Our Vision: A Multi-Scale Understanding of the Brain
In modern neuroscience, a significant chasm exists between molecular cell biology and systems-level circuit analysis. While we understand many of the "parts" of a neuron and the "outputs" of the brain, we rarely understand the intermediate logic that connects the two. Our lab is dedicated to bridging this gap. We investigate how nanoscale dynamic events, occurring within specialized subcellular compartments like the primary cilia and the nucleus, drive the molecular signaling and gene expression that dictate neuronal states, neural computation, and ultimately, complex behavior.
What We Do: The Molecular-to-Systems Pipeline
Unified by a background in both cell biology and systems neuroscience, our lab possesses the rare range of skills required to formulate and address questions across biological scales. We employ a rigorous, "top-down and bottom-up" research strategy:
Targeted Perturbation: We identify pathways with clinical relevance or noncanonical functions and use specialized AAV-CRISPR tools to perturb them in adult mice.
Behavioral Discovery: We screen for interesting behavioral phenotypes that result from these perturbations.
Multi-Scale Deconstruction: Once a phenotype is identified, we investigate every layer in between, from subcellular signaling and gene expression to real-time neural activity and circuit computation.
Core Research Program I:
Redefining Neural Computation through the Primary Cilium
Historically, neuroscience has been defined by an intense focus on how the structure and composition of axons and dendrites enable neurons to compute information and form the circuits that drive brain function. Our lab is asking a fundamental, long-overlooked question: What is the computational role of the primary cilium in the adult brain?
While long recognized as a developmental organelle, the cilium’s role in the mature nervous system remains a critical, unexplored frontier. We are working to establish the concept of the cilium as a computational microdomain, a specialized "biological antenna" that allows neurons to interpret complex neuromodulatory signals. Our ongoing research seeks to characterize how these structures enable neurons to decode neuromodulatory signals that shape flexible learning and stress coping behaviors.
By investigating how primary cilia bridge dynamic neuronal activity and experience-dependent gene regulation, we aim to provide a novel mechanistic framework for the behavioral rigidity and anxiety phenotypes characteristic of ciliopathies like Bardet-Biedl syndrome and neurodevelopmental disorders such as Autism Spectrum Disorder (ASD). By dignifying the role of the primary cilium, our work seeks to shift the paradigm of neural computation, suggesting that these subcellular microdomains are as critical to circuit function as the synapse itself.
3D volume image of mouse striatum
Yellow: neuronal cilia
Blue: serotonin axons
Red: Nuclei
Core Research Program 2:
Noncanonical Nuclear Logic in
Mature Neurons
We are interested in how the neuronal nucleus organizes gene expression to support learning and memory. This program focuses on two distinct classes of nuclear proteins that have been "re-purposed" in the adult brain:
Redefining Cell-Cycle Regulators
We investigate why proteins traditionally stereotyped as cell-cycle regulators (proto-oncogenes) are highly expressed in mature, post-mitotic neurons for entirely non-cell-cycle functions, such as scaffolding RNA processing. This work challenges biological dogma and kindles a necessary conversation between neuroscience and oncology regarding how oncogenic pathways and their clinical treatments may inadvertently affect brain function and behavior.
From Synaptic to Nuclear Scaffolds
Our lab investigates specialized scaffold proteins historically recognized for their critical roles in neurotransmission during development and their link to movement disorders like ataxia and dystonia. We have discovered that these proteins are uniquely enriched in the nuclei of specific neuromodulatory neurons in the adult brain, a departure from their established synaptic functions. In collaboration with structural and cell biologists, we are exploring how these proteins are repurposed within the nucleus to influence the neural computation essential for motor coordination and learning..
Scaffold proteins are enriched in dopamine neurons
Magenta: scaffold proteins
Yellow: dopamine neurons
Our Training Signature: Developing "Multilingual" Scientists
The hallmark of our lab is the comprehensive training our researchers receive. We believe that the next generation of neuroscientists must be "multilingual", fluent in the disparate languages of molecular, cellular, and systems biology.
Trainees in our lab receive comprehensive instruction in a vast array of techniques, including advanced molecular biology, AAV-CRISPR engineering, and computational behavior analysis. Our unique signature is teaching researchers to think across scales. By joining us, you don’t just study a molecule or a behavior; you learn to decode the functional logic that connects them, preparing you for a career at the cutting edge of integrated neurobiology.
The views and opinions expressed herein are those of the author(s) and do not represent the views and opinions of the National University of Singapore or any of its subsidiaries or affiliates