Probing a natural example of “regeneration” in the mammalian hippocampus
The goal of this project is to understand the molecules that control the integration of newborn neurons into the circuitry of the adult hippocampus. The dentate gyrus is one of the two places in the adult brain where neurogenesis persists throughout adult life. These new neurons have been implicated in synaptic plasticity in the adult brain and may also play an important role in diseases such as depression, epilepsy, stroke, and traumatic brain injury. Neurogenesis is very sensitive to functional perturbations, being increased by physiological stimuli such as exercise as well as by pathological conditions including seizures and ischemia. Perhaps more importantly in our view, the integration of these newborn neurons provides a unique window into the formidable barriers to synaptogenesis, dendritic outgrowth and circuit formation in the adult nervous system. In terms of the potential for stem cells and cell replacement approaches in the nervous system, these barriers are perhaps more daunting than even cell differentiation and survival. We would like to use the success of this natural “regeneration” to understand the molecules that prevent/enhance synaptic development and circuit formation in the adult nervous system.
To approach this problem, we first made use of a unique transgenic mouse in which newborn neurons are transiently labeled with a fluorescent marker (green fluorescent protein, GFP) (Figure 1). We used these mice to examine the development of dendrites and synapses, which revealed several distinct stages – an early stage in which dendrites are limited to the inner molecular layer of the dentate gyrus and synapses are exclusively GABAergic. We also showed that seizures accelerate the integration of newborn neurons. Our current approach is to use viral-mediated gene transfer to specifically up- or down-regulate molecules in either newborn or mature granule cells to examine their role in circuit formation. We assess the results using a variety of cellular and molecular techniques including single cell physiology in brain slices, measures of gene expression, and confocal imaging of hippocampal tissue.
Recent publications from the project
Luikart BW, Zhang W, Wayman GA, Kwon C-H, Westbrook GL, Parada LF (2008) Neurotropin dependent dendritic filopodial motility - A convergence on PI3K signaling. J Neurosci, 28, 7006-7012.
Magill ST, Cambronne XA, Luikart BW, Lioy DT, Leighton B, Westbrook GL, Mandel G and Goodman RH (2010) microRNA-132 regulates dendritic growth and arborization of adult newborn hippocampal neurons. Proc Natl Acad Sci (USA) 107, 20387-20389.
Luikart BW, Schnell E, Washburn E, Bensen AL, Tovar KR and Westbrook GL (2011) Pten knockdown in vivo increases excitatory drive onto dentate granule cells. J Neurosci, 31, 4345-4354.
Luikart BW, Perederiy J and Westbrook GL (2011) Dentate gyrus neurogenesis, integration and microRNAs. Behav Brain Res, Mar 31 [Epub ahead of print].
Parent A-S, Naveau E, Gerard A, Bourguignon J-P and Westbrook GL (2011) Early developmental actions of endocrine disruptors on the hypothalamus, hippocampus and cerebral cortex. J Toxicol Env Htlh (Part B: Critical Reviews) 14, 328-345.
Luikart BW, Bensen AL, Washburn E, Perederiy J, Su K, Li Y, Kernie S, Parada L and Westbrook GL (2011) miR-132 mediates the integration of newborn neurons into the adult dentate gyrus. PLoS One 6(5):319077.
Westbrook Lab Personnel
Gary L. Westbrook
Dr. Westbrook received clinical training in Internal Medicine and Neurology in Boston and St. Louis, and research training at the National Institutes of Health. He is Senior Scientist and Co-Director of the Vollum Institute and the Dixon Professor of Neurology at OHSU. His research interests are the mechanisms of synaptic transmission in the nervous system. Dr. Westbrook has been active in recruitment of faculty to the Jungers Center and in OHSU training activities in disease-oriented neuroscience research. He initiated the Neurobiology of Disease course in the graduate program, and currently serves as the Director of the Neuroscience Graduate Program at OHSU.
Eric is an Assistant Professor of Anesthesiology who performs his clinical work at the Portland VA and is working on his research as part of the Westbrook lab. Eric is interested in adult-generated newborn neurons and their role in neuroplasticity in the brain, with a particular interest in the synaptogenic molecules, neuroligins, as well as the cellular and network effects of concussive head injuries.
Christina joined the Westbrook lab in October 2011 from the Burnham Institute in La Jolla, California. She brings a strong background in developmental biology and stem cell biology that will greatly enhance the group.
Aesoon is a Senior Research Assistant who joined the lab in 2004 and previously worked at OHSU's West Campus. AeSoon provides invaluable molecular biology support for the project and helps manage the transgenic mouse colonies. She also asks tough questions in lab meetings to keep everyone on their toes! Outside work, AeSoon has started her own small business, designing laptop bags for women.
Julia is a recent graduate of the Neuroscience Graduate Program at OHSU and is now working as a post-doctoral fellow in the Westbrook lab. She worked as a lab assistant at UCLA from 2005-2007 after completing her undergraduate degree in psychology and neurobiology at UC Berkeley. At UCLA, Julia worked on a project examining the genes involved in language development. She is currently examining how newborn neurons respond in a classic model of neural injury, a lesion to the entorhinal cortex. This lesion removes a major input to the dentate gyrus hippocampus, and we expect that it will provide molecular insights about how newborn neurons may compensate for loss of the normal circuit organization, and thus provide a model for repair of neuronal circuits by newborn neurons or stem cells.