Research Interests

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).

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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.

Slide1

– JAK2 is an activity-dependent “elimination signal” of inactive synapses (Yasuda et al., Neuron 2021).

Synapse Elimination 101 (YouTube)

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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.

Slide2

Molecular Codes for the Establishment of Functionally Segregated Dopaminergic Circuits

[NIH R01 MH125162; with Mitsuko Watabe-Uchida]

The major goal of this project is to identify the manner and molecular mechanisms by which functionally segregated dopaminergic circuits are established in the mammalian brain.

The Nigrostriatal-Specific Dopaminergic Synapse Organizer and Parkinson’s Disease

[American Parkinson Disease Association]

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Mechanisms of Activity-Dependent Microglia-Neuron Interactions in Development and Disease

[NIH RF1 NS092578; with Beth Stevens]

Microglia, the immune cells and phagocytes in the brain, organize brain circuits by engulfing inappropriate synapses. Functional neural circuits are established by communication between neurons and microglia. In this study, we will identify the molecular cues by which microglia recognize the target synapses and their regulation by synaptic activity. We will test the idea that activity-dependent signals within neurons dynamically regulate “eat me” and “don’t eat me” signals on synapses to drive proper microglial phagocytosis of inactive synapses. We will also test the idea that aberrant activation of such signals lead to abnormal synapse loss in neurodegenerative diseases such as Huntington’s and Alzheimer’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.

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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.

Slide4

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Establishment of Parallel Cortico-Basal Ganglia Circuits by ASD-Linked Protocadherins

[Simons Foundation Autism Research Initiative (SFARI)]

Protocadherin 19 (Pcdh19), Pcdh10, and Pcdh17 are homophilic cell adhesion molecules that belong to the δ2-protocadherin family. Pcdh19 is implicated in ASD (Score 1S) and epilepsy, Pcdh10 also in ASD (Score 3), while Pcdh17 is involved in mood disorder. Each is highly expressed in the cortex and basal ganglia during development. However, the precise roles of each Pcdh in the brain, and how the mutations in each Pcdh lead to neuropsychiatric disorders are unknown.

It has been suggested that different cortical areas project to discrete regions of the basal ganglia in a highly topographic manner, creating a parallel organization of functionally segregated circuits, with limbic, associative, and sensorimotor circuits. The limbic circuit plays a key role in motivated behavior and empathic/socially appropriate behavior; the associative circuit is implicated in executive functions such as organizing behavioral responses to complex problems and cognitive function; and the sensorimotor circuit plays a role in sensorimotor modulation and movement regulation.

Interestingly, we have found that Pcdh19, Pcdh10, and Pcdh17 are expressed in distinct subregions of the striatum that are implicated in sensorimotor (posterior striatum), limbic (central/ventral), and associative (anterior) circuits, respectively. We propose that distinct δ2-Pcdhs play critical roles in establishing specific cortico-basal ganglia circuits and as a result, defects in each Pcdh manifest in a distinct disease phenotype. We will use histological, imaging, electrophysiological, and behavioral approaches with Pcdh mutant mice to reveal the molecular mechanisms by which appropriate cortico-basal ganglia circuits develop and identify the molecular and circuit mechanisms that contribute to ASD.

Cortico-basal ganglia

Female-Specific Mechanisms of Protocadherin-19 Disorder (Hoshina et al., Science 2021)

[PCDH19 Alliance]

A mismatch model for PCDH19-related disorder with epilepsy and cognitive impairment. In wild-type mice, PCDH19 binds with itself across the synapse and activate N-cadherin signaling to induce β-catenin clustering. These mice have normal cognition and long term potentiation (LTP). In male mutant mice (HEMI), which lack PCDH19, N-cadherin is unmasked and can bind to itself to cluster β-catenin so that cognition and LTP is normal. In female mutant mice with one copy of PCDH19 (HET), N-cadherin remains masked on one side of the synapse so that β-catenin cannot cluster, and cognition and LTP are impaired.

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.

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Testing Functional and Structural Connectivity in CDKL5 Deficiency Disorder as Novel Biomarkers

[CDKL5 Program of Excellence, Lulu Foundation; with Michela Fagiolini]

The major goal of this project is to elucidate the role of CDKL5 in the establishment of functional and structural neuronal connectivity and to identify novel quantitative biomarkers of CDKL5 disorder in patients. 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. We will combine in vitro and in vivo electrophysiological analysis with functional and structural imaging in both animal models of CDKL5 disorder and patients.

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Pathway-Specific Effects of Early-Life Cannabis Exposure on Dopamine Synapse Development

[Broderick Phytocannabinoid Research Grants]

The major goal of this project is to investigate the effects of neonatal and adolescent cannabis exposures on the establishment of specific dopaminergic connections in the brain and identify the underlying molecular and cellular mechanisms.