Opening Windows in the Brain
By Carol Gerwin
As a young neurobiologist, Takao Hensch, Ph.D., started exploring classic questions of brain development by studying the visual systems of mice—something most scientists considered a waste of time. “What could you possibly learn from mice?” they asked, noting the animals’ nocturnal nature and horrendous eyesight.
Twenty years and countless lab mice later, Hensch, a professor of molecular and cellular biology at Harvard and professor of neurology at Boston Children’s Hospital (BCH), has answered skeptics again and again with significant breakthroughs in how experiences shape the developing brain at the molecular level.
Hensch, who is an affiliated faculty member of the Center on the Developing Child and serves on its steering committee, focuses on “critical periods” of development. These are the spans of time early in life when the brain’s neural circuitry is most flexible, or “plastic,” and both most susceptible to, and capable of, change.
Critical periods have long been seen as windows of opportunity and vulnerability, when most children quickly learn fundamental skills, such as seeing, hearing, walking, and talking, as they interact with their environment. But the wrong balance of inputs during these intervals can cause lifelong deficiencies in the brain’s connections, leading to serious physical or mental health problems. Science has shown for years that once critical periods for certain abilities end, the brain’s circuits “hard wire,” and they become difficult, or in some cases impossible, to change.
But Hensch and his colleagues are generating an exciting new view of critical periods. Their research has revealed that it actually is possible to create additional critical periods later in life, when some areas of the brain can regain their malleability, rewire their circuits, and reopen, even permitting treatment of certain disorders.
Although his research is done in rodents, Hensch is always seeking potential human implications for his work. “It’s a topic that’s deeply important to me,” Hensch says. “How can we translate what we do in the lab to be useful to society?”
In that vein, Hensch is a member of the Center’s faculty group advising its Science of Health and Development (SHD) Initiative, which aims to advance the scientific understanding of how genes, experiences, and environmental influences interact during prenatal, child, and adolescent development to affect brain development and lifelong outcomes in health, learning, and behavior.
‘Rewiring’ Circuits, Enabling Treatment
Feature: Conte Center at Harvard
Learn more about neurobiologist Takao Hensch and his work as director of the Conte Center at Harvard, which supports multidisciplinary research into mental health disorders.
Hensch’s most recent breakthroughs and current research indeed hold promise for anyone interested in reducing symptoms of developmental disorders or mental illness with early childhood roots, such as autism or schizophrenia. Particularly intriguing is the possibility of learning how treatment might be able to take advantage of what Hensch calls “our innate powers to rewire” our brains.
Much of his research has revolved around a frequently used visual system model: scientists cover one eye of a young mouse in order to disrupt its ability to see. This mirrors the development of a child with “lazy eye,” or amblyopia, which causes the loss of visual acuity and three-dimensional vision. Amblyopia is fully treatable, by patching the good eye and giving the weaker eye a chance to develop—but only until the critical period for vision ends. This is around age 8 or 9 for humans and a few weeks’ of age for mice.
Previously, Hensch and his colleagues had discovered that typical brain development requires the right balance of excitatory and inhibitory neurotransmitters, which increase or decrease the “firing,” or electrical activity, of neurons. They realized that they could trigger brain plasticity at any age by gently disrupting that balance. For example, after knocking out one enzyme that produces the inhibitory neurotransmitter GABA, critical periods failed to begin. But then, they found, the common psychiatric drug Valium, a type of benzodiazepine, could switch it on at any age.
“Lo and behold,” recalls Hensch, “The mice suddenly switched on their plasticity, and we could cure their amblyopia not only at their regular critical period age, but at any age, even as full-blown adults.”
Most recently, Hensch’s team has identified a biological process that triggers the end of each critical period, putting molecular “brakes” on development. Their research has shown that releasing these brakes at any time restarts the critical period by increasing brain plasticity. For example, a medication used to fight the symptoms of Alzheimer’s disease, Aricept, mimics the removal of a key brake-like protein, improving communication among neurons, and paving the way for a new critical period in the visual systems of mice. This work is now moving into human research, with clinical trials at BCH to investigate treatment of amblyopia in older patients.
Unlikely Collaboration and ‘Unexpected Results’
Six years ago, when he moved to Harvard from the RIKEN Brain Science Institute in Japan, it marked a return to his alma mater—and a chance to get in on the ground floor of the Center on the Developing Child, which was also founded in 2006. Hensch was thrilled to have the opportunity to collaborate across disciplines and recalls there being “obvious, immediate” benefits to connecting with Center colleagues. “To bring all corners of the University together around this central theme [of child development] at a big place like Harvard, I found that so appealing,” he says. “It made me feel like I was part of a whole university, rather than just sitting in my lab in one corner of it.”
A favorite story is his collaboration with Charles A. Nelson III, Ph.D., a pediatric developmental neuroscientist at BCH who is also a Center steering committee member and a member of the SHD Initiative’s advisory group. An expert on the effects of the adversity of institutionalization on the development of Romanian orphans, Nelson wanted to measure physiological changes in early life stress before and after the children were moved from orphanages into foster families. But, ethically, little could be done on children.
So, with seed funding from the Center, Nelson and Hensch decided to try to simulate in mice the adverse conditions of the orphanages and to see if there were certain biomarkers, or biological indicators, in mice that might be useful for Nelson to measure in children. Together, they considered looking at the length of telomeres, the caps on chromosomes that protect them and get shorter with age and with stress. The only problem? It was another ethical dilemma: How to create a mouse orphanage.
“It’s kind of a funny story, but we had a hard time establishing a mouse model of an orphanage situation, because animals are very protected—and rightly so,” Hensch says. “But maternal separation was approved. We took newborn pups away from their mother for two hours a day—no more.”
When Nelson started his research in parallel, he and Hensch made a surprising discovery: gender differences. “Males were more sensitive to this early life stress than females,” both behaviorally and as evidenced in biomarkers. “There seems to be a gender bias to early life adversity,” Hensch says.
Hensch and Nelson had been introduced through the Center, and a collaboration such as theirs was unlikely to have developed without that connection. “That’s just one way in which bringing the right kinds of people together leads to unexpected results and unexplored research areas,” says Hensch.
Hensch says there is still “so much more” to understand about what happens when development goes awry. Some of the questions he hopes to answer: whether autism is caused by a mistiming of critical periods and whether they could be reopened, enabling opportunities for more effective treatment; whether mental illnesses like schizophrenia are caused by the brain’s refusal to turn off plasticity; and whether self-regenerating systems, such as the sense of smell, do not have a critical period at all.
“That’s the dream—to be able to understand…what turns brain plasticity on, what turns it off, so we can leverage that,” Hensch says. “If we can get in there [at the right time], maybe we can help normal development take place.”
Carol Gerwin, a freelance writer and editor specializing in education and child development, is based in Newton, Mass.
Top photo by Fred Field. Sidebar photo courtesy of Harvard Life Sciences Outreach Program.