A prominent feature of the mammalian brain is the topographical representation of the external sensory world. These maps are characterized by remarkable precision with organized arrays of afferents that project into distinct neuronal modules. This pattern undergoes activity-dependent elaboration and refinement and is subject to the influence of sensory experience during a 'critical period' of postnatal life. Mis-wiring of neuronal circuits during early life is likely to be a major cause for neurological disorders, including autism, dyslexia, schizophrenia, and congenital epilepsy.
What is the nature of such activity-dependent processes? How does sensory experience influence the organization of neural circuits? Can we extend the critical period for cortical map plasticity? In cortical sensory maps, thalamocortical afferents (TCAs) transmit peripheral sensations in organized arrays that project into distinct neuronal modules or columns. This segregated pattern undergoes activity-dependent elaboration and refinement that leads to the formation of cortical columns with very selective stimulus response preferences. In mice, each aggregate of TCAs that relays sensory information from a single whisker innervates one discrete cluster of layer IV neurons that form ?barrels? in the primary somatosensory cortex. The prominent anatomical organization of barrels has allowed the identification of several mutants with barrel map deficits, including the loss-of-function mutants of calcium/calmodulin-activated adenylyl cyclase I (AC1, a cAMP synthesizing enzyme), mGluR5 (a metabotropic glutamate receptor), and RIM1a (an active zone protein). The involvement of these proteins in synaptic function and plasticity suggests that a correlation-based mechanism underlies cortical map development.
The main goal of Dr. Lu's research is to study these mutant mice to reveal the molecular mechanisms underlying the activity-dependent processes in cortical map development. The specific aims include: 1) to reveal the roles of AC1, mGluR5, and RIM1a in regulating synaptic function and plasticity during early brain development; 2) characterize the patterns of axonal arborizations and dendritic branchings of these ?barrelless? mutant mice to uncover the anatomical substrates of these proteins; 3) elucidate the signaling cascades triggered by AC1 and mGluR5 in forming barrels. A combination of electrophysiological, pharmacological, anatomical, and biochemical approaches will be applied to characterize these mutant mice. To selectively modulate neural activity in a time- and tissue-specific manner in vivo, Dr. Lu has also set up an in-utero electroporation technique to introduce various cDNAs and short hairpin RNA (ShRNA) constructs. This knowledge should provide an important basis not only for understanding how the brain works but also for the development of therapeutic strategies to treat neurological disorders.
Carlos J Ballester Rosado, Michael J Albright, Chia-Shan Wu, Chun-Chieh Liao, Jie Zhu, Shen-Ju Chou, Dennis D O'Leary, Li-Jen Lee, and Hui-Chen Lu (2010) "mGluR5 in cortical excitatory neurons exerts both cell autonomous and nonautonomous influences on cortical somatosensory circuit formation". J. Neuroscience in press.
Hsiao-Tuan Chao, Hongmei Chen, Rodney C. Samaco, Mingshan Xue, Maria Chahrour, Jong Yoo, Jeffrey L. Neul, Shiaoching Gong, Hui-Chen Lu, Nathaniel Heintz, Marc Ekker, John L.R. Rubnenstein, Jeffrey L, Noebels, Christian Rosenmund, Huda Y. Zoghbi (2010) “GABAergic dysfunction mediates autism-like stereotypies and numerous features of Rett syndrome”, Nature, in press.
Chia-Shan Wu, Jie Zhu, Jim Wager-Miller, Shan Wang, Dennis O'Leary, Krisztina Monory, Beat Lutz, Ken Mackie, and Hui-Chen Lu (2010) “Requirement of cannabinoid CB1 receptor in cortical pyramidal neurons for appropriate development of corticothalamic and thalamocortical projections”, European J. Neuroscience, 32:693-706.
Keiko Sakai, Oliver Tiebel,; Cecilia Ljungberg, Merry Sullivan, Hey-Jeong Lee, Tomoya Terashima, Rongying Li, Kunihisa Kobayashi, Hui-Chen Lu, Lawrence Chan, Kazuhiro Oka (2009) “A neuronal VLDLR variant lacking the third complement-type repeat exhibits high capacity binding of ApoE containing lipoproteins”, Brain Research, 1276:11-21.
Wei-Chi She, Charles Quairiaux, Michael J. Albright, Yu-Chi Wang, Denisse E. Sanchez, Poh-Shing Chang, Egbert Welker, Hui-Chen Lu (2009) “Roles of mGluR5 in synaptic function and plasticity of the mouse thalamocortical pathway”, European J. Neuroscience, 29: 1379–1396 (EJN featured article).
Yuan Fan, Ping Deng, Yu-Chi Wang, Hui-Chen Lu, Zao C Xu, Paul E Schulz (2008) “Transient cerebral ischemia increases CA1 pyramidal neurons excitability”, Experimental Neurology, 212: 415-421.
Jan Mulder, Tania Aguado, Erik Keimpema, Klaudia Barabás, Carlos J. Ballester Rosado, Laurent Nguyen, Krisztina Monory, Giovanni Marsicano, Vincenzo Di Marzo, Yasmin L. Hurd, Francois Guillemo, Ken Mackie, Beat Lutz, Manuel Guzman, Hui-Chen Lu, Ismael Galve-Roperh, Tibor Harkany (2008) “Endocannabinoid signaling controls pyramidal cell specification and corticothalamic axon patterning”, Proc Natl Acad Sci U S A, 105:8760-8765.
Jane E. Lauckner, Jill B. Jensen, Huei-Ying Chen, Hui-Chen Lu, Bertil Hille, and Ken Mackie (2008) “GPR55 is a cannabinoid receptor that increases intracellular calcium and inhibits M current“, Proc Natl Acad Sci U S A, 105: 2699-2704.
Melis Inan, Hui-Chen Lu, Michael Albright, Wei-Chi She and Michael C. Crair (2006) "Barrel map development relies on PKARIIb –mediated cAMP signaling”, Journal of Neuroscience, 26: 4338-4349.
Hui-Chen Lu, Daniel A Butts, Pascal S. Kaeser, Wei-Chi She, Roger Janz and Michael C. Crair (2006) "Role of efficient neurotransmitter release in barrel map development”, Journal of Neuroscience, 26: 2692-2703.
Awards, Recognition, Appointments, and Honors
AHA-Texas Affiliate Beginning Grant-in-Aid (Starter Award) (2004-2006)
NIH NRSA postdoctoral fellowship F32NS11034-01 (2000-2003)
Max-Planck postdoctoral fellowship (1997-1998)
Deborah K. Martin Achievement Award in Biomedical Research (1997)
Markey Charitable Trust Foundation Graduate Student Fellowship (1996-1997)
|A. Sensory information detected by whiskers is transmitted through brain stem and thalamus to the primary somatosensory (S1) cortex. The clear anatomical features of “barrels”, the whisker-related patterns in S1 cortex, allowed the identifications of many “barrelless” mutant mice. B. A typical acute thalamocortical brain slice for electrophysiological recordings. C. In-utero electroporation technique is used to manipulate gene expressions in specific cortical layers. I, nuclear stain; II, GFP fluorescence from transfected cells; III, the immuno-reactivity of a barrel marker; IV a merged image. (II/III, IV, V, VI indicate cortical layers; w.m., white matter)|