The followings are our active research projects currently funded by the NIH and other agencies.
We are currently looking for motivated postdocs to join our projects (or to start new projects).
How Do Neurons in the Brain Decide to Refine Their Synaptic Connections In Vivo?
[NIH R01 MH111647]
For the brain to function properly, neurons must form active and efficient circuitry during development by refining synaptic connections, where “appropriate” neuronal connections stay (maintained) while “inappropriate” ones leave (eliminated). We will decipher how neuronal connections decide to stay or leave by identifying the molecular determinants of the refinement. Defects in synapse refinement have been implicated in various neurological and psychiatric disorders, and our work will yield novel insights into the pathophysiology and treatment of such disorders.
Finding the Projection-Specific Dopaminergic Synaptic Organizers
[NIH R01 DA042744]
Dopaminergic neurons in the midbrain are critical for the regulation of various cognitive and motor behaviors. Based on the connectivity and functionality, dopaminergic neurons in the midbrain are separated into two groups: neurons in the substantia nigra pars compacta (SNc) and those in the ventral tegmental area (VTA). SNc neurons project to the dorsal striatum (caudate putamen (CPu); the mesostriatal projection) and are involved in motor function and Parkinson’s disease; while VTA neurons mainly project to the ventral striatum (nucleus accumbens (NAc); the mesolimbic projection) and are implicated in drug addiction, depression, and schizophrenia. However, how dopaminergic synapses are established in the developing brain is unknown. The focus of this project is to understand how the projection-specific dopaminergic synaptic connections are established in the mammalian brain and to provide novel targets for treating diseases that may result from improper dopaminergic synapse formation.
Investigating CD47-SIRPα As Novel Protective Signals During CNS Synaptic Pruning
[NIH R01 NS092578; with Beth Stevens]
Microglia, the immune cells and phagocytes in the brain, organize brain circuits by engulfing inappropriate synapses. In this study, we will identify the molecular cues by which microglia recognize the target synapses, their regulation by synaptic activity, and possible involvement in neurodegenerative diseases with an emphasis on Huntington’s disease. This project will provide novel insights into the mechanisms regulating appropriate brain circuit establishment by microglia and may lead to novel treatment of neurodegenerative diseases such as Huntington’s disease.
Weaving the Neuronal Network with Target-Derived FGFs in the Developing Brain
[March of Dimes]
Abnormal formation of neuronal network in the brain contributes to various neurological and developmental disabilities that cause birth defects. This project is aimed at understanding the molecular and cellular mechanisms underlying proper neuronal network formation in the brain, focusing on the potential roles of fibroblast growth factors (FGFs) and their target genes.
There are two major types of synapses in the brain: excitatory and inhibitory. For proper functioning of the brain, these two types of synapses must form at appropriate sites during development. We have found that two distinct FGFs are critical for the differentiation of excitatory or inhibitory synapses in the mammalian brain. In this project, we will address: i) how these FGFs initiate specific synapse formation, ii) what signaling pathways these FGFs utilize for specific synapse formation, and iii) how these FGFs and their target genes contribute to neuronal network formation in the brain. This body of work will allow us to determine the fundamental mechanisms for the establishment of balanced synaptic networks in the mammalian brain, and help design strategies for treatment and prevention of neurological and developmental disabilities caused by excitatory/inhibitory imbalance.
Protocadherin-17 Dysregulation and Bipolar Disorder
[Harvard Brain Science Initiative]
Protocadherin-17 (Pcdh17) is a cell-cell adhesion molecule that is highly expressed in the developing brain. Single nucleotide polymorphisms (SNPs), a type of genetic variation among people, in the Pcdh17 gene are significantly correlated with human bipolar disorder. These SNPs may cause dysregulation of Pcdh17 expression. However, whether dysregulation of Pcdh17 expression affects brain development and contributes to bipolar disorder remains to be elucidated. We hypothesize that dysregulated Pcdh17 expression impairs neuron-neuron connections that underlie the regulation of mood, leading to bipolar disorder. We will test our hypothesis by creating novel animal models in which Pcdh17 expression is dysregulated and performing in vitro and in vivo experiments.
We are also interested in other Pcdhs and their roles in specific brain circuit formation and relevant behavior.
Testing the Role of Callosal Axon/Synapse Refinement in the Onset of CDKL5 Disorder
[Boston Children’s Hospital; with Michela Fagiolini]
The major goal of this project is to test whether defects in callosal refinement underlie CDKL5 neurodevelopmental disorder. We will test the working hypothesis that CDKL5 regulates the refinement of callosal connections across hemispheres in early postnatal life, directly affecting the maturation of visual acuity and the cortical representation of the inputs from the two eyes that allows depth perception.