New brain connections form in clusters during learning

Researchers track structural changes during formation of new memories

SANTA CRUZ, CA--New connections between brain cells emerge in clusters in the brain as animals learn to perform a new task, according to a study published in Nature on February 19 (advance online publication). Led by researchers at the University of California, Santa Cruz, the study reveals details of how brain circuits are rewired during the formation of new motor memories ceus for social workers

The researchers studied mice as they learned new behaviors, such as reaching through a slot to get a seed. They observed changes in the motor cortex, the brain layer that controls muscle movements, during the learning process. Specifically, they followed the growth of new "dendritic spines," structures that form the connections (synapses) between nerve cells.

"For the first time we are able to observe the spatial distribution of new synapses related to the encoding of memory," said Yi Zuo, assistant professor of molecular, cell and developmental biology at UC Santa Cruz and corresponding author of the paper.

In a previous study, Zuo and others documented the rapid growth of new dendritic spines on pyramidal neurons in the motor cortex during the learning process. These spines form synapses where the pyramidal neurons receive input from other brain regions involved in motor memories and muscle movements. In the new study, first author Min Fu, a postdoctoral researcher in Zuo's lab, analyzed the spatial distribution of the newly formed synapses.

Initial results of the spatial analysis showed that one third of the newly formed synapses were located next to another new synapse. These clustered synapses tended to form over the course of a few days during the learning period, when the mouse was repeatedly performing the new behavior. Compared to non-clustered counterparts, the clustered synapses were more likely to persist through the learning sessions and after training stopped.

In addition, the researchers found that after formation of the second spine in a cluster, the first spine grew larger. The size of the spine head correlates with the strength of the synapse. "We found that formation of a second connection is correlated with a strengthening of the first connection, which suggests that they are likely to be involved in the same circuitry," Zuo said. "The clustering of synapses may serve to magnify the strength of the connections."

Another part of the study also supported the idea that the clustered synapses are involved in neural circuits specific to the task being learned. The researchers studied mice trained first in one task and then in a different task. Instead of grabbing a seed, the mice had to learn how to handle a piece of capellini pasta. Both tasks induced the formation of clustered spines, but spines formed during the learning of different tasks did not cluster together.

The researchers also looked at mice that were challenged with new motor tasks every day, but did not repeat the same task over and over like the ones trained in seed-grabbing or capellini-handling. These mice also grew lots of new dendritic spines, but few of the new spines were clustered.

"Repetitive activation of the same cortical circuit is really important in learning a new task," Zuo said. "But what is the optimal frequency of repetition? Ultimately, by studying the relationship between synapse formation and learning, we want to find out the best way to induce new memories."

The study used mice that had been genetically altered to make a fluorescent protein within certain neurons in the motor cortex. The researchers used a special microscopy technique (two-photon microscopy) to obtain images of those neurons near the surface of the brain. The noninvasive imaging technique enabled them to view changes in individual brain cells of the mice before, during, and after learning a new behavior.


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In addition to Zuo and first author Min Fu, the coauthors of the paper include UCSC graduate student Xinzhu Yu and Stanford University biologist Ju Lu. This research was supported by grants from the Dana Foundation and the National Institute of Mental Health.

Mom's Love Good for Child's Brain

School-age children whose mothers nurtured them early in life have brains with a larger hippocampus, a key structure important to learning, memory and response to stress LCSW Continuing Education

The new research, by child psychiatrists and neuroscientists at Washington University School of Medicine in St. Louis, is the first to show that changes in this critical region of children's brain anatomy are linked to a mother's nurturing.

Their research is published online in the Proceedings of the National Academy of Sciences Early Edition.

"This study validates something that seems to be intuitive, which is just how important nurturing parents are to creating adaptive human beings," says first author Joan L. Luby, MD. "I think the public health implications suggest that we should pay more attention to parents' nurturing, and we should do what we can as a society to foster these skills because clearly nurturing has a very, very big impact on later development."

The brain-imaging study involved children ages 7 to 10 who had participated in an earlier study of preschool depression that Luby and her colleagues began about a decade ago. That study involved children, ages 3 to 6, who had symptoms of depression, other psychiatric disorders or were mentally healthy with no known psychiatric problems.

As part of the initial study, the children were closely observed and videotaped interacting with a parent, almost always a mother, as the parent was completing a required task, and the child was asked to wait to open an attractive gift. How much or how little the parent was able to support and nurture the child in this stressful circumstance — which was designed to approximate the stresses of daily parenting — was evaluated by raters who knew nothing about the child's health or the parent's temperament.

"It's very objective," says Luby, professor of child psychiatry. "Whether a parent was considered a nurturer was not based on that parent's own self-assessment. Rather, it was based on their behavior and the extent to which they nurtured their child under these challenging conditions."

The study didn't observe parents and children in their homes or repeat stressful exercises, but other studies of child development have used similar methods as valid measurements of whether parents tend to be nurturers when they interact with their children.

For the current study, the researchers conducted brain scans on 92 of the children who had had symptoms of depression or were mentally healthy when they were studied as preschoolers. The imaging revealed that children without depression who had been nurtured had a hippocampus almost 10 percent larger that children whose mothers were not as nurturing.

"For years studies have underscored the importance of an early, nurturing environment for good, healthy outcomes for children," Luby says. "But most of those studies have looked at psychosocial factors or school performance. This study, to my knowledge, is the first that actually shows an anatomical change in the brain, which really provides validation for the very large body of early childhood development literature that had been highlighting the importance of early parenting and nurturing. Having a hippocampus that's almost 10 percent larger just provides concrete evidence of nurturing's powerful effect."

Luby says the smaller volumes in depressed children might be expected because studies in adults have shown the same results. What did surprise her was that nurturing made such a big difference in mentally healthy children.

"We found a very strong relationship between maternal nurturing and the size of the hippocampus in the healthy children," she says.

Although 95 percent of the parents whose nurturing skills were evaluated during the earlier study were biological mothers, the researchers say that the effects of nurturing on the brain are likely to be the same, for any primary caregiver — whether they are fathers, grandparents or adoptive parents.

The fact that the researchers found a larger hippocampus in the healthy children who were nurtured is striking, Luby says, because the hippocampus is such an important brain structure.

When the body faces stresses, the brain activates the autonomic nervous system, an involuntary system of nerves that controls the release of stress hormones. Those hormones help us cope with stress by increasing the heart rate and helping the body adapt. The hippocampus is the main brain structure involved in that response. It's also key in learning and memory, and larger volumes would suggest a link to improved performance in school, among other things.

Past animal studies have indicated that a nurturing mother can influence brain development, and many studies in human children have identified improvements in school performance and healthier development in children raised in a nurturing environment. But until now, there has not been solid evidence linking a nurturing parent to changes in brain anatomy in children.

"Studies in rats have shown that maternal nurturance, specifically in the form of licking, produces changes in genes that then produce changes in receptors that increase the size of the hippocampus," Luby says. "That phenomenon has been replicated in primates, but it hasn't really been clear whether the same thing happens in humans. Our study suggests a clear link between nurturing and the size of the hippocampus."

She says educators who work with families who have young children may improve school performance and child development by not only teaching parents to work on particular tasks with their children but by showing parents how to work with their children.

"Parents should be taught how to nurture and support their children. Those are very important elements in healthy development," Luby says.

Luby JL, Barch DM, Belden A, Gaffrey MS, Tillman R, Babb C, Nishino T, Suzuki H, Botteron KN. Maternal support in early childhood predicts larger hippocampal volumes at school age. Proceedings of the National Academy of Sciences Early Edition, Jan. 30, 2012. www.pnas.org/cgi/doi/10.1073/pnas.1118003109.

Funding for this research comes from grants awarded by the National Institute of Mental Health of the National Institutes of Health (NIH).

Washington University School of Medicine's 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.

Gene Regulator in Brain’s Executive Hub Tracked Across Lifespan – NIH study

Mental illness suspect genes are among the most environmentally responsive

For the first time, scientists have tracked the activity, across the lifespan, of an environmentally responsive regulatory mechanism that turns genes on and off in the brain’s executive hub. Among key findings of the study by National Institutes of Health scientists: genes implicated in schizophrenia and autism turn out to be members of a select club of genes in which regulatory activity peaks during an environmentally-sensitive critical period in development. The mechanism, called DNA methylation, abruptly switches from off to on within the human brain’s prefrontal cortex during this pivotal transition from fetal to postnatal life. As methylation increases, gene expression slows down after birth.

Epigenetic mechanisms like methylation leave chemical instructions that tell genes what proteins to make – what kind of tissue to produce or what functions to activate. Although not part of our DNA, these instructions are inherited from our parents. But they are also influenced by environmental factors, allowing for change throughout the lifespan.

“Developmental brain disorders may be traceable to altered methylation of genes early in life,” explained Barbara Lipska, Ph.D., a scientist in the NIH’s National Institute of Mental Health (NIMH) and lead author of the study. “For example, genes that code for the enzymes that carry out methylation have been implicated in schizophrenia. In the prenatal brain, these genes help to shape developing circuitry for learning, memory and other executive functions which become disturbed in the disorders. Our study reveals that methylation in a family of these genes changes dramatically during the transition from fetal to postnatal life – and that this process is influenced by methylation itself, as well as genetic variability. Regulation of these genes may be particularly sensitive to environmental influences during this critical early life period.”

Lipska and colleagues report on the ebb and flow of the human prefrontal cortex’s (PFC) epigenome across the lifespan, February 2, 2012, online in the American Journal of Human Genetics.

“This new study reminds us that genetic sequence is only part of the story of development. Epigenetics links nurture and nature, showing us when and where the environment can influence how the genetic sequence is read,” said NIMH director Thomas R. Insel, M.D.

In a companion study published last October, the NIMH researchers traced expression of gene products in the PFC across the lifespan. The current study instead examined methylation at 27,000 sites within PFC genes that regulate such expression. Both studies examined post-mortem brains of non-psychiatrically impaired individuals ranging in age from two weeks after conception to 80 years old CADC I and II Continuing Education

In most cases, when chemicals called methyl groups attach to regulatory regions of genes, they silence them. Usually, the more methylation, the less gene expression. Lipska’s team found that the overall level of PFC methylation is low prenatally when gene expression is highest and then switches direction at birth, increasing as gene expression plummets in early childhood. It then levels off as we grow older. But methylation in some genes shows an opposite trajectory. The study found that methylation is strongly influenced by gender, age and genetic variation.

For example, methylation levels differed between males and females in 85 percent of X chromosome sites examined, which may help to explain sex differences in disorders like autism and schizophrenia.

Different genes – and subsets of genes – methylate at different ages. Some of the suspect genes found to peak in methylation around birth code for enzymes, called methytransferases, that are over-expressed in people with schizophrenia and bipolar disorder. This process is influenced, in turn, by methylation in other genes, as well as by genetic variation. So genes associated with risk for such psychiatric disorders may influence gene expression through methylation in addition to inherited DNA.

Scientists worldwide can now mine a newly created online database of PFC lifespan DNA methylation from the study. The data are accessible to qualified researchers at: http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000417.v2.p1. BrainCloud, a web browser application developed by NIMH to interrogate the study data, can be downloaded at http://BrainCloud.jhmi.edu.

Two representative genes show strikingly opposite trajectories of PFC methylation across the lifespan. Each dot represents a different brain. Usually, the more methylation, the less gene expression.
Source: Barbara Lipska, Ph.D., NIMH Clinical Brain Disorders Branch


A representative gene showing how sex can influence levels of methylation across the lifespan. Each dot represents a different brain.
Source: Barbara Lipska, Ph.D., NIMH Clinical Brain Disorders Branch

Reference:

Numata S, Ye T, Hyde TM, Guitart-Navarro X, Tao R, Wininger M, Colantuoni C, Weinberger DR, Kleinman JE, Lipska BK. DNA Methylation Signatures in Development and Aging of the Human Prefrontal Cortex. American Journal of Human Genetics, 2011. Feb 2.

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The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit the NIMH website.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit the NIH website.