A driving vision of the Neurobiology Programme at the Department is to integrate basic and translation research. Indeed, the Programme is home to attractive technical expertise and animal platform technology for such an integrative approach. The main foci of investigations are ageing, auditory physiology, cognition, developmental neurobiology, ion channel physiology and disorders, neurodegenerative diseases, pain, regenerative medicine and stroke. These investigations utilize, in part animal models, including transgenic models, of following diseased states: (a) ion channel disorders, (b) Alzheimer’s disease, (c) Parkinson’s disease, (d) amyotrophic lateral sclerosis (ALS, also known as motor neuron disease), (e) frontotemporal dementia (FTD), (f) learning and memory, (g) acute and chronic inflammatory and neuropathic pain, and (h) premature ageing and stroke. These models are studied by using a variety of techniques, ranging from in vitro patch clamp electrophysiology, in vivo electrophysiological recording from anaesthetized and behaving animal, behavioral analyses, optogenetics, neuroimaging, stem cell/brain organoid technology and molecular and cellular biology techniques, including mouse genetics, transcriptomic and bioinformatic analysis.
Besides, the Department Neurobiology Programme is home to large collaborative research programmes with a focus on memory networks, and neurodegeneration. Conversely, members of the Programme are actively involved in collaborative research with colleagues in other institutions on topics ranging from dementia, motor disorders, neurodevelopment and neuropsychiatric disorders. Such collaborations extend nationally and internationally. Furthermore, the members of the Programme are crosslinked to the Medical Sciences Cluster Neuroscience Programme at Yong Loo Lin School of Medicine and the Neurobiology and Ageing Programme at the Life Science Institute, NUS.
The research and teaching by members of the Programme has been recognized both nationally and internationally. For example, 1) the National Parkinson’s disease team comprised of Lim Kah Leong and other key leaders was recently awarded the President Science Award (2018) in recognition of their outstanding contributions in identifying clinical biomarkers, developing novel models and therapeutics for advancing the understanding and management of Parkinson’s disease, 2) Soong Tuck Wah, a pioneer in Calcium Channel Signaling, received the coveted Investigator Award from the Canada-based Association for the Study of Neuron and Disease (AND). He has also been awarded the Dr C.S Paulose Neuroscience Award (India), 3) Sanjay Khanna was awarded the Singapore Neuroscience Association - Neuroscience Educator Award (2013), 4) Andrew Tan was awarded the NUS Young Investigator Award (2016), and 5) Derrick Ong was awarded the National Research Foundation Fellowship (2017) and 6) more recently, Sajikumar Sreedharan was awarded Singapore Neuroscience Association (SNA) young neuroscientist award (2017) and Faculty Excellence Research Award for AY2016/17 by Yong Loo Lin School of Medicine.
Members of the programme are also active in dissemination of knowledge by participating in outreach programmes, such as Temasek Foundation International STEP Brain Camp which targets junior college students from ASEAN and other Asian countries, and other training programmes such as training schools organized by International Brain Research Organization (IBRO).
Programme Director of Neuroscience Programme
Area(s) of research: the forebrain basis of chronic pain, neural basis of dementia.
Representative publication: Ariffin et al., Forebrain medial septum sustains experimental neuropathic pain. Scientific Reports 8: 11892, 2018.
Key observation(s): the findings of this report, seen in juxta-position with earlier publications from the laboratory (Lee et al., PAIN 152: 2528-2542, 2011 and Ang et al., Scientific Reports 5: 15419, 2015), shows that medial septum is a nodal region where glutamatergic transmission at AMPA and NMDA receptors facilitates peripheral hypersensitivity and spontaneous pain.
Area(s) of research: Growth factor signaling in nervous system development, function and repair.
Representative publication: Sergaki et al., Compromised Survival of Cerebellar Molecular Layer Interneurons Lacking GDNF Receptors GFRα1 or RET Impairs Normal Cerebellar Motor Learning. Cell Reports , 19: 1977-1986, 2017.
Key observation(s): In this new paper, we showed how the neurotrophic factor GDNF regulates survival of molecular layer interneurons in the cerebellum to control normal cerebellar motor learning.
Area(s) of research: Physiological significance of alternative splicing or RNA editing of calcium channels.
Representative publications: Huang et al, RNA editing of the IQ domain in Ca(v)1.3 channels modulates their Ca²⁺-dependent inactivation. Neuron 73: 304-316, 2012 Huang et al., Tissue-selective restriction of RNA editing of CaV1.3 by splicing factor SRSF9. Nucleic Acid Research 46: 7323-7338, 2018.
Key observation(s): RNA editing of the Cav1.3 IQ-domain slows Ca2+-dependent inactivation and neuron-specific Cav1.3 editing is dependent on alternative splicing of the SRSF9 splicing factor.
Area(s) of research: To understand the cellular and molecular mechanisms and to study the therapeutic targets to treat ischemic stroke and vascular dementia.
Representative publication: Kim et al., Transcriptome analysis reveals intermittent fasting-induced genetic changes in ischemic stroke. Human Molecular Genetics 27: 1497-1513, 2018.
Key observation(s): Our data provide a genetic molecular framework for understanding how intermittent fasting protects brain cells against damage caused by ischemic stroke, and reveal cellular signaling and bioenergetic pathways to target in the development of clinical interventions.
Area(s) of research: Molecular Mechanism underlying neurodegeneration in Parkinson’s disease.
Representative publication: Ng et al., Genetic or pharmacological activation of the Drosophila PGC-1α ortholog spargel rescues the disease phenotypes of genetic models of Parkinson's disease. Neurobiology of Aging 55: 33-37, 2017.
Key observations: AMPK-PGC-1α axis is important for dopaminergic neuronal homeostasis; the deficiency of which may underlie neurodegeneration in PD.
Area(s) of research: Synaptic protein trafficking in brain development and neuropsychiatric and neurodegenerative disorders.
Representative publication: Butkevich et al., Phosphorylation of FEZ1 by Microtubule Affinity Regulating Kinases regulates its function in presynaptic protein trafficking. Scientific Reports 6: 26965, 2016.
Key observation(s): Formation and maintenance of mature synapses is critically dependent on FEZ1-mediated synaptic protein transport. Loss of FEZ1 function contributes to synaptic defects in neurological disorders.
Area(s) of research: Pathogenic mechanisms of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), aging and age-related neurodegeneration, functions of autophagy in neurons and glia.
Representative publication: Wang et al., Cell-autonomous requirement of TDP-43, an ALS/FTD signature protein, for oligodendrocyte survival and myelination. Proceedings of National Academy of Science U S A., in press, 2018.
Key observations: TDP-43, the key pathological hallmark for ALS and FTD, is indispensable for oligodendrocyte survival and myelination, and loss of TDP-43 in oligodendrocytes exerts no apparent toxicity on motor neurons.
Area(s) of research: Neural basis of long-term memory (LTM).
Representative publications: Dasgupta et al., Substance P induces plasticity and synaptic tagging/capture in rat hippocampal area CA2, Proceedings of National Academy of Science U S A., 114: E8741-E8749, 2017. Luo et al., (2018), Regulation of feeding by somatostatin neurons in the tuberal nucleus. Science 361: 76-81, 2018.
Key observation(s): Metaplastic regulation of memory in neurodegenerative neural networks.
Area of research: Central auditory processing and plasticity.
Representative publication: Tan et al., A spontaneous state of weakly correlated synaptic excitation and inhibition in visual cortex. Neuroscience 247: 364-375, 2013.
Key observation: The correlation between excitation and inhibition in the rat visual cortex under pentobarbital anesthesia is weaker than when up-and-down states are present.
Area(s) of research: Epigenetics in development and disease (e.g. cancer and neurological disorders).
Representative publications: Tee et al., Erk1/2 activity promotes chromatin features and RNAPII phosphorylation at developmental promoters in mouse ESCs. Cell 156: 678-690, 2014.
Key observation: Identified a functional relationship between ERK signaling and Polycomb repression that emphasizes the importance of signal-induced chromatin remodeling as a key epigenetic priming event that underlies transcriptional competence during differentiation.
Area of research: Aging neuromuscular junction and sarcopenia.
Representative publication: Tsai et al., Muscle-specific 4E-BP1 signaling activation improves metabolic parameters during aging and obesity. Journal of Clinical Investigation 125: 2952-2964, 2015.
Key observation: Muscle-specific 4E-BP1 signaling activation improves metabolic parameters and muscle activity during aging.