Profiles

John Lin

UTAS Home Dr John Lin

John Lin

Senior Lecturer in Biochemistry & Molecular Biology

Room 438-02 , Medical Science 2 (MS2)

+613 6226 4898 (phone)

john.lin@utas.edu.au

There can be a huge fuss when a point is scored in a game of sport. In men’s soccer, for instance, a player who kicks a goal might dash to the side of the field, pretend to box with the corner post, pull his shirt over his head and then wait to be mobbed by his team mates. Much less attention is given to the midfielders who chipped away to make that goal possible.

The meticulous midfield of scientific research

With this example in mind, Dr John Lin can be described as a research midfielder, although his official title is Senior Lecturer in Biochemistry and Molecular Biology in the UTAS School of Medicine. Trying to put it simply, Dr Lin modifies particular proteins in cells so that they may be manipulated by light. His fellow neuroscientists and cellular biologists can then turn the proteins on or off with the flip of a switch. These new light-responsive proteins may be ones that activate a neuron, allow chemical communication between cells, or form a memory.

‘We call ourselves protein engineers,’ Dr Lin explained. ‘We manipulate the protein and then put it into the cells that the collaborator wants to study.

‘Proteins are the building blocks of cells and pretty much every function a cell does, such as movement and reproduction, is mediated by proteins. If you can identify how the function is carried out by the cell, there’s a chance that you can manipulate it in a way that you want.

‘So while we don’t directly do anything to answer a scientific question, we do provide the tools to allow our collaborators to do that. We’re not talking physical tools here, like a hammer. Instead the tools we use are biologically active, such as DNA – but most of the time it’s protein that we manipulate to control or observe changes in behaviours.’

Manipulating biological organisms to understand them

A specific example of how Dr Lin’s tools might be used is if a researcher was investigating a system in the brain that wasn’t working. By replicating that system in an artificial way, and manipulating proteins to turn the system on and off, the researchers could observe the differences in behaviours, thus increasing our understanding.

Among the projects on which his team is currently working is one that explores the systems in the brain that relate to feelings such as fear, aggression and love. Dr Lin’s collaborators hope to manipulate the brain functions that are associated with those behaviours and study the pathways that mediate them.

‘My research provides the tools of discovery and for me, it’s kind of fun to learn new things,’ Dr Lin said.

‘It’s different to normal research in that medical research is often focused on a specific disease and a possible cure for that disease. For us, we sit in the background and ask the researcher if there’s something we can help them with – something we can make to help them fulfil their goal. We provide a product that people need instead of being the end user of the product.

‘Sometimes the public only sees the scientists who score the goal, like in a game of soccer. But a big part of the game is in the midfield and that’s where we find the details of the play. This aspect of the process is not only important but often the most exciting part.’

Dr Lin is currently collaborating on research projects in the United States, France, Denmark and Israel. He also teaches Molecular Biology and Protein Biochemistry in the School of Medicine and is responsible for developing the fluorescent protein laboratory in Techniques in Molecular Biology and Protein Biochemistry.

After gaining his PhD in New Zealand, Dr Lin was a postdoctoral fellow at the Burnham Institute (US) and a postdoctoral research fellow at the University of California, San Diego. He joined UTAS in 2014 with the purpose of starting his own research group, teaching, and providing his family with a wonderful lifestyle.

Dr. Lin joined the University of Tasmania, School of Medicine in 2014 as a Lecturer in Biochemistry and Molecular Biology. After receiving his PhD in 2005 for his work investigating the synaptic communications between neurons of the basal ganglia system, he has focused on the development of protein-based tool to monitor and manipulate cellular activities with light. The ultimate goals of developing these tools to utilise these tools to further understand how activity of individual cells or ensembles of cells in the brain lead to the behaviour of organisms.

Biography

Dr Lin completed his PhD at the University of Auckland under the supervision of Professor Janusz Lipski. He spent a brief amount of time as a postdoctoral fellow with Assistant Professor Gang Tong at the Burnham Institute (renamed Sanford Burnham Medical Research Institute in 2010) in San Diego, California in 2005. In 2006, he then joined Professor Roger Y. Tsien's research group at the University of California, San Diego as a postdoctoral research fellow. In 2014, Dr. Lin joined University of Tasmania School of Medicine as a Lecturer in Biochemistry and Molecular Biology to start his own research group.

Career summary

Qualifications

  • PhD, University of Auckland, New Zealand. 2005
  • BTech (1st Class Hons), University of Auckland, New Zealand. 2001

Languages (other than English)

Mandarin

Teaching

biochemistry, molecular biology, neurobiology, protein engineering, biophysics

Teaching expertise

Dr. Lin is a key member of the School of Medicines teaching program and is involved in a number of different units. Dr. Lin coordinates and teaches in the protein biochemistry module of the Molecular Biology and Protein Biochemistry (CBA341) unit and is responsible of developing the fluorescent protein laboratory in Techniques in Molecular Biology and Protein Biochemistry (CBA342).

Teaching responsibility

Molecular Biology and Protein Biochemistry (CBA341)

Techniques in Molecular Biology and Protein Biochemistry (CBA342)

Neuroscience B (CHP312)

Biochemistry A Pharmacy (CBA221)

Molecular Biology in Health & Disease (CBA265)

Research Invitations

  • Invited oral presentation. Australia C. Elegans Symposium. Queensland Brain Institute, Brisbane, Queensland, Australia (2017).
  • Invited oral presentation. Brain Research Center Seminar. National Tsing-hwa University, Hsinchu, Taiwan (2017).
  • Invited oral presentation. Brain Networks: from molecules to diseases symposium. Lee Kong Chian School of Medicine. Singapore (2017).
  • Invited oral presentation. Central cardiorespiratory control: Future directions annual meeting. Macquarie University, Sydney, New South Wales, Australia (2015).
  • Invited oral presentation. 25th Meeting of the International Society for Neurochemistry, Cairns, Queensland, Australia (2015)
  • Invited oral presentation. Photons and Neurons section of Photonics West conference, San Jose, California, USA (2014)
  • Invited oral presentation. Genetic manipulation of neuronal activity III conference, HHMI-Janelia Farm Research Campus, Virginia, USA (2014)
  • Invited oral presentation. Expanding the optogenetic tool box: red-light activator and synaptic inhibitor, Yokohama City University, Japan. (2012)
  • Invited oral presentation. 14th International Congress of Histochemistry and Cytochemistry, Kyoto, Japan. (2012)
  • Invited oral presentation. Towards the Second Generation of Optogenetic Tools,  Society for Neuroscience 2010, San Diego, USA. (2010)

View more on Dr John Lin in WARP

Expertise

  • Development of novel protein-based tools to manipulate cellular events
  • Neurocircuitry mapping
  • Brain function and behaviour

For more information about the Optogenetics and Protein Engineering Lab please view: Optogenetics & Protein Engineering Research Group

Research Themes

Dr. Lin's research aligns with the University's research them of Better Health. His research focused on providing novel tools for other neuroscientists and cellular biologists to better understand how cellular events in individual cells or groups of cells lead to the behaviour observed in laboratory animal models.

Collaboration

John is currently involved in several collaborative research projects in USA, France, Denmark and Israel.

Current projects

Dr. Lin is currently funded as a principle investigator for the NIH BRAIN Initiative to develop tools for Large-Scale Recording-Modulation – New Technologies (http://braininitiative.nih.gov/nih-brain-awards.htm). His current research interests is focused on the development of novel tools that can be used to map and manipulate neuronal circuitry in attempt to understand how the brain works.

Fields of Research

  • Cellular nervous system (320902)
  • Neurosciences (320999)
  • Medical molecular engineering of nucleic acids and proteins (320603)
  • Central nervous system (320903)
  • Biomolecular modelling and design (340402)
  • Sensory systems (320907)
  • Other engineering (409999)
  • Biochemistry and cell biology (310199)
  • Health services and systems (420399)
  • Animal cell and molecular biology (310902)
  • Signal transduction (310111)
  • Receptors and membrane biology (310110)
  • Peripheral nervous system (320906)
  • Synthetic biology (310113)
  • Cell neurochemistry (310104)
  • Nanobiotechnology (310607)
  • Epigenetics (incl. genome methylation and epigenomics) (310504)
  • Proteins and peptides (340407)

Research Objectives

  • Expanding knowledge in the biological sciences (280102)
  • Clinical health (200199)
  • Expanding knowledge in the environmental sciences (280111)
  • Expanding knowledge in the health sciences (280112)
  • Other health (209999)
  • Expanding knowledge in psychology (280121)
  • Expanding knowledge in the chemical sciences (280105)

Publications

Total publications

19

Highlighted publications

(5 outputs)
YearTypeCitationAltmetrics
2014Journal ArticleInagaki HK, Jung Y, Hoopfer ED, Wong AM, Mishra N, et al., 'Optogenetic control of Drosophila using a red-shifted channelrhodopsin reveals experience-dependent influences on courtship', Nature Methods: techniques for life scientists and chemists, 11 pp. 325-332. ISSN 1548-7091 (2014) [Refereed Article]

DOI: 10.1038/nmeth.2765 [eCite] [Details]

Citations: Scopus - 153Web of Science - 142

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2014Journal ArticleNabavi S, Fox R, Prolux CD, Lin J, Tsien RY, et al., 'Engineering a memory with LTD and LTP', Nature, 511, (7509) pp. 348-352. ISSN 0028-0836 (2014) [Refereed Article]

DOI: 10.1038/nature13294 [eCite] [Details]

Citations: Scopus - 469Web of Science - 438

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2013Journal ArticleLin J, Knutsen PM, Muller A, Kleinfeld D, Tsien RY, 'ReaChR: a red-shifted variant of channelrhodopsin enables deep transcranial optogenetic excitation', Nature Neuroscience, 16 pp. 1499-1508. ISSN 1097-6256 (2013) [Refereed Article]

DOI: 10.1038/nn.3502 [eCite] [Details]

Citations: Scopus - 438Web of Science - 403

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2013Journal ArticleLin J, Sann SB, Zhou K, Nabavi S, Proulx CD, et al., 'Optogenetic Inhibition of Synaptic Release with Chromophore-Assisted Light Inactivation (CALI)', Neuron, 79, (2) pp. 241-253. ISSN 0896-6273 (2013) [Refereed Article]

DOI: 10.1016/j.neuron.2013.05.022 [eCite] [Details]

Citations: Scopus - 112Web of Science - 105

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2009Journal ArticleLin J, Lin MZ, Steinbach P, Tsien RY, 'Characterization of Engineered Channelrhodopsin Variants with Improved Properties and Kinetics', Biophysical Journal, 96 pp. 1803-1814. ISSN 0006-3495 (2009) [Refereed Article]

DOI: 10.1016/j.bpj.2008.11.034 [eCite] [Details]

Citations: Scopus - 447Web of Science - 421

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Journal Article

(15 outputs)
YearCitationAltmetrics
2019Bonaventura J, Eldridge MAG, Hu F, Gomez JL, Sanchez-Soto M, et al., 'High-potency ligands for DREADD imaging and activation in rodents and monkeys', Nature communications, 10, (1) Article 4627. ISSN 2041-1723 (2019) [Refereed Article]

DOI: 10.1038/s41467-019-12236-z [eCite] [Details]

Citations: Scopus - 19Web of Science - 16

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2019Huang T-N, Hsu T-T, Lin M-H, Chuang H-C, Hu H-T, et al., 'Interhemispheric connectivity potentiates the basolateral amygdalae and regulates social interaction and memory', Cell reports, 29, (1) pp. 34-48. ISSN 2211-1247 (2019) [Refereed Article]

DOI: 10.1016/j.celrep.2019.08.082 [eCite] [Details]

Citations: Scopus - 3Web of Science - 3

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2019Pavez M, Thompson AC, Arnott HJ, Mitchell CB, D'Atri I, et al., 'STIM1 is required for remodeling of the endoplasmic reticulum and microtubule cytoskeleton in steering growth cones', Journal of Neuroscience, 39, (26) pp. 5095-5114. ISSN 0270-6474 (2019) [Refereed Article]

DOI: 10.1523/JNEUROSCI.2496-18.2019 [eCite] [Details]

Citations: Scopus - 11Web of Science - 14

Co-authors: Pavez M; Thompson AC; Arnott HJ; Young KM; Gasperini RJ; Foa L

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2017Rodriguez EA, Campbell RE, Lin JY, Lin MZ, Miyawaki A, et al., 'The growing and glowing toolbox of fluorescent and photoactive proteins', Trends in Biochemical Sciences, 42, (2) pp. 111-129. ISSN 0968-0004 (2017) [Refereed Article]

DOI: 10.1016/j.tibs.2016.09.010 [eCite] [Details]

Citations: Scopus - 244Web of Science - 244

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2016Rodriguez EA, Tran GN, Gross LA, Crisp JL, Shu X, et al., 'A far-red fluorescent protein evolved from a cyanobacterial phycobiliprotein', Nature Methods, 13, (9) pp. 763-769. ISSN 1548-7091 (2016) [Refereed Article]

DOI: 10.1038/nmeth.3935 [eCite] [Details]

Citations: Scopus - 92Web of Science - 91

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2016Sengupta A, Chaffiol A, Mace E, Caplette R, Desrosiers M, et al., 'Red-shifted channelrhodopsin stimulation restores light responses in blind mice, macaque retina, and human retina', EMBO Molecular Medicine, 8, (11) pp. 1248-1264. ISSN 1757-4676 (2016) [Refereed Article]

DOI: 10.15252/emmm.201505699 [eCite] [Details]

Citations: Scopus - 77Web of Science - 74

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2015Hooks BM, Lin JY, Guo C, Svoboda K, 'Dual-channel circuit mapping reveals sensorimotor convergence in the primary motor cortex', Journal of Neuroscience, 35, (10) pp. 4418 - 4426. ISSN 0270-6474 (2015) [Refereed Article]

DOI: 10.1523/JNEUROSCI.3741-14.2015 [eCite] [Details]

Citations: Scopus - 31Web of Science - 31

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2015Satpathy S, Batabyal S, Dhakal KR, Lin J, Kim Y-T, et al., 'Broad spectral excitation of opsin for enhanced stimulation of cells', Optics Letters, 40, (11) pp. 2465-2468. ISSN 0146-9592 (2015) [Refereed Article]

DOI: 10.1364/OL.40.002465 [eCite] [Details]

Citations: Scopus - 5Web of Science - 4

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2014Inagaki HK, Jung Y, Hoopfer ED, Wong AM, Mishra N, et al., 'Optogenetic control of Drosophila using a red-shifted channelrhodopsin reveals experience-dependent influences on courtship', Nature Methods: techniques for life scientists and chemists, 11 pp. 325-332. ISSN 1548-7091 (2014) [Refereed Article]

DOI: 10.1038/nmeth.2765 [eCite] [Details]

Citations: Scopus - 153Web of Science - 142

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2014Levin RA, Felsen CN, Yang J, Lin J, Whitney MA, et al., 'An Optimized Triple Modality Reporter for Quantitative In Vivo Tumor Imaging and Therapy Evaluation', PL o S One, 9, (5) Article e97415. ISSN 1932-6203 (2014) [Refereed Article]

DOI: 10.1371/journal.pone.0097415 [eCite] [Details]

Citations: Scopus - 13Web of Science - 12

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2014Nabavi S, Fox R, Prolux CD, Lin J, Tsien RY, et al., 'Engineering a memory with LTD and LTP', Nature, 511, (7509) pp. 348-352. ISSN 0028-0836 (2014) [Refereed Article]

DOI: 10.1038/nature13294 [eCite] [Details]

Citations: Scopus - 469Web of Science - 438

Tweet

2013Lin J, Knutsen PM, Muller A, Kleinfeld D, Tsien RY, 'ReaChR: a red-shifted variant of channelrhodopsin enables deep transcranial optogenetic excitation', Nature Neuroscience, 16 pp. 1499-1508. ISSN 1097-6256 (2013) [Refereed Article]

DOI: 10.1038/nn.3502 [eCite] [Details]

Citations: Scopus - 438Web of Science - 403

Tweet

2013Lin J, Sann SB, Zhou K, Nabavi S, Proulx CD, et al., 'Optogenetic Inhibition of Synaptic Release with Chromophore-Assisted Light Inactivation (CALI)', Neuron, 79, (2) pp. 241-253. ISSN 0896-6273 (2013) [Refereed Article]

DOI: 10.1016/j.neuron.2013.05.022 [eCite] [Details]

Citations: Scopus - 112Web of Science - 105

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2012Millar EW, Lin J, Frady P, Steinbach PA, Kristan Jr WB, et al., 'Optically monitoring voltage in neurons by photoinduced electron transfer through molecular wires', National Academy of Sciences of The United States of America. Proceedings, 109, (6) pp. 2114-2119. ISSN 0027-8424 (2012) [Refereed Article]

DOI: 10.1073/pnas.1120694109 [eCite] [Details]

Citations: Scopus - 163Web of Science - 162

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2009Lin J, Lin MZ, Steinbach P, Tsien RY, 'Characterization of Engineered Channelrhodopsin Variants with Improved Properties and Kinetics', Biophysical Journal, 96 pp. 1803-1814. ISSN 0006-3495 (2009) [Refereed Article]

DOI: 10.1016/j.bpj.2008.11.034 [eCite] [Details]

Citations: Scopus - 447Web of Science - 421

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Chapter in Book

(1 outputs)
YearCitationAltmetrics
2012Lin J, 'Optogenetic excitation of neurons with channelrhodopsins: Light instrumentation, expression systems, and channelrhodopsin variants', Optogenetics: tools for controlling and monitoring neuronal activity, Elsevier, T Knopfel, E S Boyden (ed), Amsterdam, pp. 29-48. ISBN 978-0-444-59426-6 (2012) [Research Book Chapter]

[eCite] [Details]

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Review

(2 outputs)
YearCitationAltmetrics
2019Simunovic MP, Shen W, Lin JY, Protti DA, Lisowski L, et al., 'Optogenetic approaches to vision restoration', Experimental Eye Research, 178 pp. 15-26. ISSN 0014-4835 (2019) [Substantial Review]

DOI: 10.1016/j.exer.2018.09.003 [eCite] [Details]

Citations: Scopus - 36Web of Science - 33

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2010Lin J, 'A user's guide to channelrhodopsin variants: features, limitations and future developments', Experimental Physiology, 96, (1) pp. 19-25. ISSN 0958-0670 (2010) [Substantial Review]

DOI: 10.1113/expphysiol.2009.051961 [eCite] [Details]

Citations: Scopus - 193Web of Science - 171

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Entry

(1 outputs)
YearCitationAltmetrics
2017Dominguez R, Lin J-Y, 'Channelrhodopsin', AccessScience, McGraw-Hill Education (2017) [Entry]

DOI: 10.1036/1097-8542.124530 [eCite] [Details]

Co-authors: Dominguez R

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Grants & Funding

Dr. Lin is currently funded as a principle investigator for the NIH BRAIN Initiative to develop tools for Large-Scale Recording-Modulation – New Technologies

Funding Summary

Number of grants

9

Total funding

$5,127,731

Projects

Shining light on the role of neurotrophin/Trk receptor signalling in synaptic plasticity and memory formation (2020 - 2022)$496,955
Description
Neutrophin signalling is important in learning and memory, neural development and neuronal regeneration. The importance of neurotrophin factors has been highlighted by their therapeutic potential as treatments of neurological disorders and neural injury. The neurotrophin factor BDNF, acting through TrkB receptor, has crucial roles in memory formation. TrkB receptor is a tyrosine receptor kinase that can activate multiple intracellular signalling cascades, named ERK, AKT and PLCgamma pathways. We have successfully generated an optogenetic tool that can mimic the activation of TrkB receptor, leading to the activation of these cascades. We have also generated modified versions that activate ERK and AKT but not PLCgamma, or activates PLCgamma without direct activation of ERK and AKT. Our preliminary results demonstrate that AMPA-type glutamate receptors are upregulated on the neuronal membrane after the activation of our optogenetic TrkB tool, similar to that observed with long-term potentiation (LTP). LTP is believed to be the cellular event of learning, hence our tool could potentially enhance learning in behaving animals. This proposal will utilise these tools to investigate the roles of the different signalling pathways associated with TrkB receptor on LTP induction and maintenance, understand the effects of TrkB signalling on presynaptic release and correlate these findings to the effects on learning in behaving animals. We will also develop novel intracellular nanobodies towards TrkB that would permit manipulation at the correct subcellular localisation by locating our tools to the endogenous TrkB receptors. These novel optogenetic tools will provide novel insights into the important process of learning and memory formation. This knowledge will have important implication for the utilisation of BDNF as therapeutic agents and building a new cellular model of learning and memory formation.
Funding
National Health & Medical Research Council ($496,955)
Scheme
Grant-Ideas
Administered By
University of Tasmania
Research Team
Lin J; Gell DA
Period
2020 - 2022
Grant Reference
1185565
Driverless axons: Steering Regeneration Towards The Light (2019 - 2021)$432,127
Description
Defects in the connections between nerve cells underpin many developmental disorders such as autism and mental retardation. Furthermore, defects in re-establishing nerve cell connections prevents successful regeneration after disease or trauma. Calcium is vital to nerve cells, especially as they grow and connect. This project will develop novel light-activated tools to manipulate calcium signals to control nerve cell growth and connectivity and enhance nerve regeneration.
Funding
National Health & Medical Research Council ($432,127)
Scheme
Grant-Project
Administered By
University of Tasmania
Research Team
Foa LC; Lin J; Gasperini RJ
Period
2019 - 2021
Grant Reference
1165616
Independent optical excitation of the overlapping neural population in behaving animals (2019)$48,558
Description
Current optogenetic activity of neuronal activities using channelrhodopsins does not allow for the independent stimulation of 2 neuronal populations. Able to conduct this type experiment would be greatly beneficial in neuroscientific research. This is due to the simultaneous activation of 'blue' and 'red' channelrhodopsin expressing neurons when blue light is used to stimulate the neurons. To suppress the activation of 'red' channelrhodopsin expressing neurons, it is possible to co-express in these cells a blue-light activated inhibitory channelrhodopsin that would suppress the blue light excitation of red channelrhodopsin expressing neurons. To achieve this, we would screen different red excitatory and blue inhibitory channelrhodopsin variants for kinetics, conductance and match their properties.
Funding
Lundbeck Foundation ($48,558)
Scheme
Grant
Administered By
Acadia University
Research Team
Nabavi S; Lin J
Year
2019
Selective optogenetic inhibition of neuropeptide release (2018 - 2020)$409,530
Description
The function of the brain is heavily modulated by neuropeptides released by neurons or non-neuronal cells in the brain. In the proposed project, we will develop and validate a novel technology that utilise light to inhibit the release of neuropeptide. This technology will not affect the release of synaptic vesicles containing neurotransmitter. The release of neuropeptide containing vesicles will be selectively disrupted by the use of photosensitising fluorescent protein or photodimerisers targeted to vesicles containing neuropeptides. This technology will be validated in cell cultures and C. elegans model. This technology can be used to study the functions of neuropeptides in the brain of laboratory model organisms.
Funding
National Institutes of Health ($409,530)
Scheme
Grant - BRAIN Initiative
Administered By
Tel Aviv University
Research Team
Blinder P; Lin J; Hu Z
Period
2018 - 2020
Driverless Axons: Steering Regeneration Towards The Light (2018)$24,600
Description
The intricate circuitry of the nervous system begins as developing neurons extend axons toconnect with their target cells, in a process known as axon guidance. Defects in axon guidanceunderpin a range of developmental disorders including autism and mental retardation. Inaddition, accurate axon guidance is required for successful regeneration. The distal tip of theextending axon, the growth cone is highly motile as it navigates the surrounding environment.This motility is essentially a consequence of calcium signals that control the growth conecytoskeleton. Manipulating calcium signaling to control the cytoskeleton and subsequentgrowth cone motility will provide novel insights for directing axon growth in vivo, to controlcircuit development and regeneration.
Funding
University of Tasmania ($24,600)
Scheme
Grant- Research Enhancement Program
Administered By
University of Tasmania
Research Team
Foa LC; Lin J; Gasperini RJ
Year
2018
Structure guided design of photoselectable channelrhodopsins (2017 - 2018)$134,891
Description
This proposal outlines the development of a fundamentally new optogenetic technology capable of flexibly manipulating the activity ofthousands of neurons contributing to the dynamic activity of distributed neural circuits with single neuron resolution . No method that currently exists evenremotely meets the need of flexible, selective control of thousands of neurons distributed across large volumes of the brain. Filling this methodological gap is acentral research objective of the BRAIN Initiative, because doing so will transform our ability to investigate how the nervous system encodes, processes,utilizes, stores, and retrieves information.The overall objective for this application is to acquire critical structural knowledge of photoactive states of a red-shifted channelrhodopsin and use these toengineer a photoselectable channel prototype that demonstrates the potential of our approach for future development in behaving animals. This would allowopsin-expressing neurons to be flexibly selected, activated, and deselected with light. By leveraging new structural knowledge, we anticipate that we candevelop a fundamentally new approach to optogenetics that takes us beyond genetically targeted control and into an era of functionally targeted, flexiblecontrol of any neural ensemble.The aims of our research are to obtain the first atomic structures of red-shifted channelrhodopsin mutants in three channel states, engineer a three-stateReaChR mutant with high open conductance and optimized action spectra, and demonstrate reversible photoselective control of neurons in vivo withPReaChR prototypes.
Funding
National Institutes of Health ($134,891)
Scheme
Grant - BRAIN Initiative
Administered By
University of Southern California
Research Team
Hires S; Lin J; Katritch V; Cherezov V
Period
2017 - 2018
Novel tools for manipulating neuronal activity for behavioural studies (2017 - 2020)$680,540
Description
A major challenge in neuroscience is to link the activity of individual neurons in the brain to specific behaviours.Optogenetics achieves this by using light to control the activity of neurons. While these tools have revolutionisedthe field of neuroscience and advanced our understandings of behaviours and neurocircuitry, there are limitations.This project will develop a new optogenetic approaches to control neuronal activity with spectrally distinct light andachieve higher efficiency, increased penetration into the brain and less invasiveness for the organism. Thistechnique will create new collaborative opportunities with leading neuroscientists to better understand how braincircuitry controls behaviour.
Funding
Australian Research Council ($680,540)
Scheme
Fellowship-Future
Administered By
University of Tasmania
Research Team
Lin J
Period
2017 - 2020
Grant Reference
FT160100056
Detection and manipulation of neuronal activities with a synthetic optogenetic activity-reporting transcription system (2016 - 2018)$391,012
Description
Functional neurocircuitry mapping is important for understanding mental illness such as depression, attention deficit hyperactivity disorders and post-traumatic stress disorders. Insight into how activation of specific neuronal connections leads to the performance of a behaviour and how these connections are altered or disrupted in mental illnesses will facilitate the design of effective treatments. Current techniques to map functional neurocircuitry are limited and unsuitable for large-scale systematic studies. The hypothesis central to this project is that optogenetic transcription reporter systems that can be used to identify neurons that are active during the performance of a specific behaviour by producing an exogenous effector protein as a marker for activated neurons. Furthermore, specific effector proteins can also be used for subsequent manipulation of the neurocircuitry associated with behaviour. We will test this by developing and validating two novel recombinant DNA approaches where light-responsive protein domain(s) are combined with calcium responsive protein domains and an exogenous transcription factor. We will generate an optogenetic activity-dependent transcription system based on a yeast-2-hybrid-like design (Aim 1) and a system based on light and calcium-induced recruitment of protease (Aim 2). We will then validate these tools in neurons and in vivo (Aim 3).Light responsive protein domains permit the setting of a temporal window for activity reporting. Calcium responsive protein domains will detect neuronal activity. The transcription factor will only be activated when there is both light illumination and significant neuronal activity, leading to the transcription of the effector proteins. These novel approaches will be useful in understanding the neurocircuitry under-pinning selected behaviours and detecting the alteration in neurocircuitry associated with laboratory models of mental illness.
Funding
National Health & Medical Research Council ($391,012)
Scheme
Grant-Project
Administered By
University of Tasmania
Research Team
Lin J
Period
2016 - 2018
Grant Reference
1103034
Optogenetic mapping of synaptic activity and control of intracellular signaling (2014 - 2017)$2,509,518
Description
Protein-based sensors and manipulators of cellular functions have made great strides in biological research in the last 15 years. Fluorescentproteins and microbial opsins have contributed significantly to the development and utilization of these tools and permit the investigatorsto use optical approach to observe and manipulate neuronal function in the model organisms during behaviour. These approaches arepopular among scientists due to their simplicity with the instrumentation and reagents, and have addition advantages of having hightemporal and spatial resolution and permitting genetic targeting of cell type or subcellular localization. The current tools to observe ormanipulate cellular activities with optical approach, or the optogenetic tools, have focused mainly on observing and manipulatingmembrane excitability with the fluorescent proteins-based sensors of membrane potentials and/or intracellular calcium and microbialopsins that can be used to manipulate membrane excitability. Although membrane excitability is a crucial aspect of neuronal functions,many other aspects of neuronal functions have equal importance, such as synaptic plasticity, synaptic activity and second messengermediatedintracellular pathways. Currently there are limited optogenetic tools to manipulate or observe these functions. This proposal aimsto extend the optogenetic tools available to neuroscientists to manipulate synaptic plasticity and second messenger-mediated intracellularpathways, and develop an approach where defined synaptic connections activated during a specific temporal window can be visuallyidentified. These tools will be purely genetically-encoded, which simplify the techniques for biologists and are controlled by light, which candefine the temporal windows of manipulation or reporting.
Funding
National Institutes of Health ($2,509,518)
Scheme
Grant-National Institute of Health
Administered By
University of California
Research Team
Kleinfeld D; Lin J
Period
2014 - 2017

Research Supervision

Dr. Lin is currently co-supervising several PhD students. Students with interests in scientific researches associated with neurobiology, protein engineering, optics, chemical biology are encouraged to contact Dr. Lin for potential PhD student positions within his research group.

Current

5

Completed

2

Current

DegreeTitleCommenced
PhDDevelopment of Optogenetic Approaches to Selectively Modulate G Protein Signalling2017
PhDDeveloping Systems to Optogenetically Inhibit Neuropeptide Exocytosis2018
PhDStudying Neuronal Circuit Development in the Zebrafish2018
PhDUnderstanding the role of rare Homer mutations in synaptogenesis2018
PhDManipulating cortical Activity and Behaviour using a Novel, Low Conductance, Long-lasting Excitatory Channelrhodopsin (PReaChR)2020

Completed

DegreeTitleCompleted
PhDOptogenetic Manipulation of Calcineurin Signalling
Candidate: Elise Joanna Devenish
2019
PhDDevelopment of Optogenetic Approaches to Modulate Synaptic Plasticity in the Postsynaptic Cells
Candidate: Agnieszka Miroslawa Zbela
2019