Major dopamine system helps restore consciousness after general anesthesia

Researchers may be one step closer to better understanding how anesthesia works. A study in the August issue of Anesthesiology, the official medical journal of the American Society of Anesthesiologists® (ASA®), found stimulating a major dopamine-producing region in the brain, the ventral tegmental area (VTA), caused rats to wake from general anesthesia, suggesting that this region plays a key role in restoring consciousness after general anesthesia. Activating this region at the end of surgery could provide a novel approach to proactively induce consciousness from anesthesia in surgical patients, researchers say.

"While generally safe, it is well known that patients should not be under general anesthesia longer than necessary," said Ken Solt, M.D., lead author, Massachusetts General Hospital Department of Anesthesia, Critical Care and Pain Medicine and assistant professor of anesthesia, Harvard Medical School, Boston. "Currently, there are no treatments to reverse the effects of general anesthesia. We must wait for the anesthetics to wear off. Having the ability to control the process of arousal from general anesthesia would be advantageous as it might speed recovery to normal cognition after surgery and enhance operating room (O.R.) efficiencies."

Although the brain circuits that drive the process of emerging from general anesthesia are not well understood, recent studies suggest that certain arousal pathways in the brain may be activated by certain drugs to promote consciousness. The authors previously reported that methylphenidate (Ritalin), a drug used to treat attention deficit hyperactivity disorder, awakened rats from general anesthesia by activating dopamine-releasing pathways.

In the current study, rats were given the general anesthetics isoflurane or propofol. Once unconscious, researchers performed targeted electrical stimulation, through implanted steel electrodes, on the two major regions of the rats’ brains that contain dopamine-releasing cells – the VTA (the area of the brain that controls cognition, motivation and reward in humans) and the substantia nigra, which controls movement.

Researchers found that electrical stimulation of the VTA caused the rats to regain consciousness, suggesting that dopamine released from cells in this area of the brain is likely involved in arousal. Interestingly, electrical stimulation of the VTA had an effect similar to that of the drug methylphenidate in restoring consciousness after anesthesia.

"We now have evidence that dopamine released by cells in the VTA is mainly responsible for the awakening effect seen with methylphenidate," said Dr. Solt. "Because dopamine-releasing cells in the VTA are important for cognition, we may be able to use drugs that act on this region not only to induce consciousness in anesthetized patients, but to potentially treat common postoperative emergence-related problems such as delirium and restore cognitive function."

‘Free choice’ in primates can be altered through brain stimulation

When electrical pulses are applied to the ventral tegmental area of their brain, macaques presented with two images change their preference from one image to the other. The study by researchers Wim Vanduffel and John Arsenault (KU Leuven and Massachusetts General Hospital) is the first to confirm a causal link between activity in the ventral tegmental area and choice behaviour in primates.

The ventral tegmental area is located in the midbrain and helps regulate learning and reinforcement in the brain’s reward system. It produces dopamine, a neurotransmitter that plays an important role in positive feelings, such as receiving a reward. “In this way, this small area of the brain provides learning signals,” explains Professor Vanduffel. “If a reward is larger or smaller than expected, behavior is reinforced or discouraged accordingly.”

Causal link

This effect can be artificially induced: “In one experiment, we allowed macaques to choose multiple times between two images – a star or a ball, for example. This told us which of the two visual stimuli they tended to naturally prefer. In a second experiment, we stimulated the ventral tegmental area with mild electrical currents whenever they chose the initially nonpreferred image. This quickly changed their preference. We were also able to manipulate their altered preference back to the original favorite.”

The study, which will be published online in the journal Current Biology on 16 June, is the first to confirm a causal link between activity in the ventral tegmental area and choice behaviour in primates. “In scans we found that electrically stimulating this tiny brain area activated the brain’s entire reward system, just as it does spontaneously when a reward is received. This has important implications for research into disorders relating to the brain’s reward network, such as addiction or learning disabilities.”

Could this method be used in the future to manipulate our choices? “Theoretically, yes. But the ventral tegmental area is very deep in the brain. At this point, stimulating it can only be done invasively, by surgically placing electrodes – just as is currently done for deep brain stimulation to treat Parkinson’s or depression. Once non-invasive methods – light or ultrasound, for example – can be applied with a sufficiently high level of precision, they could potentially be used for correcting defects in the reward system, such as addiction and learning disabilities.”

How the Brain Remembers Pleasure and Its Implications for Addiction

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 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.”

(Image: Corbis)

How two brain areas interact to trigger divergent emotional behaviors

New research from the University of North Carolina School of Medicine for the first time explains exactly how two brain regions interact to promote emotionally motivated behaviors associated with anxiety and reward.

The findings could lead to new mental health therapies for disorders such as addiction, anxiety, and depression. A report of the research was published online by the journal, Nature, on March 20, 2013.

Located deep in the brain’s temporal lobe are tightly packed clusters of brain cells in the almond shaped amygdala that are important for processing memory and emotion. When animals or people are in stressful situations, neurons in an extended portion of the amygdala called the bed nucleus of the stria terminalis, or BNST, become hyperactive.

But, almost paradoxically, neurons in the BNST, which modulate fear and anxiety, reach into a portion of the midbrain that’s involved in behavioral responses to reward, the ventral tegmental area, or VTA.

“For many years it’s been known that dopamine neurons in the VTA are involved in reward processing and motivation. For example, they’re activated during exposure to drugs of abuse and naturally rewarding experiences,” says study senior author Garret Stuber, PhD, assistant professor in the departments of Psychiatry and Cell Biology and Physiology, and the UNC Neuroscience Center.  “On the one hand, you have this area of the brain – the BNST – that’s associated with aversion and anxiety, but it’s in direct communication with a brain reward center. We wanted to figure out exactly how these two brain regions interact to promote different types of behavioral responses related to anxiety and reward.”

In the past, researchers have tried to get a glimpse into the inner workings of the brain using electrical stimulation or drugs, but those techniques couldn’t quickly and specifically change only one type of cell or one type of connection. But optogenetics, a technique that emerged about seven years ago, can.

In the technique, scientists transfer light-sensitive proteins called “opsins” – derived from algae or bacteria that need light to grow – into the mammalian brain cells they wish to study. Then they shine laser beams onto the genetically manipulated brain cells, either exciting or blocking their activity with millisecond precision.

Suzanne Dickson: Brain mechanisms of food reward

Studying what makes us want to eat, could help devise approaches to prevent obesity, which is becoming widespread in Europe.

Suzanne Dickson is a Professor of physiology and neuroendocrinology at the Institute of Neuroscience and Physiology, based at the Sahlgrenska Academy at the University of Gothenburg, Sweden. She tells youris.com about her involvement in the EU funded NeuroFAST project. Her focus is on the impact of appetite-regulating gut hormones on parts of the brain that influence food preference and food reward.

This research is also driven by the huge unmet need of treating the growing group of obese patients.

What is the focus of your work relating to food and the brain?
We work on food reward, which involves neurobiological circuits linked to the addiction process. We decided to work on this because increasing evidence linked excessive over-eating to brain pathways involved in reward, including pathways known to be targets for addictive drugs.  Over-eating can be influenced by genetic predisposition traits, psychiatric diseases, cues from the environment that trigger expectation of a food reward. Other factors include socio-economic pressures, stressful lifestyle including stress in the workplace or home.

What is the nature of food reward?
Our specific focus is on the property of the reward value. If animals find food rewarding, they will display altered behaviours that indicate that the reward value of the food is changed. Members of our team are working with sugars, fats and combinations of the above. We have also been working in clinical projects with foods of similar taste but with altered caloric value. By targeting brain mechanisms involved in food reward, we hope to reveal new mechanisms that will help develop new treatment strategies for obesity.

We have studied an area of the brain called ventral tegmental area (VTA) is a key node in the brain’s reward pathway. It is the home of the dopamine cells that are activated by rewards, including food rewards. Its role is very complex. Many believe that these cells are involved in food searching behaviours or food motivation, for example. However, they also can be activated simply by cues associated with foods akin to deciding to consume a chocolate bar by the sight of one at the cashier in a supermarket and novelty of the reward stimulus appears to play a role.

Did you identify the difference between the brain’s pleasure center and hunger center?
The pleasure centres are involved in food intake that is linked to its reward value. Whether we are hungry or fed, by raising the reward value of food the reward system encourages us to eat more, especially rewarding food. This system has been critical during the evolution process to ensure survival from famine. In our modern environment that generates obesity, food reward is no longer our friend as it encourages us to over-indulge in sweet and fatty food, even when we are not hungry.

By contrast, the hunger pathways can be considered more primitive. They detect and respond to nutrient deficit. If we enter negative energy balance, homeostatic pathways become activated informing higher feeding networks to initiate feeding behaviours.

What strategies have studied to try and find ways to limit over-eating?
We have recently learned from the field of bariatric—weight loss—surgery that it is possible to change reward behaviour towards food. This involves unknown mechanisms that are likely linked to the brain’s food reward system. We focus particularly on a hormone called ghrelin whose secretion is altered after bariatric surgery. We hope to reveal new information that is of clinical and therapeutic relevance for future drug strategies for this disease area.

So far, in the laboratory, we have learned a lot about the basic brain mechanisms controlling food reward and the role played by gut hormones in regulating these. We therefore know a lot more about mechanisms—namely about the brain systems and circuits underpinning over-eating—especially for calorie dense foods.

(Image credit: Zorrilla Laboratory, The Scripps Research Institute)

When food porn holds no allure: the science behind satiety

New research from the University of British Columbia is shedding light on why enticing pictures of food affect us less when we’re full.

“We’ve known that insulin plays a role in telling us we’re satiated after eating, but the mechanism by which this happens is unclear,” says Stephanie Borgland, an assistant professor in UBC’s Dept. of Anesthesiology, Pharmacology and Therapeutics and the study’s senior author.

In the new study published online this week in Nature Neuroscience, Borgland and colleagues found that insulin – prompted by a sweetened, high-fat meal – affects the ventral tegmental area (VTA) of the brain, which is responsible for reward-seeking behaviour. When insulin was applied to the VTA in mice, they no longer gravitated towards environments where food had been offered.

“Insulin dulls the synapses in this region of the brain and decreases our interest in seeking out food,” says Borgland, “which in turn causes us to pay less attention to food-related cues.”

“There has been a lot of discussion around the environmental factors of the obesity epidemic,” Borgland adds, pointing to fast food advertising bans in Quebec, Norway, the U.K., Greece and Sweden. “This study helps explain why pictures or other cues of food affect us less when we’re satiated – and may help inform strategies to reduce environmental triggers of overeating.”

The VTA has also been shown to be associated with addictive behaviours, including illicit drug use. Borgland says better understanding of the mechanism in this region of the brain could, in the long run, inform diagnosis and treatment.

(Image: Shutterstock)

Researchers both induce, relieve depression symptoms in mice by stimulating single brain region with light

Researchers at Stanford University have successfully induced and relieved depression-like deficiencies in both pleasure and motivation in mice by controlling just a single area of the brain known as the ventral tegmental area. It is the first time that well-defined types of neurons within a specific brain region have been directly tied to the control of myriad symptoms of major depressive illness.

In the paper published in Nature on Dec. 12, Stanford bioengineer Karl Deisseroth, MD, PhD, and a team including postdoctoral scholars Kay Tye, PhD, and Melissa Warden, PhD, and research assistant Julie Mirzabekov have used a technique known as optogenetics to pinpoint a specific brain location that produces multiple depression-like symptoms. The region in question is the ventral tegmental area, or VTA, a source of dopamine and a central player in the brain’s internal motivation and reward systems.

“We have for the first time directly tied dopamine neurons in the VTA to controlling and relieving these very different and diverse symptoms,” said Deisseroth, the study’s senior author and a professor of bioengineering and of psychiatry and behavioral sciences. “While depression is a complex disease with still many unknowns, this knowledge may help launch new kinds of investigation into the pathways of depression in the brain, and develop concepts to help people suffering from depression.”

Deisseroth’s team was able to both induce and relieve multiple depression-like symptoms in laboratory mice by genetically modifying the dopamine neurons in the VTA to be sensitive to light. Using fiber optic cables inserted in rodents’ brains, they could then instantaneously produce and inhibit the depression-like symptoms by turning the light on and off. This research technique, developed by Deisseroth at Stanford in 2005, is known as optogenetics.