Human behavior guided by fast changes in dopamine levels

What happens in the human brain when we learn from positive and negative experiences? To help answer that question and better understand decision-making and human behavior, scientists are studying dopamine.

Dopamine is a neurotransmitter produced in the brain that serves as a chemical messenger, facilitating communication between nerve cells in the brain and the body. It is involved in functions such as movement, cognition and learning. While dopamine is most known for its association with positive emotions, scientists are also exploring its role in negative experiences.

Now, a new study from researchers at Wake Forest University School of Medicine shows that dopamine release in the human brain plays a crucial role in encoding both reward and punishment prediction errors. This means that dopamine is involved in the process of learning from both positive and negative experiences, allowing the brain to adjust and adapt its behavior based on the outcomes of these experiences.

The study was published today in Science Advances.

"Previously, research has shown that dopamine plays an important role in how animals learn from 'rewarding' (and possibly 'punishing') experiences. But, little work has been done to directly assess what dopamine does on fast timescales in the human brain," said Kenneth T. Kishida, Ph.D., associate professor of physiology and pharmacology and neurosurgery at Wake Forest University School of Medicine. "This is the first study in humans to examine how dopamine encodes rewards and punishments and whether dopamine reflects an 'optimal' teaching signal that is used in today's most advanced artificial intelligence research."

For the study, researchers on Kishida's team utilized fast-scan cyclic voltammetry, an electrochemical technique, paired with machine learning, to detect and measure dopamine levels in real-time (i.e., 10 measurements per second). However, this method is challenging and can only be performed during invasive procedures such as deep-brain stimulation (DBS) brain surgery. DBS is commonly employed to treat conditions such as Parkinson's disease, essential tremor, obsessive-compulsive disorder and epilepsy.

Kishida's team collaborated with Atrium Health Wake Forest Baptist neurosurgeons Stephen B. Tatter, M.D., and Adrian W. Laxton, M.D., who are also both faculty members in the Department of Neurosurgery at Wake Forest University School of Medicine, to insert a carbon fiber microelectrode deep into the brain of three participants at Atrium Health Wake Forest Baptist Medical Center who were scheduled to receive DBS to treat essential tremor.

While the participants were awake in the operating room, they played a simple computer game. As they played the game, dopamine measurements were taken in the striatum, a part of the brain that is important for cognition, decision-making, and coordinated movements.

During the game, participants' choices were either rewarded or punished with real monetary gains or losses. The game was divided into three stages in which participants learned from positive or negative feedback to make choices that maximized rewards and minimized penalties. Dopamine levels were measured continuously, once every 100 milliseconds, throughout each of the three stages of the game.

"We found that dopamine not only plays a role in signaling both positive and negative experiences in the brain, but it seems to do so in a way that is optimal when trying to learn from those outcomes. What was also interesting, is that it seems like there may be independent pathways in the brain that separately engage the dopamine system for rewarding versus punishing experiences. Our results reveal a surprising result that these two pathways may encode rewarding and punishing experiences on slightly shifted timescales separated by only 200 to 400 milliseconds in time," Kishida said.

Kishida believes that this level of understanding may lead to a better understanding of how the dopamine system is affected in humans with psychiatric and neurological disorders. Kishida said additional research is needed to understand how dopamine signaling is altered in psychiatric and neurological disorders.

"Traditionally, dopamine is often referred to as 'the pleasure neurotransmitter,"' Kishida said. "However, our work provides evidence that this is not the way to think about dopamine. Instead, dopamine is a crucial part of a sophisticated system that teaches our brain and guides our behavior. That dopamine is also involved in teaching our brain about punishing experiences is an important discovery and may provide new directions in research to help us better understand the mechanisms underlying depression, addiction, and related psychiatric and neurological disorders."

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How does dopamine regulate both learning and motivation?

A new study from the Netherlands Institute for Neuroscience brings together two schools of thought on the function of the neurotransmitter dopamine: one saying that dopamine provides a learning signal, the other saying that dopamine drives motivation. 'But it is probably both', says Ingo Willuhn.

It is well-known that the dopamine system is implicated in signaling reward-related information as well as in actions that generate rewarding outcomes. This can be investigated using either Pavlovian and operant conditioning experiments. Pavlovian conditioning describes how your brain makes an association between two situations or stimuli that previously seemed unrelated. A famous example is Pavlov's experiment, where a dog heard a sound before receiving food. After several such pairings of the sound with food delivery, the sound alone began to cause the dog to salivate. Operant conditioning, or instrumental learning, differs from this in that the behavior of an individual is important to earn a food reward. Meaning that the individual after hearing a sound, has to perform a so-called operant action to receive the reward. In animal experiments, such a operant response is often the pressing of a lever.

Dopamine measurements in nucleus accumbens

In the final PhD paper of Jessica Goedhoop in collaboration with Tara Arbab and Ingo Willuhn from the Netherlands Institute for Neuroscience, they take a closer look at the role of dopamine signaling in learning and motivation. The team directly compared the two conditioning paradigms: male rats underwent either Pavlovian or operant conditioning while dopamine release was measured in the nucleus accumbens, a brain region central for processing this information. During the experiments a cue light was illuminated for a duration of 5 seconds. For the Pavlovian group, a food pellet was delivered into the reward magazine directly after the cue light turned off. For the operant conditioning group, turning off the cue light was followed by extension of the lever below the cue light into the operant box. The lever was retracted after one lever press, which immediately resulted in the delivery of one food pellet reward into the food magazine. If there was no lever press within 5 seconds after lever extension, the lever was retracted and no reward was delivered.

Sustained dopamine release in operant conditioning

Rats in both groups released the same quantity of dopamine at the onset of the reward-predictive cue. However, only the operant-conditioning group showed a subsequent, sustained plateau in dopamine concentration throughout the entire 5-second cue presentation (throughout cue presentation and before lever press). This dopamine sustainment was observed reliably and consistently throughout systematic manipulation of experimental parameters and behavioral training. Therefore, the researchers believe that sustained dopamine levels may be an intermediate between learning and action, conceptually related to the motivation to generate a reward-achieving action.

Ingo Willuhn: 'There have been a lot of studies on dopamine. We have a decent idea of when dopamine is released in the brain, but there is still lots of discussion on what the precise variables are that determine such dopamine signaling. Essentially discussion on what dopamine "means." To investigate this, scientists usually perform either Pavlovian or operant conditioning experiments. But they test slightly different things. Both have to do with learning an association between a neutral stimulus and a reward. But operant conditioning requires the motivation to perform an action in addition to that (to earn the reward). Therefore, we compared the two types of conditioning in the same experiment.'

Adding a piece to the puzzle

'Our results bring together the two camps of scientists that often battle with each other: one says that dopamine is a so-called reward-prediction error signal, meaning that dopamine is released when something better than expected happens, and is suppressed when something worse than expected happens. It is a learning (or teaching) signal. The other camp says that this is not true. They say that dopamine has something to do with motivation. Increased dopamine release will invigorate the subjects and they work harder to get the reward. There have been a few attempts in the past to bring these two camps together, but there is still need for more knowledge on the subject.'

'What we saw in our study is that only in the operant-learning task dopamine levels stayed high. It seems that the motivation is encoded in this plateau. Reward prediction is the initial dopamine peak, but how much the signal stays up, reflects motivation. Thus, our paper suggests that there is a possibility that dopamine is involved in both, learning and motivation. The next steps will be to get more details out of this. We need to replicate the experiments and make them more sophisticated. The more sophisticated you make it, the more precise our predictions have to be. We are going to build on it and see whether it still holds up.'

Implications

'Dopamine is not only involved in everyday life but also in disorders such as addiction, Parkinson's disease, and schizophrenia. Because of the two camps existing, there is disagreement about what happens exactly. For example, some researchers say that when addicts take drugs dopamine release increases and as a consequence all the environmental cues become more meaningful. Addicts learn that these cues are associated with the drug and they take more and more drug, because they are constantly reminded of the drug everywhere. In this view, addiction is misguided learning. Other researchers would say that motivation to take the drug intensifies with more frequent drug intake, because the drug elevates dopamine release. This study indicates that it may be both. Depending on the precise timing, both systems could be the driver, and both could be involved.'

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Whether physical exertion feels 'easy' or 'hard' may be due to dopamine levels, study suggests

Dopamine, a brain chemical long associated with pleasure, motivation and reward-seeking, also appears to play an important role in why exercise and other physical efforts feel "easy" to some people and exhausting to others, according to results of a study of people with Parkinson's disease led by Johns Hopkins Medicine researchers. Parkinson's disease is marked by a loss of dopamine-producing cells in the brain over time.

The findings, published online April 1 in NPG Parkinson's Disease, could, the researchers say, eventually lead to more effective ways to help people establish and stick with exercise regimens, new treatments for fatigue associated with depression and many other conditions, and a better understanding of Parkinson's disease.

"Researchers have long been trying to understand why some people find physical effort easier than others," says study leader Vikram Chib, Ph.D., associate professor in the Department of Biomedical Engineering at the Johns Hopkins University School of Medicine and research scientist at the Kennedy Krieger Institute. "This study's results suggest that the amount of dopamine availability in the brain is a key factor."

Chib explains that after a bout of physical activity, people's perception and self-reports of the effort they expended varies, and also guides their decisions about undertaking future exertions. Previous studies have shown that people with increased dopamine are more willing to exert physical effort for rewards, but the current study focuses on dopamine's role in people's self-assessment of effort needed for a physical task, without the promise of a reward.

For the study, Chib and his colleagues from Johns Hopkins Medicine and the Kennedy Krieger Institute recruited 19 adults diagnosed with Parkinson's disease, a condition in which neurons in the brain that produce dopamine gradually die off, causing unintended and uncontrollable movements such as tremors, fatigue, stiffness and trouble with balance or coordination.

In Chib's lab, 10 male volunteers and nine female volunteers with an average age of 67 were asked to perform the same physical task -- squeezing a hand grip equipped with a sensor -- on two different days within four weeks of each other. On one of the days, the patients were asked to take their standard, daily synthetic dopamine medication as they normally would. On the other, they were asked not to take their medication for at least 12 hours prior to performing the squeeze test.

On both days, the patients were initially taught to squeeze a grip sensor at various levels of defined effort, and then were asked to squeeze and report how many units of effort they put forth.

When the participants had taken their regular synthetic dopamine medication, their self-assessments of units of effort expended were more accurate than when they hadn't taken the drug. They also had less variability in their efforts, showing accurate squeezes when the researchers cued them to squeeze at different levels of effort.

In contrast, when the patients hadn't taken the medication, they consistently over-reported their efforts -- meaning they perceived the task to be physically harder -- and had significantly more variability among grips after being cued.

In another experiment, the patients were given a choice between a sure option of squeezing with a relatively low amount of effort on the grip sensor or flipping a coin and taking a chance on having to perform either no effort or a very high level of effort. When these volunteers had taken their medication, they were more willing to take a chance on having to perform a higher amount of effort than when they didn't take their medication.

A third experiment offered participants the choice between getting a small amount of guaranteed money or, with the flip of a coin, getting either nothing or a higher amount of money. Results showed no difference in the subjects on days when they took their medication and when they did not. This result, researchers say, suggests that dopamine's influence on risk-taking preferences is specific to physical effort-based decision-making.

Together, Chib says, these findings suggest that dopamine level is a critical factor in helping people accurately assess how much effort a physical task requires, which can significantly affect how much effort they're willing to put forth for future tasks. For example, if someone perceives that a physical task will take an extraordinary amount of effort, they may be less motivated to do it.

Understanding more about the chemistry and biology of motivation could advance ways to motivate exercise and physical therapy regimens, Chib says. In addition, inefficient dopamine signaling could help explain the pervasive fatigue present in conditions such as depression and long COVID, and during cancer treatments. Currently, he and his colleagues are studying dopamine's role in clinical fatigue.

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Boost in nerve-growth protein helps explain why running supports brain health

Exercise increases levels of a chemical involved in brain cell growth, which bolsters the release of the "feel good" hormone dopamine, a new study shows. Dopamine is known to play a key role in movement, motivation, and learning.

Experts have long understood that regular running raises dopamine activity in the brain and may protect nerve cells from damage. In addition, past research has tied exercise-driven boosts in the dopamine-triggering chemical called brain-derived neurotrophic factor (BDNF) and in dopamine levels to improvements in learning and memory. However, the precise way these three factors interact has until now remained unclear.

Led by researchers at NYU Grossman School of Medicine, the investigation showed that mice running on a wheel for 30 days had a 40% increase in dopamine release in the dorsal stratium, the part of the brain involved in movement, compared to levels in mice that did not exercise. The runners also showed a nearly 60% increase in BDNF levels compared to their non-running counterparts. Notably, the increase in dopamine release remained elevated even after a week of rest. Additionally, when BDNF levels were artificially reduced, running did not lead to additional dopamine release.

"Our findings suggest that BDNF plays a key role in the long-lasting changes that occur in the brain as a result of running," says study lead author and neurobiologist Guendalina Bastioli, PhD. "Not only do these results help explain why exercise makes you move, think, and feel better, they also show that these benefits continue even if you do not work out every day," adds Bastioli, a postdoctoral fellow in the Department of Neuroscience at NYU Langone Health.

While researchers have previously measured dopamine activity during running, the new investigation provides insight into the longer-term behavior of the hormone and its effects on the brain well after exercise stops, according to Bastioli. The report is publishing online May 16 in the Journal of Neuroscience.

For the investigation, researchers provided dozens of male mice with unlimited access to either a freely rotating wheel or a locked wheel that could not move. After one month, the team measured dopamine release and BDNF levels in brain slices. They repeated this same process on a new group of rodents, some of which had been genetically modified to produce half as much BDNF as regular mice.

The study authors note that patients with Parkinson's disease and other movement disorders are often treated with drugs that mimic dopamine's effects on motor neurons. However, the mechanism behind dopamine's role in this protective benefit of exercise had not been thoroughly explored.

"Our results help us understand why exercise alleviates the symptoms of Parkinson's disease, as well as those of neuropsychiatric disorders such as depression," says study senior author and neuroscientist Margaret Rice, PhD. "Now that we know why physical activity helps, we can explore it as a means of augmenting or even replacing the use of dopamine-enhancing drugs in these patients."

Rice, a professor in the Departments of Neurosurgery and Neuroscience and Physiology at NYU Langone, cautions that while the preliminary findings in rodents were promising, future studies in humans will be required to fully understand the role of BDNF and dopamine in Parkinson's disease.

She adds that the study team next plans to investigate the relationship between exercise and these chemicals in female mice, which notably run more frequently than males. In addition, the researchers intend to directly examine whether active mice indeed have improved motor skills compared with those with limited physical activity.

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A key brain region for substance use disorders now has a searchable atlas of distinct cell populations

In a work of systematic biology that advances the field, University of Alabama at Birmingham researchers have identified 16 distinct cell populations in a complex area of the midbrain called the ventral tegmental area, or VTA.

The VTA is important for its role in the dopamine neurotransmission involved in reward-directed behavior. Substance use disorders involve dysregulation of these reward circuits, leading to repeated drug-seeking despite adverse consequences. These include more than 100,000 drug overdose deaths in the United States in the most recent year. The VTA also has a role in several other neuropsychiatric disorders.

Thus, expanding knowledge of its function is a start to explaining the mechanisms for substance use disorders involving drugs like cocaine, alcohol, opioids and nicotine, or psychiatric disorders like schizophrenia and attention deficit hyperactivity, or ADHD.

Dopamine is one of the neurotransmitters used by the brain as chemical messengers to send signals between nerve cells. While decades of research have focused on dopaminergic neurotransmission in the VTA, there is also substantial evidence for the importance of two other neurotransmitters acting in the VTA in reward-related behaviors -- GABA and glutamate. There is also evidence for "combinatorial" neurons that can potentially synthesize and release multiple neurotransmitters. These suggest an additional layer of complexity in VTA cellular and synaptic function.

Systematic biology is the science of classification, and it usually refers to the classification of organisms with regard to their natural relationships. The UAB VTA study classifies cell populations to extend and deepen previous work on the different cell types in the VTA, to provide a starting point for deciphering the relationships among these cells and their broad connections to other areas of the brain. The research, published in Cell Reports, was led by co-first authors Robert A. Phillips III and Jennifer J. Tuscher, Ph.D., and corresponding author Jeremy J. Day, Ph.D.

The 16 distinct cell populations were identified by differences in gene expression after single-nucleus RNA sequencing of 21,600 cells from the rat VTA, creating a searchable online atlas of the VTA. The rat is the prime model for reward and substance use studies. This unbiased approach -- in contrast to previous studies that selected some subsets of cells for RNA sequencing -- was used to create the largest and most comprehensive single-cell transcriptomic analysis focused exclusively on the composition and molecular architecture of the VTA.

Though it was well known that the VTA is composed of heterogeneous cell types, the UAB atlas expands those studies in several key ways.

"For example, previous single-cell sequencing studies were conducted exclusively in the mouse brain and have relied primarily on sequencing a subset of fluorescence-activated cell sorting-isolated midbrain dopaminergic populations, rather than sampling all VTA cell types," Day said. "Notably, our sequencing dataset focuses exclusively on VTA sub-regions, unlike other studies that have focused on pooled cells from the mouse substantia nigra and VTA or a subset of fluorescently tagged cells from general midbrain regions."

The 16 distinct cell populations include classic dopaminergic neurons, three subsets of glutamatergic neurons and three subsets of GABAergic neurons, as well as nine other cell types, including astrocytes and glial cells.

After sub-clustering neuronal cells, the UAB researchers also identified four sub-clusters that may represent neurons capable of combinatorial neurotransmitter release. They also identified selective gene markers for classically defined dopamine neurons and for the combinatorial neurons. A selective marker allows viral targeting of distinct VTA subclasses for functional studies.

The researchers also examined sub-clusters for opioid neuropeptides and their receptors, and identified pan-neuronal increased expression for risk genes associated with schizophrenia and "smoking initiation," as well as enrichment of ADHD risk genes in two glutamatergic neuronal populations.

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Flies possess more sophisticated cognitive abilities than previously known

As they annoyingly buzz around a batch of bananas in our kitchens, fruit flies appear to have little in common with mammals. But as a model species for science, researchers are discovering increasing similarities between us and the miniscule fruit-loving insects.

In a new study, researchers at the University of California San Diego's Kavli Institute for Brain and Mind (KIBM) have found that fruit flies (Drosophila melanogaster) have more advanced cognitive abilities than previously believed. Using a custom-built immersive virtual reality environment, neurogenetic manipulations and in vivo real-time brain-activity imaging, the scientists present new evidence Feb. 16 in the journal Nature of the remarkable links between the cognitive abilities of flies and mammals.

The multi-tiered approach of their investigations found attention, working memory and conscious awareness-like capabilities in fruit flies, cognitive abilities typically only tested in mammals. The researchers were able to watch the formation, distractibility and eventual fading of a memory trace in their tiny brains.

"Despite a lack of obvious anatomical similarity, this research speaks to our everyday cognitive functioning -- what we pay attention to and how we do it," said study senior author Ralph Greenspan, a professor in the UC San Diego Division of Biological Sciences and associate director of KIBM. "Since all brains evolved from a common ancestor, we can draw correspondences between fly and mammalian brain regions based on molecular characteristics and how we store our memories."

To arrive at the heart of their new findings the researchers created an immersive virtual reality environment to test the fly's behavior via visual stimulation and coupled the displayed imagery with an infra-red laser as an averse heat stimulus. The near 360-degree panoramic arena allowed Drosophila to flap their wings freely while remaining tethered, and with the virtual reality constantly updating based on their wing movement (analyzed in real-time using high-speed machine-vision cameras) it gave the flies the illusion of flying freely in the world. This gave researchers the ability to train and test flies for conditioning tasks by allowing the insect to orient away from an image associated with the negative heat stimulus and towards a second image not associated with heat.

They tested two variants of conditioning, one in which flies were given visual stimulation overlapping in time with the heat (delay conditioning), both ending together, or a second, trace conditioning, by waiting 5 to 20 seconds to deliver the heat after showing and removing the visual stimulation. The intervening time is considered the "trace" interval during which the fly retains a "trace" of the visual stimulus in its brain, a feature indicative of attention, working memory and conscious awareness in mammals.

The researchers also imaged the brain to track calcium activity in real-time using a fluorescent molecule they genetically engineered into their brain cells. This allowed the researchers to record the formation and duration of the fly's living memory since they saw the trace blinking on and off while being held in the fly's short-term (working) memory. They also found that a distraction introduced during training -- a gentle puff of air -- made the visual memory fade more quickly, marking the first time researchers have been able to prove such distractedness in flies and implicating an attentional requirement in memory formation in Drosophila.

"This work demonstrates not only that flies are capable of this higher form of trace conditioning, and that the learning is distractible just like in mammals and humans, but the neural activity underlying these attentional and working memory processes in the fly show remarkable similarity to those in mammals," said Dhruv Grover, a UC San Diego KIBM research faculty member and lead author of the new study. "This work demonstrates that fruit flies could serve as a powerful model for the study of higher cognitive functions. Simply put, the fly continues to amaze in how smart it really is."

The scientists also identified the area of the fly's brain where the memory formed and faded -- an area known as the ellipsoid body of the fly's central complex, a location that corresponds to the cerebral cortex in the human brain.

Further, the research team discovered that the neurochemical dopamine is required for such learning and higher cognitive functions. The data revealed that dopamine reactions increasingly occurred earlier in the learning process, eventually anticipating the coming heat stimulus.

The researchers are now investigating details of how attention is physiologically encoded in the brain. Grover believes the lessons learned from this model system are likely to directly inform our understanding of human cognition strategies and neural disorders that disrupt them, but also contribute to new engineering approaches that lead to performance breakthroughs in artificial intelligence designs.

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A new understanding of mental illness

The causes of psychiatric disorders are poorly understood. Now, in work led by researchers at McGill University, there is evidence that a wide range of early onset psychiatric problems (from depression, anxiety and addictions to dyslexia, bulimia, and ADHD) may be largely due to the combination of just three factors. The first is biological -- in the form of individual variability in the brain's dopamine reward pathway. The second is social -- and points to the important role of early childhood neglect or abuse. And the third is psychological -- and relates to temperament, and particularly to tendencies toward impulsivity and difficulty controlling emotions. These findings have implications for understanding both the causes of a wide range of psychiatric disorders and the features worth targeting in early intervention efforts.

"Until recently, it was thought that psychiatric disorders reflected discrete disease entities, each with their own unique causes," says Marco Leyton, the senior author on a recent study published in Neuropsychopharmacologyand a professor in McGill's Department of Psychiatry and Senior Scientist at the Research Institute of the McGill University Health Centre. "The present research upends this idea, suggesting instead that most early onset disorders largely reflect differential expressions of a small number of biological, psychological and social factors."

First study to combine three key factors: temperament, trauma and dopamine

Earlier research has suggested that each of the three factors, in isolation, has at least modest effects on the development of psychiatric disorders. In comparison, the authors of this new study had the first ever opportunity to examine all three factors together. Fifty-two young people, living in the Montreal or Quebec City areas (30 women and 22 men), who have been followed since birth by Jean Séguin (Université de Montréal) and Michel Boivin (Université Laval), had brain imaging scans (PET and MRI) that measured features of their dopamine reward pathway. These brain features were then combined with information about their temperamental traits and histories of early life adversity.

High accuracy & potential predictive value of approach

Strikingly, this combination of just three factors predicted, with over 90% accuracy, which participants had mental health problems either in the past or during the study's three-year follow-up period. Indeed, since the results are so novel and potentially so important, CIHR has provided an additional two million dollars to double the sample size and follow the participants through to their mid-20s. "And the results do need to be replicated, both in larger and ethnically more diverse groups," emphasizes the paper's first author, Maisha Iqbal, a graduate student in McGill's Integrated Program in Neuroscience. "If replicated, our research could transform the way we think about mental illnesses."

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To do or not to do: Cracking the code of motivation

Our motivation to put effort for achieving a goal is controlled by a reward system wired in the brain. However, many neuropathological conditions impair the reward system, diminishing the will to work. Recently, scientists in Japan experimentally manipulated the reward system network of monkeys and studied their behavior. They deciphered a few critical missing pieces of the reward system puzzle that might help in increasing motivation.

Why do we do things? What persuades us to put an effort to achieve goals, however mundane? What, for instance, drives us to search for food? Neurologically, the answer is hidden in the reward system of the brain -- an evolutionary mechanism that controls our willingness to work or to take a risk as the cost of achieving our goals and enjoying the perceived rewards. In people suffering from depression, schizophrenia, or Parkinson's disease, often the reward system of the brain is impaired, leading them to a state of diminished motivation for work or chronic fatigue.

To find a way to overcome the debilitating behavioral blocks, neuroscientists are investigating the "anatomy" of the reward system and determining how it evaluates the cost-benefit trade-off while deciding on whether to pursue a task. Recently, Dr. Yukiko Hori of National Institutes for Quantum and Radiological Science and Technology, Japan, along with her colleagues have conducted a study that has answered some of the most critical questions on benefit- and cost-based motivation of reward systems. The findings of their study have been published in PLoS Biology.

Discussing what prompted them to undertake the study, Dr. Hori explains: "Mental responses such as 'feeling more costly and being too lazy to act,' are often a problem in patients with mental disorders such as depression, and the solution lies in the better understanding of what causes such responses. We wanted to look deeper into the mechanism of motivational disturbances in the brain."

To do so, Dr. Hori and her team focused on dopamine (DA), the "neurotransmitter" or the signaling molecule that plays the central role in inducing motivation and regulation of behavior based on cost-benefit analysis. The effect of DA in the brain transmits via DA receptors, or molecular anchors that bind the DA molecules and propagate the signals through the neuronal network of the brain. However, as these receptors have distinct roles in DA signal transduction, it was imperative to assess their relative impacts on DA signaling. Therefore, using macaque monkeys as models, the researchers aimed to decipher the roles of two classes of DA receptors -- the D1-like receptor (D1R) and the D2-like receptor (D2R) -- in developing benefit- and cost-based motivation.

In their study, the researchers first trained the animals to perform "reward size" tasks and "work/delay tasks." These tasks allowed them to measure how perceived reward size and required effort influenced the task-performing behavior. Dr. Takafumi Minamimoto, the corresponding author of the study explains, "We systematically manipulated the D1R and D2R of these monkeys by injecting them with specific receptor-binding molecules that dampened their biological responses to DA signaling. By positron emission tomography-based imaging of the brains of the animals, the extent of bindings or blockades of the receptors was measured." Then, under experimental conditions, they offered the monkeys the chance to perform tasks to achieve rewards and noted whether the monkeys accepted or refused to perform the tasks and how quickly they responded to the cues related to the tasks.

Analysis of these data unearthed some intriguing insights into the neurobiological mechanism of the decision-making process. The researchers observed that decision-making based on perceived benefit and cost required the involvement of both D1R and D2R, in both incentivizing the motivation (the process in which the size of the rewards inspired the monkeys to perform the tasks) and in increasing delay discounting (the tendency to prefer immediate, smaller rewards over larger, but delayed rewards). It also became clear that DA transmission via D1R and D2R regulates the cost-based motivational process by distinct neurobiological processes for benefits or "reward availability" and costs or "energy expenditure associated with the task." However, workload discounting -- the process of discounting the value of the rewards based on the proportion of the effort needed -- was exclusively related to D2R manipulation.

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'Feel good' brain messenger can be willfully controlled, new study reveals

From the thrill of hearing an ice cream truck approaching to the spikes of pleasure while sipping a fine wine, the neurological messenger known as dopamine has been popularly described as the brain's "feel good" chemical related to reward and pleasure.

A ubiquitous neurotransmitter that carries signals between brain cells, dopamine, among its many functions, is involved in multiple aspects of cognitive processing. The chemical messenger has been extensively studied from the perspective of external cues, or "deterministic" signals. Instead, University of California San Diego researchers recently set out to investigate less understood aspects related to spontaneous impulses of dopamine. Their results, published July 23 in the journal Current Biology, have shown that mice can willfully manipulate these random dopamine pulses.

Rather than only occurring when presented with pleasurable, or reward-based expectations, UC San Diego graduate student Conrad Foo led research that found that the neocortex in mice is flooded with unpredictable impulses of dopamine that occur approximately once per minute.

Working with colleagues at UC San Diego (Department of Physics and Section of Neurobiology) and the Icahn School of Medicine at Mount Sinai in New York, Foo investigated whether mice are in fact aware that these impulses -- documented in the lab through molecular and optical imaging techniques -- are actually occurring. The researchers devised a feedback scheme in which mice on a treadmill received a reward if they showed they were able to control the impromptu dopamine signals. Not only were mice aware of these dopamine impulses, the data revealed, but the results confirmed that they learned to anticipate and volitionally act upon a portion of them.

"Critically, mice learned to reliably elicit (dopamine) impulses prior to receiving a reward," the researchers note in the paper. "These effects reversed when the reward was removed. We posit that spontaneous dopamine impulses may serve as a salient cognitive event in behavioral planning."

The researchers say the study opens a new dimension in the study of dopamine and brain dynamics. They now intend to extend this research to explore if and how unpredictable dopamine events drive foraging, which is an essential aspect of seeking sustenance, finding a mate and as a social behavior in colonizing new home bases.

"We further conjecture that an animal's sense of spontaneous dopamine impulses may motivate it to search and forage in the absence of known reward-predictive stimuli," the researchers noted.

In their efforts to control dopamine, the researchers clarified that dopamine appears to invigorate, rather than initiate, motor behavior.

"This started as a serendipitous finding by a talented, and curious, graduate student with intellectual support from a wonderful group of colleagues," said study senior co-author David Kleinfeld, a professor in the Department of Physics (Division of Physical Sciences) and Section of Neurobiology (Division of Biological Sciences). "As an unanticipated result, we spent many long days expanding on the original study and of course performing control experiments to verify the claims. These led to the current conclusions."

Scientists find neurochemicals have unexpectedly profound roles in the human brain

 In first-of-their-kind observations in the human brain, an international team of researchers has revealed two well-known neurochemicals -- dopamine and serotonin -- are at work at sub-second speeds to shape how people perceive the world and take action based on their perception.

The discovery shows researchers can continually and simultaneously measure the activity of both dopamine and serotonin -- whose receptor and uptake sites are therapeutic targets for disorders ranging from depression to Parkinson's disease -- in the human brain.

Furthermore, the neurochemicals appear to integrate people's perceptions of the world with their actions, indicating dopamine and serotonin have far more expansive roles in the human nervous system than previously known.

Known as neuromodulators, dopamine and serotonin have traditionally been linked to reward processing -- how good or how bad people perceive an outcome to be after taking an action.

The study online today in the journal Neuron opens the door to a deeper understanding of an expanded role for these systems and their roles in human health.

"An enormous number of people throughout the world are taking pharmaceutical compounds to perturb the dopamine and serotonin transmitter systems to change their behavior and mental health," said P. Read Montague, senior author of the study and a professor and director of the Center for Human Neuroscience Research and the Human Neuroimaging Laboratory at the Fralin Biomedical Research Institute at Virginia Tech Carilion. "For the first time, moment-to-moment activity in these systems has been measured and determined to be involved in perception and cognitive capacities. These neurotransmitters are simultaneously acting and integrating activity across vastly different time and space scales than anyone expected."

Better understanding of the underlying actions of dopamine and serotonin during perception and decision-making could deliver important insight into psychiatric and neurological disorders, the researchers said.

"Every choice that someone executes involves taking in information, interpreting that information, and making decisions about what they perceived," said Kenneth Kishida, a corresponding author of the study and an assistant professor of physiology and pharmacology, and neurosurgery, at Wake Forest School of Medicine. "There's a whole host of psychiatric conditions and neurological disorders where that process is altered in the patients, and dopamine and serotonin are prime suspects."

Lack of chemically specific methods to study neuromodulation in humans at fast time scales has impeded understanding of these systems, according to Montague, who is an honorary professor at the Wellcome Center for Human Neuroimaging at University College London and a professor of physics at the Virginia Tech College of Science.

But now, in first-ever measurements, scientists used an electrochemical method called "fast scan cyclic voltammetry," which employs a small carbon fiber microelectrode that has low voltages ramped across it for real-time detection of dopamine and serotonin activity.

In the study, researchers recorded fluctuations in dopamine and serotonin using specially designed electrodes in five patients undergoing deep brain stimulation electrode implantation surgery to treat essential tremor or Parkinson's disease. Patients were awake during surgery, playing a computer game designed to quantify aspects of thought and behavior while the measurements were taken.

On each round of the game, patients briefly viewed a cloud of dots and were asked to judge the direction they were moving. The method, designed by corresponding author Dan Bang, a Sir Henry Wellcome Postdoctoral Fellow, and Steve Fleming, a Sir Henry Dale/Royal Society Fellow, both at the Wellcome Center for Human Neuroimaging at University College London, helped indicate that dopamine and serotonin were involved in simple perceptual decisions, outside of the traditional context of rewards and losses.

"These neuromodulators play a much broader role in supporting human behavior and thought, and in particular they are involved in how we process the outside world," Bang said. "For example, if you move through a room and the lights are off, you move differently because you're uncertain about where objects are. Our work suggests these neuromodulators -- serotonin in particular -- are playing a role in signaling how uncertain we are about the outside environment."

Montague and Kishida, along with Terry Lohrenz, a research assistant professor, and Jason White, a senior research associate, now both at the Fralin Biomedical Research Institute, started working on a new statistical approach to identify dopamine and serotonin signals while still at the Baylor College of Medicine in Houston, Texas.

"Ken rose to the challenge of doing fast neurochemistry in human beings during active cognition," Montague said. "A lot of other good groups of scientists were not able to do it. Aside from the computation of enormous amounts of data, there are complicated issues to solve, including great, fundamental algorithmic tasks."

Until recently, only slow methodologies such as PET scanning could measure the impact of neurotransmitters, but they were nowhere near the frequency or volume of the second-to-second measurements of fast scan cyclic voltammetry.

The measurements in the new study were taken at the Wake Forest Baptist Medical Center, and involved neurosurgical teams led by Adrian W. Laxton and Stephen B. Tatter.

"The enthusiasm the neurosurgeons have for this research is derived from the same reasons that drove them to be doctors -- first and foremost, they want to do the best for their patients, and they have a real passion for understanding how the brain works to improve patient outcomes," said Kishida, who oversaw the data collection in the operating room during the surgeries. "Both are collaborative scientists along with Charles Branch, the chair of the neurosurgery department at Wake Forest, who has been an amazing advocate for this work."

Likewise, Montague said, "You can't do it without the surgeons being real, shoulder-to-shoulder partners, and certainly not without the people who let you make recordings from their brains while they are having electrodes implanted to alleviate the symptoms of a neurological disorder."

Montague had read a study in the Proceedings of the National Academy of Sciences that prompted him to approach colleagues Bang and Fleming at University College London to tailor a task for patients to perform during surgery that would reveal sub-second dopamine and serotonin signaling in real-time inference about the external world -- separate from their often-reported roles in reward-related processes.

"I said I have this new method to measure dopamine and serotonin, but I need you to help with the task," Montague said. "They ended up in the study. The research really took a lot of hard work and an integrated a constellation of people to obtain these results."

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New dopamine sensors could help unlock the mysteries of brain chemistry

 In 2018, Lin Tian and her team at UC Davis Health developed dLight1, a single fluorescent protein-based biosensor. This family of highly specific sensors detects dopamine, a hormone released by neurons to send signals to other nerve cells. When combined with advanced microscopy, dLight1 provides high resolution, real-time imaging of the spatial and temporal release of dopamine in live animals.

Recently, Tian and her team succeeded in expanding the color spectrum of the dLight1 sensor. In an article published Sept. 7 in Nature Methods, they introduced two new spectral variants of dLight1: the yellow YdLight1 and the red RdLight1.

"The new sensors will help researchers to detect and monitor different information processing activities in the brain," said Lin Tian, associate professor of biochemistry and molecular medicine and the lead author on the study. "With the different colors, we will be able to see multiple neurochemical release and neural activities at the same time."

The RdLight1 permits the simultaneous assessment of dopamine, pre- or post-synaptic neuronal activity and the glutamate release in specific types of cells and neuronal projections in animals. Its increased light penetration and imaging depth provide enhanced dopamine signal quality. This allows researchers to optically dissect dopamine's release and model its effects on neural circuits.

As a neurotransmitter, dopamine plays an important role in movement, attention, learning and the brain's pleasure and reward system.

"These exciting new tools opened a new door to developing color-shifted neurochemical indicators. Together with other tools, they have great potential to unlock the mysteries of brain chemistry in health and disease," Tian said. "The knowledge we gain from these sensors will facilitate the development of safer next-generation therapies to neuropsychiatric disorders such as depression, anxiety, schizophrenia and addiction."

From Science Daily

Study finds dopamine, biological clock link to snacking, overeating and obesity

Clock and eating concept.

During the years 1976 through 1980, 15% of U.S. adults were obese. Today, about 40% of adults are obese. Another 33% are overweight.

Coinciding with this increase in weight are ever-rising rates of heart disease, diabetes, cancer and health complications caused by obesity, such as hypertension. Even Alzheimer's disease may be partly attributable to obesity and physical inactivity.

"The diet in the U.S. and other nations has changed dramatically in the last 50 years or so, with highly processed foods readily and cheaply available at any time of the day or night," Ali Güler, a professor of biology at the University of Virginia, said. "Many of these foods are high in sugars, carbohydrates and calories, which makes for an unhealthy diet when consumed regularly over many years."

In a study published Thursday in the journal Current Biology, Güler and his colleagues demonstrate that the pleasure center of the brain that produces the chemical dopamine, and the brain's separate biological clock that regulates daily physiological rhythms, are linked, and that high-calorie foods -- which bring pleasure -- disrupt normal feeding schedules, resulting in overconsumption. Using mice as study models, the researchers mimicked the 24/7 availability of a high-fat diet, and showed that anytime snacking eventually results in obesity and related health problems.

Güler's team found that mice fed a diet comparable to a wild diet in calories and fats maintained normal eating and exercise schedules and proper weight. But mice fed high-calorie diets laden with fats and sugars began "snacking" at all hours and became obese.

Additionally, so-called "knockout" mice that had their dopamine signaling disrupted -- meaning they didn't seek the rewarding pleasure of the high-fat diet -- maintained a normal eating schedule and did not become obese, even when presented with the 24/7 availability of high-calorie feeds.

"We've shown that dopamine signaling in the brain governs circadian biology and leads to consumption of energy-dense foods between meals and during odd hours," Güler said.

Other studies have shown, Güler said, that when mice feed on high-fat foods between meals or during what should be normal resting hours, the excess calories are stored as fat much more readily than the same number of calories consumed only during normal feeding periods. This eventually results in obesity and obesity-related diseases, such as diabetes.

Speaking of the modern human diet, Güler said, "The calories of a full meal may now be packed into a small volume, such as a brownie or a super-size soda. It is very easy for people to over-consume calories and gain excessive weight, often resulting in obesity and a lifetime of related health problems.

"Half of the diseases that affect humans are worsened by obesity. And this results in the need for more medical care and higher health care costs for individuals, and society."

Güler said the human body, through thousands of years of evolution, is hard-wired to consume as much food as possible as long as it's available. He said this comes from a long earlier history when people hunted or gathered food and had brief periods of plenty, such as after a kill, and then potentially lengthy periods of famine. Humans also were potential prey to large animals and so actively sought food during the day, and sheltered and rested at night.

"We evolved under pressures we no longer have," Güler said. "It is natural for our bodies as organisms to want to consume as much as possible, to store fat, because the body doesn't know when the next meal is coming.

"But, of course, food is now abundant, and our next meal is as close as the kitchen, or the nearest fast-food drive-through, or right here on our desk. Often, these foods are high in fats, sugars, and therefore calories, and that's why they taste good. It's easy to overconsume, and, over time, this takes a toll on our health."

Additionally, Güler said, prior to the advent of our electricity-powered society, people started the day at dawn, worked all day, often doing manual labor, and then went to sleep with the setting of the sun. Human activity, therefore, was synchronized to day and night. Today, we are working, playing, staying connected -- and eating -- day and night. This, Guler said, affects our body clocks, which were evolved to operate on a sleep-wake cycle timed to daytime activity, moderate eating and nighttime rest.

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Evidence in mice that childhood asthma is influenced by the neurotransmitter dopamine

Neurons that produce the neurotransmitter dopamine communicate with T cells to enhance allergic inflammation in the lungs of young mice but not older mice, researchers report November 19 in the journal Immunity. The findings potentially explain why asthma susceptibility is higher in children than in adults. By highlighting the important role of interactions between the nervous system and the immune system in childhood asthma, the results could lead to new strategies for treating the common chronic disease.

"This is the first study that reveals a contribution of age-related nerve-T cell communication to susceptibility to the development of asthma in young children," says senior study author Xingbin Ai, a Harvard researcher at Brigham & Women's Hospital and Massachusetts General Hospital. "Since asthma often starts in early childhood, we believe that the identification of disease mechanisms unique to young age will provide novel therapeutic targets for early intervention of asthma."

Asthma is a potentially life-threatening chronic condition that intermittently inflames and narrows the airways in the lungs, causing wheezing, chest tightness, shortness of breath, and coughing. Although medical treatment and management of environmental triggers can help control symptoms, there is currently no cure for the disease. In the United States, asthma affects more than 26 million people, including an estimated 6 million children. In fact, it is one of the most common long-term diseases of childhood.

Ai and colleagues suspected that the nervous system, which communicates with the immune system to regulate inflammation, might explain the high prevalence of asthma in children. As the nervous system continues to develop after birth, neurons may modulate tissue inflammation in an age-related manner.

In the new study, Ai and colleagues investigated the role of the developing nervous system in asthma characterizing early age. The researchers discovered that sympathetic nerves innervating the mouse lung primarily produced dopamine in early postnatal life but another neurotransmitter called norepinephrine in adult life. A similar pattern was evident when they compared lung and lymph node tissues from children up to 13 years of age and adults ranging in age from 40 to 65 years.

In addition, the researchers found that dopamine released by sympathetic nerves innervating the lung binds to the dopamine neurotransmitter receptor on CD4+ T helper cells to promote their differentiation into asthma-exacerbating Th2 cells, thereby enhancing lung inflammation. By contrast, norepinephrine-producing nerves in the adult lung had no such effect. Importantly, the findings reveal the similarity between mice and humans in terms of the innervation of dopamine-producing nerves in the early lung and the T cell response to dopamine.

In mouse models of allergen exposure, the dopamine-DRD4 pathway significantly increased Th2 cell inflammation in the lung tissue of neonatal mice, reducing mucus overproduction and airway hyper-responsiveness. By contrast, these effects were either not evident or much weaker in adult mice exposed to allergens.

Taken together, these findings demonstrate that the dopamine-DRD4 signaling between sympathetic nerves and CD4+ T helper cells in the lung plays an important role in augmenting allergic inflammation in early life. By facilitating inflammation, dopamine-producing nerves may endow the early lung with a mechanism of tissue repair following infection, which may be advantageous when the lung is immature and vulnerable to pathogens.

"Our findings provide evidence for the involvement of the communication between nerves and immune cells in susceptibility to asthma in early life," Ai says. "It is important to emphasize that simply generically blocking the nerve-immune cell communication is not a good solution, as nerves play important roles in regulating functions of the airway, such as breathing. We will need to identify more specific pathways along the nerve-immune cell axis for therapeutic targeting."

Toward this goal, the researchers will set out to identify druggable targets to disrupt the nerve-T cell communication that goes awry upon allergen exposure. They will also evaluate whether this age-related communication impacts the progression of asthma from childhood to adulthood, and if so, how disease progression can be prevented. Another avenue of future research will be to investigate how allergen exposure and viral infection may affect nerve development in the lung, thereby triggering asthma in children.

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