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Unraveling the brain’s reward circuits

Unraveling the brain’s reward circuits

To some, a chocolate cake may spark a shot of pleasure typically associated with illicit drugs. A new study by Penn biologists offers some insights into that link, revealing new information about how the brain responds to rewards such as food and drugs.

In the work, which appears this week online in the journal Neuron, a team led by Assistant Professor J. Nicholas Betley, postdoctoral researcher Amber L. Alhadeff, and graduate student Nitsan Goldstein of the School of Arts and Sciences shows that, in mice, consuming food turns down the activity of neurons that signal hunger in the brain via a different pathway than alcohol and drugs, which can likewise act as appetite suppressants. Yet the research also reveals that the circuits that trigger the pleasurable release of dopamine are interconnected with the activity of hunger neurons, suggesting that drugs and alcohol can hijack not only the brain’s reward circuits but also those responsible for signaling hunger, serving to create a behavior that reinforces itself.

“Signals of reward, whether it’s food or drugs, access the brain through different pathways,” says Betley, senior author on the work. “But once they’re in the brain, they engage an interconnected network between hypothalamic hunger neurons and reward neurons. It could be that drugs are reinforced not only by increasing a dopamine spike, but also by decreasing the activity of hunger neurons that make you feel bad.”

With a greater understanding of these pathways, the researchers say their findings could inform the creation of more effective weight loss drugs or even addiction therapies.

Betley and colleagues’ work has previously shown infusing any type of macronutrient (any calorie-containing food) into a mouse turned down the activity of AgRP neurons, which are responsible for the unpleasant feelings associated with hunger. The signal by which the stomach tells the brain it has consumed food travels along what is known as the vagal nerve.

Curious about whether alcohol, which is also caloric, could trigger the same effect, they found that it did so in mice, even when the vagal pathway was disrupted.

“If we cut that highway, highly caloric and rewarding foods like fat can no longer get that signal to the hunger neurons, but ethanol could,” says Alhadeff.

The team next tried to do the same thing with cocaine, nicotine, and amphetamine, drugs that have been shown to have appetite suppressing activity, and found the same thing. It’s the first time, the team says, that a non-nutrient has been shown to regulate AgRP neurons for a sustained period of time.

“What is exciting is that the results suggest there are pharmacological mechanisms out there that can be harnessed to reduce the activity of these neurons to alleviate hunger if someone was on a weight-loss diet,” Alhadeff says.

Knowing that alcohol and drugs also trigger the release of dopamine, a neurotransmitter associated with a sensation of “reward” that is also implicated in addiction, the team observed that dopamine neuron activity increased in parallel to the decrease in AgRP neuron activity.

They went after that lead. Using a technique by which they could activate AgRP neurons without depriving an animal of food, the researchers explored how these hunger neurons influence dopamine signaling. In the absence of a food reward, they found little response in the dopamine neurons to activation of AgRP neurons. But when an animal with active AgRP was fed, the surge of dopamine was even higher than it would have been normally, without activated AgRP neurons. In other words, AgRP neurons made food more “rewarding” when the animals were hungry.

“We were surprised to find these AgRP neurons seemed to be signaling the dopamine neurons, but we couldn’t detect that until the animal gets the reward,” Goldstein says. “This suggested that either an indirect or modulatory circuit mediates the interaction between hunger and reward neurons in the brain.”

The same thing happened when the animal received a drug, such as nicotine.

Moving ahead, the research team is investigating the differences between the reward signals that come from alcohol and drugs versus food and unpacking the connection they have revealed between the dopamine neurons and AgRP neurons. Using sophisticated new technology, they’ll also be studying individual neurons to see if the effects they’ve observed are due to the activity of small subpopulations of neurons in the brain.

If they’re successful at identifying a new, druggable pathway that could target these linked circuits, Betley says it would be welcome, as many currently available weight-loss drugs have unpleasant side effects such as nausea.

“It’s hard to have somebody adhere to these drugs when they’re feeling poorly,” he says. “Our findings suggest there are multiple ways into the brain, and maybe by combining these strategies we can overcome these problems.”

Materials provided by the University of Pennsylvania

revealing hidden features using power of light

Revealing ‘hidden’ phases of matter through the power of light

Most people think of water as existing in only one of three phases: solid ice, liquid water, or gas vapour. But matter can exist in many different phases—ice, for example, has more than ten known phases, or ways that its atoms can be spatially arranged. The widespread use of piezoelectric materials, such as microphones and ultrasound, is possible thanks to a fundamental understanding of how an external force, like pressure, temperature, or electricity, can lead to phase transitions that imbue materials with new properties.

A new study finds that a metal oxide has a “hidden” phase, one that gives the material new, ferroelectric properties, the ability to separate positive and negative charges, when it is activated by extremely fast pulses of light. The research was led by MIT researchers Keith A. Nelson, Xian Li, and Edoardo Baldini, in collaboration with Andrew M. Rappe and graduate students Tian Qiu and Jiahao Zhang. The findings were published in Science.

Their work opens the door to creating materials where one can turn on and off properties in a trillionth of a second with the flick of a switch, now with much better control. In addition to changing electric potential, this approach could be used to change other aspects of existing materials—turning an insulator into a metal or flipping its magnetic polarity, for example.

“It’s opening a new horizon for rapid functional material reconfiguration,” says Rappe.

The group studied strontium titanate, a paraelectric material used in optical instruments, capacitors, and resistors. Strontium titanate has a symmetric and nonpolar crystal structure that can be “pushed” into a phase with a polar, tetragonal structure with a pair of oppositely charged ions along its long axis.

Nelson and Rappe’s previous collaboration provided the theoretical basis for this new study, which relied on Nelson’s experience using light to induce phase transitions in solid materials, along with Rappe’s knowledge in developing atomic-level computer models.

“[Nelson is] the experimentalist, and we’re the theorists,” says Rappe. “He can report what he thinks is happening based on spectra, but the interpretation is speculative until we provide a strong physical understanding of what happened.”

With recent improvements in technology and additional knowledge gained from working with terahertz frequencies, the two chemists set out to see if their theory, now more than one decade old, held true. Rappe’s challenge was to complement Nelson’s experiments with an accurate computer-generated version of strontium titanate, with every single atom tracked and represented, that responds to light in the same manner as the material being tested in the lab.

They found that when strontium titanate is excited with light, the ions are pulled in different directions, with positively charged ions moving in one direction and negatively charged ions in the other. Then, instead of the ions immediately falling back into place, the way a pendulum would after it’s been pushed, vibrational movements induced in the other atoms prevent the ions from swinging back immediately.

It’s as if the pendulum, at the moment that it reaches the maximum height of its oscillation, is diverted slightly off course where a small notch holds it in a place away from its initial position.

Thanks to their strong history of collaboration, Nelson and Rappe were able to go back and forth from the theoretical simulations to the experiments, and vice versa, until they found experimental evidence that showed that their theory held true.

“It’s been a really awesome collaboration,” says Nelson. “And it illustrates how ideas can simmer and then return in full force after more than 10 years.”

The two chemists will collaborate with engineers on future applications-driven research, such as creating new materials that have hidden phases, changing light-pulse protocols to create longer lasting phases, and seeing how this approach works for nanomaterials. For now, both researchers are excited about their results and where this fundamental breakthrough could lead to in the future.

“It’s the dream of every scientist—to hatch an idea together with a friend, to map out the consequence of that idea, then to have a chance to translate it into something in the lab, it’s extremely gratifying. It makes us think we’re on the right track towards the future,” says Rappe.

Materials provided by the University of Pennsylvania

nap midday

Children who nap midday are happier, excel academically, and have fewer behavioral problems

Ask just about any parent whether napping has benefits and you’ll likely hear a resounding “yes,” particularly for the child’s mood, energy levels, and school performance. New research from the University of Pennsylvania and the University of California, Irvine, published in the journal SLEEP backs up that parental insight.

A study of nearly 3,000 fourth, fifth, and sixth graders ages 10-12 revealed a connection between midday napping and greater happiness, self-control, and grit; fewer behavioral problems; and higher IQ, the latter particularly for the sixth graders. The most robust findings were associated with academic achievement, says Penn neurocriminologist Adrian Raine, a co-author on the paper.

“Children who napped three or more times per week benefit from a 7.6% increase in academic performance in Grade 6,” he says. “How many kids at school would not want their scores to go up by 7.6 points out of 100?”

Sleep deficiency and daytime drowsiness are surprisingly widespread, with drowsiness affecting up to 20% of all children, says lead author on the study Jianghong Liu, a Penn associate professor of nursing and public health. What’s more, the negative cognitive, emotional, and physical effects of poor sleep habits are well-established, and yet most previous research has focused on preschool age and younger.

That’s partially because in places like the United States, napping stops altogether as children get older. In China, however, the practice is embedded into daily life, continuing through elementary and middle school, even into adulthood. So, Liu and Raine, with Penn biostatistician Rui Feng, UC Irvine sleep researcher Sara Mednick and others, turned to the China Jintan Cohort Study, established in 2004 to follow participants from toddlerhood through adolescence.

From each of 2,928 children, the researchers collected data about napping frequency and duration once the children hit Grades 4 through 6, as well as outcome data when they reached Grade 6, including psychological measures like grit and happiness and physical measures such as body mass index and glucose levels. They also asked teachers to provide behavioral and academic information about each student. They then analyzed associations between each outcome and napping, adjusting for sex, grade, school location, parental education, and nightly time in bed.

It was the first comprehensive study of its kind, Mednick says. “Many lab studies across all ages have demonstrated that naps can show the same magnitude of improvement as a full night of sleep on discrete cognitive tasks. Here, we had the chance to ask real-world, adolescent schoolchildren questions across a wide range of behavioral, academic, social, and physiological measures.”

Predictably, she adds, “the more students sleep during the day, the greater the benefit of naps on many of these measures.”

Though the findings are correlational, the researchers say they may offer an alternative to the outcry from pediatricians and public health officials for later school start times. “The midday nap is easily implemented, and it costs nothing,” says Liu, particularly if accompanied by a slightly later end to the day, to avoid cutting into educational time. “Not only will this help the kids, but it also takes away time for screen use, which is related to a lot of mixed outcomes.”

Future directions could look at why, for example, children with better-educated parents nap more than children with less educated parents, or whether, by investigating the influence of culture and personality, nap interventions could be advanced on a global scale. Ideally, a randomized control trial would get at causation questions like whether napping leads to better academic achievement or whether they’re linked in some other way. However, none of this is yet in the works.

For now, the researchers say they hope the results of this current study can inform future interventional work that targets adolescent sleepiness.

Materials provided by University of Pennsylvania