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Satellite meeting organised by Professor Graham Collingridge FRS, Professor Tim Bliss FRS and Professor Richard Morris CBE FRS
This is a residential conference, which allows for increased discussion and networking. It is free to attend, however participants need to cover their accommodation and catering costs if required.
Biographies of the organisers and speakers are available below and you can also download the programme (PDF). Recorded audio of the presentations will be available on this page after the event
Participants are also encouraged to attend the related scientific discussion meeting Long-term potentiation: enhancing neuroscience for 40 years which immediately precedes this event.
Enquiries: Contact the events team
Professor Graham Collingridge FMedSci FRS, University of Bristol, UKOrganiser
Graham Collingridge is the Professor of Neuroscience in Anatomy in the School of Physiology & Pharmacology at the University of Bristol, UK. From 1999 until 2012 he was also the Director of the MRC Centre for Synaptic Plasticity. In 2001 he was elected a fellow of The Royal Society. His research interests are in the molecular mechanisms of synaptic plasticity. He is particularly interested in how glutamate receptors and their downstream effectors are involved in the mechanisms of long-term potentiation (LTP) and long-term depression (LTD) in the hippocampus and other regions of the mammalian brain.
Professor Tim Bliss FMedSci FRS, National Institute for Medical Research, UKOrganiser
Tim Bliss was born in England and gained his PhD at McGill University in Canada. In 1967 he joined the MRC National Institute for Medical Research in Mill Hill, London, where he was Head of the Division of Neurophysiology from 1988 till 2006. His work with Terje Lømo in Per Andersen’s laboratory at the University of Oslo in the late 1960’s established the phenomenon of long-term potentiation (LTP) as the dominant synaptic model of how the mammalian brain stores memories. Since then he has worked on many aspects of LTP, including presynaptic mechanisms responsible for the persistent increase in synaptic efficacy that characterizes LTP, and the relationship between synaptic plasticity and memory. He is a Fellow of the Royal Society, and of the Academy of Medical Sciences. He shared the Bristol Myers Squibb award for Neuroscience with Eric Kandel in 1991. In 2011 he received an honorary degree from Dalhousie University. In May 2012 he gave the annual Croonian Lecture at the Royal Society on ‘The Mechanics of Memory’.
Professor Richard Morris CBE FRS, University of Edinburgh, UK
Richard Morris is Professor of Neuroscience at the University of Edinburgh and Director of the Centre for Cognitive and Neural Systems. He read Natural Sciences at the University of Cambridge followed by a DPhil at Sussex University. He moved to Scotland in 1977 where he developed the watermaze in the Gatty Marine Laboratory at the University of St Andrews, moving in 1986 to the University of Edinburgh where he was appointed full Professor in 1993. His scientific interests are in the neurobiology of learning and memory, and his research included the first demonstration that hippocampal NMDA receptors are necessary for spatial learning, the development of the synaptic tagging and capture hypothesis of protein synthesis-dependent long-term potentiation and, most recently, work on the role of mental schemas in systems consolidation. He is an elected Fellow of the AAAS, of the American Academy of Arts and Sciences, and of the Norwegian Academy of Science and Letters, and was elected a Fellow of the Royal Society in 1997. He was appointed a CBE in 2007.
Professor Nigel Emptage, Oxford University, UKThe role of glutamate autoreceptors in plasticity
Nigel Emptage is the Professor of Neuropharmacology within the Department of Pharmacology at the University of Oxford (UK) and the Nuffield Research Fellow of Lincoln College, Oxford. He moved to Oxford from the National Institute for Medical Research, London where he worked with Tim Bliss and Alan Fine to develop optical methods with which to measure synaptic activity. The approach, measuring increases in intracellular Ca2+ in response to physiological stimuli, has permitted data to be gathered both about the expression mechanisms of LTP as well as fundamental Ca2+ signalling pathways in neurones. This approach remains at the core of the laboratory’s ongoing research.
A rise in [Ca2+]i provides the trigger for neurotransmitter release at neuronal boutons. Measurement of the action potential-evoked [Ca2+]i in the boutons of Schaffer collaterals reveals that the trial-by-trial amplitude of the evoked Ca2+ transient is bimodally distributed. We have found that ‘large’ Ca2+ transients occur when presynaptic NMDA receptors are activated following transmitter release, thus they serve as autoreceptors.
Since autoreceptors ‘report’ transmitter release on a trial-by-trial basis we have used this to estimate the probability of release, (pr). We have used this novel estimator to show that pr increases following the induction of LTP providing a further experimental strategy with which it is possible to demonstrate that LTP produces changes at the presynaptic locus.
Recently, we sought to identify a functional role for presynaptic NMDA autoreceptors. We find that they form part of a signalling network at the synapse that regulates pr following the induction of LTP and LTD.
Professor Ole Paulsen, University of Cambridge, UKLeft-right asymmetry of hippocampal LTP: implications for memory and memory disorders
Ole Paulsen is the Professor of Physiology at the University of Cambridge. Following Medical School in Oslo, Norway, he did his PhD with Professor Per Andersen in the Department of Neurophysiology, University of Oslo. He served as Departmental Lecturer in the Department of Pharmacology at Oxford 1994-2000, and as University Lecturer 2000-2009 in the Department of Physiology at Oxford, which merged into the Department of Physiology, Anatomy & Genetics. His research focuses on the relationships between network architecture, circuit dynamics and synaptic plasticity in normal behaviour as well as in brain disorders.
Synaptic plasticity is the best-supported cellular model for learning and memory. It proposes that the timing and/or pattern of neuronal activity lead to long-lasting changes in synaptic weights that carry a memory trace. Using optogenetics we have investigated timing-dependent synaptic plasticity in the mouse hippocampus and found a striking left-right asymmetry of hippocampal plasticity. This talk will present recent data indicating that this left-right asymmetry extends to high-frequency stimulation-induced LTP, long-term memory processing, as well as amyloid beta-induced synaptic changes with relevance to Alzheimer's disease. These results suggest that hippocampal memory is routed via distinct left-right pathways that are differentially vulnerable in neurodegenerative disease.
Professor Dmitri Rusakov, University College London, UKThe role of astroglia in encoding synaptic plasticity
Dmitri Rusakov graduated with Masters in Physics (Distinction) in 1984 from Dnepropetrovsk State University and obtained a PhD in Neurobiology and Biophysics in 1988 from Bogomoletz Institute of Physiology in Kiev, Ukraine. He was Senior Research Associate at Bogomoletz Institute from 2000; Departmental and Named Research Fellow at the Open University (UK) in 1993-1998 (with Mike Stewart); Research Associate at NIMR, Mill Hill, London (with Alan Fine and Tim Bliss) from 1998; MRC Career Development Award fellow from 1999 (NIMR, Mill Hill); and moved to UCL Institute of Neurology in 2000. Senior Wellcome Trust Fellow from 2003, renewed in 2008; Reader in Neuroscience (2004), Professor of Neuroscience (2007) at University College London. Elected to Academia Europaea in 2012, Wellcome Trust Principal Fellow from 2013.
Experimental evidence has emerged pointing to diverse and rapid interactions between astroglia and synaptic circuits. We have found that in the hippocampus Ca2+ dependent release of the NMDAR co-agonist D-serine from astrocytes is required for the induction of the classical form of LTP at nearby synapses. However, the underlying principles of intracellular Ca2+ signal integration and transfer by astrocytes remain poorly understood. We combined patch-clamp electrophysiology with two-photon excitation imaging, photo-bleaching monitoring, super-resolution STED microscopy and quantitative 3D EM to characterise quantitatively the fine morphology, intracellular diffusion properties, and Ca2+ homeostasis in common protoplasmic astroglia. Guided by such observations, we have designed a realistic NEURON-style model of the typical passive astrocyte. In parallel, we have developed a life-time fluorescence imaging method to monitor Ca2+ landscapes in astrocytes and in neighbouring synaptic structures with unprecedented sensitivity. Integrating these strategies is helping us to understand cellular machineries that enable astroglia to regulate local synaptic circuitry.
Dr John Isaac, Eli Lilly, UKReactivation of plasticity at layer 4 inputs to barrel cortex after loss of competing sensory input
John Isaac obtained a BSc in Pharmacology and Biochemistry at the University of Southampton in 1990 and remained at Southampton for his graduate work, studying mechanisms of epilepsy with Professor Howard Wheal. In 1994 he joined Dr Robert Malenka’s laboratory at University of California San Francisco working on mechanisms of long-term synaptic plasticity in hippocampus and somatosensory cortex, also in close collaboration with Dr Roger Nicoll. After completion of this postdoc, John joined Graham Collingridge’s laboratory at University of Bristol UK in 1996, where he completed a one year postdoc before establishing his own lab at Bristol. He rose up through the ranks to Professor before leaving in 2004 to set up a lab at the Intramural Program at NINDS/NIH in Bethesda, MD, USA studying mechanisms and roles of synaptic plasticity in developing cortical circuits. In 2010 he left NIH to join Eli Lilly and Company at their neuroscience research campus near Windlesham in Surrey, UK. At Lilly he leads a team of labs dedicated to identifying new therapies for Alzheimer’s disease and schizophrenia. John’s scientific interests centre on synaptic mechanisms in circuit function, and how dysfunction causes psychiatric and neurological disease.
The adult brain is known to undergo experience-dependent plasticity in response to sensory manipulations or peripheral nerve injuries, both in animals and humans. However, the sites and mechanisms of such plasticity are poorly explored, partly due to a lack of approaches allowing unbiased mapping of plasticity sites that can be combined with studies of underlying mechanisms. Here, we combined fMRI, and in vivo and in vitro electrophysiology to study plasticity induced by unilateral infraorbital nerve resection in 4-6 week-old rats. BOLD imaging and manganese-enhanced MRI revealed circuit changes in spared layer 4 (L4) barrel cortex in response to unilateral infraorbital nerve resection. In vivo and brain slice electrophysiology showed that the increased activation of L4 could be accounted for by a selective strengthening of the thalamocortical (TC) inputs to L4 stellate cells. This effect was mediated by a specific increase in postsynaptic strength and in the number of functional synapses. We are currently investigating whether a reactivation of long-term synaptic plasticity contributes to these synaptic changes. Our work shows that the TC input is a site for robust plasticity in 4-6 week old rats, after the end of the previously defined critical period for this input. Thus, TC inputs may represent a major site for adult plasticity challenging the consensus that adult plasticity occurs primarily at cortico-cortical connections.
Dr Céline Nicolas, University of Bristol, UKJAK/STAT and LTD
After hergraduation as a vet in Nantes (France) in 2004, Céline Nicolas started a PhD in the same city, at L’institut du Thorax, managed by Denis Escande. She investigated the physiological involvement of newly identified protein partners of a cardiac potassium channel, KCNQ1. During this time, she learnt different techniques, mainly electrophysiology (patch-clamp), biochemistry and immunocytochemistry. After receiving her PhD in 2007, she joined Graham Collingridge’s team in Bristol in 2008, thanks to a French fellowship. Since then, she has been working on the molecular mechanisms of NMDA receptor-dependent long term depression (LTD), deciphering the signalling pathways involved in this process. After the finding that GSK3β is the only serine/threonine kinase involved in LTD, they used different techniques and approaches to find that the JAK/STAT pathway is also involved in LTD. They are now trying to understand how this pathway is regulated and can modulate synaptic plasticity.
The Janus kinase (JAK) / signal transducer and activator of transcription (STAT) pathway is involved in many cellular processes, including cell growth and differentiation. It is activated by various extracellular factors and regulates the transcription of many genes. Of the four JAK isoforms and seven STAT isoforms known, JAK2 and STAT3 are highly expressed in the brain where they are present in the postsynaptic density (PSD). Using a variety of complementary approaches, we show that the JAK/STAT pathway plays an essential role in the induction of NMDA-receptor dependent long-term depression (NMDAR-LTD) in the hippocampus. However, JAK has no effect on LTP, depotentiation or mGluR-induced LTD.
We identified JAK2 and STAT3 as the isoforms activated and involved in NMDAR-LTD. We also show that the translocation of STAT3 into the nucleus, which occurs just after the induction of LTD, is not required for the induction of LTD, at least in the first 3 hours after induction. Although the role of STAT3 in the dendrites remains to be identified, it can be concluded that the JAK/STAT pathway has a key role in synaptic plasticity in the CNS.
Dr Robert Nisticò, Sapienza University of Rome, CERC – S. Lucia Foundation IRCCS, Rome and EBRI – Rita-Levi Montalcini Foundation, Italy Synaptic plasticity in multiple sclerosis and experimental autoimmune encephalomyelitis
Dr Nisticò is currently Professor of Pharmacology, Faculty of Pharmacy and Medicine, Sapienza University of Rome, Group leader at the CERC – S. Lucia Foundation IRCCS, Rome and Visiting Scientist at the EBRI – Rita-Levi Montalcini Foundation, Rome, Italy. He graduated from Universita' Cattolica del Sacro Cuore, School of Medicine - Rome, Italy:(1993 to 1999 Doctor of Medicine and Surgery Diploma, cumlaude) and (2000-2003) Specialization in Psychiatry. From 2002 to 2005 he was a Research fellow at the University of Bristol, School of Medical Sciences, MRC Centre for Synaptic Plasticity.
His scientific activities include:
He is a Member of the Editorial Board of Journal of Alzheimer’s disease, NeuroMolecular Medicine, ISRN Stroke, Nature Scientific Reports (NPG), European Journal of Neurodegenerative diseases, World Journal of Pharmacology and, World Journal of Methodology. From 2012 to 2015 he is Honorary special Lecturer at the School of Pharmacy, Nottingham, UK .
Dr Nisticò is author or co-author of approximately 150 publications of which 70 full papers (PubMed source) in international indexed journals, 5 book chapters and more than 100 abstracts of communications in national and international meetings.
Approximately half of all patients with multiple sclerosis (MS) experience cognitive dysfunction including learning and memory impairment. Recent studies suggest that hippocampal pathology is involved, although the mechanisms underlying these deficits remain poorly understood. Evidence obtained from a mouse model of MS, the experimental autoimmune encephalomyelitis (EAE), suggests that in the hippocampus of EAE mice long-term potentiation (LTP) is favored over long-term depression (LTD) in response to repetitive synaptic activation, through a mechanism dependent on enhanced IL-1β released from infiltrating lymphocytes or activated microglia. Facilitated LTP during an immune-mediated attack might underlie functional recovery, but also cognitive deficits and excitotoxic neurodegeneration. Having identified that pro-inflammatory cytokines such as IL-1β can influence synaptic function and integrity in early MS, it is hoped that new treatments targeted toward preventing synaptic pathology can be developed.
Dr Andreas Lüthi, Friedrich Miescher Institute for Biomedical Research, SwitzerlandA role for inhibition in associative fear conditioning
Biography not yet available
Classical fear conditioning is one of the most powerful models to study the neuronal substrates of associative learning and the mechanisms of memory formation in the mammalian brain. In unraveling the substrates of memory storage in fear conditioning and other learning paradigms, the major focus has been the study of excitatory elements of the brain. However, interneurons are critical components of neuronal networks and inhibition plays an important role in shaping network activity and regulating cellular plasticity, so it is surprising that little is known about the involvement of inhibitory circuits in learning and memory. Over the past few years, we have started to dissect amygdala circuitry with the overall aim to understand the computations that are performed by its elements during associative learning. In my talk, I will show recent data indicating that dis-inhibition mediated by distinct subpopulations of interneurons in amygdala is an important mechanism gating the acquisition of conditioned fear responses.
Professor Eunjoon Kim, Institute for Basic Science (IBS) and Korea Adv Inst of Sci and Technol (KAIST), KoreaLong-term depression and synaptic adhesion molecules
Eunjoon Kim is Director of Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS) and Professor in the Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST). His main interest in research is to understand how neuronal synapses are organized at the molecular level, and how defective synaptic proteins lead to diverse neuropsychiatric disorders including autism spectrum disorders and ADHD. Dr. Kim was trained at Busan National University (BS), KAIST (MS), Michigan State University (PhD), and Harvard University (postdoc) and is an elected Member of The National Academy of Science (Korea).
Long-term depression (LTD) reduces the functional strength of excitatory synapses through mechanisms that include the removal of AMPA glutamate receptors from the postsynaptic membrane. LTD induction is also known to result in structural changes at excitatory synapses, including the shrinkage of dendritic spines. Synaptic adhesion molecules are thought to contribute to the development, function, and plasticity of neuronal synapses largely through their trans-synaptic adhesions. However, little is known about how synaptic adhesion molecules are altered during LTD. We report here that NGL-3 (netrin-G ligand-3), a postsynaptic adhesion molecule that trans-synaptically interacts with the LAR family of receptor tyrosine phosphatases and intracellularly with the postsynaptic scaffolding protein PSD-95, undergoes a proteolytic cleavage process in an activity dependent manner. NGL-3 cleavage is induced by NMDA treatment in cultured neurons and low frequency stimulation in brain slices and requires the activities of NMDA receptors, matrix metalloproteinases (MMPs), and presenilin/g-secretase. These results suggest that NGL-3 is a novel substrate of MMPs and g-secretase and that NGL-3 cleavage may regulate synaptic adhesion during LTD.
Dr Jenni Harvey, University of Dundee, UKLeptin regulation of hippocampal synaptic function in health and disease
Jenni Harvey is a senior lecturer in the Division of Neuroscience at the University of Dundee and has a long standing interest in neuronal synaptic mechanisms, in particular the cellular basis for activity-dependent synaptic plasticity in the CNS. Her research is focused on understanding how the molecular processes of synaptic plasticity are influenced by hormonal systems. In recent years JH’s group has been at the forefront of research into the neurobiology of the hormone leptin and has been instrumental in identifying several key roles for leptin in regulating hippocampal synaptic function. JH’s group were the first to show that leptin enhances NMDAR function and facilitates hippocampal LTP. Recently, she has shown that leptin modulates various forms of activity-dependent hippocampal synaptic plasticity via altering glutamate receptor trafficking processes. A major focus of her current research is in determining the cellular mechanisms underlying leptin regulation of hippocampal synaptic function and also how leptin dysfunction impacts on excitatory synaptic function in health and disease.
It is well documented that the hormone leptin plays a key role in regulating food intake and body weight via its actions in the hypothalamus. However, leptin receptors are widely expressed in the brain and evidence is growing that leptin has the ability to influence many central processes. Indeed, recent studies indicate that leptin has cognitive enhancing properties as it markedly facilitates the cellular events underlying hippocampal-dependent learning and memory including effects on glutamate receptor trafficking, neuronal morphology and activity-dependent synaptic plasticity. Recent evidence indicates that the ability of leptin to regulate hippocampal synaptic function markedly declines with age. Moreover, aberrant leptin function has been linked to neurodegenerative disorders like Alzheimer’s disease (AD). The evidence supporting a cognitive enhancing role for the hormone leptin and the therapeutic potential of using leptin-based agents to treat age-related neurodegenerative disorders will be discussed.
Dr Inbal Israely, Champalimaud Center for the Unknown, PortugalActivity dependent restructuring of synaptic inputs
Dr Israely is a native of California, and received her BSc in Molecular Biology from the University of California, San Diego, in 1996. She conducted her graduate research at the University of California, Los Angeles, in the laboratory of Dr Xin Liu and in collaboration with Dr Alcino Silva, where she studied how the loss of a neural specific adhesion protein leads to impairments in cognitive function. After completing her PhD in 2004, Dr Israely wanted to explore how the regulation of single proteins in response to neuronal activity could lead to changes in brain function. She joined Susumu Tonegawa's lab at MIT, where, using two-photon imaging and glutamate uncaging, she examined the learning rules associated with long lasting structural and functional changes at individual synapses. In 2009, she moved to Portugal to start her own group in the Neuroscience Program of the Champalimaud Foundation. Her laboratory, Neuronal Structure and Function, is interested in understanding how information is physically stored in the brain, how information leads to structural changes at individual synapses and in neural circuits, and how aberrant structural changes may lead to certain forms of mental retardation.
Brain circuits can be structurally rearranged with experience, and synaptic connections can grow and be eliminated even in adult brains.
Many of these changes are long lasting and require the synthesis of new proteins. We are interested in elucidating the learning rules which govern plasticity at individual inputs, both functionally and structurally. We previously demonstrated that spine growth can be cooperative in a protein synthesis dependent manner, and that the simultaneous potentiation of spines induces competition for plasticity, which results in bi-directional changes in spine volume.
The mechanisms which regulate spine shrinkage, however, remain unclear. We examine the structural correlates of a protein synthesis dependent form of synaptic depression, mediated by metabotropic glutamate receptors, and find that in response to the global induction of LTD, a majority of spines shrink or are eliminated. These effects can be observed up to 24 hours following plasticity, and require new protein synthesis. Interestingly, synaptic activity is also needed for spine shrinkage, although not NMDA receptor function. Finally, we use two-photon imaging and glutamate uncaging to stimulate and monitor plasticity at single spines. Therefore, we explore how different forms of activity influence synaptic structure and function, and how information is encoded in a circuit.
Professor Haruhiko Bito, University of Tokyo Grad School of Medicine, JapanDeciphering biochemical information processing during plasticity at single synapses
Haruhiko Bito graduated from University of Tokyo with an MD and a PhD in Biochemistry in 1993. After finishing a postdoc in Molecular and Cellular Physiology at Stanford as a HFSP long-term fellow, Dr Bito started his own laboratory in Pharmacology at Kyoto University in 1997. He expanded his research group significantly, when he moved to chair the Department of Neurochemistry at the University of Tokyo in 2003. The ambition of Dr Bito’s laboratory is to go beyond just understanding the makeup of the synapses, and to tease apart some of the molecular and cellular principles underlying activity-dependent changes in neuronal circuitry at single synapse resolution.
The nervous system adapts to a fluctuating environment through activity-dependent modulation of neuronal properties such as synaptic plasticity. The direction and extent of such sustainable modulation is determined by the stimulus parameters, suggesting that the biochemical machineries that operate at synapses can readily compute the input information. Ca2+- and calmodulin-dependent kinase II (CaMKII) and calcineurin appear to play key roles in these processes. However, several important theoretical postulates underlying the role of CaMKII and calcineurin during synaptic plasticity—e.g. that CaMKII in spines functions as a high-frequency input detector or that calcineurin is uniquely activated by low-frequency stimulation—remain untested in living neurons. Furthermore, whether and how the information encoded in glutamate release rates at individual synapses can be reliably converted into biochemical activation patterns of these postsynaptic enzymes also remains unexplored. To address these questions, we developed a novel dual FRET imaging platform and recorded CaMKIIα and calcineurin activities in hippocampal neurons, while varying glutamate uncaging frequencies. Five Hz spine glutamate uncaging strongly stimulated calcineurin but not CaMKIIα, with little spine morphological change. In contrast, 20Hz spine glutamate uncaging which induced spine growth activated both CaMKIIα and calcineurin, with distinct spatiotemporal kinetics. Higher temporal resolution recording in the soma revealed that CaMKIIα activity summed supralinearly and sensed both higher frequency and input number, thus acting as an input frequency/number decoder. In contrast, calcineurin activity summated sublinearly with increasing input number and showed little frequency-dependence, thus functioning as an input number counter. Further analyses of the dual recording of Ca2+ transients and downstream enzyme activities revealed that this distinction in fact resulted from the differential decoding of Ca2+ amplitudes vs Ca2+ integrals by CaMKII and calcineurin, respectively. These results provide evidence that CaMKIIα and calcineurin are activated through distinct non-linear Ca2+ decoding mechanisms, and fine-tuned to unique bandwidths, thus computing distinct input variables in an asymmetric, rather than opposing manner. Deciphering critical rules underlying key enzymatic information processing at excitatory synapses enhance our understanding of the temporal and spatial dynamics of molecular memory events underlying synaptic plasticity and learning & memory.
Dr Santiago Canals, Instituo de Neurociencias, Consejo Superior de Investigaciones Científicas y Universidad Miguel HernándezLTP-Induced Neural Network Reorganization: fMRI and electrophysiological evidences
Santiago Canals studied biology in the Complutense University (Madrid, Spain) where he specialized in neurobiology and graduated in 1997. After one year in the Cajal Institute (CSIC, Madrid) working on the neurochemistry of myelin proteins he moved to the Ramón y Cajal Hospital to conduct his PhD in the Neurobiology Research Department working on cellular and molecular aspects of Parkinson’s Disease in animal models (1999-2003). During a first postdoc in the Hospital Ramón y Cajal (2003-2004) he worked on the electrophysiology of neuronal dendrites, their role in input integration and firing decisions. In 2005 he was awarded a Long-Term Fellowship of the Human Frontiers Science Program and moved to the Max Planck Institute for Biological Cybernetics in Tübingen (Germany) to work with Prof. Nikos Logothetis (2005-2008). There he contributed to the development of new magnetic resonance imaging (MRI) techniques and combined functional MRI with electrophysiology and electric micro-stimulation in rats to investigate functional connectivity in long range networks. In 2009 he returns to Spain to start in the Neuroscience Institute (CSIC-UMH, Alicante) the laboratory of Plasticity of Brain Networks. The laboratory is interested in the mechanisms of information routing in the complex network of parallel and highly distributed connections implemented in the brain, using learning and drug addiction in rodents as experimental models.
Encoding patterns of synaptic activity into a long-term memory requires molecular and physiological changes at the cellular level but also network interactions. While the cellular mechanisms linking synaptic plasticity to memory have been intensively studied, those regulating network interactions have received less attention. Combining high-resolution fMRI and in vivo electrophysiology we demonstrate a functional remodeling of long-range hippocampal networks induced by long-term potentiation of synaptic plasticity in the perforant pathway. We will present the results of our last experiments investigating the cellular mechanism underlying this synapse-to-network transformation.
Professor Cliff Abraham, University of Otago, New ZealandMetaplasticity: changing the future of synaptic plasticity
Cliff Abraham is a Professor of Psychology and Director of the University of Otago’s Brain Health Research Centre. He received a BA with Distinction in Psychology from the University of Virginia, and a PhD in Neuroscience from the University of Florida. After five years of postdoctoral research with Graham Goddard at the University of Otago and with Holger Wigström and Bengt Gustafsson at the University of Gothenburg, he returned to the Psychology Department at Otago, chairing the department in 2003-2005. In 1997 he was elected a Fellow of the Royal Society of New Zealand, and in 2009 was awarded the University of Otago’s Distinguished Research Medal. Professor Abraham’s research is focused on the neural mechanisms of learning and memory, “metaplasticity”, and the neural mechanisms of memory disorders such as Alzheimer’s disease.
Like memory, synaptic plasticity is regulated by many intrinsic and extrinsic variables that affect the neuronal "state". One variable increasingly realised to affect neuronal state is the history of activity in the relevant neural network. We have termed such regulation "metaplasticity". Metaplasticity mechanisms are varied, and likely serve diverse functions. They also range in extent from being synapse-specific to cell-wide. Cell-wide metaplasticity is of particular interest as it can subserve homeostatic control of plasticity thresholds, thereby helping to impart stability to neuronal activity and network function through prevention of runaway synaptic potentiation or depression. The need for such control has been reported in many computational models of plasticity, but experimental demonstrations of such effects are few. Recently we have shown that cell-wide metaplasticity can occur in hippocampal slices in a way that could mediate homeostatic control of synaptic efficacy. Surprisingly, investigations of its mechanisms have indicated a role for intercellular communication, including a contribution by astrocytes. These findings suggest the possibility that homeostatic metaplasticity mechanisms can function at the network level.
Supported by the New Zealand Marsden Fund, the Health Research Council and the Neurological Foundation of New Zealand.
Dr Sam Cooke, Howard Hughes Medical Institute, MIT, USAHebb’s Original Exemplar – plasticity in primary visual cortex enables the detection of novelty
Dr Cooke's major research interest is the biological basis of learning and memory. There are three overarching questions that drive his research: First, how is the nervous system modified to store information in a retrievable fashion for very long periods of time? Second, how are these processes disrupted in psychiatric disorders? Third, can these processes be harnessed to recover function after injury or deprivation? These are questions that he has sought to address throughout his research career. Initially, while obtaining a PhD at University College London under the tutelage of Professor Chris Yeo, he studied the involvement of cerebellar cortical plasticity in associative motor learning. Subsequently, in the laboratory of Doctor Tim Bliss at the National Institute for Medical Research, he investigated key molecular mechanisms in the hippocampus that contribute to episodic-like memory, notably those that also support late long-term potentiation (L-LTP). Most recently, in Professor Mark Bear’s laboratory at the Massachusetts Institute of Technology, he has focused on the neural basis of perceptual learning in primary visual cortex. Continuing work on this phenomenon is providing unexpected insight into psychiatric disorders and may deliver methods to recover function after visual deprivation early in life.
The cerebral neocortex stores memory. Understanding how this storage occurs requires identification of simple forms of memory that rely upon plasticity within circumscribed areas. As Donald Hebb originally surmised, the primary sensory cortices are likely to be the most experimentally tractable due to their proximity to sensory input, and he therefore chose perceptual learning in primary visual cortex (V1) of the rodent as a central example to expound his theories of how the brain stores information. Here I revisit Hebb’s ideas to consider roles for homo-synaptic plasticity in the modification of vision and behaviour through experience. I will describe a form of visual learning in the mouse that is highly selective for stimulus orientation. The resulting memory, sometimes described as familiarity, is manifested as behavioural habituation and likely serves an important function throughout the animal kingdom, enabling organisms to devote cognition to novel elements of the environment that may carry threat or yield reward. During my talk I will describe results revealing that this form of learning is mediated by input-specific synaptic plasticity within V1 that shares many of the features of canonical long-term potentiation (LTP).
Professor Sumantra Chattarji, National Centre for Biological Sciences, IndiaThe amygdala versus hippocampus: contrasting patterns of plasticity in health and disease
Sumantra Chattarji is a Professor of Neurobiology at the National Centre for Biological Sciences in Bangalore, India. He received his Master’s degree in Physics from the Indian Institute of Technology, Kanpur. He then went on to do a Ph.D. in Biophysics, under the supervision of Terry Sejnowski, at the Johns Hopkins University and Salk Institute. Afterpost-doctoral research at Yale University and MIT, he started his own laboratory in Bangalore in 1999. His research has shown that prolonged stress leaves its mark by enhancing both the physiological and structural basis of synaptic connectivity in the amygdala, thereby triggering the emotional symptoms observed in stress-related psychiatric disorders. His lab also studies synaptic defects and their reversal in Fragile X Syndrome, the leading identified cause of autism. He was awarded the International Senior Research Fellowship by The Wellcome Trust, UK and the Vision 2008 Award by the Fragile X Research Foundation, USA. He is also the Director of the recently established Center for Brain Development and Repair at The Institute for Stem Cell Biology and Regenerative Medicine in Bangalore.
The rapid and efficient encoding of fear memories by a brain structure called the amygdala help us cope with threatening stimuli in the future, but also come with a high price tag. These emotional memories etched into the amygdala can become maladaptive. For example, high anxiety and fear are cardinal symptoms of many stress disorders like PTSD. Our study provides insights into the cellular mechanisms underlying these powerful emotional symptoms of stress disorders. We report that chronic stress creates new synaptic contacts that are endowed with more memory-making molecules, which serve as ideal cellular substrates for imprinting powerful emotional memories
Dr Serge Laroche, Centre of Neuroscience Paris-Sud, CNRS & University Paris-Sud, FranceBrain plasticity and memory: LTP and beyond
Serge Laroche is Director of Research at CNRS and director of the Centre of Neuroscience Paris-Sud at University Paris-Sud in Orsay, France. The research is centred on the neurobiological bases of memory and focuses on the cellular and molecular mechanisms underlying synaptic plasticity and memory function, and on the neural mechanisms of memory dysfunction. The approach, from genes to function, is directed at the identification of cellular and synaptic changes underlying learning and memory, and at the functional characterisation of the role of signalling cascades, transcriptional regulators, and the regulation of genes and proteins underlying different phases of plasticity and forms of memory. The research covers different facets, ranging from the mechanisms and function of synaptic plasticity to the role of adult neurogenesis and to investigation of the cellular and molecular mechanisms underlying memory dysfunction in animal models of neurodegenerative diseases and of intellectual deficiency disorders of genetic origins. This is complemented by the exploration of the potential of environmental, pharmacological or genetic therapies.
A defining characteristic of the brain is its remarkable capacity to undergo activity-dependent functional and structural remodelling via mechanisms of plasticity that form the basis of our capacity to encode and retain memories. The prevailing model of how our brain stores new information about relationships between events or new abstract constructs suggests it resides in activity-driven modifications of synaptic strength and remodelling of neural networks brought about by cellular and molecular changes within the neurons activated during learning. To date, the idea that a form of activity-dependent synaptic plasticity known as long-term potentiation, or LTP, plays a central role in the laying down of memories has received considerable support. Beyond this mechanism of plasticity at the synapse, adult neurogenesis, the birth and growth of new neurons, is another form of neural plasticity which occurs continuously in defined brain regions such as the dentate gyrus of the hippocampus and there is accumulating evidence that this form of neural plasticity also contributes to memory function. Based on work on the role of the transcriptional regulator Zif268, I will review recent evidence which support the idea that in this neurogenic region of the hippocampus, synaptic plasticity and neurogenesis are functionally linked mechanisms of brain plasticity that are essential to store memory memories.
Dr Mark Mayford, Scripps Research Institute, USAGenetic control of memory circuits
Dr Mayford is Associate Professor in the Department of Molecular & Cellular Neuroscience at the Scripps Research Institute. He received his PhD in Molecular Biology from the University of Wisconsin-Madison. He did post-doctoral work at Columbia University in New York with Dr Eric Kandel where he worked on the role of synaptic plasticity in learning and memory. He moved to University of California San Diego as an Assistant Professor in Neuroscience in 1997 before moving to Scripps in 2000. He work mouse genetics to investigate the cellular and molecular mechanisms of memory, focusing on genetic manipulation of neural circuits that are activated specifically during the learning process.
When we learn new information we use only a tiny fraction of the neurons in our brain for that particular memory trace. In this lecture I will discuss recent results from our lab that seek to develop genetic tools to target the sparse subset of neurons associated with a particular specific memory trace. We used a cfos-promoter based system to drive expression of a mutant muscarinic receptor hM3Dq (DREADD) into neurons activated by environmental stimuli. Neurons expressing the hM3Dq can be stimulated to fire action potentials by administration of a specific chemical ligand. We found that mice can incorporate anatomically dispersed artificial stimulation of neurons into a discrete memory trace. These results suggest the ability to incorporate internally generated neural activity into memory representations as a mechanism for linking new learning with previously acquired information.
Dr David Bannerman, University of Oxford , UKIs hippocampal LTP really the neural substrate of associative, long-term spatial memory?
Having obtained a BSc (Hons) in Pharmacology from the University of Bristol (1989), Dr Bannerman studied for a PhD in Neuroscience with Professor Richard Morris at the University of Edinburgh (1995 - The relationship between hippocampal long-term potentiation and spatial learning). He then worked in the Department of Experimental Psychology at the University of Oxford with Professors Sue Iversen and Nick Rawlins, and now has his own lab there. Current research focuses primarily on the role of the hippocampus and frontal cortex in not only learning and memory but also other aspects of behaviour such as emotionality and decision making. In particular, they are studying the contribution to behaviour of different sub-regions within these areas and the role of different forms of synaptic plasticity in different kinds of information processing and response selection.
Recent studies with transgenic mice lacking NMDARs in the hippocampus challenge the longstanding hypothesis that hippocampal LTP-like mechanisms underlie the encoding and storage of associative, long-term spatial memories. Hippocampus-specific NMDAR knockout mice (Grin1ΔDGCA1 mice) acquired the standard, fixed location, hidden escape platform version of the watermaze task perfectly well. In a spatial discrimination watermaze task with two visually identical beacons, Grin1ΔDGCA1 mice were again perfectly capable of learning the spatial location of the platform (as measured using probe tests, with the platform and beacons removed from the pool), but were more likely to choose the incorrect, decoy beacon and made more errors overall. This deficit was primarily seen on trials when the mice were started from close to the decoy beacon. Thus, Grin1ΔDGCA1 mice exhibit normal associative spatial memory but are unable to use spatial information to inhibit a conditioned, but inappropriate, behavioural tendency to approach any beacon that looks correct. Extra-hippocampal NMDARs are important for acquiring long-term spatial memories in the watermaze. Thus, it may not be the synaptic plasticity/memory hypothesis that is wrong. Instead, it may be the role of the hippocampus that needs re-examination. Hippocampal NMDARs may perform a critical role for resolving conflict or uncertainty, such as occurs with ambiguous or overlapping memories.
Public lecture 5 Dec
Conference 11 Dec
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