NEURASMUS Annual Meeting and Workshop

 NEURASMUS Annual Meeting and Workshop University of Coimbra July 1-­‐5, 2013 Program and Abstract Book Welcome to the NEURAMUS annual meeting in Coimbra The annual meeting brings together NEURASMUS students from Bordeaux, Amsterdam, Berlin, Göttingen and Coimbra. We look forward to learning from your work at the Master talks. We invite you to get to know neuroscience research at the Center for Neuroscience and Cell Biology (CNC) focused on The changing brain: from plasticity to brain diseases and brain repair. CNC scientists and invited speakers will discuss advances, changes of paradigm, breakthroughs... and look into the future of brain science and contributions to brain health. To improve brain health we planned a hiking trip and good food... We hope that you will leave Coimbra even more excited about neuroscience and the future. Neurasmus @ UC Day 1 -­‐ Monday, July 1 CNC auditorium Faculty of Medicine (Campus I) Opening session Prof. Bruno Trindade (Vice-­‐Director of the Faculty of Science and Technology:) Prof. Catarina Oliveira (President of CNC) Prof. Arsélio Pato de Carvalho (former President of CNC) Prof. Carlos Palmeira (Director of the Department of Life Sciences) Dr. Filomena Marques de Carvalho (Head of the International Relations Office) Day 1 -­‐ Monday, July 1 CNC auditorium Faculty of Medicine (Campus I) 8:45 9:15 10:00 Registration Opening session Talks by Master students (year 2) Chairpersons: Daniel Voisin and Eskedar Angamo 10:00 -­‐ 10:25 The role of Scrib1 in brain development Tamrat Mamo (Neurocentre Magendie, University of Bordeaux) 10:25 -­‐ 10:50 New G-­‐protein Signalling links PCP and Cilia Aysegul Ozgur Gezer (Neurocentre Magendie, University of Bordeaux) Coffee break 11:20 -­‐ 11:45 Calmodulin/Munc13-­‐1 Dependency on Vesicle Reloading at the Cerebellar Mossy Fiber Synapse Julio Santos Viotti (Georg-­‐August University Göttingen) 11:45 -­‐ 12:10 Does an individual astrocyte release purines in adult rat hippocampus? Pei Zhang (Neurocentre Magendie, INSERM U862) 12:10 -­‐ 12:35 Effect of Pituitary Adenylate Cyclase-­‐Activating Polypeptide (PACAP) on hepatic VLDL-­‐triglyceride secretion Violeta Castelo Székely (Netherlands Institute for Neuroscience) 12:45 Lunch (Cafeteria of Science Museum) 14:30 Talks by Master students (year 2) Chairpersons: Will Smeets and Oksana Trotsenko 14:30 -­‐ 14:55 Neuronal signatures of fear memory Nikolas Karalis (University of Bordeaux) 14:55 -­‐ 15:20 The impact of Sleepiness on the Procedural Memory and Quantitative EEG in Sleep Disordered Patients Ioanina Sorana Lazar (Charité -­‐ Universitätsmedizin Berlin) 15:20 -­‐ 15:45 The effect of oxytocin and early life stress in resting state connectivity Ana Lucia Herrera Meléndez (Charité -­‐ Universitätsmedizin Berlin) Coffee break 16:15 -­‐ 16:40 Social influences on utility and preferences in an auction game Esperanza Jubera-­‐García (Berlin School of Mind and Brain) 16:40 -­‐ 17:05 Linking daily life activity to cognitive health in ageing: an Ecological Momentary Assessment study Natalie Rens (INCIA) 19:30 Dinner (Casa da Escrita) Day 2 -­‐ Tuesday July 2 Tryp Hotel 9:00 -­‐ 11:00 Parallel meetings: BoE, Board of Education (Room Lousã) BoSt, Board of Students (Room Gardunha) Coffee break 11:30 -­‐ 12:30 BoE and BoSt joint meeting (Room Vasco Mexia) Lunch (Hotel) 15:30 -­‐ 17:30 Guided tour to historic UC 20:00 Dinner Students initiative -­‐ Dux Quinta de São Luiz Day 3 -­‐ Wednesday, July 3 Hiking trip and picnic at Buçaco Dinner at a seaside village -­‐ Costa Nova (Dori) Day 4 -­‐ Thursday, July 4 Auditorium I, Faculty of Medicine, Campus III Workshop: The changing brain: from plasticity to brain diseases and brain repair... looking into the future Chairperson: Carlos Duarte Modulation of hippocampal glutamatergic synapses by ghrelin Ana Luísa Carvalho Group Glutamatergic Synapses: formation and regulation, CNC 10:00 -­‐ 10:30 Pivotal role of astrocytes in the control of plasticity and damage of brain circuits Rodrigo Cunha Group Neuromodulation, CNC 10:30 -­‐ 11:00 Regulation of synapse assembly through local protein dynamics Ramiro Almeida Group Glutamatergic Synapses: formation and regulation, CNC 9:30 -­‐ 10:00 Coffee break 11:30 -­‐ 12:20 BDNF translation in dendrites: when, where and how? Enrico Tongiorgi Laboratory of Cellular and Molecular Neuroanatomy, B.R.A.I.N. Centre for Neuroscience, University of Trieste, Italy 12:30 Lunch Chairperson: Emília Duarte 14:30 -­‐ 15:20 New trends in translational neuroscience Miguel Castelo-­‐Branco Functional Imaging and Phenotyping of Complex Diseases, IBILI, University of Coimbra 15:20 -­‐ 15:50 Neuronal dysfunction in Alzheimer's disease: a focus on mitochondrial and nuclear signaling Ana Cristina Rego Group Mitochondrial Dysfunction and Signalling in Neurodegeneration, CNC 15:50 -­‐ 16:20 Mitochondrial involvement in autophagic dysfunction: a way to Parkinson’s disease Sandra Morais Cardoso Group Molecular Mechanisms of Disease, CNC Coffee break 16:50 -­‐ 17:40 Cellular and in vivo models to elucidate LRRK2 signalling cascades Kristof van Kolen Janssen Pharmaceutica, Beerse, Belgium 19:00 Visit and Dinner (St. Clara-­‐a-­‐Velha Monastery) Day 5 -­‐ Friday, July 5 Auditorium I, Faculty of Medicine, Campus III Workshop: The changing brain: from plasticity to brain diseases and brain repair... looking into the future Chairperson: Ana Luísa Carvalho Excitotoxic cell death: more than just glutamate Carlos Duarte Group Neuronal Cell Death and Neuroprotection, CNC 10:00 -­‐ 10:30 Genetic and optogenetic dissection of neuronal circuits João Peça Group Glutamatergic Synapses: formation and regulation, CNC 10:30 -­‐ 11:00 Adult neurogenesis: the death of a dogma, the birth of new promises Jorge Valero Group Neuroprotection and Neurogenesis in Brain Repair, CNC 9:30 -­‐ 10:00 Coffee break 11:30 -­‐ 12:00 Viral vectors for gene transfer to the brain: from animal models to gene therapy Luís Pereira de Almeida Group Vectors and Gene Therapy, CNC 13:30 Lunch (Loggia, Machado de Castro Museum) Afternoon Informal lab visits Dinner (Casas do Bragal) 20:00 Talks by Master Students Abstracts The role of Scrib1 in brain development Tamrat Mamo, Jerome Ezan and Mireille Montcouquiol Neurocentre Magendie, University of Bordeaux Scribble (Scrib1) is an evolutionarily conserved protein that belongs to the LAP family and is known, among other functions, to regulate the establishment of apicobasal polarity and presynaptic architecture in Drosophila. Its mammalian homolog Scrib1 has been implicated in cancer, neural tube closure, and planar cell polarity (PCP). Genome wide association studies have shown that Scrib1 mutation in humans is implicated in brain disorders including Autism spectrum disorders. Scrib1 spontaneous mutation in the Circletail mutant mouse causes severe brain and neural tube damages, which results in neonatal lethality. Therefore, its role in developing brain is unclear. Here, we used conditional knock out mouse lines to decipher its role in shaping the brain. In Emx1-­‐Scrib1 conditional knockout mice where Scrib1 is deleted early in development in neural progenitors, neurons and glia, we observed inter-­‐hemispheric connectivity defects such as loss of dorsal hippocampal commissure and complete agenesis of corpus callosum, especially in the caudal part of the forebrain. We also observed defects in midline glial localization which are responsible for callosal axon guidance during middline crossing. Furthermore, using markers for cortical layers, we show that Scrib1 deletion affects layer formation in the cortex. We did not observe similar phenotype when Scrib1 is only deleted in postmitotic neurons or glia. Our data suggests that deletion of Scrib1 in neural progenitors leads to deficient migration and differentiation of callosal projection neurons leading to different brain disorders associated with connectivity defects. Keywords: Corpus callosum, planar polarity. New G-­‐protein Signalling links PCP and Cilia Aysegul Ozgur Gezer, Jerome Ezan and Mireille Montcouquiol Neurocentre Magendie, University of Bordeaux Planar cell polarity (PCP) is defined as a polarity of a cell or a tissue within the plane of an epithelium. It can be the orientation of an appendage at the surface of a cell and perpendicular to the epithelium, or the coordination of the orientation of all of the appendages within the tissue. PCP is an important concept that is involved in wide range of mechanisms from asymmetric cell division to coordinated migration. It is controlled by asymmetric segregation of core PCP proteins in the cells. Besides, in ciliated mammalian cells, the early migration of the primary cilium to the specific location in the cells also determine a PCP axis. Defects in core PCP proteins and/or cilia migration disrupts PCP, but the phenotype-­‐s due to the PCP defects and cilia defects are not completely congruent. These results strongly suggest the existence of another PCP signaling, acting parallel to the classical core PCP signaling. The link between those signaling pathways is important if we want to dissect the mechanisms behind the wide range of pathologies related with PCP and cilia. In our group, we identified a new G-­‐protein dependent signaling pathway composed of five proteins. Those proteins are asymmetrically localized in the hair cells of the cochlear epithelium, our model system. Using transgenic mice, imaging and in vitro explant, we show that this new signaling controls primary cilium migration. Therefore, this new signaling pathway bridges the PCP and cilia, two crucial developmental concepts. Keywords: Planar Polarity, Primary Cilia. Calmodulin/Munc13-­‐1 Dependency on Vesicle Reloading at the Cerebellar Mossy Fiber Synapse Julio Santos Viotti, Nils Brose and Stefan Hallermann Georg-­‐August University Göttingen High-­‐frequency transmission between neurons relies on efficient reloading of vesicle at the release site. At some synapses, the binding of Calmodulin, a Calcium binding messenger protein, to Munc13-­‐1, an essential priming factor, is important for vesicle reloading. Here, I analyze the role of Calmodulin-­‐Munc13-­‐1 binding for vesicle reloading at cerebellar mossy fiber to granule cell synapses, which transmit signals at extremely high frequency and exhibit exceptionally rapid vesicle reloading. I used knock-­‐in 2+
mice, in which the binding of Munc13-­‐1 and Ca /Calmodulin does not occur, and analyzed the recovery from synaptic depression after trains of stimuli with different frequencies. A significant but small impairment of vesicle reloading was observed in the mutants, with no effects on release probability and readily releasable pool size. Thus, Munc13-­‐1 and Calmodulin, together, are revealed to play a role in the short-­‐term plasticity of these specialized synapses, however, the small effect indicates that other mechanisms contribute to the reloading of vesicles at this synapse. Keywords: Munc13; Calmodulin; Cerebellar mossy fiber; vesicle reloading; short-­‐term plasticity. Does an individual astrocyte release purines in adult rat hippocampus? Pei Zhang, Aude Panatier and Stephane Oliet Neurocentre Magendie, INSERM U862 Nowadays, the concept of tripartite synapse is becoming increasingly accepted. It is well established that astrocytes detect synaptic activity and in turn release gliotransmitters to regulate the efficacy of transmission. In the hippocampus of adult rats, astrocytes release D-­‐serine, the co-­‐agonist of synaptic glutamatergic NMDA receptors. To go further in our understanding of information processing in adult rat hippocampus, we wanted to investigate if, as in juvenile rats, astrocytes release purines to facilitate glutamatergic synaptic transmission. This preliminary project will give the possibility to investigate in the future if an individual astrocyte releases more than one type of gliotransmitters, such as D-­‐serine and purines. To this end, we first developed in the laboratory the recording of field potentials through an astrocytic patch pipette in order to test whether an individual astrocyte releases purines, as it has been shown for d-­‐serine. Preliminary data suggest that in adult rat hippocampus, astrocytes release purines at synapses with low transmission efficacy to facilitate them. Keywords: astrocyte, gliotransmission, electrophysiology-­‐ Effect of Pituitary Adenylate Cyclase-­‐Activating Polypeptide (PACAP) on hepatic VLDL-­‐triglyceride secretion Violeta Castelo Székely, Andries Kalsbeek and Madeleine L. Drent Netherlands Institute for Neuroscience Objective. The neuropeptide Pituitary Adenylate Cyclase-­‐Activating Polypeptide (PACAP) and its receptors are widely expressed in the hypothalamus, the main brain area in the control of energy homeostasis. Intracerebroventricular (i.c.v.) infusion of PACAP in the rat has been shown to affect food intake, body temperature, endogenous glucose production and autonomic nervous system activity. In the present study, we investigated the effect of central administration of PACAP on triglyceride production in the rat liver and the involvement of the autonomic nervous system (ANS) in mediating this effect. Research Design and Methods. Hepatic triglyceride secretion into the bloodstream was determined during i.c.v. infusion of PACAP-­‐38, whereas the role of the autonomic innervation of the liver was assessed by selective hepatic sympathetic or parasympathetic denervation. Results. I.c.v. infusion of PACAP caused a significant decrease in plasma triglyceride concentration. Furthermore, plasma glucose levels increased. Hepatic sympathectomy or parasympathectomy did not significantly occlude those effects. Discussion and future directions. This study points towards a role of centrally administered PACAP on the regulation of peripheral metabolism. An involvement of the ANS could not be detected so far; thus further experiments should aim at elucidating the underlying mechanism. Keywords: PACAP, Autonomic Nervous System, hypothalamus, VLDL-­‐
triglyceride metabolism, glucose metabolism. Neuronal signatures of fear memory Nikolaos Karalis and Cyril Herry Universite Bordeaux 2 One of the major questions in modern neuroscience is how neuronal circuits mediate behavior. Over the past decades, classical auditory fear conditioning has emerged as a powerful behavioral model for the study of the neuronal basis of learning. In this paradigm, an auditory stimulus is repeatedly associated with a mild aversive stimulus and a fear memory is formed. The repetitive exposure to non-­‐reinforced presentations of the auditory stimulus leads to the temporary inhibition of fear responses a phenomenon labeled fear extinction, and the formation of a new extinction memory. Fear and extinction memories are believed to be acquired and stored within distinct but interacting neuronal networks. The three main structures involved in fear and extinction behavior are the basolateral amygdala, the medial prefrontal cortex and the hippocampus. Recent data suggest that neuronal synchronization among the constituents of this tripartite circuit might mediate fear and extinction behavior. To further evaluate this hypothesis and in an effort to identify the mechanisms of neuronal synchronization that underlie this circuit, neuronal activity was simultaneously recorded in all three structures in behaving animals undergoing an auditory fear conditioning paradigm. Our results identify a novel 4 Hz rhythm in the prefrontal cortex and the amygdala during fear behavior which transiently synchronizes the activity between the two structures. This work, in conjunction with the prior knowledge on the functional connectivity between these structures provides preliminary evidence on the possibility of a multiplexed timing mechanism based on this 4 Hz oscillation that modulates neuronal activity and controls fear behavior. Keywords: in vivo electrophysiology, auditory fear conditioning, medial prefrontal cortex, local field potentials, synchronization The impact of Sleepiness on the Procedural Memory and Quantitative EEG in Sleep Disordered Patients Ioanina Sorana Lazar and Thomas Penzel Sleep Center, CC11, Charite Universitätsmedizin, Berlin, Germany Sleep consists of approximately 90 minutes cycles of non-­‐REM (3 stages) and REM sleep. It is thought that the procedural memory is consolidated mainly by the rapid-­‐eye-­‐movement (REM) sleep, but there is also evidence that the stage 2 of non-­‐REM sleep and the sleep spindles can also play a role in the acquisition of skills that are similar to the ones already developed[1, 2]. Moreover, it is of high interest to analyze the performance of the sleep disorder patients using a Divided Attention Steering Stimulator (DASS) as a procedural task, considering that sleepiness is an important factor for the occurrence of accidents. [3] Obstructive sleep apnea syndrome (OSAS), for example, makes the subjects to be 7 fold more liable to be involved in a car crash compared with healthy individuals [4], this risks being remarkably decreased after treatment[5]. Besides, electroencephalography can provide good indicators for the level of sleepiness and performance during driving as in the case of the delta-­‐theta waves [6]. We studied 21 patients aged between 22 and 65 years, 10 OSAS patients and 11 subjects diagnosed with other sleep disorders. They underwent a training session in the evening with DASS (that consists of 3 types of road visibility-­‐ all, near and far field), 2 psychological tests (Flexibility and Go No Go Test) and completed the Karolinska Sleepiness Scale (KSS) and Epworth Sleepiness Scale (ESS). In the next morning, they performed the real tests and completed again the KSS. Four of the OSAS were treated and the tests were repeated in the morning after their treatment. The results from the morning tests were correlated significantly to their evening training performance (for 2 roads), the time spent in Stage 2 of Sleep(for 2 roads), ESS(for one road). The performance results between the 2 groups did not show statistical significance neither for DASS, nor for the psychological tests. Other results are still being processed. [1] Marshall L., Born J., The contribution of sleep to hippocampus-­‐dependent memory consolidation, TRENDS in Cognitive Sciences 2007, (10):442-­‐450. [2] Smith C., MacNeill C, Impaired motor memory for a pursuit rotor task following Stage 2 sleep loss in college students, J Sleep Res. 1994, 3(4):206-­‐213. [3] Smolensky MH, Di Milia L, Ohayon MM, Philip P., Sleep disorders, medical conditions, and road accident risk, Accid Anal Prev. 2011 Mar;43(2):533-­‐48. [4] Findley L.J., Unverzagt M.E., Suratt P.M., Automobile accidents involving patients with obstructive sleep apnea, Am. Rev. Respir Dis. 1988, 138(2): 337-­‐340. [5] George CF., Reduction in motor vehicle collisions following treatment of sleep apnoea with nasal CPAP, Thorax. 2001, 56(7):508-­‐12. [6] Chuang S. W., Ko L. W., Lin Y. P., Huang R. S., Jung T. P., Lin C. T., Co-­‐modulatory spectral changes in independent brain processes are correlated with task performance, NeuroImage 2012, (62):1469–1477. The effect of oxytocin and early life stress in resting state connectivity Ana Lucia Herrera Meléndez, Yan Fan and Malek Bajbouj Charité -­‐ Universitätsmedizin Berlin Exposure to Early Life Stress (ELS) is associated with an increased risk to develop psychiatric diseases in the adulthood. There is evidence for morphological and functional alterations in the brain in subjects with a history of ELS. Furthermore, previous studies show that the hypothalamic-­‐
pituitary-­‐adrenal (HPA) axis, which is one of the main mediators of the stress response is also altered by ELS exposure. HPA responsitvity is measured as cortisol elevation during stress, which has shown to be malleable via intranasal oxytocin administration . However the effect of oxytocin in subjects exposed to ELS still remains unknown. In the present study we sought to answer this question and additionally to map the resting state connectivity (rs-­‐fMRI) in subjects with a history of ELS. This study is conducted on a sample comprising of 10 men with a history or ELS and 10 controls with a healthy childhood, assessed by the Childhood Trauma Questionnaire (CTQ). All participants were aged between 18 to 37 years. Each subject was administered oxytocin and placebo in two separated sessions, with sequences counter-­‐balanced across subjects. We examined the images acquired during the 8.05 min eyes-­‐open rs-­‐fMRI with different parameters including Regional Homogeinity (ReHo), fractional Amplitude of Low Frequency Fluctuations (fALFF) and Degree Centrality and carried a second level statistical analysis with a 2-­‐by-­‐2 factorial design (high/low ELS x oxytocin/placebo). The ELS exposed subjects had a higher score for emotional neglect, emotional abuse and physical neglect. The analysis showed that the subjects with ELS exposure had a higher ReHo in the left and right occipital cortex, when compared to the low-­‐ELS group. Additionnally, the low-­‐ELS group revealed a higher ReHo in the right amygdala and right temporal gyrus. The fALFF analysis exposed a positive interaction between oxytocin administration and ELS in the right insula. Furthermore the Degree Centrality was influenced by a positive interaction between oxytocin and ELS in two clusters belonging to the right precentral gyrus and one cluster in the left claustrum. This study is an exploratory analysis of the influence of oxytocin in the rs-­‐
fMRI of subjects with ELS. There is previous evidence for changes in the occipital cortex in people with childhood maltreatment, which suggests that the sensory system that process the adverse stimulus might be modified after exposure. A deeper analysis should be made to undermine the implications in the changes in fALFF and Degree Centrality. Since most of the previous studies are done in functional long distance connectivity, this analysis gives the first insight into the changes in local connectivity in people with ELS and the influence by oxytocin. Keywords: ELS, oxytocin, ReHo, fALFF Degree Centrality. Social influences on utility and preferences in an auction game Esperanza Jubera-­‐García, Ray Dolan and Ulf Toelch Berlin School of Mind and Brain (Humbolt University) Since the classic works of Sherif and Ash there is ample evidence how we are swayed by the opinion of others under a wide range of conditions often deviating from standard models of rational choice. One example emerges from common value auctions where overbidding effects are closely associated with perceived competition. One interpretation is that participants assign an intrinsic utility to winning and losing an auction against others that is based on their social preferences. This in turn predicts that such a tendency is stable across contexts. Here, we investigate this in an auction game where dyads of players repeatedly bid for one out of five real items that could actually be obtained at the end of the experiment. Players’ item preferences were derived from initial bids as an indicator for the utility of each item. We show that bidding decisions across contexts are not only mediated by general social preferences but interact with differences in players’ utility for the auction items. Players are consistently willing to increase bids when other player preferences were equal or higher. This in turn can lead to preference switches within individuals. We discuss these results on the basis of a set of computational models that capture these interactions. Keywords: social decision-­‐making, all-­‐pay auctions, utility. Linking daily life activity to cognitive health in ageing: an Ecological Momentary Assessment study Natalie Rens, Gwaenelle Catherine, Amandine Pelletier and Joel Swendsen INCIA Ageing is associated with structural alterations in the brain which lead to cognitive decline. Previous studies have suggested that daily life activities such as exercise, leisure and intellectually stimulating activities contribute to the preservation of cognitive health. Ambulatory monitoring techniques, such as Ecological Momentary Assessment (EMA), offer the advantage of real-­‐time analysis of such behaviours in an ecologically valid environment. These techniques overcome the barrier of recall bias associated with previous retrospective-­‐based methods. We applied a novel combination of EMA with structural and diffusion MRI to investigate the relationship between daily life activities and cerebral integrity in a population of older adults. EMA was found to be well-­‐accepted in this population, which was demonstrated by the ease of completion and high general compliance. The MRI analyses revealed positive associations of activity with grey matter volume specifically within the right posterior insular cortex and left inferior parietal lobe. These effects were strongest for global activity, but also with frequency of exercise and leisure activities. Neuroprotective effects in white matter diffusion indices (fractional anisotropy and mean diffusivity) were broadly present in tracts related to motor and cognitive function, and correlated to global activity and exercise. Overall, these results demonstrate the feasibility of EMA in the domain of cognitive ageing and support future applications in this field. Keywords: Ecological Momentary Assessment; MRI; ageing; cognition; daily life activities Workshop Biosketches of Speakers Abstracts Ana Luisa Carvalho Group Leader Glutamatergic Synapses: formation and regulation, CNC Ana Luisa Carvalho graduated in Biochemistry in 1993 from the University of Coimbra, where she also did her PhD in 1999, studying AMPA receptor regulation by phosphorylation, in a collaborative project between Euclides Pires and Carlos Duarte at the University of Coimbra, and Richard Huganir at the Johns Hopkins University School of Medicine (USA). She got appointed as an Assistant Professor at the University of Coimbra in 1999. Since 2004 she is a Tenured Assistant Professor at the Department of Life Sciences, University of Coimbra, and leads the research group on Glutamatergic Synapses at the CNC-­‐Center for Neuroscience and Cell Biology. She did a sabbatical at the laboratory of Ann Marie Craig at the University of British Columbia (Canada) in 2006/2007. She is interested in the molecular and cellular mechanisms of synaptic plasticity. Modulation of hippocampal glutamatergic synapses by ghrelin 1,2
1
1
Luís F Ribeiro , Tatiana Catarino , Sandra D Santos , J Fiona van 1,2
3
1,2
Leeuwen , José A Esteban , Ana Luísa Carvalho 1
CNC-­‐Center for Neuroscience and Cell Biology, University of Coimbra, 2
Portugal; Department of Life Sciences, University of Coimbra, Portugal; 3
Centro de Biología Molecular “Severo Ochoa”, Consejo Superior de Investigaciones Científicas (CSIC) / Universidad Autónoma de Madrid, Madrid, Spain. Ghrelin is a peptide mainly produced by the stomach and released into circulation, affecting energy balance and growth hormone release. These effects are guided largely by the expression of the ghrelin receptor (GHS-­‐
R1a) in the hypothalamus and pituitary. However, GHS-­‐R1a is expressed in other brain regions, including in the hippocampus, where its activation enhances memory retention. Herein, we explore the molecular mechanism underlying the hippocampal action of ghrelin. Our data show that GHS-­‐R1a is localized in the vicinity of hippocampal excitatory synapses, and that its activation increases delivery of AMPA receptors (AMPARs) to synapses. These changes are paralleled by functional modifications at excitatory synapses. Moreover, GHS-­‐R1a activation enhances two different paradigms of long-­‐term potentiation in the hippocampus and increases AMPARs and stargazin phosphorylation. These results indicate that GHS-­‐R1a activation enhances excitatory synaptic transmission in the hippocampus by regulating AMPARs trafficking. Rodrigo A. Cunha Group Leader Neuromodulation, CNC Rodrigo A. Cunha is a Professor at the Faculty of Medicine of the University of Coimbra, Director of the Department of External relation of the Center for Neurosciences and Cell Biology and part of the Steering Committee of the European Neuroscience Campus. He heads the group ‘Purines at CNC’ composed by 5 staff PhD researchers, 1 technician, 8 pos-­‐docs, 11 PhD students, with an h-­‐factor of 43. The group focuses on the purine-­‐based modulation systems in brain circuits. The most relevant contributions of the group were the definition of the role of adenosine A2A receptors in the role of synaptic plasticity and their main role in operating the neuroprotective potential of caffeine in different animal models of disease such as Parkinson’s or Alzheimer’s disease, chronic stress or epilepsy. This heralds the proposal that A2A receptors are key modulators of information flow in brain circuits, making then promising targets to manage conditions such as Alzheimer’s disease or depression. Pivotal role of astrocytes in the adenosine-­‐mediated control of plasticity and damage of brain circuits Rodrigo A. Cunha Center for Neurosciences and Cell Biology, and Faculty of Medicine, University of Coimbra, Portugal. Chronic consumption of caffeine is inversely correlated with the incidence of Parkinson’s disease, depression or dementia associated with aging or Alzheimer’s disease (AD). We now used different animal models of brain disorders to attempt tackling putative mechanisms associated with these beneficial effects of caffeine. In animal models of AD and PD, we found that the neuroprotective effects of caffeine were largely mimicked by selective antagonists of adenosine A2A receptors (A2AR) rather than A1R. A2AR can control synaptic damage by controlling intracellular calcium entry and its handling by mitochondria. Accordingly, A2AR robustly control synaptic apoptosis. In parallel, A2AR also control neuroinflammation, namely the amplification of microglia responses and the impact of pro-­‐
inflammatory cytokines on neuronal viability. A2AR not only play a role on the expression of neuronal damage, but play a key role in the definition of the window of plasticity in neuronal circuits. Accordingly, different behavioural responses tightly associated with synaptic plasticity are under A2AR-­‐mediated control, in particular sensitization to drugs of abuse such as cocaine, fear responses, or ´depressive’-­‐like responses triggered by different chronic stressors. In all these situations, there is an abnormal up-­‐
regulation of synaptic A2AR associated with abnormal plastic changes and the blockade of A2AR curtails abnormal responses. The use of cell-­‐selective A2AR transgenic mice has revealed that all these behaviour are mainly controlled by the presynaptic A2AR, whereas the most abundant striatal A2AR only fine-­‐tune these responses. All together, these results prompt A2AR as the likely molecular target of caffeine to normalise brain function and prevent neurodegeneration. More recent work revealed that A2AR are also present in astrocytes, where they control the uptake of glutamate. Notably, the manipulation of these astrocytic A2AR actively participate in the control of synaptic plasticity phenomena and their manipulation leads to a profound re-­‐adaptation of glutamatergic synapses. Furthermore, the elimination of A2AR in astrocytes leads to the emergence of endophenotypes pertinent to schizophrenia, while affording a robust protection against features characteristic of Alzheimer’s or Parkinson’s disease. This constitutes a shift from neuronal to astrocytic control operated by adenosine A2A receptors to control the flow of information in neuronal circuits and the demise of neurodegeneration. (Supported by FCT, DARPA and CAPES-­‐FCT) Ramiro D. Almeida Assistant Researcher Glutamatergic Synapses: formation and regulation, CNC Ramiro Almeida conducted his graduate studies with Dr. Carlos Duarte at Center for Neuroscience, University of Coimbra, where he studied the mechanisms of neurotrophin-­‐induced survival of hippocampal neurons challenged with an excitotoxic stimulus. He then became interested in a recently described pro-­‐apoptotic effect of proneurotrophins through the low affinity neurotrophin receptor p75. Dr. Almeida then joined the laboratory of Dr. Barbara Hempstead, at Weill Medical College of Cornell University, where the pro-­‐apoptotic actions of proneurotrophins were first described. He helped to establish the role of proNGF and proBDNF as death ligands in different neuronal populations. During his training in the neurotrophin field he became increasingly interested in particular aspects of neuronal development, which are modulated by these molecules, such as axonal growth and synapse formation. He then joined Dr. Samie Jaffrey’s lab also at Weill Medical College of Cornell University, to study the mechanisms of local translation in different aspects of neurodevelopment. Dr. Almeida is currently an Assistant Investigator at Center for Neuroscience and Cell Biology where he is exploring how intra-­‐axonal mRNA translation regulates axonal outgrowth and synapse formation. Regulation of synapse assembly through local protein dynamics Ramiro Almeida CNC-­‐Center for Neuroscience and Cell Biology, University of Coimbra, Portugal Local control of protein composition in dendrites and axons is currently under intense investigation. Recent studies identified a large number of mRNAs localized at distal axons and growth cones, suggesting that local axonal translation may play an important role in different steps of neuronal development. In line with these evidences, early studies in axons demonstrated the requirement of local translation during axon chemotrophic responses to guidance cues. Moreover, it was demonstrated that local axonal translation is required for other neurodevelopmental mechanisms, such as axonal outgrowth, neuronal survival and axon regeneration. Interestingly, recent studies in Aplysia, suggest that local translation might be important for synapse formation. However, the role of local protein synthesis in presynaptic differentiation is largely unknown. The goal of our studies is to determine if local protein synthesis is required for presynaptogenesis. Using a novel platform, a microfluidic chamber system which allows the physical separation of axons from cell bodies and dendrites, we were able to specifically manipulate axons without the cell body contribution. Our results demonstrate that FGF22 induced the clustering of synaptic vesicles, a hallmark of presynaptic assembly, when added specifically to axons. Moreover, FGF22 leads to the phosphorylation of 4E-­‐BP1, a translational repressor, in an asymmetric pattern. Our findings also demonstrate that two mechanistically distinct protein synthesis inhibitors block FGF22-­‐induced presynaptogenesis when applied specifically to axons. Taken together our results show that FGF22 activates cap-­‐dependent translation and that this intra-­‐axonal mRNA translation is required for presynaptic differentiation in CNS neurons. Enrico Tongiorgi Group Leader B.R.A.I.N. Centre for Neuroscience, University of Trieste Trieste, Italy Neurobiologist, member of the World Academy of Arts and Sciences (since 2012). He graduated in 1988 with 110 cum laude in Biology from the University of Pisa, Italy with a thesis on protein phosphorylation in the nervous system of the Leech. After graduation he worked for one year at the Neurobiology Institute, University of Heidelberg with a scholarship from the Accademia dei Lincei. From 1990 to 1994 he has carried out his PhD at the ETH Zurich in the lab of Melitta Schachner, working on the embryonic development of the nervous system in Zebrafish. He returned back to Italy in 1994 at SISSA-­‐Trieste with a post-­‐doctoral fellowhip from UNIDO to work with Antonino Cattaneo on the role of neurotrophins in the postnatal maturation of the brain. In 1997, he was short-­‐term visiting scientist at MRC Cambridge (UK). From 1998 to 2012 he became Assistant professor and since 2012 Associate professor at the University of Trieste where, since 2000, he directs the Laboratory of Cellular and Molecular Neuroanatomy at the Department of Life Sciences. He was director of the Center for Neuroscience BRAIN in 2005-­‐2008. In 2004 he won the 1st prize for the best business idea of the competition StartCup University of Trieste. He is the director of confocal microscopy service of the University and he is responsible of a service of analysis for the detection of antineural antibodie for the local hospitals. Enrico Tongiorgi is the founder of the International Master of Science in Neuroscience where he teaches Applied Neurobiology and Cellular Neuroscience. Since 1998, has received funding for 25 projects, of which 21 as coordinator. He is evaluator of 27 scientific journals and the editorial board of three journals (Frontiers, Nature Publishing Group and Hindawi). He was a member of the committees and evaluators of national funding agencies from 7 countries and the Third World Academy of Sciences. Author of 1 patent, 60 papers in international journals, 4 book chapters, 2 popular books. He has been invited to give numerous seminars and lectures in 12 different countries. BDNF TRANSLATION IN DENDRITES DURING PLASTICITY: WHERE, WHEN, AND HOW? BAJ G., PINHEIRO V., VAGHI V., TONGIORGI E. Dept. of Life Sci., BRAIN Centre for Neuroscience, Univ. of Trieste, Trieste, Italy Various forms of long-­‐term, or homeostatic plasticity require translation of Brain-­‐derived neurotrophic factor (BDNF). However, the molecular mechanisms involved in BDNF protein biosynthesis are poorly known and complicated because there are multiple BDNF mRNA splice variants all producing the same protein. In addition, BDNF mRNA isoforms have different distribution between the soma and dendrites and are translated in different cell compartments to produce local effects. Based on these observations we proposed the “spatial code hypothesis of BDNF splice variants”. In this context, we studied BDNF translation in dendrites focusing on the main dendritic BDNF mRNA variant exon-­‐6. We analyzed where BDNF is translated in response to neuronal activation using densitometric analysis of immunofluorescence in primary, secondary and higher order of dendrites, and corresponding branching points, and we found increase in all compartments. Analyzing when BDNF translation occurs in dendrites, we found several phases of recurrent translation and release, starting after 15 min of stimulation. To investigate how is BDNF translated we created a novel luciferase assay and using KCl and specific kinase inhibitors, we identified two pathways controlling 5’UTR-­‐dependent translation involving Erk and mTOR and three 3’UTR-­‐dependent pathways involving Aurora-­‐A, CaMKII and Src kinases. We also investigated where the components of the translational machinery downstream these pathways are located in the different dendritic compartments and how their localization changes in response to neuronal activity and found that some are localized constitutively throughout the entire dendrites length while others are regulated. Finally, we found a different colocalization of BDNF with Golgi stack or Trans-­‐Golgi network depending on the distance from the soma or proximity to a branching point. Our study unravels the basic mechanisms of BDNF biosynthesis in dendrites. (Telethon, Fondaz. San Paolo) Miguel Castelo-­‐Branco Group Leader Image Processing, Functional Imaging and Phenotyping of Complex Diseases IBILI, University of Coimbra MCB obtained his MD PhD in 1999 (supervisors: Wolf Singer, Max-­‐Planck Institute for Brain research, Frankfurt, Germany and José Cunha-­‐Vaz, University of Coimbra, Portugal). He is now Associate Professor at the University of Coimbra, and has held a Professorship in Psychology in 2000 at the University of Maastricht, the Netherlands. Before, he was shortly a Postdoctoral fellow at the Max-­‐Planck-­‐Institute for Brain Research, Germany where he had also performed his PhD work (1994-­‐1999). His achievements are well reflected in publications in top General Journals, such as Nature and PNAS and Top Clinical Translational research journals such as Journal of Clinical Investigation, Brain as well as others in the field of Human Neurophysiology and Neuroscience (The Journal of Neuroscience, The Journal of Neurophysiology, Human Brain Mapping, Neuroimage, Cerebral Cortex, Neuron and others). MCB has made interdisciplinary contributions in the fields of Cognitive Neuroscience, Human and Animal Neurophysiology, Visual Neuroscience, Human Psychophysics, Functional Brain Imaging and translational research in Neurology. His lab has formerly accomplishing tasks in the context of several European Networks, (Evi-­‐Genoret, BACS, two e-­‐Rare Consortia, and a European Project on Neurofeedback), and has succeed in collaborating with labs working in other fields of knowledge such as Human Genetics and Clinical Neuroscience. MCB has also been successful in generating interdisciplinary work with scientists working in the field of neuropsychology, neuroinformatics and neuroengineering. This enabled proof of concept publications showing the effectiveness of brain computer interfaces and neurofeedback in normal and neurological populations. MCB has been awarded several National and International Prizes and is the Scientific Coordinator of the National Functional Brain Imaging Scientific initiative. His lab is representing his own host University in this national Imaging Consortium. He is also the Director of ICNAS, a Medical Imaging Infrastructure at the University of Coimbra and IBILI, a Research Unit of our National Scientific System. Under his leadership IBILI was classified as an Excellent Research Unit by international evaluation panels. He also has strong experience in preclinical and clinical research (including clinical trials involving drug therapies). He has also been involved in “spin-­‐off” initiatives and entrepreneurial consortia between academia and the industry. A. Cristina Rego Group Leader Mitochondrial Dysfunction and Signalling in Neurodegeneration, CNC AC Rego is Assistant Professor with 'Agregação' of Biochemistry and Neuroscience at the Fac. Medicine, University of Coimbra, and head of the research group ‘Mitochondrial Dysfunction and Signaling in Neurodegeneration’ (http://www.cnbc.pt/research/areaA1_2.asp?lg=2) at the Center for Neuroscience and Cell Biology (CNC) since 2003. AC Rego received the PhD in Cell Biology in 1999 at the same University. Her PhD thesis focused on retinal cell neurodegeneration under oxidative stress and ischemia conditions. As a postdoctoral fellow in the lab of Prof. David G. Nicholls, at University of Dundee, Scotland, U.K., and at the Buck Institute, Novato, CA, U.S.A., AC Rego analysed in-­‐situ mitochondrial dysfunction and calcium homeostasis during excitotoxicity and neuroapoptosis, contributing for the understanding of calcium-­‐linked mitochondrial deregulation following activation of glutamate receptors. From 2004-­‐2005 AC Rego was the coordinator of the BEB PhD Programme at CNC. AC Rego is currently focused on studying modified intracellular signaling pathways and transcriptional deregulation relevant for mitochondrial and cellular function in neurodegenerative disorders, namely Huntington’s, Parkinson’s and Alzheimer’s diseases. Key cellular mechanisms are studied, such as excitotoxicity, mitochondrial and metabolic dysfunction, oxidative stress and calcium deregulation in cell and animal disease models, and human peripheral blood cells. Funding from was obtained from: HighQ Foundation (USA), Lundbeck Foundation, Univ Coimbra III and FCT (PT). AC Rego published 76 original and review papers and 9 book chapters, and is a member of the board of the Sociedade Portuguesa de Neurociências (SPN). Neuronal dysfunction in Alzheimer’s disease: a focus on mitochondrial and nuclear signaling A. Cristina Rego CNC-­‐Center for Neuroscience and Cell Biology, and Faculty of Medicine, University of Coimbra, Coimbra, Portugal Cognitive deficits in Alzheimer’s disease (AD) are thought to be related to synaptic dysfunction in response to amyloid beta-­‐peptide (Aβ) accumulation. Aβ has been described to cause mitochondrial dysfunction and oxidative stress as well as to interfere with N-­‐methyl-­‐D-­‐aspartate receptors (NMDARs) activity, a relevant mechanism in Aβ-­‐induced calcium rise and neuronal dysfunction. Furthermore, recent data has proposed changes in transcription deregulation in AD. Therefore, we will describe the changes in mitochondrial dysfunction and transcription factors linked to NMDAR-­‐dependent calcium changes and further present the evidences of oxidative stress involving deregulation of Nrf2 (a nuclear transcription factor that mediates the expression of relevant detoxifying and antioxidant proteins), which may constitute early events in AD pathogenesis. Supported by QREN DoIT and FCT projects PTDC/SAU-­‐NEU/71675/2006 and PEst-­‐C/SAU/LA0001/2011. Sandra Morais Cardoso Group Leader Molecular Mechanisms of Disease, CNC Dr Sandra Morais Cardoso holds a BSc in Biology, a MSc and a PhD in Cell Biology. She is currently an Assistant Professor at the Faculty of Medicine and Research Scientist at Center for Neurosciences and Cell Biology of the University of Coimbra, where she co-­‐heads the research group ‘Molecular Mechanisms of Disease’. Her research interests are focused on the impact of mitochondrial dysfunction on microtubule-­‐dependent traffic and quality control mechanisms, namely macroautophagy and the ubiquitin proteasomal system, in the pathogenesis of Alzheimer’s and Parkinson’s diseases. Dr Cardoso has published over 50 papers with an h factor of 23 and over 2850 citations. She has supervised 1 post-­‐doc, 4 PhD students and 6 MSc students. She is/was a PI of different scientific projects with 206,316 Euros of funding. Currently she has active collaboration with Russell H Swerdlow from Kansa University, USA, and Marcia C Haigis from Harvard Medical School, USA. Mitochondrial involvement in autophagic dysfunction: a way to Parkinson’s disease. Sandra Morais Cardoso CNC-­‐Center for Neuroscience and Cell Biology, and Faculty of Medicine, University of Coimbra, Coimbra, Portugal Neurons are exquisitely dependent on quality control systems to maintain a healthy intracellular environment. A permanent assessment of protein and organelle “quality” allows a coordinated action between repair and clearance of damage proteins and dysfunctional organelles. Impairments in the intracellular clearance mechanisms in long-­‐lived post mitotic cells, like neurons, result in the progressive accumulation of damaged organelles and aggregates of aberrant proteins. Using cells bearing Parkinson disease (PD) patients’ mitochondria, we demonstrated that aberrant accumulation of autophagosomes in PD, commonly interpreted as an abnormal induction of autophagy, is instead due to defective autophagic clearance. This defect is a consequence of alterations in the microtubule network driven by mitochondrial dysfunction that hinder mitochondria and autophagosome trafficking. We uncover mitochondria and microtubule-­‐directed traffic as main players in the regulation of autophagy in PD. Cellular and in vivo models to elucidate LRRK2 signalling cascades Kristof Van Kolen Janssen Pharmaceutica, Beerse, Belgium Leucine-­‐rich repeat kinase 2 (LRRK2) is one of the genes associated with autosomal dominant forms of Parkinson’s disease (PD). It encodes a large protein which has several functional domains, including a kinase domain. Many mutations in the gene have been identified and several have been shown to segregate with PD (Zimprich et al, 2004). Interestingly, the most prevalent mutation, G2019S, is located in the kinase domain of the protein and associated with an increased kinase activity (West et al, 2005). This suggests that LRRK2 kinase activity might play an important role in disease pathology. However, at present the function of LRRK2 remains poorly understood and it remains speculative in which physiological pathways LRRK2 plays a role. Understanding the function of the protein’s kinase domain and identification of substrates of LRRK2 are crucial to provide insight in LRRK2 mediated signal transduction. Here we describe two sensitive assays to monitor LRRK2 expression and kinase activity and we shed light on the physiological role of LRRK2 by proposing a role in endocytosis in fly and mammalian neurons through the phosphorylation of endophilin A1 at Ser75 which controls the membrane association of endophilin. Carlos Duarte Group Leader Neuronal Cell Death and Neuroprotection, CNC Carlos B. Duarte graduated in Biology at the University of Coimbra (1987) and obtained the PhD in Cell Biology at the same University in 1993. He is presently Associate Professor at the Department of Life Sciences of the University of Coimbra and leader of the group ‘Neuronal Cell Death and Neuroprotection’ at the Center for Neuroscience and Cell Biology. The main scientific interests of his research group are: i) the molecular mechanisms of synaptic dysregulation in brain ischemia; ii) the role of brain-­‐derived neurotrophic factor (BDNF) in the late phase of long-­‐term potentiation in the hippocampus, and the effects of BDNF in local protein synthesis at the synapse. He is the co-­‐author of about 100 scientific publications with more than 2000 citations. Carlos Duarte received the award for Excellence in Research by the Portuguese Research Council (FCT) in 2005 and is presently member of the Editorial Board of the Journal of Neuroscience Research and Neurochemical Research. Excitotoxic cell death: more than just glutamate Carlos B. Duarte, Miranda Mele, João T. Costa, Michele Curcio, João R. Gomes CNC -­‐ Center for Neuroscience and Cell Biology, and Department of Life Sciences, University of Coimbra, Coimbra, 3004-­‐517 Coimbra, Portugal Reduction in the blood flow to the brain following cardiac arrest or ischemic stroke decreases the supply of oxygen, glucose and other blood-­‐
carried fuels, leading to neuronal death. Under the latter conditions the region of the brain that is most affected, the ischemic core, fully depends on the oxygen and glucose provided by the affected blood vessel, while the penumbra region, the area surrounding the infarcted core, is not as much affected due to the blood supply by the collateral circulation. Neurons in the core region die rapidly by necrosis while delayed neuronal death in the penumbra region occurs by an apopoptotic-­‐like mechanism. Extracellular accumulation of glutamate with a consequent overactivation of glutamate receptors plays a key role in neuronal death in the ischemic brain – excitotoxic cell death. However, there are also evidences pointing to a dysregulation of the GABAergic synapses in the ischemic brain, which should further contribute to an imbalance between excitatory/inhibitory neurotransmission and to neuronal death. We have been investigating the pre-­‐ and post-­‐synaptic alterations in GABAergic synapses in the hippocampus, a brain region highly sensitive to ischemic injury, under excitotoxic conditions and in brain ischemia. Excitotoxic stimulation of cultured hippocampal neurons with glutamate induces a calpain-­‐mediated cleavage of the vesicular GABA transporter, and similar effects are observed following transient focal ischemia in mice. Since the cleaved transporters are not targeted to the synapse, this mechanism is likely to downregulate the exocytotic release of GABA. The abundance of GABAA receptors (GABAAR) at synaptic sites, regulated by their lateral mobility at the plasma membrane and their trafficking to and from the cell surface, is a key mechanism for determining the strength of synaptic inhibition and for regulating the correct balance between excitation/inhibition in neuronal circuits. Gephyrin, the principal scaffold protein of GABAergic synapses, plays an important role in the stabilization of GABAARs at synapses, by cross-­‐linking the receptor molecules to tubulin and actin cytoskeleton. We found that gephyrin is truncated in hippocampal neurons subjected to excitotoxic conditions or to in vitro ischemia, as well as in transient focal brain ischemia in vivo, giving rise to two cleavage products. Studies performed in cultured hippocampal neurons suggest that this cleavage disrupts the two-­‐dimensional hexagonal gephyrin lattice, thereby decreasing the number of synaptic GABAAR clusters. Transient in vitro ischemia also induces GABAAR dephosphorylation followed by a clathrin-­‐mediated internalization, and the downregulation of surface GABAAR was coupled to cell death in cultured hippocampal neurons. These results suggest that inhibition of GABAAR dephosphorylation may be an important neuroprotective strategy in brain ischemia.
João Peça FCT Investigator Glutamatergic Synapses: formation and regulation, CNC João Peça did his PhD at the Duke University Medical Center with Guoping Feng. He later moved to MIT as a Research Fellow and collaborated with Ann Graybiel and Guoping Feng to continue developing neuroscience specific tools and addressing questions relating to the influence of discrete neuronal circuits in the etiology of neuropsychiatric disorders. Since 2013, João Peça is starting as an Assistant Researcher at the Center for Neuroscience and Cell Biology in the University of Coimbra. The two main focus of research are: 1. The development of innovative tools to study neural circuits in vivo 2. Understanding the neural circuits and genes controlling social behavior 3. Modeling of human neuropsychiatric disorders in mice. Genetic and Optogenetic Dissection of Neuronal Circuits //From circuits to behavior, in the healthy and the diseased brain// João Peça CNC-­‐Center for Neuroscience and Cell Biology, University of Coimbra, Portugal In this talk we will discuss how specific tools may be used to further our understanding of the brain, synaptic function and how we can probe the synaptic circuits that control behavior. Starting with genetic manipulation, the knockouts of SAPAP3 and Shank3 demonstrate a key role in cortico-­‐
striatal communication and provide a link to disorders such as autism and OCD. In a second part we will address how optogenetic tools may be used to manipulate circuit activity in the brain to help dissect information pathways or in some cases how they can be used to directly control animal behavior. Jorge Valero Postdoctoral fellow Neuroprotection and Neurogenesis in Brain Repair, CNC Dr. Jorge Valero graduated in Biochemistry by the University of Salamanca in 2001 and obtained the grade of Salamanca in 2003. He completed a PhD degree in Neuroscience by the same University in 2007 and received the Doctorate extraordinary prize in 2008. Dr Valero scientific work has been aimed to understand the role of adult neurogenesis during neurodegenerative processes. His thesis work analyzes the effects of the degeneration of olfactory bulb mitral cells in adult neurogenesis. In 2007, he did a short-­‐term postdoctoral stay at the Institute of Psychiatry (King's College of London, UK) to analyze adult neurogenesis in a mouse model of an infantile neurodegenerative disease. From 2008 to 2011, he conducted a research project aimed to analyze hippocampal memory and neurogenesis deficits in a mouse model of Alzheimer's disease at the Universitat Autònoma of Barcelona under the supervision of Dr. Carlos A. Saura. Since 2011, he is a FCT postdoctoral fellow at the Center for Neuroscience and Cell Biology (CNC, University of Coimbra) where he analyzes the effects of neuroinflammation in memory and hippocampal neurogenesis in a mouse model of Alzheimer's disease. Adult neurogenesis: the death of a dogma, the birth of new promises. Jorge Valero CNC-­‐Center for Neuroscience and Cell Biology, University of Coimbra, Portugal For many years the idea that "no new neurons are produced in the adult brain" constituted a dogma that was abolished during the last decade of the past century. However, the death of this dogma led to some collateral damages. The first studies made in 1962 by Joseph Altman demonstrating the existence of adult neurogenesis gave his laboratory a brief golden decade that continued with a time of marginalization and disqualification (http://neurondevelopment.org/Laboratory-­‐History). This fact forced Altman and his pupils to move on and change the focus of their research. Again, more than ten years later, two researchers, Michael Kaplan and Fernando Nottebohm, challenged the dogma and were severely criticized. Indeed, for Kaplan it almost suppose the death of his scientific carrier (Kaplan, 2001: Environment complexity stimulates visual cortex neurogenesis: death of a dogma and a research career). It was not till the late 1990's when several publications verifying the existence of adult neurogenesis in the mammalian brain led finally, for those who wanted to believe, to the death of the dogma. During the late 90's and the beginning of this century many scientist opted to assume that adult neurogenesis is just a remnant of embryonic development and lacks of functional interest. However, many evidences claim that newly generated neurons do play a role in central nervous system function, at least in rodents. The existence of adult neurogenesis has been shown in humans but it remains to be clearly demonstrated its impact on human cognitive function. Nevertheless, nowadays, there is a great optimism about the therapeutic potential of manipulating adult neurogenesis and neural stem cells to cure brain diseases. At the end, the death of this dogma has conclude with the birth of new promises and will lead, at least, to a better understanding of our ever-­‐
changing brain. Luís Pereira de Almeida Principal Investigator Vectors and Gene Therapy, CNC Luís Pereira de Almeida (luispa@ci.uc.pt) graduated in Pharmaceutical Sciences at University of Coimbra in 1991. After 2 years as chief of production at Laboratorios Delta, Rotta Research Group in Queluz, later integrated the Faculty of Pharmacy as teaching assistant at the laboratory of Pharmaceutical Technology and developed a master thesis on modeling dissolution of drugs. Later, with a fellowship from the Portuguese Foundation for Science and technology developed his PhD project at the Gene Therapy Center, Centre Hôpitalier Universitaire Vaudois and Faculty of Medicine in Lausanne, Switzerland from 1998 to 2001. Assistant professor at the Faculty of Pharmacy, University of Coimbra since 2003, is involved in the coordination of the Masters in Pharmaceutical Biotechnology and teaches at graduate and undergraduate levels. His research activity is developed at the Center for Neuroscience and Cell Biology of the University of Coimbra (CNC), Portugal where he is principal investigator and member of the board. He spent short sabbatical leaves at CEA, Saclay in France (2005) and at the Massachussetts Institute of Technology (2010). The research of his group has been focused on gene therapy approaches for neurodegenerative disorders with a focus on Machado-­‐Joseph disease/spinocerebellar ataxia type 3, including disease modifying and gene silencing approaches, autophagy activation and proteolysis inhibition, works published over forty papers cited over 700 times, in journals such as Brain (3), Annals of Neurology, Human Molecular Genetics, PLoS One, Human Gene Therapy and The Journal of Neuroscience, awarded with prizes by the Portuguese Society for Neurosciences (2009, 2011, 2012, 2013), the Portuguese Society of Human Genetics (2009), and Fundação Pulido Valente (2012). For some years coordinated the Doctoral Program in Experimental Biology and Biomedicine of CNC and has been organizing advanced courses on “Neurodegenerative diseases”, “Principles and Practice in Drug Development” (MIT Portugal -­‐PhD Program)”, “Nuclear biology and gene therapy” and “Gene and cell therapy for the CNS”. Luis Pereira de Almeida is or has been responsible for 15 research projects funded by the Portuguese Foundation for Science and Technology, QREN-­‐ Mais Centro, the Association Française de Myopathies, private funds, the National Ataxia Foundation (USA) and leads one of the twelve European research groups that constitute the Marie Curie Initial Training Network “TreatPolyQ” within the 7th Framework Program of the European Union. NOTES NOTES NOTES NOTES NEURASMUS Partners Sponsors