The Brain on Stress: Vulnerability and Plasticity of the Prefrontal Cortex over the Life Course

The prefrontal cortex (PFC) is involved in working memory and self-regulatory and goal-directed behaviors and displays remarkable structural and functional plasticity over the life course. Neural circuitry, molecular profiles, and neurochemistry can be changed by experiences, which influence behavior as well as neuroendocrine and autonomic function. Such effects have a particular impact during infancy and in adolescence. Behavioral stress affects both the structure and function of PFC, though such effects are not necessarily permanent, as young animals show remarkable neuronal resilience if the stress is discontinued. During aging, neurons within the PFC become less resilient to stress. There are also sex differences in the PFC response to stressors. While such stress and sex hormone-related alterations occur in regions mediating the highest levels of cognitive function and self-regulatory control, the fact that they are not necessarily permanent has implications for future behavior-based therapies that harness neural plasticity for recovery.

'Singing' rats show hope for older humans with age-related voice problems

A new study shows that the vocal training of older rats reduces some of the voice problems related to their aging, such as the loss of vocal intensity that accompanies changes in the muscles of the larynx. This is an animal model of a vocal pathology that many humans face as they age. The researchers hope that in the future, voice therapy in aging humans will help improve their quality of life.

The research appears in The Journals of Gerontology.

University of Illinois speech and hearing science professor Aaron Johnson, who led the new study along with his colleagues at the University of Wisconsin, said that aging can cause the muscles of the larynx, the organ that contains the vocal folds, to atrophy. This condition, called presbyphonia, may be treatable with vocal training, he said.

Johnson said in a healthy, young larynx the vocal folds completely close and open during vibration. This creates little puffs of air we hear as sound. In people with presbyphonia, however, the atrophied vocal folds do not close properly, resulting in a gap during vocal fold vibration.

Degradation of the neuromuscular junction, or the interface between the nerve that signals the vocal muscle to work and the muscle itself, also contributes to the symptoms of presbyphonia, Johnson said. In a healthy human, when the signal reaches the neuromuscular junction, it triggers a release of chemicals that signal the muscle to contract. But an age-related decline in the neuromuscular junction can cause weakness and fatigue in the muscle, and may result in a person having a breathy or weak voice and to become fatigued as a result of the extra effort needed to communicate.

Surgery and injections may help correct the gap between the vocal folds seen in presbyphonia, but these invasive procedures are often not viable in the elderly population, Johnson said.

His previous experience working with the elderly as a former classical singer and voice teacher propelled Johnson to “become interested in what we can do as we get older to keep our voices healthy and strong.”

“We know exercise strengthens the limb musculature, but we wanted to know if vocal exercise can strengthen the muscles of the voice,” Johnson said.

To find out if vocal training could have an effect on the strength and physiology of the vocal muscles in humans, Johnson turned to a rat model. Rats make ultrasonic vocalizations that are above the range of human hearing, but special recording equipment and a computer that lowers the frequency of the rat calls allows humans to perceive them. (They sound a bit like bird calls).

Because rats and humans utilize similar neuromuscular mechanisms to vocalize, the rats make ideal subjects for the study of human vocal characteristics, Johnson said.

Both the treatment and control groups contained old and young male rats. In the treatment group, a female rat was placed into a cage with a male rat. When the male expressed interest in her, the female was removed from the cage, causing the male rat to vocalize. The male was rewarded with food for these vocalizations, and after eight weeks of this operant conditioning in which rewards were only given for certain responses, all of the rats in the treatment group had been trained to increase their number of vocalizations during a training session.

At the end of the eight-week period, the researchers measured the intensity of the rats’ vocalizations and analyzed the animals’ larynges to see whether the training had any effect on the condition of their neuromuscular junctions. 

The researchers found the trained old and young rats had similar average vocal intensities, but the untrained older rats had lower average intensities than both the trained rats and the young rats that had not been trained. They also found several age-related differences within the groups’ neuromuscular mechanisms.

“Other research has found that in the elderly, there is a dispersion, or breaking apart, of the neuromuscular junction at the side that is on the muscle itself,” Johnson said. “We found that in the older rats that received training, it wasn’t as dispersed.”

These “singing rats” are the “first evidence that vocal use and vocal training can change the neuromuscular system of the larynx,” Johnson said. 

“While this isn’t a human study, I think this tells us that we can train ourselves to use our voices and not only reduce the effects of age on the muscles of our voices, but actually improve voices that have degraded,” Johnson said.

The link between circadian rhythms and aging

Human sleeping and waking patterns are largely governed by an internal circadian clock that corresponds closely with the 24-hour cycle of light and darkness. This circadian clock also controls other body functions, such as metabolism and temperature regulation.

Studies in animals have found that when that rhythm gets thrown off, health problems including obesity and metabolic disorders such as diabetes can arise. Studies of people who work night shifts have also revealed an increased susceptibility to diabetes.

A new study from MIT shows that a gene called SIRT1, previously shown to protect against diseases of aging, plays a key role in controlling these circadian rhythms. The researchers found that circadian function decays with aging in normal mice, and that boosting their SIRT1 levels in the brain could prevent this decay. Conversely, loss of SIRT1 function impairs circadian control in young mice, mimicking what happens in normal aging. 

Since the SIRT1 protein itself was found to decline with aging in the normal mice, the findings suggest that drugs that enhance SIRT1 activity in humans could have widespread health benefits, says Leonard Guarente, the Novartis Professor of Biology at MIT and senior author of a paper describing the findings in the June 20 issue of Cell.

“If we could keep SIRT1 as active as possible as we get older, then we’d be able to retard aging in the central clock in the brain, and health benefits would radiate from that,” Guarente says.

Staying on schedule

In humans and animals, circadian patterns follow a roughly 24-hour cycle, directed by the circadian control center of the brain, called the suprachiasmatic nucleus (SCN), located in the hypothalamus.

“Just about everything that takes place physiologically is really staged along the circadian cycle,” Guarente says. “What’s now emerging is the idea that maintaining the circadian cycle is quite important in health maintenance, and if it gets broken, there’s a penalty to be paid in health and perhaps in aging.”

Last year, Guarente found that a robust circadian period correlated with longer lifespan in mice. That got him wondering what role SIRT1, which has been shown to prolong lifespan in many animals, might play in that phenomenon. SIRT1, which Guarente first linked with aging more than 15 years ago, is a master regulator of cell responses to stress, coordinating a variety of hormone networks, proteins and genes to help keep cells alive and healthy.

To investigate SIRT1’s role in circadian control, Guarente and his colleagues created genetically engineered mice that produce different amounts of SIRT1 in the brain. One group of mice had normal SIRT1 levels, another had no SIRT1, and two groups had extra SIRT1 — either twice or 10 times as much as normal.

Mice lacking SIRT1 had slightly longer circadian cycles (23.9 hours) than normal mice (23.6 hours), and mice with a 10-fold increase in SIRT1 had shorter cycles (23.1 hours).

In mice with normal SIRT1 levels, the researchers confirmed previous findings that when the 12-hour light/dark cycle is interrupted, younger mice readjust their circadian cycles much more easily than older ones. However, they showed for the first time that mice with extra SIRT1 do not suffer the same decline in circadian control as they age.

The researchers also found that SIRT1 exerts this control by regulating the genes BMAL and CLOCK, the two major keepers of the central circadian clock.

Enhancing circadian function

A growing body of evidence suggests that being able to respond to large or small disruptions of the light/dark cycle is important to maintaining healthy metabolic function, Guarente says.

“Essentially we experience a mini jet lag every day because the light cycle is constantly changing. The critical thing for us is to be able to adapt smoothly to these jolts,” Guarente says. “Many studies in mice say that while young mice do this perfectly well, it’s the old mice that have the problem. So that could well be true in humans.”

If so, it could be possible to treat or prevent diseases of aging by enhancing circadian function — either by delivering SIRT1 activators in the brain or developing drugs that enhance another part of the circadian control system, Guarente says.

“I think we should look at every aspect of the machinery of the circadian clock in the brain, and any intervention that can maintain that machinery with aging ought to be good,” he says. “One entry point would be SIRT1, because we’ve shown in mice that genetic maintenance of SIRT1 helps maintain circadian function.”

Some SIRT1 activators are now being tested against diabetes, inflammation and other diseases, but they are not designed to cross the blood-brain barrier and would likely not be able to reach the SCN. However, Guarente believes it could be possible to design SIRT1 activators that can get into the brain.

Roman Kondratov, an associate professor of biology at Cleveland State University, says the study raises several exciting questions regarding the potential to delay or reverse age-related changes in the brain through rejuvenation of the circadian clock with SIRT1 enhancement.

“The importance of this study is that it has both basic and potentially translational applications, taking into account the fact that pharmacological modulators of SIRT1 are currently under active study,” Kondratov says.

Researchers in Guarente’s lab are now investigating the relationship between health, circadian function and diet. They suspect that high-fat diets might throw the circadian clock out of whack, which could be counteracted by increased SIRT1 activation.

(Image: Wikimedia Commons)

The Hallmarks of Aging

Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. This deterioration is the primary risk factor for major human pathologies, including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases. Aging research has experienced an unprecedented advance over recent years, particularly with the discovery that the rate of aging is controlled, at least to some extent, by genetic pathways and biochemical processes conserved in evolution. This Review enumerates nine tentative hallmarks that represent common denominators of aging in different organisms, with special emphasis on mammalian aging. These hallmarks are: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. A major challenge is to dissect the interconnectedness between the candidate hallmarks and their relative contributions to aging, with the final goal of identifying pharmaceutical targets to improve human health during aging, with minimal side effects.

Reducing caloric intake delays nerve cell loss

Activating an enzyme known to play a role in the anti-aging benefits of calorie restriction delays the loss of brain cells and preserves cognitive function in mice, according to a study published in the May 22 issue of The Journal of Neuroscience. The findings could one day guide researchers to discover drug alternatives that slow the progress of age-associated impairments in the brain.

Previous studies have shown that reducing calorie consumption extends the lifespan of a variety of species and decreases the brain changes that often accompany aging and neurodegenerative diseases such as Alzheimer’s. There is also evidence that caloric restriction activates an enzyme called Sirtuin 1 (SIRT1), which studies suggest offers some protection against age-associated impairments in the brain.

In the current study, Li-Huei Tsai — director of the Picower Institute for Learning and Memory and Picower Professor of Neuroscience at MIT — along with postdoc Johannes Gräff and others at MIT tested whether reducing caloric intake would delay the onset of nerve cell loss that is common in neurodegenerative disease, and if so, whether SIRT1 activation was driving this effect. The group not only confirmed that caloric restriction delays nerve cell loss, but also found that a drug that activates SIRT1 produces the same effects.

“There has been great interest in finding compounds that mimic the benefits of caloric restriction that could be used to delay the onset of age-associated problems and/or diseases,” says Dr. Luigi Puglielli, who studies aging at the University of Wisconsin, Madison, and was not involved in this study. “If proven safe for humans, this study suggests such a drug could be used as a preventive tool to delay the onset of neurodegeneration associated with several diseases that affect the aging brain.”

In the study, Tsai’s team first decreased the normal diets of mice genetically engineered to rapidly undergo changes in the brain associated with neurodegeneration by 30 percent. Following three months on the diet, the mice completed several learning and memory tests. “We not only observed a delay in the onset of neurodegeneration in the calorie-restricted mice, but the animals were spared the learning and memory deficits of mice that did not consume reduced-calorie diets,” Tsai says.

Curious if they could recreate the benefits of caloric restriction without changing the animals’ diets, the scientists gave a separate group of mice a drug that activates SIRT1. Similar to what the researchers found in the mice exposed to reduced-calorie diets, the mice that received the drug had less cell loss and better cellular connectivity than the mice that did not receive the drug. Additionally, the mice that received the drug treatment performed as well as normal mice in learning and memory tests.

“The question now is whether this type of treatment will work in other animal models, whether it’s safe for use over time, and whether it only temporarily slows down the progression of neurodegeneration or stops it altogether,” Tsai says.

Mediterranean diet seems to boost ageing brain power

A Mediterranean diet with added extra virgin olive oil or mixed nuts seems to improve the brain power of older people better than advising them to follow a low-fat diet, indicates research published online in the Journal of Neurology Neurosurgery and Psychiatry.

The authors from the University of Navarra in Spain base their findings on 522 men and women aged between 55 and 80 without cardiovascular disease but at high vascular risk because of underlying disease/conditions.

These included either type 2 diabetes or three of the following: high blood pressure; an unfavourable blood fat profile; overweight; a family history of early cardiovascular disease; and being a smoker.

Participants, who were all taking part in the PREDIMED trial looking at how best to ward off cardiovascular disease, were randomly allocated to a Mediterranean diet with added olive oil or mixed nuts or a control group receiving advice to follow the low-fat diet typically recommended to prevent heart attack and stroke

A Mediterranean diet is characterised by the use of virgin olive oil as the main culinary fat; high consumption of fruits, nuts, vegetables and pulses; moderate to high consumption of fish and seafood; low consumption of dairy products and red meat; and moderate intake of red wine.

Participants had regular check-ups with their family doctor and quarterly checks on their compliance with their prescribed diet.

After an average of 6.5 years, they were tested for signs of cognitive decline using a Mini Mental State Exam and a clock drawing test, which assess higher brain functions, including orientation, memory, language, visuospatial and visuoconstrution abilities and executive functions such as working memory, attention span, and abstract thinking.

At the end of the study period, 60 participants had developed mild cognitive impairment: 18 on the olive oil supplemented Mediterranean diet; 19 on the diet with added mixed nuts; and 23 on the control group.

A further 35 people developed dementia: 12 on the added olive oil diet; six on the added nut diet; and 17 on the low fat diet.

The average scores on both tests were significantly higher for those following either of the Mediterranean diets compared with those on the low fat option.

These findings held true irrespective of other influential factors, including age, family history of cognitive impairment or dementia, the presence of ApoE protein—associated with Alzheimer’s disease—educational attainment, exercise levels, vascular risk factors; energy intake and depression.

The authors acknowledge that their sample size was relatively small, and that because the study involved a group at high vascular risk, it doesn’t necessarily follow that their findings are applicable to the general population.

But they say, theirs is the first long term trial to look at the impact of the Mediterranean diet on brain power, and that it adds to the increasing body of evidence suggesting that a high quality dietary pattern seems to protect cognitive function in the ageing brain.