SEMINARS

Seminar：From understanding neural plasticity to drug discovery for neurodegenerative diseases

Title: From understanding neural plasticity to drug discovery for neurodegenerative diseases Speaker: Professor Nancy Y. Ip, Division of Life Science and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China Time: 21st Oct, 2013 (Monday), 10:00 Place: Room205, Administration Building Host: Professor Shuming Duan Introduction Neurodegenerative diseases, such as Alzheimer’s disease, are emerging to become a major health burden in societies with a large aging population. Increasing evidence suggests that dysfunction in neural communication plays a key role in the onset and progression of neurodegenerative diseases.Neurons in the brain communicate with each other through chemical transmission at specialized structures known as synapses. Experience-dependent modification of synaptic transmission or synaptic plasticity forms the cellular basis of cognitive functions such as learning and memory. Loss of synapsesor impaired synaptic plasticity hasbeen observed at early stages of Alzheimer’s disease before extensive neuronal death. Thus, explicating the molecular mechanisms involved in the establishment and remodeling of synapsesis pivotal for identifying new drug targets and developing neurotherapeutic agents. Synaptic remodeling is believed to be precisely regulated by the co-ordinated activation of diverse cell surface receptors. My laboratory is interested in understanding howneurons transduce signals from these cell surface receptors to regulatesynapse function and plasticityof the adult brain under normal and diseased conditions.We have recently identified distinct receptor-mediated signaling pathways that can positively or negatively regulate neurotransmission, thereby differentially promote the strengthening and weakening of existing synapses. For example, the receptor tyrosine kinase TrkB binds to the growth factor BDNF and modulates structural changes of the synapse during memory formation. Similarly, the G-protein-coupled receptor melanocortin-4 receptor (MC4R), the cognate receptor of the neuropeptide α-MSH, enhances hippocampal synaptic plasticity through the regulation of synapse morphology and the trafficking of neurotransmitter receptors. On the other hand, another receptor tyrosine kinase, EphA4, is a major negative regulator of neurotransmission. Activation of EphA4 attenuates synaptic transmission by promoting the degradation of neurotransmitter receptors and the loss of synaptic contacts. We further demonstrate that EphA4 is important in mediating the synaptic dysfunctions during the progression of Alzheimer’s disease, suggesting that this receptor is a promising target for developing new treatments for this devastating neurodegenerative disease. In our attempt to translate our discoveries from basic research to the development of neurotherapeutic agents, we have leveraged our research strengths in molecular neuroscience and Chinese medicine (CM) to establish a focused drug discovery program in search of new drug leads, including those that can regulate synaptic activity.Our major objective is to utilize a systematic knowledge-based approach to screen for neuroactive lead compounds from CM. Through discovery ofnew molecular targets in neurodegenerative diseases, we have screened for potential modulators of these targets using specific bioassay platforms or structure-based molecular docking approach. Natural compounds from CM that display high binding affinity to specific molecular targets have been identified and characterized. This drug discovery strategy has proven to be a very effective approach in identifying potential drug candidates, some of which are currently at various stages of pre-clinical development for neurological disorders.

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Seminar:A disinhibitory microcircuit in the somatosensory cortex

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Seminar:Deep tissue imaging

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Seminar: Mechanisms of pathological emotional memory: from animal to human

Mechanisms of pathological emotional memory: from animal to human by Professor Lin Lu, M.D., Ph.D., the director of Sixth Hospital, Peking University and the director of National Institute on Drug Dependence, Peking University. Host：Professor Jianhong Luo Time：13:30, 14th Sep., 2013 Place：Lecture hall, Annex building, School of Medicine Introduction： Normal emotional memory system is critical for survival across species. However, when individuals are exposed to the traumatic experience or addictive drugs, the emotional memory system is engaged in the pathological learning underlying the related diseases. Since disruption of emotional memories has been taken as a promising avenue to treat the diseases such as addiction and post-traumatic stress disorder (PTSD), uncovering the neuronal mechanisms of emotional memory is one of the most important scientific questions in neuroscience field. Our laboratory has been investigating the abnormal synaptic and behavioral plasticity during different pathological memory phases, such as consolidation, reconsolidation, extinction and maintenance, and we also have been exploring new pharmacological and behavioral strategies for addiction and PTSD. We discovered that cyclin-dependent kinase 5 activity in basolateral amygdala plays a critical role in the consolidation, retrieval and reconsolidation of cocaine-associated memories. We also discovered molecular basis for the maintenance of drug-associated memories, and that protein kinase M zeta is a critical cellular substrate for the maintenance of memories of drug-related cues. Considering that most of the pharmacological compounds used in these studies are not suitable for human use, we developed a new nontoxic behavioral procedure to prevent drug craving and relapse. We found a memory retrieval-extinction procedure can decrease conditioned drug effects and drug seeking in rat models of relapse and drug craving in abstinent heroin addicts. In rats, the daily retrieval of drug-associated memories for 10 min or 1 h (within reconsolidation time window) but not 6 h (out of reconsolidation time window) before extinction sessions attenuates drug-induced reinstatement, spontaneous recovery and renewal of conditioned drug effects and drug seeking. In heroin addicts, the retrieval of drug-associated memories for 10 min before extinction sessions attenuates cue-induced heroin craving 1, 30 and 180 days later. Nevertheless, there are also some limitations in retrieval-extinction procedures. For example, the effect of this procedure is specific to the reactivated conditioned stimulus (CS), and it is ineffective after prolonged drug abstinence. Now we are exploring a new behavioral procedure - unconditioned stimulus (UCS) retrieval-extinction procedure. We found non-contingent cocaine or heroin injections (UCS retrieval) 1 h but not 9 h prior to the extinction sessions decrease reinstatement, spontaneous recovery and renewal of drug seeking. Unlike the CS-retrieval-extinction manipulation, the UCS-retrieval-extinction manipulation inhibits drug seeking induced by discrete drug-associated cues not present during extinction training and also inhibits drug seeking when the manipulation starts after 28 abstinence days. Injections of propranolol (a beta adrenoceptor antagonist previously shown to disrupt memory reconsolidation) immediately after UCS-memory-retrieval, inhibit cocaine seeking behavior induced by discrete drug-associated cues. PTSD is also pathological emotional memory. Moreover, in real life, a traumatic event can be associated with several cues, each of which can potentially trigger recollection of the event and elicit fear reactions. Thus, we have also applied the UCS retrieval-extinction to target diverse cues associated with an aversive event that have caused fear memories. We found that presentation of US alone at a lower intensity can make associations between different CS and the US susceptible to disruption by extinction training during reconsolidation; these disruptive effects persist for at least half a year. Moreover, the disruption of reconsolidation is selective to the activated US. These findings demonstrate a modified US retrieval-extinction strategy that may lead to new therapeutic approaches for drug addiction and PTSD.

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Seminar: Application of MDL theory in human connectomics

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Seminar: Ion Channel Regulation in Health and Disease

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Seminar: Glial control of depressive-like behaviors

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Seminar: Molecular sensors and modulators of thermo-reception

**Speaker: Dr. Xuming Zhang (University of Cambridge) **Time: 2013.5.20 2:00-3:00pm. **Venue:Research Building, Room 502 **Host by: Prof. Xiao-ming LI **Brief Introduction: Education: Ph.D in pathology and pathophysiology, Department of Pathology, Tonjing Medical College of Huazhong University of Science and Technology, China. (2001) (first class) M.D. in clinical medicine, Hubei University of Science and Technology, China. (1996) (Top 1 class) Employment and research experience: 01/06/2009 ? present Group leader, Department of Pharmacology, University of Cambridge, Cambridge, UK 01/01/2009 ? 01/06/2009 Senior Postdoctoral Fellow, Department of Pharmacology, University of Cambridge, Cambridge, UK 15/01/2002 ? 30/12/2008 Postdoctoral Fellow, Department of Pharmacology, University of Cambridge, Cambridge, UK Sept. 1996 ? Aug. 2001 Ph.D, Department of Pathology, Tongji Medical College of Huazhong University of Science and Technology, China. **Abstract: The sensation of temperature is one of the most fundamental sensory functions across all species allowing organisms to select their preferred habitat temperatures. Aberrant temperature sensation (e.g., cold allodynia) is associated with many disease conditions such as pain and chemotherapy, and is detrimental to the well being of animals and humans. The detection of temperatures is initiated by the activation of thermo-sensitive sensory neurons expressing temperature-sensitive ion channels that act as direct thermal sensors by converting thermal energy into nerve impulses. The thermal sensitivity of these ion channels can be altered by many modulating factors through various signalling mechanisms, leading to abnormal temperature sensations under pathological conditions. Understanding of the activation and modulation of these temperature-sensitive ion channels is providing fundamental basis for developing novel therapeutic targets for the treatment of neurological disorders such as pain.

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Seminar: The roles of Eph receptors and actin cytoskeleton in the regulation of synaptic morphology

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Semilar: The stressed hippocampus and lost memories: focusing on the CRH-CRHR1 system and synaptic a

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