How the Brain Remembers Pleasure: Implications for Addiction

How the Brain Remembers Pleasure: Implications for Addiction

  8:46:00 PM    Science Lover

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Key details of the way nerve cells in the brain remember pleasure are revealed in a study by University of Alabama at Birmingham (UAB) researchers published today in the journal Nature Neuroscience. The molecular events that form such "reward memories" appear to differ from those created by drug addiction, despite the popular theory that addiction hijacks normal reward pathways.

Brain activity (artist's rendering). 
(Credit: © James Steidl / Fotolia)

Brain circuits have evolved to encourage behaviors proven to help our species survive by attaching pleasure to them. Eating rich food tastes good because it delivers energy and sex is desirable because it creates offspring. The same systems also connect in our mind's environmental cues with actual pleasures to form reward memories.

This study in rats supports the idea that the mammalian brain features several memory types, each using different circuits, with memories accessed and integrated as needed. Ancient memory types include those that remind us what to fear, what to seek out (reward), how to move (motor memory) and navigate (place memory). More recent developments enable us to remember the year Columbus sailed and our wedding day.

"We believe reward memory may serve as a good model for understanding the molecular mechanisms behind many types of learning and memory," said David Sweatt, Ph.D., chair of the UAB Department of Neurobiology, director of the Evelyn F. McKnight Brain Institute at UAB and corresponding author for the study. "Our results provide a leap in the field's understanding of reward-learning mechanisms and promise to guide future attempts to solve related problems such as addiction and criminal behavior."

The study is the first to illustrate that reward memories are created by chemical changes that influence known memory-related genes in nerve cells within a brain region called the ventral tegmental area, or VTA. Experiments that blocked those chemical changes -- a mix of DNA methylation and demethylation -- in the VTA prevented rats from forming new reward memories.

Methylation is the attachment of a methyl group (one carbon and three hydrogens) to a DNA chain at certain spots (cytosine bases). When methylation occurs near a gene or inside a gene sequence, it generally is thought to turn the gene off and its removal is thought to turn the gene on. This back-and-forth change affects gene expression without changing the code we inherit from our parents. Operating outside the genetic machinery proper, epigenetic changes enable each cell type to do its unique job and to react to its environment.

Furthermore, a stem cell in the womb that becomes bone or liver cells must "remember" its specialized nature and pass that identity to its descendants as they divide and multiply to form organs. This process requires genetic memory, which largely is driven by methylation. Note, most nerve cells do not divide and multiply as do other cells. They can't, according to one theory, because they put their epigenetic mechanisms to work making actual memories.

Natural pleasure versus addiction

The brain's pleasure center is known to proceed through nerve cells that signal using the neurochemical dopamine and generally is located in the VTA. Dopaminergic neurons exhibit a "remarkable capacity" to pass on pleasure signals. Unfortunately, the evolutionary processes that attached pleasure to advantageous behaviors also accidentally reinforced bad ones.

Addiction to all four major classes of abused drugs -- psychostimulants, opiates, ethanol and nicotine -- has been linked to increased dopamine transmission in the same parts of the brain associated with normal reward processing. Cues that predict both normal reward and effects of cocaine or alcohol also make dopamine nerve cells fire as do the experiences they recall. That had led to idea that drug addiction must take over normal reward-memory nerve pathways.

Along those lines, past research has argued that dopamine-producing neurons in the VTA -- and in a region that receives downstream dopamine signals from the VTA called the nucleus accumbens (NAC) -- both were involved in natural reward and drug-addiction-based memory formation. While that may true to some extent, this study revealed that blocking methylation in the VTA with a drug stopped the ability of rats to attach rewarding experiences to remembered cues but doing so in the NAC did not.

"We observed an important distinction, not in circuitry, but instead in the epigenetic regulation of that circuitry between natural reward responses and those that occur downstream with drugs of abuse or psychiatric illness," said Jeremy Day, Ph.D., a post-doctoral scholar in Sweatt's lab and first author for this study. "Although drug experiences may co-opt normal reward mechanisms to some extent, our results suggest they also may engage entirely separate epigenetic mechanisms that contribute only to addiction and that may explain its strength."

To investigate the molecular and epigenetic changes in the VTA, researchers took their cue from 19th century Russian physiologist Ivan Pavlov, who was the first to study the phenomenon of conditioning. By ringing a bell each day before giving his dogs food, Pavlov soon found that the dogs would salivate at the sound of the bell.

In this study, rats were trained to associate a sound tone with the availability of sugar pellets in their feed ports. This same animal model has been used to make most discoveries about how human dopamine neurons work since the 1990s, and most approved drugs that affect the dopamine system (e.g. L-Dopa for Parkinson's) were tested in it before being cleared for human trials.

To separate the effects of memory-related brain changes from those arising from the pleasure of the eating itself, the rats were separated into three groups. Rats in the "CS+" rats got sugar pellets each time they heard a sound cue. The "CS-" group heard the sound the same number of times and received as many sugar pellets -- but never together. A third tone-only group heard the sounds but never received sugar rewards.

Rats that always received sugar with the sound cue were found to poke their feed ports with their noses at least twice as often during this cue as control rats after three, 25-sound-cue sessions. Nose pokes are an established measure of the degree to which a rat has come to associate a cue with the memory of a tasty treat.

The team found that those CS+ rats (sugar paired with sound) that were better at forming reward memories had significantly higher expression of the genes Egr1 and Fos than control rats These genes are known to regulate memory in other brain regions by fine-tuning the signaling capacity of the connections between nerve cells. In a series of experiments, the team next revealed the methylation and demethylation pattern that drove the changes in gene expression seen as memories formed.

The study demonstrated that reward-related experiences caused both types of DNA methylation known to regulate gene expression.

One type involves attaching methyl groups to pieces of DNA called promoters, which reside immediately upstream of individual gene sequences (between genes), that tell the machinery that follows genetic instructions to "start reading here." The attachment of a methyl group to a promoter generally interferes with this and silences a nearby gene. However, ancient organisms such as plants and insects have less methylation between their genes, and more of it within the coding regions of the genes themselves (within gene bodies). Such gene-body methylation has been shown to encourage rather than silence gene expression.

Specifically, the team reported that two sites in the promoter for Egr1 gene were demethylated during reward experiences and, to a greater degree, in rats that associated the sugar with the sound cue. Conversely, spots within the gene body of both Egr1 and Fos underwent methylation as reward memories formed.

"When designing therapeutic treatments for psychiatric illness, addictions or memory disorders, you must profoundly understand the function of the biological systems you're working with," Day said. "Our field has learned from experience that attempts to treat addiction with something that globally impairs normal reward perception or reward memories do not succeed. Our study suggests the possibility that future treatments could dial down drug addiction or mental illness without affecting normal rewards."

Along with Sweatt and Day, authors for the study were Daniel Childs, Mikael Guzman-Karlsson, Mercy Kibe, Jerome Moulden, Esther Song and Absar Tahir within the Department of Neurobiology and the Evelyn F. McKnight Brain Institute at University of Alabama at Birmingham. This work is supported by the National Institute on Drug Abuse (DA029419), the National Institute on Mental Health (MH091122 and MH057014), and the Evelyn F. McKnight Brain Research Foundation.

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Researchers use mobile phones to measure happiness

Researchers use mobile phones to measure happiness

  10:01:00 AM    Science Lover

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Researchers at Princeton University are developing ways to use mobile phones to explore how one's environment influences one's sense of well-being.

Locations of study subjects on world map. Credit: Demography

In a study involving volunteers who agreed to provide information about their feelings and locations, the researchers found that cell phones can efficiently capture information that is otherwise difficult to record, given today's on-the-go lifestyle. This is important, according to the researchers, because feelings recorded "in the moment" are likely to be more accurate than feelings jotted down after the fact.

To conduct the study, the team created an application for the Android operating system that documented each person's location and periodically sent the question, "How happy are you?"

The investigators invited people to download the app, and over a three-week period, collected information from 270 volunteers in 13 countries who were asked to rate their happiness on a scale of 0 to 5. From the information collected, the researchers created and fine-tuned methods that could lead to a better understanding of how our environments influence emotional well-being. The study was published in the June issue of Demography.

The mobile phone method could help overcome some of the limitations that come with surveys conducted at people's homes, according to the researchers. Census measurements tie people to specific areas—the census tracts in which they live—that are usually not the only areas that people actually frequent.

"People spend a significant amount of time outside their census tracks," said John Palmer, a graduate student in the Woodrow Wilson School of Public and International Affairs and the paper's lead author. "If we want to get more precise findings of contextual measurements we need to use techniques like this."

Palmer teamed up with Thomas Espenshade, professor of sociology emeritus, and Frederic Bartumeus, a specialist in movement ecology at the Center for Advanced Studies of Blanes in Spain, along with Princeton's Chang Chung, a statistical programmer and data archivist in the Office of Population Research; Necati Ozgencil, a former Professional Specialist at Princeton; and Kathleen Li, who earned her undergraduate degree in computer science from Princeton in 2010, to design the free, open source application for the Android platform that would record participants' locations at various intervals based on either GPS satellites or cellular tower signals.

Though many of the volunteers lived in the United States, some were in Australia, Canada, China, France, Germany, Israel, Japan, Norway, South Korea, Spain, Sweden and the United Kingdom.

Palmer noted that the team's focus at this stage was not on generalizable conclusions about the link between environment and happiness, but rather on learning more about the mobile phone's capabilities for data collection. "I'd be hesitant to try to extend our substantive findings beyond those people who volunteered." he said.

However, the team did obtain some preliminary results regarding happiness: for example, male subjects tended to describe themselves as less happy when they were further from their homes, whereas females did not demonstrate a particular trend with regards to emotions and distance.

"One of the limitations of the study is that it is not representative of all people," Palmer said. Participants had to have smartphones and be Internet users. It is also possible that people who were happy were more likely to respond to the survey. However, Palmer said, the study demonstrates the potential for mobile phone research to reach groups of people that may be less accessible by paper surveys or interviews.

Palmer's doctoral dissertation will expand on this research, and his adviser Marta Tienda, the Maurice P. During Professor in Demographic Studies, said she was excited to see how it will impact the academic community. "His applied research promises to redefine how social scientists understand intergroup relations on many levels," she said.


This study involved contributions from the Center for Information Technology Policy at Princeton University, with institutional support from the National Institutes of Health Training Grant T32HD07163 and Infrastructure Grant R24HD047879.

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Report:A Semi-Floating Gate Transistor for Low-Voltage Ultrafast Memory and Sensing Operation

Report:A Semi-Floating Gate Transistor for Low-Voltage Ultrafast Memory and Sensing Operation

  10:19:00 AM    Science Lover

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Researchers at Fudan University in China have discovered a way to speed up traditional computer transistors by embedding tunneling field-effect transistors (TFETs) in them. In their paper published in the journal Science, the team describes how embedding TFETs in such transistors allows for them to be run with less power, which in turn causes them to run faster.

Schematic view of an SFG memory cell. A pn junction diode between the FG and D makes the FG semi-floating. The device’s symbolic representation is also shown. Credit: Science 9 August 2013: Vol. 341 no. 6146 pp. 640-643 DOI: 10.1126/science.1240961

Most modern computers are run with either metal-oxide-semiconductor field-effect transistors (MOSFETs) or a variation of them called floating-gate (FG) MOSFETs. Such transistors are now reaching their physical limit as far as how thin they can be—just a few atoms thick. For that reason, researchers have been looking for other ways to get more bang for their buck. In this new effort, the researchers turned to TFETs, which use quantum tunneling to move electrons through very thin material.

TFETs have traditionally been used in very low power devices. In this endeavor, they researchers created a TFET that could be used to control the electrodes that monitor the flow of electricity into a MOSFET—in this case, the floating-gate variety (it has an additional electrode gate that allows a charge to be retained). The idea is that if the gate could be made to open and close faster, the transistor as a whole would operate faster. Current chips require a build-up of charge before the gate can be opened or closed—which requires time. TFETs, because they require less power, don't take as long to do their work, thus embedding one in a floating gate-MOSFET would alleviate the necessity of power buildup prior to gate changes, allowing for quicker opening and closing. That's exactly what the team in China has done. Testing thus far has shown MOSFETs with embedded TFETs have improved transistor speeds as well as reduced power requirements.

The team reports that because of the way their TFETs are constructed, embedding them in current model MOSFETs should not require reconfiguration or the use of any new materials. This means that the new TFET technology could be put into use almost immediately, bumping up the speed of computers and hand held devices while lessening the amount of energy used, resulting in longer battery life.

More information: A Semi-Floating Gate Transistor for Low-Voltage Ultrafast Memory and Sensing Operation, Science 9 August 2013: Vol. 341 no. 6146 pp. 640-643 DOI: 10.1126/science.1240961

ABSTRACT

As the semiconductor devices of integrated circuits approach the physical limitations of scaling, alternative transistor and memory designs are needed to achieve improvements in speed, density, and power consumption. We report on a transistor that uses an embedded tunneling field-effect transistor for charging and discharging the semi-floating gate. This transistor operates at low voltages (?2.0 volts), with a large threshold voltage window of 3.1 volts, and can achieve ultra–high-speed writing operations (on time scales of ~1 nanosecond). A linear dependence of drain current on light intensity was observed when the transistor was exposed to light, so possible applications include image sensing with high density and performance.

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