A research team led by Jackson Laboratory Professor and Howard Hughes Investigator Susan Ackerman, Ph.D., has pinpointed a surprising mechanism behind neurodegeneration in mice, one that involves a defect in a key component of the cellular machinery that makes proteins, known as transfer RNA or tRNA.

The researchers report in the journal Science that a mutation in a gene that produces tRNAs operating only in the central nervous system results in a “stalling” or pausing of the protein production process in the neuronal ribosomes. When another protein the researchers identified, GTPBP2, is also missing, neurodegeneration results.

“Our study demonstrates that individual tRNA genes can be tissue-specifically expressed in vertebrates,” Ackerman says, “and mutations in such genes may cause disease or modify other phenotypes. This is a new area to look for disease mechanisms.”

Neurodegeneration—the process through which mature neurons decay and ultimately die—is poorly understood, yet it underlies major human diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and ALS (amyotrophic lateral sclerosis, also known as Lou Gehrig’s disease).

While the causes of neurodegeneration are still coming to light, there is mounting evidence that neurons are exquisitely sensitive—much more so than other types of cells—to disruptions in how proteins are made and how they fold.

tRNAs are critical in translating the genetic code into proteins, the workhorses of the cell. tRNAs possess a characteristic cloverleaf shape with two distinct “business” ends—one that reads out the genetic code in three-letter increments (or triplets), and another that transports the protein building block specified by each triplet (known as an amino acid).

In higher organisms, tRNAs are strikingly diverse. For example, while there are 61 distinct triplets that are recognized by tRNAs in humans, the human genome contains roughly 500 tRNA genes. To date little is known about why they are so numerous, whether they carry out overlapping or redundant functions, or whether they possibly have roles beyond the making of proteins.

“Multiple genes encode almost all tRNA types,” Ackerman says. “In fact, AGA codons are decoded by five tRNAs in mice. Until now, this apparent redundancy has caused us to completely overlook the disease-causing potential of mutations in tRNAs, as well as other repetitive genes.”

Ackerman and her colleagues at The Jackson Laboratory in Bar Harbor, Maine, and Farmington, Conn., The Scripps Research Institute in LaJolla, Calif., and Kumamoto University in Japan pinpointed a mutation in the tRNA gene n-Tr20 as a genetic culprit behind the neurodegeneration observed in mice lacking GTPBP2.

Remarkably, the tRNA’s activity is confined to the brain and other parts of the central nervous system, in both mice and humans. The tRNA encoded by n-Tr20 recognizes the triplet code, AGA (which specifies the amino acid arginine).

The n-Tr20 defect disrupts how proteins are made. Specifically, it causes the “factories” responsible for synthesizing proteins, called ribosomes, to stall when they encounter an AGA triplet.

Such stalling can be largely overcome, thanks to the work of a partner protein called GTPBP2. But when this partner is missing—as it is in the mutant mice that Ackerman and her colleagues studied—the stalling intensifies. This is thought to be a driving force behind the neurodegeneration seen in these mice.

(Source: jax.org)

Unlocking the secrets to better treating the pernicious disorders of obesity and dementia reside in the brain, according to a paper from American University’s Center for Behavioral Neuroscience. In the paper, researchers make the case for treating obesity with therapies aimed at areas of the brain responsible for memory and learning. Furthermore, treatments that focus on the hippocampus could play a role in reducing certain dementias.

"In the struggle to treat these diseases, therapies and preventive measures often fall short. This is a new way for providers who treat people with weight problems and for researchers who study dementias to think about obesity and cognitive decline," said Prof. Terry Davidson, center director and lead study author.

In the paper, published in the journal Physiology & Behavior, Davidson and colleague Ashley A. Martin review research findings linking obesity with cognitive decline, including the center’s findings about the “vicious cycle” model, which explains how weight-challenged individuals who suffer from particular kinds of cognitive impairment are more susceptible to overeating.

Obesity, Memory Deficits and Lasting Effects

It is widely accepted that overconsumption of dietary fats, sugar and sweeteners can cause obesity. These types of dietary factors are also linked to cognitive dysfunction. Foods that are risk factors for cognitive impairment (i.e., foods high in saturated fats and simple carbohydrates that make up the modern Western diet) are so widespread and readily available in today’s food environment, their consumption is all but encouraged, Davidson said.

Across age groups, evidence reveals links between excess food intake, body weight and cognitive dysfunction. Childhood obesity and consumption of the Western diet can have lasting effects, as seen through the normal aging process, cognitive deficits and brain pathologies. Several analyses of cases of mild cognitive impairment progressing to full-blown cases of Alzheimer’s disease show that the first signs of brain disease can occur at least 50 years prior to the emergence of serious cognitive dysfunction. These signs originate in the hippocampus, the area of the brain where memory, learning, decision making, behavior control and other cognitive functions come into play.

Still, most research on the role of the brain in obesity focuses on areas thought to be involved with hunger motivation (e.g., hypothalamus), taste (e.g., brain stem), reinforcement (e.g., striatum) and reward (e.g., nucleus accumbens) or with hormonal or metabolic disorders. This research has not yet been successful in generating therapies that are effective in treating or preventing obesity, Davidson says.

Vicious Cycle

Experiments in rats by Davidson and colleagues show that overconsumption of the Western diet can damage or change the blood-brain barrier, the tight network of blood vessels protecting the brain and substrates for cognition. Certain kinds of dementias are known to arise from the breakdown in these brain substrates.

"Breakdown in the blood-brain barrier is more rationale for treating obesity as a learning and memory disorder," Davidson said. "Treating obesity successfully may also reduce the incidence of dementias, because the deterioration in the brain is often produced by the same diets that promote obesity."

The “vicious cycle” model AU researchers put forth says eating a Western diet high in saturated fats, sugar and simple carbohydrates produces pathologies in brain structures and circuits, ultimately changing brain pathways and disrupting cognitive abilities.

It works like this: People become less able to resist temptation when they encounter environmental cues (e.g., food itself or the sight of McDonald’s Golden Arches) that remind them of the pleasures of consumption. They then eat more of the same type of foods that produce the pathological changes in the brain, leading to progressive deterioration in those areas and impairments in cognitive processes important for providing control over one’s thoughts and behaviors. These cognitive impairments can weaken a person’s ability to resist thinking about food, making them more easily distracted by food cues in the environment and more susceptible to overeating and weight gain.

"People have known at least since the time of Hippocrates that one key to a healthy life is to eat in moderation. Yet many of us are unable to follow that good advice," Davidson said. "Our work suggests that new therapeutic interventions that target brain regions involved with learning and memory may lead to success in controlling both the urge to eat, as well as the undesirable consequences produced by overeating."

(Source: eurekalert.org)

Mozart, Beethoven or even Shakespeare — pregnant mothers have been known to expose their babies to many forms of auditory stimulation. But according to researchers at the University of Florida, all a baby really needs is the music of mom’s voice.

Research published in the most recent issue of the journal Infant Behavior and Development shows that babies in utero begin to respond to the rhythm of a nursery rhyme — showing evidence of learning — by 34 weeks of pregnancy and are capable of remembering a set rhyme until just prior to birth. Nursing researcher Charlene Krueger and her team studied pregnant women who recited a rhyme to their babies three times a day for six weeks, beginning at 28 weeks’ gestational age, which is the start of the third trimester of pregnancy.

“The mother’s voice is the predominant source of sensory stimulation in the developing fetus,” said Krueger, an associate professor in the UF College of Nursing. “This research highlights just how sophisticated the third trimester fetus really is and suggests that a mother’s voice is involved in the development of early learning and memory capabilities. This could potentially affect how we approach the care and stimulation of the preterm infant.”

Krueger’s team recruited 32 pregnant women during their 28th week of pregnancy, as determined by fetal ultrasound. The participants were between 18 and 39 years of age, spoke English as a primary language and were pregnant with their first baby. Once recruited, the women were randomly assigned to either an experimental or a control group. The mean age of the women in the group was 25. In addition, 68 percent of the women were white, 28 percent were black and 4 percent were of another race or ethnicity.

From 28 to 34 weeks of pregnancy, all mothers in the study recited a passage or nursery rhyme out loud twice a day and then came in for testing at 28, 32, 33 and 34 weeks’ gestation. To determine whether the fetus could remember the pattern of speech at 34 weeks of age, all mothers were asked to stop speaking the passage. Then the fetuses were tested again at 36 and 38 weeks’ gestational age.

During testing, researchers used a fetal heart monitor, similar to what is used during traditional labor and delivery, to record heart rate and determine any changes. Researchers interpret a small heart rate deceleration in the fetus as an indicator of learning or familiarity with a stimulus.

At testing, the fetuses in the experimental group were played a recording of the same rhyme their mother had been reciting at home but spoken by a female stranger. Those in the control group heard a different rhyme also spoken by a stranger. This was to help determine if the fetus was responding simply to its mother’s voice or to a familiar pattern of speech, which is a more difficult task, Krueger said.

The researchers found that the fetus’ heart rate began to respond to the familiar rhyme recited by a stranger’s voice by 34 weeks of gestational age — once the mother had spoken the rhyme out loud at home for six weeks. They continued to respond with a small cardiac deceleration for as long as four weeks after the mother had stopped saying the rhyme until about 38 weeks. At 38 weeks, there was a statistically significant difference between the two groups in responding to the strangers’ recited rhymes — the experimental group who heard the original rhyme responded with a deeper and more sustained cardiac deceleration, whereas the control group who heard a new rhyme responded with a cardiac acceleration.

Further research is needed to more fully understand how ongoing development affects learning and memory, Krueger said. Her aim is to recognize how this type of research can influence care in preterm infants and their long-term outcomes.

“This study helped us understand more about how early a fetus could learn a passage of speech and whether the passage could be remembered weeks later even without daily exposure to it,” Krueger said. “This could have implications to those preterm infants who are born before 37 weeks of age and the impact an intervention such as their mother’s voice may have on influencing better outcomes in this high-risk population.”

(Source: news.ufl.edu)

Contrary to previous assumptions, researchers find that preschoolers are able to gauge the strength of their memories and make decisions based on their self-assessments. The study findings are published in Psychological Science, a journal of the Association for Psychological Science.

“Previously, developmental researchers assumed that preschoolers did not introspect much on their mental states, and were not able to reflect on their own uncertainty when problem solving,” says psychological scientist Emily Hembacher of the University of California, Davis, lead author of the study. “This is partly because young children are not usually able to tell us much about their own mental processes due to verbal limitations.”

In several previous studies in their lab, Hembacher and co-author Simona Ghetti observed that preschoolers reported feeling uncertain after giving wrong answers during tasks, suggesting the preschoolers were capable of metacognition — the ability to evaluate one’s own thoughts and mental states.

The researchers decided to examine preschoolers’ metacognition about their memories, given its importance for learning.  They investigated whether kids could assess their confidence in their memories and use those assessments in deciding whether to exclude answers they had generated but were unsure of when given the option.

Eighty-one children ages 3, 4, and 5 participated in the study.  The preschoolers viewed a series of drawings of various items, such as a piano or a balloon.  Half of the images were presented once, and the other half were shown twice.  Next, the children were presented with a pair of images: one they had seen, and a new one they had not seen.  The children were instructed to pick which image they’d seen before in the previous task.

After making their choice, the preschoolers rated how confident they were that their choice was correct.  They then sorted their answers into two boxes.  One box was for the responses that children were confident about and wanted researchers to evaluate for a prize.  The other one was for responses the children thought might be mistaken and that they didn’t want researchers to see.

The data revealed that only 4- and 5-year-olds reported being less confident in their incorrect than their correct memory responses.  They were also more confident about images they’d seen twice, suggesting that they could distinguish between stronger and weaker memories. Older preschoolers were also more likely to decide whether they wanted researchers to see their answers based on their confidence level.

Although 3-year-olds didn’t display the same kind of metacognitive capability on individual responses, the data showed that 3-year-olds who had scored well reported higher confidence overall than kids who hadn’t scored as well.

When the researchers analyzed just the correct answers, they found that preschoolers of all ages sorted responses they weren’t as confident about to the box they didn’t want researchers to evaluate.  So, while they may not be as advanced as their older peers, even children as young as 3 seem to display some ability to reflect on their own knowledge.

The findings contribute to research on the reliability of children’s eyewitness testimony in a court of law, and they carry important implications for educational practices.

“Previous emphasis on the development of metacognition during middle childhood has influenced education practices aimed at strengthening children’s monitoring and control of their own learning,” says Hembacher. “Now we know that some of these ideas may be adapted to meet preschoolers’ learning needs.”

(Source: psychologicalscience.org)