 5Joint Laboratory for Neuroscience and Innovative Drug Research, College of Pharmacy, Jinan University, Guangzhou, People’s Republic of China Neuroserpin is a serine-protease inhibitor that is mainly expressed in the cerebral cortex and has a role in the neuroprotection following hypoxia-ischaemia. Several studies have demonstrated its function in preserving vascular membrane integrity of blood-brain barrier and protecting neurons from ischaemia-induced cell death in the adult. These make neuroserpin a promising therapeutic agent in preventing neuronal death following hypoxia-ischaemia that could be particularly relevant in conditions such as neonatal hypoxia and stroke (Millar et al., 2017 Frontiers in Cellular Neuroscience). We are currently investigating the role of neuroserpin in neonatal hypoxia in mouse models and therefore we wanted to compare the expression pattern in mouse and human during ‘physiological' cortical development. We obtained human brain samples from the Oxford Brain Bank and King's College London (REC 07/H0707/139, gestational week 13, 14, 16, 18, 19, 21, 22, 25 and 40). Neuroserpin was expressed from the earliest age examined (13gw) and has been localized to migrating neurons particularly abundant i) in the germinal zone ii) in the interface of the marginal zone and cortical plate, iii) the deep cortical plate and iv) the subplate. These results were corroborated by using different antibodies against neuroserpin (Abcam ab 55587 and ab 33077), PAS-Alciane Blue and Nissl-stainings. The earlier localizations of neuroserpin- immunoreactive migrating neurons were retained during the second trimester. By full term, neuroserpin-immunoreactive positive neurons formed four characteristic bands in the developing cortex situated i) between the marginal zone and the upper cortical plate, ii) in the upper cortical plate, iii) in the lower cortical plate and iv) in the still present but thinner layer of subplate. Morphological assessment of cortical plate neurons and colocalization experiments have shown that the majority of the neuroserpin-immunopositive neurons were SMI31.1-immunopositive pyramidal cells and to a lesser extent they were calretinin-immunopositive interneurons situated mainly in the upper cortical plate. Our future goal is to give a detailed description of the neuroserpin-immunopositive migrating neurons throughout the first and third trimester as well as early childhood and compare their localization between diagnostic groups such as acute and chronic hypoxia. Funded by the Medical Research Council Grant numbers: G00700311 and G00900901; Clarendon Fund, University of Oxford; The Academy of Medical Sciences Newton Advanced Fellowship in partnership with The Royal Society and The National Natural Science Foundation of China for collaborative projects (UK/China grant numbers: NA160314/816110158). CALRETININ INTERNEURON DENSITY IN THE CAUDATE NUCLEUS IS LOWER IN AUTISM SPECTRUM DISORDER Adorjan I1,3, Ahmed B1, Feher V3, Torso M2, Krug K1, Esiri M2, Chance SA2, Szele FG1* 1Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK 2Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, UK 3Department of Anatomy, Histology and Embryology, Semmelweis University, Budapest, Hungary Autism spectrum disorder is a debilitating condition with possible neurodevelopmental origins but unknown neuroanatomical correlates. Whereas investigators have paid much attention to the cerebral cortex few studies have detailed the basal ganglia in autism. The caudate nucleus in particular is a nexus of converging circuits including a massive corticostriatal input and therefore it may serve as a node for the pathophysiology of autism spectrum disorder. We used immunohistochemistry
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