Messy children make better learners

Attention, parents: The messier your child gets while playing with food in the high chair, the more he or she is learning.

Researchers at the University of Iowa studied how 16-month-old children learn words for nonsolid objects, from oatmeal to glue. Previous research has shown that toddlers learn more readily about solid objects because they can easily identify them due to their unchanging size and shape. But oozy, gooey, runny stuff? Not so much.

New research shows that changes if you put toddlers in a setting they know well. In those instances, word learning increases, because children at that age are “used to seeing nonsolid things in this context, when they’re eating,” says Larissa Samuelson, associate professor in psychology at the UI who has worked for years on how children learn to associate words with objects. “And, if you expose them to these things when they’re in a highchair, they do better. They’re familiar with the setting and that helps them remember and use what they already know about nonsolids.”

In a paper published in the journal Developmental Science, Samuelson and her team at the UI tested their idea by exposing 16-month-olds to 14 nonsolid objects, mostly food and drinks such as applesauce, pudding, juice, and soup. They presented the items and gave them made-up words, such as “dax” or “kiv.” A minute later, they asked the children to identify the same food in different sizes or shapes. The task required the youngsters to go beyond relying simply on shape and size and to explore what the substances were made of to make the correct identification and word choice.

Not surprisingly, many children gleefully dove into this task by poking, prodding, touching, feeling, eating—and yes, throwing—the nonsolids in order to understand what they were and make the correct association with the hypothetical names. The toddlers who interacted the most with the foods—parents, interpret as you want—were more likely to correctly identify them by their texture and name them, the study determined. For example, imagine you were a 16-month-old gazing at a cup of milk and a cup of glue. How would you tell the difference by simply looking?

“It’s the material that makes many nonsolids,” Samuelson notes, “and how children name them.”

The setting matters, too, it seems. Children in a high chair were more apt to identify and name the food than those in other venues, such as seated at a table, the researchers found.

“It turns out that being in a high chair makes it more likely you’ll get messy, because kids know they can get messy there,” says Samuelson, the senior author on the paper.

The authors say the exercise shows how children’s behavior, environment (or setting), and exploration help them acquire an early vocabulary—learning that is linked to better later cognitive development and functioning.

“It may look like your child is playing in the high chair, throwing things on the ground, and they may be doing that, but they are getting information out of (those actions),” Samuelson contends. “And, it turns out, they can use that information later. That’s what the high chair did. Playing with these foods there actually helped these children in the lab, and they learned the names better.”

“It’s not about words you know, but words you’re going to learn,” Samuelson adds.

Kids whose bond with mother was disrupted early in life show changes in brain

Children who experience profound neglect have been found to be more prone to a behavior known as “indiscriminate friendliness,” characterized by an inappropriate willingness to approach adults, including strangers.

UCLA researchers are now reporting some of the first evidence from human studies suggesting that this behavior is rooted in brain adaptations associated with early-life experiences. The findings appear in the Dec. 1 issue of the peer-reviewed journal Biological Psychiatry.

The UCLA group used functional magnetic resonance imaging (fMRI) to demonstrate that youths who experienced early maternal deprivation — specifically, time in an institution such as an orphanage prior to being adopted — show similar responses to their adoptive mother and to strangers in a brain structure called the amygdala; for children never raised in an institutional setting, the amygdala is far more active in response to the adoptive mother.

This reduced amygdala discrimination in the brain correlated with parental reports of indiscriminate friendliness. The longer the child spent in an institution before being adopted, the greater the effects.

"The early relationship between children and their parents or primary caregivers has implications for their social interaction later in life, and we believe the amygdala is involved in this process," said Aviva Olsavsky, a resident physician in psychiatry at the Semel Institute for Neuroscience and Human Behavior at UCLA and the study’s first author. "Our findings suggest that even for children who have formed attachments to their adoptive parents, this early period of deprivation has led to changes in the brain that were likely adaptations and that may persist over time."

Indiscriminate friendliness is in some sense a misnomer. The behavior is not characterized by a deep friendliness but simply by a lack of reticence that most young children show toward strangers.

"This can be a very frightening behavior for parents," said Nim Tottenham, an associate professor of psychology at UCLA and the study’s senior author. "The stranger anxiety or wariness that young children typically show is a sign that they understand their parents are very special people who are their source of security. That early emotional attachment serves as a bedrock for many of the developmental processes that follow."

Located in the limbic system of the brain, the amygdala is involved in a variety of functions, including detecting the salience of stimuli, and is believed to play an important role in intense relationships and attachments. Studies in rodents have found that the process of forming a maternal bond early in life has powerful effects on amygdala development and attachment-related behaviors. Research has also shown that youths whose early childhood did not include the typical caregiving experience may exhibit a variety of behaviors, including indiscriminate friendliness, but such behavior had not been well characterized at the brain level.

For the study, 67 youths between the ages of 4 and 17 underwent fMRI while they were shown pictures of their adoptive mother and of an unfamiliar female. Approximately half the children had spent time in institutions, ranging from five months to about five-and-a-half years, before being adopted. As part of the study, the parents of the participating children were given a questionnaire designed to gauge the likelihood of their child wandering away with a stranger, as well as how trusting the child was with new adults.

The UCLA researchers found that while the typically raised children exhibited higher amygdala signals for their mothers relative to strangers, the previously institutionalized youths showed amygdala responses to strangers that were similar to those they showed toward their adoptive mothers. Additionally, the children with a history of institutional rearing showed greater amygdala reactivity to strangers than did the typically raised children. Reduced amygdala differentiation was correlated with greater reports of indiscriminate friendliness by the parents.

In order to understand the heterogeneity of the sample, the researchers examined the role of age at adoption. They found that children who had been adopted later displayed the least discrimination on the scans and the greatest degree of indiscriminate behavior.

The study raised several questions: What, if any, effects does early maternal deprivation has on children as they move into adulthood? And do these findings also apply to less severe forms of deprivation, such as neglectful home environments? The researchers are continuing to use fMRI to examine the role of parents in brain development and the contribution of early experiences to mental health outcomes later in life.

A single spray of oxytocin improves brain function in children with autism

A single dose of the hormone oxytocin, delivered via nasal spray, has been shown to enhance brain activity while processing social information in children with autism spectrum disorders, Yale School of Medicine researchers report in a new study published in the Dec. 2 issue of Proceedings of the National Academy of Sciences.

“This is the first study to evaluate the impact of oxytocin on brain function in children with autism spectrum disorders,” said first author Ilanit Gordon, a Yale Child Study Center adjunct assistant professor, whose colleagues on the study included senior author Kevin Pelphrey, the Harris Professor in the Child Study Center, and director of the Center for Translational Developmental Neuroscience at Yale.

Gordon, Pelphrey, and their colleagues conducted a double-blind, placebo-controlled study of 17 children and adolescents with autism spectrum disorders. The participants, between the ages of 8 and 16.5, were randomly given either oxytocin spray or a placebo nasal spray during a task involving social judgments. Oxytocin is naturally occurring hormone produced in the brain and throughout the body.

“We found that brain centers associated with reward and emotion recognition responded more during social tasks when children received oxytocin instead of the placebo,” said Gordon. “Oxytocin temporarily normalized brain regions responsible for the social deficits seen in children with autism.”

Gordon said oxytocin facilitated social attunement, a process that makes the brain regions involved in social behavior and social cognition activate more for social stimuli (such as faces) and activate less for non-social stimuli (such as cars).

“Our results are particularly important considering the urgent need for treatments to target social dysfunction in autism spectrum disorders,” Gordon added.

Brain Connectivity Study Reveals Striking Differences Between Men and Women

A new brain connectivity study from Penn Medicine published today in the Proceedings of National Academy of Sciences found striking differences in the neural wiring of men and women that’s lending credence to some commonly-held beliefs about their behavior.

In one of the largest studies looking at the “connectomes” of the sexes, Ragini Verma, PhD, an associate professor in the department of Radiology at the Perelman School of Medicine at the University of Pennsylvania, and colleagues found greater neural connectivity from front to back and within one hemisphere in males, suggesting their brains are structured to facilitate connectivity between perception and coordinated action. In contrast, in females, the wiring goes between the left and right hemispheres, suggesting that they facilitate communication between the analytical and intuition.

“These maps show us a stark difference—and complementarity—in the architecture of the human brain that helps provide a potential neural basis as to why men excel at certain tasks, and women at others,” said Verma.

For instance, on average, men are more likely better at learning and performing a single task at hand, like cycling or navigating directions, whereas women have superior memory and social cognition skills, making them more equipped for multitasking and creating solutions that work for a group. They have a mentalistic approach, so to speak.

Past studies have shown sex differences in the brain, but the neural wiring connecting regions across the whole brain that have been tied to such cognitive skills has never been fully shown in a large population.

In the study, Verma and colleagues, including co-authors Ruben C. Gur, PhD, a professor of psychology in the department of Psychiatry, and Raquel E. Gur, MD, PhD, professor of Psychiatry, Neurology and Radiology, investigated the gender-specific differences in brain connectivity during the course of development in 949 individuals (521 females and 428 males) aged 8 to 22 years using diffusion tensor imaging (DTI). DTI is water-based imaging technique that can trace and highlight the fiber  pathways connecting the different regions of the brain, laying the foundation for a structural connectome or network of the whole brain.

This sample of youths was studied as part of the Philadelphia Neurodevelopmental Cohort, a National Institute of Mental Health-funded collaboration between the University of Pennsylvania Brain Behavior Laboratory and the Center for Applied Genomics at the Children’s Hospital of Philadelphia. 

The brain is a roadmap of neural pathways linking many networks that help us process information and react accordingly, with behavior controlled by several of these sub-networks working in conjunction. 

In the study, the researchers found that females displayed greater connectivity in the supratentorial region, which contains the cerebrum, the largest part of the brain, between the left and right hemispheres. Males, on the other hand, displayed greater connectivity within each hemisphere. 

By contrast, the opposite prevailed in the cerebellum, the part of the brain that plays a major role in motor control, where males displayed greater inter-hemispheric connectivity and females displayed greater intra-hemispheric connectivity. 

These connections likely give men an efficient system for coordinated action, where the cerebellum and cortex participate in bridging between perceptual experiences in the back of the brain, and action, in the front of the brain, according to the authors. The female connections likely facilitate integration of the analytic and sequential processing modes of the left hemisphere with the spatial, intuitive information processing modes of the right side.

The authors observed only a few gender differences in the connectivity in children younger than 13 years, but the differences were more pronounced in adolescents aged 14 to 17 years and young adults older than 17.

The findings were also consistent with a Penn behavior study, of which this imaging study was a subset of, that demonstrated pronounced sexual differences.  Females outperformed males on attention, word and face memory, and social cognition tests. Males performed better on spatial processing and sensorimotor speed. Those differences were most pronounced in the 12 to 14 age range.

“It’s quite striking how complementary the brains of women and men really are,” said Dr. Ruben Gur.  “Detailed connectome maps of the brain will not only help us better understand the differences between how men and women think, but it will also give us more insight into the roots of neurological disorders, which are often sex related.”

Next steps are to quantify how an individual’s neural connections are different from the population; identify which neural connections are gender specific and common in both; and to see if findings from functional magnetic resonance imaging (fMRI) studies fall in line with the connectome data.

Mapping the entire brain with new and improved Brainbow II technology

Among the many great talks at the recent annual meeting of the Society for Neuroscience were three special lectures given sequentially during the evenings. The first described how we might translate the known circuit diagram of the worm, and the range of neural activities it supports, into it’s play in a 2D world. The second followed with how we might trace the trickle of information from the larger 3D world, through the more complex theater of the fly brain, and back out again. The third, and most gripping story in the trilogy, was Jeff Lichtman’s talk about using his new technology—known as Brainbow II— to turn the wild synaptic jungle into a tame and completely taxonomized arboretum which we can browse at our leisure.

A movie of a millimeter-sized worm learning to recognize and wriggle free from a mini-lariat may not be the critics choice. However, considering that the critical neurons and synapses involved in this particular behavior can now be genetically isolated, and watched in detail, many neurobiologists are fairly excited. We still don’t have whole-brain electrical activity maps for the 302 neurons (and 50 glial cells) in this creature, or even high resolution calcium clips of these cells—but that may not be required. Many neurons do not bother to use discrete spikes when they are only sending signals across short distances, and sometimes they don’t even bother to build axons.

In this case, if we want to understand how the worm acquires the lariat escape trick, perhaps we might instead just watch its mitochondria as their host neurons stir in seeming alarm. Indeed if we were to watch nothing but mitochondria, most of what we might learn about a given neuron through the use of a whole host of other imaging technologies, is already contained within their dynamics. One could probably infer not just the membraneous outlines of a neuron by watching the limits of mitochondrial excursions, but also infer the changes in the shape of the individual neurites. Further in this vein, we also now appreciate that mitochondria don’t just respond to the calcium flows mentioned above, they are in fact calcium-controlling organelles by trade.

One thing that we learned from Brainbow I, which was further highlighted with the expanded palette of Brainbow II, is that labeling everything can be as bad as labeling nothing at all. Part of Brainbow II’s feature set, is more control for the selective labeling of synapses from different kinds of interneurons, and also the processes of glial cells. In order to reap the benefits of Brainbow II technology and create detailed computer reconstructed images of these cells, Lichtman’s group had to build high speed brain slicing and processing instruments, as well as high power electron microscopes to create the images.

Lichtman reported that together with Zeiss, a new high-throughput 61-beam scanning electron microscope is currently under development. This massive device does not look like something that could just be slid into an elevator and sent to a fourth-floor lab. I asked @zeiss_optics about pricing and availability on this behemoth, along with focused ion beam attachment, and they said that they are offering a nice rebate on orders of two or more. Even still, the result of many months of protected effort has thus far only yielded the structure of just a small piece of brain.

But what a structure it is. The crowning achievement, shown at the convention was distilled into a cylindrical EM reconstruction of a piece of mouse brain smaller than a grain of sand. In the center of this volume was the proximal shaft of a pyramidal cell apical dendrite surrounded by all manner of synaptic elements. If you were ever confounded by the famous 4-color mapping thereom, then Brainbow-style synapse tracing may not be for you. In this volume there are around 680 nerve fibers that can be resolved, together with 774 synapses. A key finding by Lichtman is that mere contact alone, does not a synapse make. By tracking perfectly resolved synaptic vesicles, he was able to show that of every ten plausible synaptic options, perhaps only one or two neighboring profiles turned out to be an actual synapse.

The final point Lichtman made is that now that it is possible to extract the complete membrane topology, including organelles, of an arbitrary region of the brain, formerly unimagined questions might be posed and answered with the click of a mouse. The question he alluded to is the one I raised above, namely, how are the mitochondria distributed, and what are they doing? While this is in large part, a question for live, video microscopy, much can be learned about the state of a given synapse just prior to being fixed by it’s mitochondria. Similarly, much might be also be inferred about the next plausible state of the neural geometry under consideration, provided one knows what to look for.

The one finding here that Lichtman mentioned was that axons have relatively small mitochondria compared to those in the body and dendrites. That may be a seemingly sterile finding when considered alone. But that same afternoon at the conference, there was an exciting talk describing how certain mitochondria are extravasated, or expelled, by axons in the visual system. They are then taken up by astrocytes for processing—a rather surprising finding. It has been known that in some organs mitochondria can be exchanged between cells, much to the benefit of the recipient cell, though for neurons, this is the first report of such phenomena. I did look later at the literature, and this fractionation of mitochondria by size in the polar elements of neurons has actually been known for some time, leading one to guess what other potential findings the Lichtman group might actually possess.

What Lichtman presented is really not a connectome, or a “netlist” of circuit board connections, per say. To date, nobody has even put force a reasonable transform to derive a connectome from a given 3D membrane mesh topology, or even of what use it would be if we had one. Meanwhile, attempts to model the fissions, fusions, and general ramblings of the mitochondria as a function of their genetic makeup, and the positions they take up inside the cell, have already begun. If genetically questionable mitochondria with expired membrane potentials tend to be degraded by fusion with lysosomes near the nucleus, we might ask, can they be blamed for pumping out axons and transporting themselves as far away as possible—even out of the cell entirely?

Clearly, anthropomorphizing mere motile sacks of DNA and enzymes is not the only tool we have to hack the brain. But insofar as the brain is just a complex system of microscopic tubes, it may make sense to take a closer look at the creatures that build and maintain them. In this light, the science of connectomes becomes the science of mitochondria, the mitochondriome perhaps. As much as we can better understand the collective activity of the brain through the remembrance of neurons as once-feral protists now encased in the skull, our understanding of neurons is enhanced by recalling their mitochondria as once-free bacteria now largely trapped in them.

Mice can ‘warn’ sons, grandsons of dangers via sperm

Lab mice trained to fear a particular smell can transfer the impulse to their unborn sons and grandsons through a mechanism in their sperm, a study reveals.

The research claims to provide evidence for the concept of animals “inheriting” a memory of their ancestors’ traumas, and responding as if they had lived the events themselves.

It is the latest find in the study of epigenetics, in which environmental factors are said to cause genes to start behaving differently without any change to their underlying DNA encoding.

"Knowing how ancestral experiences influence descendant generations will allow us to understand more about the development of neuropsychiatric disorders that have a transgenerational basis," says study co-author Brian Dias of the Emory University School of Medicine in Atlanta, Georgia.

And it may one day lead to therapies that can soften the memory “inheritance”.

For the study, Dias and co-author Kerry Ressler trained mice, using foot shocks, to fear an odour that resembles cherry blossoms.

Later, they tested the extent to which the animals’ offspring startled when exposed to the same smell. The younger generation had not even been conceived when their fathers underwent the training, and had never smelt the odour before the experiment.

The offspring of trained mice were “able to detect and respond to far less amounts of odour… suggesting they are more sensitive” to it, says Ressler co-author of the study published in the journal Nature Neuroscience.

They did not react the same way to other odours, and compared to the offspring of non-trained mice, their reaction to the cherry blossom whiff was about 200 percent stronger, he says.

The scientists then looked at a gene (M71) that governs the functioning of an odour receptor in the nose that responds specifically to the cherry blossom smell.

Epigenetic marks

The gene, inherited through the sperm of trained mice, had undergone no change to its DNA encoding, the team found.

But the gene did carry epigenetic marks that could alter its behaviour and cause it to be “expressed more” in descendants, says Dias.

This in turn caused a physical change in the brains of the trained mice, their sons and grandsons, who all had a larger glomerulus - a section in the olfactory (smell) unit of the brain.

"This happens because there are more M71 neurons in the nose sending more axons" into the brain, says Dias.

Similar changes in the brain were seen even in offspring conceived with artificial insemination from the sperm of cherry blossom-fearing fathers.

The sons of trained mouse fathers also had the altered gene expression in their sperm.

"Such information transfer would be an efficient way for parents to ‘inform’ their offspring about the importance of specific environmental features that they are likely to encounter in their future environments," says Ressler.

Happening in humans?

Commenting on the findings, British geneticist Marcus Pembrey says they could be useful in the study of phobias, anxiety and post-traumatic stress disorders.

"It is high time public health researchers took human transgenerational responses seriously," he said in a statement issued by the Science Media Centre.

"I suspect we will not understand the rise in neuropsychiatric disorders or obesity, diabetes and metabolic disruptions generally without taking a multigenerational approach."

Wolf Reik, epigenetics head at the Babraham Institute in England, says such results were “encouraging” as they suggested that transgenerational inheritance does exist, but cannot yet be extrapolated to humans.

The pauses that refresh the memory

Certain symptoms of schizophrenia may arise from uncontrolled activation of neurons that help to build memories during periods of rest

Sufferers of schizophrenia experience a broad gamut of symptoms, including hallucinations and delusions as well as disorientation and problems with learning and memory. This diversity of neurological deficits has made schizophrenia extremely difficult for scientists to understand, thwarting the development of effective treatments. A research team led by Susumu Tonegawa from the RIKEN–MIT Center for Neural Circuit Genetics has now revealed disruptions in the activity of particular clusters of neurons that might account for certain core symptoms of this disorder. 

Tonegawa’s laboratory previously found that mice lacking the protein calcineurin in certain regions of the brain exhibit many behavioral deficits that are characteristic of schizophrenia. In their most recent study, the researchers sought out physiological alterations at the single-cell or circuit level that could connect the absence of the calcineurin protein in the brain with these behavioral impairments. 

Their study focused on the hippocampus, a region of the brain associated with memory and spatial learning. Within the hippocampus, specialized ‘place cells’ switch on and off as an animal explores its environment. During subsequent periods of wakeful rest, these place cells continue to fire in patterns that essentially ‘replay’ recent wanderings, allowing the brain to build memories based on these experiences. The researchers used precisely positioned electrodes to measure differences in brain activity in these cells for normal mice and the calcineurin-deficient mouse model of schizophrenia.

Remarkably, essentially identical place-cell activity patterns were observed for both sets of mice during active exploration. Once the animals were at rest, however, the calcineurin-deficient mice displayed a dramatic increase in place-cell activity. In the normal hippocampus, the resting replay process depended on sequential activity from place cells corresponding to specific, real-world spatial coordinates. In contrast, this correlation was all but lost in the calcineurin-deficient mice. Instead, these neurons often seemed to fire indiscriminately, creating high levels of ‘noise’ that overwhelmed actual location information and thwarted memory formation. 

“Our study provides the first potential evidence of disorganized thinking processes in a schizophrenia model at the single-cell and circuit level,” says Junghyup Suh, a member of Tonegawa’s research team. These findings fit with an emerging model that suggests that schizophrenic symptoms may arise from excess activation of brain regions within a ‘default mode network’—which includes the hippocampus—during wakeful rest. “Neurobiological approaches that can calm down the default mode network may therefore open up new avenues to alleviating symptoms or curing this mental disorder,” says Suh.