Source: Interfolio F180
Hollis Cline, PhD
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
Ph.D. (Neurobiology), University of California, Berkeley, 1985B.A. (Biology), Bryn Mawr College, 1977
Professional Experience
Post-Graduate Education1985-1989 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 Neuroscience & Chemical Physiology, The Scripps Research Institute, CA
2016-present, Co-Chair, Dept. of Neuroscience, Scripps Reseach, CA
Other Joint Appointments Adjunct Professor, University of California San Diego
Adjunct Professor, Salk Institute for Biological Studies
Awards & Professional Activities
AAAS: Member, Neuroscience Nominating CommitteeAAAS: Electorate Nomination Committee (2004-2006)
Society for Neuroscience: Councilor (2002-2006)
Society for Neuroscience: Program Committee (2001-2004)
NINDS Board of Scientific Counselors (2004-2007)
Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Exec Committee (1998-2006), Founding member
Society for Neuroscience: Secretary (2010-2013)
National Eye Institute, Advisory Council Member (2011-2015)
NICHD Division of Intramural Research, Blue Ribbon Panel Member (2012-2014)
Society for Neuroscience: President (2015-2016)
National Institute of Neurological Disorders and Stroke, Advisory Council (2018-2021)
Awards and Honors
NIH Director's Pioneer Award
AAAS Fellow (2012)
TSRI Outstanding Mentor Award (2013)
Director, Neurobiology Course, Marine Biological Laboratory, Woods Hole, MA (2008-2009)
Mika Salpeter Lifetime Achievement Award (2019)
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 Publications
Schiapparelli, Lucio M.; Sharma, Pranav; He, Hai- Y.; Li, Jianli; Shah, Sa H.; McClatchy, Daniel B.; Ma, Yuanhui; Liu, Han-Hsuan H.; Goldberg, Jeffrey L.; Yates, John R.; Cline, Hollis T. Proteomic screen reveals diverse protein transport between connected neurons in the visual system. Cell Reports 2022, 38, 110287.
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Ta, Aaron C.; Huang, Lin- C.; McKeown, Ca R.; Bestman, J E.; Van Keuren-Jensen, Kendall; Cline, Hollis T. Temporal and spatial transcriptomic dynamics across brain development in Xenopus laevis tadpoles. G3 (Bethesda, Md.) 2022, 12, jkab387.
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Gore, Sayali V.; James, Eric J.; Huang, Lin- C.; Park, Jenn J J.; Berghella, Andrea; Thompson, Adrian; Cline, Hollis T.; Aizenman, Carlos Role of matrix metalloproteinase-9 in neurodevelopmental disorders and plasticity in Xenopus tadpoles. eLife 2021, 10.
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Faulkner, Regina L.; Wall, Nicholas R.; Callaway, Edward M.; Cline, Hollis T. Application of Recombinant Rabies Virus to Xenopus Tadpole Brain. 2021.
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