Stories about: brain development

Mapping mosaicism: Tracing subtle mutations in our brains

brain genetic mosaicism
(Erik Jacobsen, Threestory Studio. Used with permission.)

DNA sequences were once thought to be the same in every cell, but the story is now known to be more complicated than that. The brain is a case in point: Mutations can arise at different times in brain development and affect only a percentage of neurons, forming a mosaic pattern.

Now, thanks to new technology described last week in Neuron, these subtle “somatic” brain mutations can be mapped spatially across the brain and even have their ancestry traced.

Like my family, who lived in Eastern Europe, migrated to lower Manhattan and branched off to Boston, California and elsewhere, brain mutations can be followed from the original mutant cells as they divide and migrate to their various brain destinations, carrying their altered DNA with them.

“Some mutations may occur on one side of the brain and not the other,” says Christopher Walsh, MD, PhD, chief of Genetics and Genomics at Boston Children’s Hospital and co-senior author on the paper. “Some may be ‘clumped,’ affecting just one gyrus [fold] of the brain, disrupting just a little part of the cortex at a time.”

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Five people, one mutation and the evolution of human language

The Sylvian fissure (BodyParts3D/Wikimedia Commons)

Five people with an unusual pattern of brain folds have afforded a glimpse into how the human brain may have evolved its language capabilities.

How the human brain develops its hills and valleys—expanding its surface area and computational capacity—has been difficult to study. Mice, the staple of scientific research, lack folds in their brains.

Christopher Walsh, MD, PhD, head of the Division of Genetics and Genomics at Boston Children’s Hospital, runs a brain development and genetics clinic and has spent 25 years studying people in whom the brain formation process goes awry. Some brains are too small (microcephaly). Some have folds, or gyri, that are too broad and thick (pachygyria). Some are smooth, lacking folds altogether (lissencephaly). And some have an abnormally large number of small, thin folds—known as polymicrogyria.

In 2005, studying people with polymicrogyria, Walsh and colleagues identified a mutation in a gene known as GPR56, a clue that this gene helps drive the formation of folds in the cortex of the human brain.

In a study published in today’s issue of Science, Walsh and his colleagues focused on five people whose brain MRIs showed polymicrogyria, but just in one location—near a large, deep furrow known as the Sylvian fissure, which includes the brain’s primary language area.

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Neuronal migration and a well-configured cortex: A neuroscientist looks back

Normal brain and Double Cortex-Courtesy Christopher Walsh(Above: In double cortex syndrome, causing epilepsy and mental retardation, an extra cortex forms just beneath the cerebral cortex [right]. The causative DCX mutation interferes with migration of neurons during the cortex’s early development. Courtesy Walsh Lab)

The journal Neuron, celebrating its 25th anniversary, recently picked one influential neuroscience paper from each year of the publication. In this two-part series, we feature the two Boston Children’s Hospital’s scientists who made the cut. The Q&A below is adapted with kind permission from Cell Press. (See part 1)

Key to well-tuned brain function is the migration of neurons to precise locations as the brain develops. The long journey begins deep inside the brain and ends in the outer cerebral cortex—where our highest cognitive functions lie. Christopher Walsh, MD, PhD, has shown that several genetic mutations causing neurodevelopmental disorders disrupt this neuronal migration, landing neurons in the wrong places. Each gene governs a specific sub-task: one kicks off the migration process; others stop migration when neurons have arrived in the right location.

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Microglia’s role in brain development: A neuroscientist looks back

The journal Neuron, celebrating its 25th anniversary, recently picked one influential neuroscience paper from each year of the publication. In this two-part series, we feature the two Boston Children’s Hospital’s scientists who made the cut. The Q&A below is adapted with kind permission from Cell Press.

Microglial cell with synapses
CAUGHT IN THE ACT: This microglial cell is from the lateral geniculate nucleus, which receives visual input from the eyes. The red and blue are synapses that it has engulfed. (Blue synapses represent inputs from the same-side eye; red, the opposite-side eye.)

In 2012, Beth Stevens, PhD, and colleagues provided a new understanding of how glial cells shape healthy brain development. Glia were once thought to be merely nerve “glue” (the meaning of “glia” from the Greek), serving only to protect and support neurons. “In the field of neuroscience, glia have often been ignored,” Stevens told Vector last year.

No longer. Stevens’s 2012 paper documented that microglia—glial cells best known for their immune function—are no passive bystanders. They get rid of excess connections, or synapses, in the developing brain the same way they’d dispatch an invading pathogen—by eating them.

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Mapping the wiring of the developing brain in 3D

Ed. note: Last week we wrote about Jurriaan Peters, MD’s brain network analysis in children with autism. In the second of our two part series on brain mapping, we talk about ways of mapping the brain’s physical wiring.

(AMagill/Flickr)

At the most basic level, the brain is a collection of wires, albeit a really complex one.

But how during development do nerve fibers thread their way through the growing brain and make the right connections?

The answer to that question could reveal more about the nature of conditions like autism spectrum disorders—which, as we reported about a year and a half ago, seem to have their roots in structurally altered brain pathways.

“We know very little about what’s happening in the developing brain in three dimensions,” says Emi Takahashi, PhD, a researcher in the Fetal-Neonatal Neuroimaging & Developmental Science Center (FNNDSC) at Boston Children’s Hospital. “With histology techniques, we can achieve a two-dimensional view over small areas, but it’s hard to know which fiber bundles are growing in which ways during different stages of development in the whole brain.”

But new MRI-based technologies are quickly closing that knowledge gap, giving us our first high-resolution peek into how the developing brain wires itself up.

Using something called high angular resolution diffusion imaging (HARDI) MRI, Takahashi and her colleagues (including neuroradiologist and FNNDSC director P. Ellen Grant, MD) can trace the three-dimensional pathways within the growing brain via stunning images like these:

Courtesy Cerebral Cortex (Takahashi et al., 2012)

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Could “network” analysis of the brain explain autism’s features?

Ed note: The Obama administration is expected to unveil plans for a decade-long Brain Activity Map project next month. This is Part One of a two-part series on brain mapping.

autism
How is information routed in the brains of children with autism? (Image: Jpatokal/Wikimedia Commons)

It’s now pretty well accepted that autism is a disorder of brain connectivity—demonstrated visually with advanced MRI techniques that can track the paths of nerve fibers. Recent exciting work analyzing EEG recordings supports the idea of altered connectivity, while suggesting the possibility of a diagnostic test for autism.

But what’s happening on a functional level? A study published this week zooms out to take a 30,000-foot view, tracking how the brain routes information in children with autism—in much the way airlines and electrical grids are mapped—and assessing the function of the network as a whole.

“What we found may well change the way we look at the brains of autistic children,” says investigator Jurriaan Peters, MD, of the Department of Neurology at Boston Children’s Hospital.

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Your brain on neglect: The evidence

D Sharon Pruitt/Flickr

If there wasn’t enough reason to be concerned about children suffering psychological and physical neglect—by their family, in foster homes, or from war or weather catastrophes—we now have three good lines of evidence that neglect harms a child’s developing brain.

But there’s also hope that some of this harm can be undone if caught in time.

Impaired IQ

The first evidence comes from cognitive studies done in Romania, where the Bucharest Early Intervention Project (BEIP) has transferred some children reared in its infamous orphanages, selected at random, into quality foster care homes. In 2007, Charles Nelson, PhD, and colleagues documented cognitive impairment in institutionalized children, but also showed improvement when children were placed in good foster homes, especially when they were placed before age 2.

Further evidence—brain imaging—comes from a more recent study by Nelson’s colleague Margaret Sheridan, PhD.

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Immune cells “sculpt” brain circuits — by eating excess connections

The above movie shows an immune cell caught in the act of tending the brain—it’s just eaten away unnecessary connections, or synapses, between neurons.

That’s not something these cells, known as microglia, were previously thought to do. As immune cells, it was thought that their job was to rid the body of unwanted pathogens and debris, by engulfing and digesting them.

The involvement of microglia in the brain’s development has started to be recognized only recently. The latest research finds that microglia tune into the brain’s cues, akin to the way they survey their environment for invading microbes, and get rid of excess synapses the same way they’d dispatch these invaders—by eating them.

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Innovation Day at Children’s Hospital Boston: A preview

Valentine's Day is Innovation Day (image: Richard Giles/Flickr)

In a series of 17 short TED-style talks next Tuesday, February 14, clinicians and scientists from Children’s will present new products, processes and technologies to make health care safer, better and less expensive. The event, from 1-5 p.m. Eastern, is sponsored by the Innovation Acceleration Program. It’s now running a wait list, but you can also watch the live stream or track the proceedings on Twitter (#iDay) or via @science4care. Here’s a small sampling of next week’s presenters; for details, read the press release or view the full agenda.

Diagnosing lazy eye when it’s most treatable: in preschoolers

If lazy eye, or amblyopia, is caught early – ideally, before age 5 – it’s easily treated by patching the “good” eye, forcing the child to use and strengthen the weaker eye. But if it goes unnoticed, the weak, unused eye can slowly go blind,

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Dodging the long-term cognitive effects of early-life seizures

Seizures seem to strengthen and “lock in” synapses too soon, leaving no room for development. (Image: Ice synapses, Joe Flintham/Flickr)

It’s well known that babies who have seizures soon after birth have roughly a 50-50 chance of developing long-term intellectual and memory deficits and cognitive disorders like autism. But until now, it wasn’t understood why these deficits occur, much less how to prevent them from happening.

In the December 14 Journal of Neuroscience, researchers at Children’s Hospital Boston, led by neurologist-neuroscientist Frances Jensen, detail in a rat model how early-life seizures affect brain development at the cellular and molecular level. But more to the point, they show that it might be possible to ward off these effects with drug treatment soon after the seizure – using a drug called NBQX or similar drugs that are already approved by the FDA.

Jenson was particularly interested in what seizures do to synapses, the connections between neurons that are rapidly developing in the infant brain.

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