New life

Repeated binge drinking during adolescence can affect brain functions in future generations, potentially putting offspring at risk for such conditions as depression, anxiety, and metabolic disorders, a Loyola University Chicago Stritch School of Medicine study has found.

"Adolescent binge drinking not only is dangerous to the brain development of teenagers, but also may impact the brains of their children," said senior author Toni R. Pak, PhD, an associate professor in the Department of Cell and Molecular Physiology of Loyola University Chicago Stritch School of Medicine.

The study by Dr. Pak, first author Anna Dorothea Asimes, a PhD student in Dr. Pak's lab, and colleagues was presented Nov. 14, 2016 at Neuroscience 2016, the annual meeting of the Society for Neuroscience.

The study, which was based on an animal model, found that adolescent binge drinking altered the on-off switches of multiple genes in the brains of offspring. When genes are turned on, they instruct cells to make proteins, which ultimately control physical and behavioral traits. The study found that in offspring, genes that normally are turned on were turned off, and vice versa.

Teenage binge drinking is a major health concern in the United States, with 21 percent of teenagers reporting they have done it during the past 30 days. Among drinkers under age 21, more than 90 percent of the alcohol is consumed during binge drinking episodes. Binge drinking is defined as raising the blood alcohol concentration to 0.08 percent, the legal driving limit, within two hours (generally about five drinks for a male and four drinks for a female).

In the study, one group of adolescent male and female rats was exposed to alcohol in amounts comparable to six binge drinking episodes. The rats mated after becoming sober and the females remained sober during their pregnancies. (Thus, any effects on offspring could not be attributed to fetal alcohol syndrome.) The alcohol-exposed rats were compared to a control group of rats that were not exposed to alcohol.

In the offspring of alcohol-exposed rats, researchers examined genes in the hypothalamus, a region of the brain involved in many functions, including reproduction, response to stress, sleep cycles and food intake. Researchers looked for molecular changes to DNA that would reverse the on-off switches in individual genes. They found 159 such changes in the offspring of binge-drinking mothers, 93 gene changes in the offspring of binge-drinking fathers and 244 gene changes in the offspring of mothers and fathers who both were exposed to binge drinking.

The study is the first to show a molecular pathway that teenage binge drinking by either parent can cause changes in the neurological health of subsequent generations.

While findings from an animal model do not necessarily translate to humans, there are significant similarities between the study's animal model and humans, including their metabolism of alcohol, the function of the hypothalamus, and the pattern and amount of binge drinking, Pak said.

The study was supported by a grant from the National Institute on Alcohol Abuse and Alcoholism. It is titled "Binge alcohol consumption during puberty causes altered DNA methylation in the brain of alcohol-naive offspring."

No comments

A gene that regulates bone growth and muscle metabolism in mammals may take on an additional role as a promoter of brain maturation, cognition and learning in human and nonhuman primates, according to a new study led by neurobiologists at Harvard Medical School.

Describing their findings in the Nov. 10 issue of Nature, researchers say their work provides a dramatic illustration of evolutionary economizing and creative gene retooling -- mechanisms that contribute to the vast variability across species that share nearly identical set of genes yet differ profoundly in their physiology.

The research reveals that osteocrin -- a gene found in the skeletal muscles of all mammals and well-known for its role in bone growth and muscle function -- is completely turned off in rodent brains yet highly active in the brains of nonhuman primates and humans.

Notably, osteocrin was found predominantly in cells of the neocortex -- the most evolved part of the primate brain, which regulates sensory perception, spatial reasoning and higher-level thinking and language in humans.

The gene's marked presence in an area of the brain responsible for higher-level function and thought, the researchers said, suggests a possible role in the development of cognition, a cardinal feature that distinguishes the brains of human and nonhuman primates from those of other mammals.

Brain development in humans and other primates is profoundly affected by sensory experience and social interactions. Scientists have long sought to unravel genes in the brain that are turned on and off by experiences to fuel the rise of brain functions unique to such complex species.

The HMS team's findings -- part of an ongoing quest to elucidate the mechanisms that underlie human brain development, function and disease -- reveal that osteocrin is precisely one such gene, activated by sensory stimulation. Furthermore, the team added, this is the first illustration of evolutionary gene repurposing in the brain.

"We have uncovered what we believe is a critical clue into the evolution of the human brain, one that gives us a glimpse into the genetic mechanisms that may account for differences in cognition between mice and humans," said senior investigator Michael Greenberg, the Nathan Marsh Pusey Professor of Neurobiology and chair of the HMS Department of Neurobiology.

For their experiments, the team analyzed RNA levels -- the molecular footprints of gene activity -- in the brain cells of mice, rats and humans. Although many of the same genes were activated in both mouse and human brain cells, the scientists observed, a small subset of genes was activated solely in human brain cells. Much to the scientists' surprise, the bone gene osteocrin was most highly expressed in the human brain, yet completely shut off in the brain cells of mice.

Going a step further, the scientists placed brain cells from all three species in lab dishes and chemically re-created conditions that mimic sensory stimulation. Chemical stimulation activated osteocrin selectively in excitatory neurons, so called for their role in stimulating rather than dampening nerve signaling. But researchers noted something even more intriguing: The activity of the gene was most intense in neurons of the neocortex, the topmost layer of cells covering the brain and responsible for higher-level cognition, such as long-term memory, thought and language. At the same time, osteocrin was noticeably absent from other parts of the brain responsible for noncognitive functions such as spatial navigation, balance, breathing, heart rate and temperature control.

When researchers compared osteocrin levels to levels of another brain protein, BDNF, well known for its role in neuronal growth and repair, they noticed another striking difference. While BDNF was present throughout the brain, osteocrin was restricted to the neocortex and, to a lesser extent, the amygdala, an area of the brain thought to play a role in memory formation, decision making and emotional responses. Osteocrin was also markedly expressed in cells of the temporal lobe, which houses functions such as learning, memory and audio-visual processing -- and the occipital lobe, which houses the visual cortex, the area of the brain responsible for the processing of visual information.

Further analysis revealed that in the primate brain, sensory stimulation appears to switch on osteocrin through a previously unknown DNA enhancer. Enhancers -- snippets of DNA that act as the genome's regulators -- are the "handles" that turn on some genes while shutting off others. In doing so, enhancers can profoundly alter genetic expression, fueling dramatic differences between organisms with nearly identical DNA. The rodent versions of osteocrin lacked the stimulation-activated DNA enhancer, the analysis showed.

In yet another critical observation, researchers found the osteocrin enhancer was, in turn, switched on by a protein called MEF2. Mutations in MEF2 are a well-established cause of intellectual disability and neurodevelopmental disorders, so the link between the two begs further study, the researchers said, as it may portend a role for osteocrin in such developmental anomalies.

"Humans share many genes with rodents and as much as 90 percent of their DNA in some parts of the genome," says co-first author Gabriella Boulting, a neurobiologist at HMS. "In this case we see how turning up the expression of the same gene in a different location may precipitate dramatic differences in the function of brain cells."

Further analysis revealed that osteocrin's activation curbed the growth of neuronal dendrites -- branchlike projections responsible for transmitting signals from one brain cell to the next.

"Restricting dendritic growth is a precision-enhancing mechanism, essential to ensuring that neuronal wires don't get crossed and compromise signal transmission from one cell to the next," says study first co-author Bulent Ataman, a neurobiologist at HMS.

This observation, Ataman added, suggests that osteocrin's activity may help enhance nerve cell agility and proper signal transmission to ensure robust communication across neurons.

To confirm that the activity-induced gene expression observed in nerve cells in the lab also occurred in the functioning, intact brain, researchers temporarily blocked vision in one eye of a macaque, a common technique to study activity-triggered brain plasticity and visually-induced gene activation in the visual cortex. This proof-of-concept experiment, they surmised, would reveal whether osteocrin is, indeed, awakened by visual stimulation and shut off by its absence. A day later, the researchers observed that osteocrin expression was markedly higher in cells from the visually intact parts of the macaque brain, compared with cells in vision-deprived areas.

The findings illustrate a foundational principle in neurobiology -- abnormal visual experiences can interfere with the development and function of brain cells in the visual cortex, a phenomenon first described more than 50 years ago by David Hubel and Torsten Wiesel, two of the founding members of the Department of Neurobiology at HMS. The two shared the 1981 Nobel Prize in Physiology or Medicine for their discoveries on visual information processing in the brain.

"Nature and nurture interact to wire up the brain, and abnormal vision can alter that wiring," said Margaret Livingstone, the Takeda Professor of Neurobiology at HMS. "Our observations reveal the molecular basis for what Hubel and Wiesel observed more than half a century ago."

Researchers say their findings have sparked more questions, including exactly how osteocrin interacts with neurons, precisely what factors regulate its expression and, most importantly, how it can alter brain physiology in disease and health.

No comments

Are humans the only animal that knows what they don’t know? A study by researchers at Yale and Harvard shows that rhesus monkeys also spontaneously recognize when they are ignorant and need to seek out more information.

The findings are published in Psychological Science, a journal of the Association for Psychological Science.

“Metacognition— the ability to think about our own thoughts— has long been considered a hallmark of being human,” said Laurie Santos, Yale psychological scientist and senior author of the study. “We all know the difference between feeling like we know something for sure and feeling like we’re not all that certain. We know when we need to Google something.”

But do other animals recognize their own uncertainty? Previous studies have shown that animals can recognize when they are uncertain, but these animals were typically exposed to the experimental problem over an extended period of time.

“But that is different from what we see in humans,” said Alexandra Rosati, an evolutionary biologist at Harvard and lead author of the study. “We wanted to know if monkeys could engage in metacognition on the spot when confronted with a brand-new problem.”

Rosati and Santos devised a clever experiment to test whether free-ranging rhesus monkeys spontaneously know when they need more information. They gave a total of 120 monkeys a chance to search for food that was placed into a structure.

In some cases, the structure was composed two cylinders arranged in a V-shape. When monkeys were able to see which cylinder the food went into, they quickly ran to that spot to retrieve the food. But when monkeys weren’t sure which cylinder contained the food, they instead ran to the junction of the two cylinders so that they could check the contents of both before they committed to searching one container.

When they were presented with a single tube that had no center opening, they rarely approached the center, even when they had not seen which side of the cylinder the food went into. This suggests that the monkeys were aware of the fact that no additional information could be gained by looking at the center of the cylinder.

Together, these results show that the monkeys spontaneously used information about their own knowledge states when figuring out how to search for the food.

No comments

Follow Us

Popular Posts

All Post

About Me