Completing the Circuit
From anxiety to cerebral palsy, our scientists explore the wide-ranging consequences of disruptions in brain development
Some birth defects such as cardiac problems, airway malformations and liver and gut disorders are so extensive that survival depends on immediate medical intervention.
Other defects that occur are more subtle.
Prenatal defects in how the brain is assembled can lead to cognitive defects, emotional and behavioral disorders and deficiencies in motor skills and language development. However, these problems often do not reveal themselves until a child begins growing up.
At Cincinnati Children’s, as investigators gain new understanding of the molecular pathways that guide brain development in utero, they are beginning to pinpoint precisely when, where and how the process can go wrong.
These insights eventually could lead to life-altering treatments for conditions ranging from post-traumatic stress disorder and ADHD to cerebral palsy and learning disabilities.
The roots of fear
Much of what makes us human comes from the telencephalon, or the forebrain — the region that controls cognition, emotion and purposeful movements.
Kenneth Campbell, PhD, a researcher in the Division of Developmental Biology, has been studying the molecular mechanisms that guide the formation of the mouse telencephalon during embryonic development.
His work focuses on understanding how disruptions in the formation of basal ganglia within the subcortical telencephalon may contribute to ADHD, Tourette syndrome and obsessive-compulsive disorder (OCD).
In the past year, Campbell’s research also has delved into the realm of emotional control. Campbell is studying the formation of the amygdala, a portion of the limbic brain that plays a major role in controlling emotions. Specifically, Campbell and colleagues are mapping out the brain circuitry involved in fear and anxiety.
Early results from this work were published in the May 19, 2010, edition of the Journal of Neuroscience. The paper, by Campbell and lead author Ronald Waclaw, MS, PhD, Division of Experimental Hematology and Cancer Biology, describes the origins of neurons that later connect to form the fear circuit of the developing mouse.
They reported a novel origin of the progenitor cells that migrate and differentiate into intercalated cells (ITCs), which are fundamental for the control of fear responses. Campbell’s work has focused on identifying the transcription factors that mark distinct amygdalar progenitors and regulate their differentiation.
He and Waclaw have developed mouse models that produce far fewer ITCs than normal. His team is studying these mice (Gsx2 and Sp8 mutants) to determine how their fear response varies from normal.
“How we respond to fear is a crucial aspect of normal human behavior,” Campbell says. “What holds us back? What allows us to take risks?
“The structure of the amygdala is one of the least well-understood areas within the telencephalon,” he continues. “As we characterize how the amygdala forms, we will gain new understanding of what comprises a normal fear circuit and what comprises an unhealthy one.”
Such understanding could shed new light on many conditions. Fear is linked to post-traumatic stress syndrome, which affects many children who survive disasters, injuries and physical or sexual abuse. Fear-and-anxiety-related stress also helps trigger unusual behaviors in OCD and Tourette syndrome.
Eventually, Campbell’s research will help untangle which aspects of fear response are innate, and which are learned. Once the circuit of fear is better understood, improved therapies might be developed to hit more specific targets in the brain – potentially helping control unhealthy fear responses without causing other unwanted impacts on the brain.
Connections that matter
The brain’s white matter consists mainly of long, myelin-coated axons that relay motor and sensory information from the brain to the body and vice versa.
Defects in white matter can result in a wide variety of neurological deficits, including cerebral palsy, learning disabilities and behavior disorders. However, little is known about how healthy white matter forms.
Understanding this process is especially important because a rising number of infants are surviving extremely premature birth, only to grow up with a range of disabilities later in life.
As many as 50 percent of very low birthweight preterm babies (those born weighing less than 1,500 grams) suffer neurological deficits and developmental disabilities. These brain-related problems have many causes: lack of oxygen, lack of blood flow, infections and drug exposures. But MRI studies reveal a common thread – many of these deficits can be traced to disruptions in the healthy formation of white matter.
At Cincinnati Children’s, Andrea Pardo, MD, a resident in the Division of Neurology, is working with Masato Nakafuku, MD, PhD, a researcher in Developmental Biology, to describe in detail how white matter forms, how defects can occur, and at which critical points developmental problems might happen.
During development, brain stem cells begin dividing to generate three key types of brain cells: neurons, astrocytes and oligodendrocytes. The oligodendrocytes go on to form white matter.
Crucial steps in white matter development occur between 23 and 32 weeks of gestation — the same time when many preterm births occur. Most premature infants avoid brain complications. However, extremely premature babies often suffer neurological consequences, even with the advent of surfactant to help infants survive until their under-formed lungs mature. Late preterm infants are also at risk for developmental delays, as oligodendrocytes continue to form well after 32 weeks of gestation.
“NICUs are getting better at maintaining healthy oxygen levels. However, some hypoxia is almost inevitable, and, these white matter-forming cells are very susceptible to damage at this crucial stage of development,” Pardo says.
The Children’s team is working to more fully describe the stages of oligodendrocyte development at the molecular level, from brain stem cells all the way to fully mature, myelin-coating cells. Investigators are going beyond known descriptions of critical proteins that are active during various stages of development to describe transcription factors that control those proteins.
So far, this research has identified three key transcription factors, each of which is active only during brief windows of time. If hypoxia occurs during one of those windows, these transcription factors do not function properly and white matter formation gets thrown off-track. As a result, surviving premature infants can wind up with white matter injury. The more extreme the damage, the more extreme the symptoms.
This line of research remains in very early stages. Eventually, the researchers believe it might be possible to up-regulate those critical transcription factors, thus providing a form of protection against hypoxia that could give preterm infants better odds of achieving normal brain development.
The ultimate goal, Nakafuku says, is to develop treatments that can protect and enhance white matter formation while the brain is still developing in the weeks and months after a premature birth, similar to how artificial surfactant supports immature lungs.
“We do not want to wait until the child grows old enough to detect the problem. Then, it would be too late,” Nakafuku says. “We want to find a treatment that can prevent the damage from occurring in the first place.”
