702 North Walnut Grove Ave.
Bloomington, IN 47405-2204
Miswiring of neuronal circuits during early life is likely to be a major cause of neurological disorders, including autism and schizophrenia. The Lu lab is interested in how activity-dependent processes during brain development fine-tune the establishment of neural circuits and how sensory experiences affect neural circuit wiring and cognitive behaviors. Specifically, we are interested in exploring the role of the metabotropic glutamate receptor 5 (mGluR5), a group 1 metabotropic glutamate receptor. mGluR5 mutations have been identified in some ADHD and schizophrenic patients. We employ mouse genetic tools to understand the contribution of mGluR5 signaling in specific neuronal populations to sensory circuit formation, synaptic function/plasticity, and behavior. We are also exploring the role of the endogenous cannabinoid (endocannabinoid) system in fetal brain development and investigating how prenatal cannabis exposure affects brain development and later behaviors. Understanding the effects of endocannabinoids during neural circuit formation will not only shed light on normal brain development and function but will also allow us to assess endocannabinoid-based therapies and the effects of cannabis use on the developing fetus.
Proper brain function requires an active maintenance program to sustain neuronal health. Environmental stressors detrimentally impact the nervous system, predisposing it to neuronal dysfunction and degeneration if neuroprotective mechanisms are weakened. Recent studies by others and us revealed that NMNAT2 (nicotinamide mononucleotide adenylyl transferase 2) is a neuroprotective protein that is central to maintain neuronal integrity and facilitate proper neural function throughout life. NMNAT2 abundance is significantly reduced in Alzheimer’s Disease (AD) brains. Increasing Nmnat2 expression in neurodegenerative animal models reduced neurodegeneration. We hope to elucidate the mechanisms underlying NMNAT2’s neuroprotection and how NMNAT2 expression is down-regulated in pathological conditions. In addition, we hope to develop NMNAT2-specific therapies to prevent or reduce neurodegeneration.
You can’t get frustrated by critics or limitations. If you are motivated and like what you do, you will find a way.Hui-Chen Lu, Ph.D.
Written by: Elisabeth Andrews
Growing up in Taiwan in the 1970s, money was scarce in Hui-Chen Lu’s household. Toys were rarely purchased, so Lu made her own, crafting figurines from found objects like paper scraps and cherry pits.
Her attention turned to science when, at ten years old, she was tasked with assisting in her grandmother's bookshop. There she discovered a series that captivated her imagination.
"Instead of fairy tales, the books that intrigued me were the ones we called 'curiosity books,'" she recalls. "They had titles like, 'Why Does the Rainbow Have Seven Colors?'"
With this interest awakened, Lu was delighted when her middle school biology teacher led her students outside to find specimens.
"We would chase after butterflies and different kinds of insects," she remembers. Examining their wings, eyes, and bodies, she says, "I began to appreciate the diversity of patterns in the natural world."
Although the cultural expectation at the time was for young women to become housewives, Lu was determined to find her own path as a scientist. After completing daily chores of cleaning, laundry, and caring for the family, she would push herself to excel in her academic coursework and prepare for college entrance exams.
Her motivation paid off when she was accepted to pursue a degree in zoology at National Taiwan University. In addition to a foundation in molecular and biochemical science, she gained practical experience in the lab, where she learned the key lessons of "failure, frustration, and how to seek help," she says.
Unexpectedly, Lu also discovered that her years of housework served her exceptionally well. "To succeed as a scientist, you need to have good hands," she explains. "You need accuracy so you don't destroy things. Doing chores from an early age gave me those fine motor skills."
Precision became especially critical when Lu pursued an undergraduate research opportunity working with fruit flies in the Institute of Molecular Biology at Academia Sinica in Taiwan. Although the institute was an hour and a half from her university (by scooter through Taipei traffic), the training she acquired in genetic engineering was so valuable that she decided to stay on as a technician for a year after graduation.
The timing proved fortuitous, as the following year the Baylor College of Medicine in Houston offered its first developmental biology PhD program. Lu joined a class of just three initial students, learning about embryonic development by examining fertilized chicken eggs.
"I would make a little hole at the top of the egg and cover it with Scotch tape," she describes. "Every couple of hours I would pull back the tape and see what had happened."
During her first year in Ph.D. studies as a rotation student under Gregor Eichele, Lu investigated how morphogen gradients and Hox genes control the body's front-to-back and head-to-tail axes. While pregnant with her first child, Lu demonstrated the evolutionary conservation of Hox genes by implanting a chicken gene into a fruit fly in collaboration with IU biologist Thomas Kaufman.
Starting a family while in graduate school brought not only practical challenges – there was no nanny budget in her stipend – but also risks related to her perceived career growth. Juggling the demands of work and family required help from friends and colleagues in Houston, yet as Lu explains, "Funding agencies expect you to move to different institutions," she says. "How else can you prove you are gaining new skills and independence?"
Drawing on the resourcefulness that served her in childhood, Lu resolved to progress her career while remaining at Baylor. She diversified her training through a postdoc under neuroscientist Michael Crair. As her two sons began reaching developmental milestones, Lu grew increasingly interested in brain development. When she took on an assistant professorship in the same department, objections from traditional funders led her to a bridge grant from the American Heart Association to produce pilot data. This creative approach paid off: the resulting data earned Lu her first NIH grant, which enabled her to become a tenure-track independent investigator.
"I had to take a very frugal approach, borrowing equipment from colleagues and collaborating extensively – which in the end made a higher impact," Lu says.
Those studies, which used mouse models to examine synaptic transmission, caught the attention of a private foundation with an interest in neurodegeneration. After speaking with their representatives, "I began to see that aging is just the other end of development," she says.
Approaching neurodegeneration through the lens of neurodevelopment enabled Lu to ask groundbreaking questions, such as how the body maintains the health of its neuronal networks and how "critical windows" of neuroplasticity are opened at specific points in time. In her subsequent post at Baylor’s Neurological Research Institute, and now at the Gill Center, Lu explores neural circuits over the course of the lifespan, from the effects of different inputs on neural circuit formation to the factors that can increase or prevent neurodegeneration. She is also investigating biomarkers of brain health: Lu's mouse studies indicate that elevated microRNA levels appear in the blood prior to symptoms of numerous ailments including inflammation and Alzheimer's Disease.
Summing up her history of defying expectations and turning challenges into advantages, Lu says, "You can’t get frustrated by critics or limitations. If you are motivated and like what you do, you will find a way."