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Scripps Research Joint Appointments

Department of Chemical Physiology
Professor, Dorris Neuroscience Center
Professor, Kellogg School of Science and Technology
Faculty, Kellogg School of Science and Technology

Other Joint Appointments

Adjunct Professor, UCSD

Research Focus

Understanding how experience controls brain development.

My laboratory is interested in the role of sensory experience in controlling the development, function and plasticity of the visual circuit and how circuit development and function become disrupted in neurodevelopmental disorders. We conduct state of the art experiments in visual circuit development using molecular genetic manipulations, electrophysiological methods, in vivo time-lapse imaging, electron microscopy and behavior. Over the past 20 years we have demonstrated roles for a variety of activity-dependent mechanisms in controlling structural plasticity of neuronal dendrites and axons, synaptic maturation and topographic map formation. This body of work has helped to generate a comprehensive understanding of the role of experience in shaping brain development. Two key points to emerge from our research is that circuit formation in vivo is a dynamic process throughout development that is continuously guided by experience, and that the basic mechanisms governing brain development, plasticity, information processing and organizational principles of brain circuits are highly conserved across vertebrates. More recently we have begun to address the role of activity-dependent mechanisms in the development of the functional visual circuit, assessed by in vivo recordings of visual responses in intact animals and behavioral assays. This series of studies has revealed critical molecular/genetic players required for the integration of neurons into functional circuits in vivo.

 

Research Projects

The Dynamic Connectome

A thorough understanding of circuit development and brain function requires knowledge of the connectivity of brain networks. In vivo time-lapse imaging of dendritic and axonal structures have shown that they are dynamic over the timecourse of hours and days. Importantly the structural dynamics are the physical substrate of synaptic dynamics and therefore dynamics in the connectivity map. We have begun to assess the dynamics in the connectivity map of the optic tectum by combining in vivo time lapse imaging with serial section electron microscopy and three-dimensional reconstruction of optic tectal neuronal dendrites and axons. We use 2 photon time lapse imaging of GFP expressing neurons in living animals to identify dynamic branches within neurons and serial section electron microscopy (EM) to generate 3 dimensional reconstructions of labeled neurons and their synaptic partners. By comparing the live imaging data and the serial section EM data, we determine the synaptic connectivity and ultrastructural synaptic features of dynamics and stable dendritic and axonal branches. This type of analysis will allow us to identify stable and dynamic components of the connectome and to determine how connectivity changes with experience and under conditions that model human neurodevelopemental diseases.

Regulation of Neurogenesis

The development of brain networks depends of the spatial and temporal control of cell proliferation and differentiation. We have recently begun several projects to investigate the control of neurogenesis in the tadpole brain. A significant advantage of studying neurogenesis in tadpoles is that the animals develop externally so the entire process from progenitor cell proliferation to neuronal differentiation and integration into brain circuits can be easily visualized and manipulated in the intact animal. We have recently found that visual experience controls neurogenesis and we have conducted microarray analysis to identify candidate molecular genetic pathways through which sensory experience controls neurogenesis.

Balanced inhibition in Visual circuit function and behavior

The retinotectal system processes and integrates visual and mechanosensory information and controls behavioral responses to sensory inputs. The interaction between excitatory and inhibitory synaptic inputs is essential for these brain functions. Excitatory synaptic activity is balanced by inhibitory synaptic input throughout the CNS. Despite the widespread expectation that balanced inhibition to excitation is essential for circuit function and information processing, the consequences of manipulating the ratio of inhibition to excitation on information processing and behavior have not been directly tested. We are using in vivo imaging, electrophysiological methods and behavior combined with molecular genetic manipulations to determine the function of inhibition in visual system function. These projects will the mechanisms controlling the development of inhibitory and excitatory neurons and explore the consequences of disrupting the balance of inhibition to excitation in the intact brain, akin to deficits in information processing seen in neurodevelopmental disorders such as autism spectrum disorders.

Education

B.A., Biology, Bryn Mawr College
Ph.D., Neurobiology, University of California, Berkeley, 1985

Professional Experience

Post-Graduate Education

1985-1989 Postdoctoral Fellow, (Advisor: M. Constantine-Paton), Department of Biology, Yale University, New Haven, CT. The role of NMDA receptors in development of the topographic retinotectal projection.

1989-1990 Postdoctoral Fellow, (Advisor: R. Tsien), Department of Molecular and Cellular Physiology, Beckman Center, Stanford University Medical Center, Stanford, CA. Calcium imaging in optic tectal cell cultures.

1995 Student, Cloning of Neural Genes Summer Course, Cold Spring Harbor Laboratory.

Employment

1976 Student Research Assistant, (C. DeDuve), Lab of Biochemical Cytology, The Rockefeller University

1977-1979 Research Assistant, (A. S. Schneider) Department of Endocrinology, Sloan Kettering Memorial Cancer Institute

1990-1993 Assistant Professor, Department of Physiology and Biophysics, The University of Iowa, Iowa City, Iowa

1994-1996 Assistant Professor, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York

1997-1998 Associate Professor, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York

1998-2008 Professor, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York

2000-2008 Charles and Marie Robertson Professor of Neuroscience, Cold Spring Harbor Laboratory

2002-2006 Director of Research, Cold Spring Harbor Laboratory

2008- Professor, Depts of Cell Biology & Chemical Physiology, The Scripps Research Institute, CA

Awards & Professional Activities

Activities

AAAS: Member, Neuroscience Nominating Committee
AAAS: Electorate Nomination Committee (2004-2006)
Society for Neuroscience: Councilor (2002-2006)
Society for Neuroscience: Program Committee (2001-2004)
Society for Neuroscience: Secretary (2010-)
Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Executive Committee (1998-2006), Founding member

Awards and Honors

NIH Director's Pioneer Award
Associate, Neuroscience Institute, La Jolla, CA
NINDS Board of Scientific Counselors (2004-2007)
Director, Neurobiology Course, Marine Biological Laboratory, Woods Hole, MA (2008-2009)

Professional Memberships

Society for Neuroscience
American Academy for the Advancement of Science
American Society for Cell Biology
American Physiological Society

Editorial Boards

Frontiers in Neural Circuits
Journal of Developmental Neurobiology
Neural Development

Selected References

He, H.Y. and Cline, HT (2011) Diadem X: Automated 4 Dimensional Analysis of Morphological Data. Neuroinformatics (in press)

Chiu, SL and Cline, HT (2010) Insulin receptor signaling in the development of neuronal structure and function. Neural Dev 5:7 PMID: 20230616

Ruthazer, E.S., Schohl, A., Schwartz, N., Tavakoli, A. Tremblay, M and Cline, H.T. (2010) Axons and Dendrites: In Vivo Time-Lapse Imaging of Neuronal Development in Xenopus. in Imaging:  A Laboratory Manual (eds. R. Yuste, F. Lani and A. Konnerth), Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY.

Li, J., Erisir, A. and Cline, H.T. (2010) Rapid synaptic rearrangements during CNS circuit development revealed by combined in vivo time-lapse imaging and serial section electron microscopy. Neuron (in press).

Wurdak, H, Zhu, S., Min, K H, Aimone, L, Lairson, LL, Watson, J, Chopluk, G, Demas, J., Charette, B., Weerapana, E., Cravatt, B.F., Cline, H.T., Peters, E.C., Zhang, J., Walker, J.R., Wu. C., Chang, J., Tuntland, T., Cho, C.Y., Schultz, P.G. (2010) A small molecule accelerates neuronal differentiation in the adult rat. PNAS 107(38):16542-16547.

Sharma, P and Cline, HT (2010) Visual Activity Regulates Neural Progenitor Cells in Developing Xenopus CNS through Musashi1. Neuron 68:442-455

Li, J. and Cline H.T. (2010) Visual deprivation increases accumulation of dense core vesicles in developing optic tectal synapses in Xenopus laevis. J. Comp. Neurol 518: 2365-2381. PMID: 20437533

Li, J., Wang, Y., Chiu, SL., and Cline, H.T. (2010) Membrane targeted horseradish peroxidase as a marker for correlative fluorescence and electron microscopy studies. Front. Neural Circuits 2010 Feb 26;4:6 PMCID: PMC2831632

Bestman, J.E., and Cline, H.T. (2009) The relationship between dendritic branch dynamics and CPEB-labeled RNP granules captured in vivo. Front Neural Circuits 3:10 PMCID: PMC2742666

Ewald, R.C., and Cline, H.T. (2009) Cloning and Phylogenetic Analysis of NMDA Receptor Subunits NR1, NR2A and NR2B in Xenopus laevis Tadpoles. Frontiers in Molecular Neuroscience 2:4 PMCID: PMC2759366

Chen, C-M., Chiu, S-L., and Cline, H.T. (2009) Co-expression of Argonaute2 enhances short hairpin RNA-induced RNA interference in Xenopus CNS neurons in vivo. Frontiers in Neurosci. 9;3:63 PMCID: PMC2858607

Shen, W., Santos Da Silva, J., He, H.H. and Cline, H.T. (2009) Type A GABA_AR-receptor-dependent synaptic transmission sculpts dendritic arbor structure in Xenopus laevis in vivo. J Neuroscience 29: 5032-5043. PMCID: PMC2706946

Bestman, J.E., and Cline, H.T. (2009) The relationship between dendritic branch dynamics and CPEB labeled RNP granules captured in vivo. Front Neural Circuits 3:10 PMCID:PMC2742666

Hiramoto, M. and Cline, H.T. (2009) Convergence of multisensory inputs into Xenopus tadpole tectum. Developmental Neurobiology 69: 969-971. PMID: 19813244

Thirumalai V., Cline H.T. (2008) A commanding control of behavior. Nat Neurosci. 11:246-248. PMID: 18301430

Ewald, R. E. and Cline, H.T. (2008) NMDA Receptors and Brain Development in Biology of the NMDA receptor (ed A. M. Van Dongen) CRC Press.

Haas, K. and Cline, H.T. (2008) The regulation of dendritic arbor development and plasticity by glutamatergic synaptic input:  a review of the synaptotrophic hypothesis. J. Physiol. 586: 1509-17. PMCID: PMC2375708

Bestman, J.E., and Cline, H.T. (2008) The RNA binding protein CPEB controls dendrite growth and neural circuit assembly in vivo. PNAS: 105: 20494-20499. PMCID: PMC2629308

Thirumalai, V., and Cline, H.T. (2008). Endogenous dopamine suppresses initiation of swimming in pre-feeding zebrafish larvae. J Neurophysiol. 100:1635-1648.

Chiu, S.L., Chen, C.M., and Cline, H.T. (2008). Insulin receptor signaling regulates synapse number, dendritic plasticity, and circuit function in vivo. Neuron 58, 708-719.

Van Keuren-Jensen, K.R., and Cline, H.T. (2008). Homer proteins shape Xenopus optic tectal cell dendritic arbor development in vivo. Dev Neurobiol. 68:1315-1324. PMID: 18636533

Bestman, J.E., and Cline, H.T. (2008) The RNA binding protein CPEB controls dendrite growth and neural circuit assembly in vivo. PNAS: 105: 20494-20499. PMCID: PMC2629308

Akerman, CJ, and Cline, H.T. (2007) Refining the roles of GABAergic transmission during neural circuit formation. TINS 30: 382-389.

Links

The Dynamic Connectome

How Brain Circuits Are Built

Activity-dependent Regulation of Neurogenesis

The Scripps Research Institute

The Dorris Neuroscience Center

UCSD Neuroscience Program

Innovative Approaches to Study Brain Development

Postdoctoral Training Information

Kellogg School of Science & Technology @ TSRI