Neural development

Brain Researchers Discover How Retinal Neurons Claim the Best Connections

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Discovery may shed light on brain disease, development of regenerative therapies

Real estate agents emphasize location, location, and – once more for good measure – location. It’s the same in a developing brain, where billions of neurons vie for premium property to make connections. Neurons that stake out early claims often land the best value, even if they don’t develop the property until later.

Scientists at the Virginia Tech Carilion Research Institute and the University of Louisville have discovered that during neurodevelopment, neurons from the brain’s cerebral cortex extend axons to the edge of the part of the brain dedicated to processing visual signals – but then stop. Instead of immediately making connections, the cortical neurons wait for two weeks while neurons from the retina connect to the brain.

Now, in a study to be published in the Nov. 14 issue of the journal Cell Reports, the scientists have discovered how. The retinal neurons stop their cortical cousins from grabbing prime real estate by controlling the abundance of a protein called aggrecan.

Understanding how aggrecan controls the formation of brain circuits could help scientists understand how to repair the injured brain or spinal cord after injury or disease.

“Usually when neuroscientists talk about repairing injured brains, they’re thinking about putting neurons, axons, and synapses back in the right place,” said Michael Fox, an associate professor at the Virginia Tech Carilion Research Institute and lead author of the study. “It may be that the most important synapses – the ones that drive excitation – need to get there first. By stalling out the other neurons, they can get the best spots. This study shows that when we think about repairing damaged neural networks, we need to consider more than just where connections need to be made. We also need to think about the timing of reinnervation.”

The researchers genetically removed the retinal neurons, which allowed the cortical axons to move into the brain earlier than they normally would.

“We were interested in what environmental molecular cues allow the retinal neurons to control the growth of cortical neurons,” said Fox, who is also an associate professor of biological sciences in Virginia Tech’s College of Science. “After years of screening potential mechanisms, we found aggrecan.”

Aggrecan is a protein that has been well studied in cartilage, bones, and the spinal cord, where it is abundant after injuries. According to Fox, aggrecan may be able to isolate damaged areas of the spinal cord to stop inflammation and prevent further destruction. The downside, however, is that aggrecan inhibits axonal growth, which prevents further repair from taking place.

“Axons see this environment and either stop growing or turn around and grow in the opposite direction,” said Fox.

Although it is less studied in the developing brain, aggrecan appears in abundance there. In the new study, the researchers found that retinal neurons control aggrecan in a region that receives ascending signals from retinal cells as well as descending signals from the cerebral cortex.

Once the retinal neurons have made connections, they cause the release of enzymes that break down the aggrecan, allowing cortical neurons to move in.

Fox said it is interesting that the retinal axons can grow in this region of the developing brain, despite the high levels of aggrecan. He suspects that it may be because retinal neurons express a receptor – integrin – that cortical axons do not express.

The study, “A molecular mechanism regulating the timing of corticogeniculate innervation,” is by Fox, Jianmin Su, a research assistant professor, and Carl Levy, an undergraduate from Suffolk, Va., all with the Virginia Tech Carilion Research Institute; graduate student Justin Brooks and undergraduate Jessica Wang from Virginia Commonwealth University; and Tania Seabrook, a postdoctoral associate, and William Guido, a professor and the chair of the Department of Anatomical Sciences and Neurobiology, both with the University of Louisville School of Medicine.

Childhood Poverty Linked to Poor Brain Development.

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Exposure to poverty in early childhood negatively affects brain development, but good-quality caregiving may help offset this effect, new research suggests.

A longitudinal imaging study shows that young children exposed to poverty have smaller white and cortical gray matter as well as hippocampal and amygdala volumes, as measured during school age and early adolescence.

“These findings extend the substantial body of behavioral data demonstrating the deleterious effects of poverty on child developmental outcomes into the neurodevelopmental domain and are consistent with prior results,” the investigators, with lead author Joan Luby, MD, Washington University School of Medicine in St. Louis, Missouri, write.

However, the investigators also found that the effects of poverty on hippocampal volume were influenced by caregiving and stressful life events.

The study was published online October 28 in JAMA Pediatrics.

Powerful Risk Factor

Poverty is one of the most powerful risk factors for poor developmental outcomes; a large body of research shows that children exposed to poverty have poorer cognitive outcomes and school performance and are at greater risk for antisocial behaviors and mental disorders.

However, the researchers note, there are few neurobiological data in humans to inform the mechanism of these relationships.

“This represents a critical gap in the literature and an urgent national and global public health problem based on statistics that more than 1 in 5 children are now living below the poverty line in the United States alone,” the authors write.

To examine the effects of poverty on childhood brain development and to understand what factors might mediate its negative impact, the researchers used magnetic resonance imaging (MRI) to examine total white and cortical gray matter as well as hippocampal and amygdala volumes in 145 children aged 6 to 12 years who had been followed since preschool.

The researchers looked at caregiver support/hostility, measured observationally during the preschool period, and stressful life events, measured prospectively.

The children underwent annual behavioral assessments for 3 to 6 years prior to MRI scanning and were annually assessed for 5 to 10 years following brain imaging.

Household poverty was measured using the federal income-to-needs ratio.

“Toxic” Effect

The researchers found that poverty was associated with lower hippocampal volumes, but they also found that caregiving behaviors and stressful life events could fully mediate this negative effect.

“The finding that the effects of poverty on hippocampal development are mediated through caregiving and stressful life events further underscores the importance of high-quality early childhood caregiving, a task that can be achieved through parenting education and support, as well as through preschool programs that provide high-quality supplementary caregiving and safe haven to vulnerable young children,” the investigators write.

In an accompanying editorial, Charles A. Nelson, PhD, Boston Children’s Hospital and Harvard Medical School, in Massachusetts, notes that the findings show that early experience “weaves its way into the neural and biological infrastructure of the child in such a way as to impact development trajectories and outcomes.”

“Exposure to early life adversity should be considered no less toxic than exposure to lead, alcohol or cocaine, and, as such it merits similar attention from health authorities,” Dr. Nelson writes.

Study Shows How Infections in Newborns are Linked to Later Behavior Problems

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In animal study, inflammation stops cells from accessing iron needed for brain development

Researchers exploring the link between newborn infections and later behavior and movement problems have found that inflammation in the brain keeps cells from accessing iron that they need to perform a critical role in brain development.

Specific cells in the brain need iron to produce the white matter that ensures efficient communication among cells in the central nervous system. White matter refers to white-colored bundles of myelin, a protective coating on the axons that project from the main body of a brain cell.

The scientists induced a mild E. coli infection in 3-day-old mice. This caused a transient inflammatory response in their brains that was resolved within 72 hours. This brain inflammation, though fleeting, interfered with storage and release of iron, temporarily resulting in reduced iron availability in the brain. When the iron was needed most, it was unavailable, researchers say.

What’s important is that the timing of the inflammation during brain development switches the brain’s gears from development to trying to deal with inflammation,” said Jonathan Godbout, associate professor of neuroscience at The Ohio State University and senior author of the study. “The consequence of that is this abnormal iron storage by neurons that limits access of iron to the rest of the brain.”

The cells that need iron during this critical period of development are called oligodendrocytes, which produce myelin and wrap it around axons. In the current study, neonatal infection caused neurons to increase their storage of iron, which deprived iron from oligodendrocytes.

In other mice, the scientists confirmed that neonatal E. coli infection was associated with motor coordination problems and hyperactivity two months later – the equivalent to young adulthood in humans. The brains of these same mice contained lower levels of myelin and fewer oligodendrocytes, suggesting that brief reductions in brain-iron availability during early development have long-lasting effects on brain myelination.

The timing of infection in newborn mice generally coincides with the late stages of the third trimester of pregnancy in humans. The myelination process begins during fetal development and continues after birth.

Though other researchers have observed links between newborn infections and effects on myelin and behavior, scientists had not figured out why those associations exist. Godbout’s group focuses on understanding how immune system activation can trigger unexpected interactions between the central nervous system and other parts of the body.

“We’re not the first to show early inflammatory events can change the brain and behavior, but we’re the first to propose a detailed mechanism connecting neonatal inflammation to physiological changes in the central nervous system,” said Daniel McKim, a lead author on the paper and a student in Ohio State’s Neuroscience Graduate Studies Program.

The neonatal infection caused several changes in brain physiology. For example, infected mice had increased inflammatory markers, altered neuronal iron storage, and reduced oligodendrocytes and myelin in their brains. Importantly, the impairments in brain myelination corresponded with behavioral and motor impairments two months after infection.

Though it’s unknown if these movement problems would last a lifetime, McKim noted that “since these impairments lasted into what would be young adulthood in humans, it seems likely to be relatively permanent.”

The reduced myelination linked to movement and behavior issues in this study has also been associated with schizophrenia and autism spectrum disorders in previous work by other scientists, said Godbout, also an investigator in Ohio State’s Institute for Behavioral Medicine Research (IBMR).

 

This current study did not identify potential interventions to prevent these effects of early-life infection. Godbout and colleagues theorize that maternal nutrition – a diet high in antioxidants, for example – might help lower the inflammation in the brain that follows a neonatal infection.

“The prenatal and neonatal period is such an active time of development,” Godbout said. “That’s really the key – these inflammatory challenges during critical points in development seem to have profound effects. We might just want to think more about that clinically.”