1. Why does prenatal alcohol exposure increase the likelihood of addiction?

    July 21, 2017 by Ashley

    From the University at Buffalo press release:

    One of the many negative consequences when fetuses are exposed to alcohol in the womb is an increased risk for drug addiction later in life. Neuroscientists in the University at Buffalo Research Institute on Addictions are discovering why.

    Through a research grant from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) of the National Institutes of Health (NIH), Senior Research Scientist Roh-Yu Shen, PhD, is studying how prenatal alcohol exposure alters the reward system in the brain and how this change continues through adulthood.

    The key appears to lie with endocannibinoids, cannabis-like chemicals that are produced by the brain itself.

    “By understanding the role endocannibinoids play in increasing the brain’s susceptibility to addiction, we can start developing drug therapies or other interventions to combat that effect and, perhaps, other negative consequences of prenatal alcohol exposure,” Shen says.

    Prenatal alcohol exposure is the leading preventable cause of birth defects and neurodevelopmental abnormalities in the United States. Fetal Alcohol Spectrum Disorders (FASD) cause cognitive and behavioral problems. In addition to increased vulnerability of alcohol and other substance use disorders, FASD can lead to other mental health issues including Attention Deficit Hyperactivity Disorder (ADHD), depression, anxiety and problems with impulse control.

    After the prenatal brain is exposed to alcohol, the endocannibinoids have a different effect on certain dopamine neurons which are involved in addicted behaviors than when brain is not exposed to alcohol,” Shen says. “The end result is that the dopamine neurons in the brain become more sensitive to a drug of abuse’s effect. So, later in life, a person needs much less drug use to become addicted.”

    Specifically, in the ventral tegmental area (VTA) of the brain, endocannibinoids play a significant role in weakening the excitatory synapses onto dopamine neurons. The VTA is the part of the brain implicated in addiction, attention and reward processes. However, in a brain prenatally exposed to alcohol, the effect of the endocannabinoids is reduced due to a decreased function of endocannabinoid receptors. As a result, the excitatory synapses lose the ability to be weakened and continue to strengthen, which Shen believes is a critical brain mechanism for increased addiction risk.


  2. Brain area involved in addiction activated earlier by cocaine consumption than thought

    June 6, 2017 by Ashley

    From the McGill University press release:

    Even among non-dependent cocaine users, cues associated with consumption of the drug lead to dopamine release in an area of the brain thought to promote compulsive use, according to researchers at McGill University.

    The findings, published in Scientific Reports, suggest that people who consider themselves recreational users could be further along the road to addiction than they might have realized.

    “The study provides evidence that some of the characteristic brain signals in people who have developed addictions are also present much earlier than most of us would have imagined,” says Marco Leyton, an expert on the neurobiology of drug use and addictions and professor in McGill’s Department of Psychiatry.

    Researchers have known for many years that cocaine use triggers the release of dopamine, a neurotransmitter involved in the brain’s reward system. In people with addictions, cues associated with drug use create the same effect. Visual cues — such as seeing someone using cocaine — are enough to trigger dopamine release and lead to craving.

    Scientists have long believed that, as addiction progresses, cue-induced release of dopamine shifts to the dorsal striatum, a structure deep inside the brain extensively studied for its role in the way we respond to rewards.

    “This area of the brain is thought to be particularly important for when people start to lose control of their reward-seeking behaviours,” Prof. Leyton says. “The dorsal part of the striatum is involved in habits — the difference, for example, between getting an ice cream because it will feel good versus being an automatic response that occurs even when it is not enjoyable or leads to consequences that you would rather avoid, such as weight gain or serious health hazards.”

    This switch from voluntary to habitual behaviour is thought to play an important role in the development of uncontrollable and compulsive drug use and the progression to addiction,” adds Sylvia Cox, a postdoctoral researcher at the McConnell Brain Imaging Center and the paper’s first author.

    To better understand how soon this effect might be seen, Professor Leyton’s team used positron emission tomography (PET) scans to look at what happens in the dorsal striatum of recreational cocaine users.

    The scientists created highly personalized cues by filming participants ingesting cocaine in the laboratory with a friend with whom they had used the drug before. During a later session, subjects underwent a PET scan while watching the video of their friend taking cocaine. Exposure to the cocaine-related cues increased both craving and dopamine release in the dorsal striatum.

    “An accumulation of these brain triggers might bring people closer to the edge than they had realized.” The findings also underscore the “importance of providing help early” to avoid the severe effects of dependency, he adds.


  3. High-fat diet alters reward system in rats

    by Ashley

    From the Society for Neuroscience press release:

    Exposure to high-fat diet from childhood may increase the sensitivity of the dopamine system later in adulthood, according to a study in male rats published in eNeuro. The research describes potential mechanisms that, if translated to humans, may drive people to seek foods that contribute to obesity.

    Dopamine is a neurotransmitter that plays an important role in sensitization — the process by which repeated administration of a reward, being pharmacological such as amphetamine or natural such as highly palatable food, causes an increase in response to the reward.

    In this study, Guillaume Ferreira and colleagues investigated the effects of high-fat diet exposure on sensitization to amphetamine, a psychostimulant acting through the dopamine system. The authors found that male rats fed a high-fat diet for three months, from weaning to adulthood, exhibited increased locomotor activity in response to a second injection of amphetamine, as well as increased activity of dopamine cells in the ventral tegmental area (VTA) and dopamine release in the nucleus accumbens (NAc). These findings reveal that the development of the VTA-NAc pathway during adolescence is influenced by a high-fat diet, which may lead to long-term changes in reward-seeking behavior.


  4. Scientific discovery may change treatment of Parkinson’s

    April 3, 2017 by Ashley

    From the University of Turku press release:

    When monitoring Parkinson’s disease, SPECT imaging of the brain is used for acquiring information on the dopamine activity. A new study conducted in Turku, Finland, shows that the dopamine activity observed in SPECT imaging does not reflect the number of dopamine neurons in the substantia nigra, as previously assumed.

    One of the most significant changes in the central nervous system in Parkinson’s disease is the loss of dopamine-producing neurons in the substantia nigra, causing a drop in dopamine levels in the brain.

    “Low dopamine level in the brain is linked with the central motor symptoms of Parkinson’s disease, i.e. tremor or shaking, muscle stiffness and slowness of movements,” says Docent of Neurology Valtteri Kaasinen from the University of Turku.

    Decreased dopamine activity can be detected with a single-photon emission computed tomography (SPECT) imaging of the brain. This method is widely used in the diagnostics of Parkinson’s disease in Europe and the United States.

    The study conducted at the University of Turku and Turku University Hospital shows that the dopamine activity observed in SPECT imaging does not reflect the number of dopamine neurons in the substantia nigra, contrary to what has been thought. According to Kaasinen, this is an important result as it proves that the correlation between the number of neurons and dopamine activity is not straightforward.

    “This must be considered in the future when developing treatments that affect the number of neurons in the substantia nigra. It also seems that SPECT imaging is not a suitable method for monitoring treatment research results in advanced Parkinson’s disease when studying treatments that affect the number of neurons in the substantia nigra,” says Kaasinen.

    In the study, post-mortem neuron numbers in the substantia nigra were calculated for patients with Parkinson’s disease who had been examined with dopamine transporter SPECT before death. The number of neurons cannot be calculated during a patient’s lifetime since the substantia nigra is located deep within the midbrain where biopsy is impossible in vivo.


  5. Spiritual retreats change feel-good chemical systems in the brain

    March 28, 2017 by Ashley

    From the Thomas Jefferson University press release:

    More Americans than ever are turning to spiritual, meditative and religious retreats as a way to reset their daily life and enhance wellbeing. Now, researchers at The Marcus Institute of Integrative Health at Thomas Jefferson University show there are changes in the dopamine and serotonin systems in the brains of retreat participants. The team published their results in Religion, Brain & Behavior.

    “Since serotonin and dopamine are part of the reward and emotional systems of the brain, it helps us understand why these practices result in powerful, positive emotional experiences,” said Andrew Newberg, M.D., Director of Research in the Marcus Institute of Integrative Health. “Our study showed significant changes in dopamine and serotonin transporters after the seven-day retreat, which could help prime participants for the spiritual experiences that they reported.”

    The post-retreat scans revealed decreases in dopamine transporter (5-8 percent) and serotonin transporter (6.5 percent) binding, which could make more of the neurotransmitters available to the brain. This is associated with positive emotions and spiritual feelings. In particular, dopamine is responsible for mediating cognition, emotion and movement, while serotonin is involved in emotional regulation and mood.

    The study, funded by the Fetzer Institute, included 14 Christian participants ranging in age from 24 to 76. They attended an Ignatian retreat based on the spiritual exercises developed by St. Ignatius Loyola who founded the Jesuits. Following a morning mass, participants spent most of the day in silent contemplation, prayer and reflection and attended a daily meeting with a spiritual director for guidance and insights. After returning, study subjects also completed a number of surveys which showed marked improvements in their perceived physical health, tension and fatigue. They also reported increased feelings of self-transcendence which correlated to the change in dopamine binding.

    “In some ways, our study raises more questions than it answers,” said Dr. Newberg. “Our team is curious about which aspects of the retreat caused the changes in the neurotransmitter systems and if different retreats would produce different results. Hopefully, future studies can answer these questions.”


  6. Even after treatment, brains of anorexia nervosa patients not fully recovered

    March 19, 2017 by Ashley

    From the University of Colorado Anschutz Medical Campus press release:

    Even after weeks of treatment and considerable weight gain, the brains of adolescent patients with anorexia nervosa remain altered, putting them at risk for possible relapse, according to researchers at the University of Colorado Anschutz Medical Campus.

    The study, published last week in the American Journal of Psychiatry, examined 21 female adolescents before and after treatment for anorexia and found that their brains still had an elevated reward system compared to 21 participants without the eating disorder.

    “That means they are not cured,” said Guido Frank, MD, senior author of the study and associate professor of psychiatry and neuroscience at the University of Colorado School of Medicine. “This disease fundamentally changes the brain response to stimuli in our environment. The brain has to normalize and that takes time.”

    Brain scans of anorexia nervosa patients have implicated central reward circuits that govern appetite and food intake in the disease. This study showed that the reward system was elevated when the patients were underweight and remained so once weight was restored.

    The neurotransmitter dopamine might be the key, researchers said.

    Dopamine mediates reward learning and is suspected of playing a major role in the pathology of anorexia nervosa. Animal studies have shown that food restriction or weight loss enhances dopamine response to rewards.

    With that in mind, Frank, an expert in eating disorders, and his colleagues wanted to see if this heightened brain activity would normalize once the patient regained weight. Study participants, adolescent girls who were between 15 and 16 years old, underwent a series of reward-learning taste tests while their brains were being scanned.

    The results showed that reward responses were higher in adolescents with anorexia nervosa than in those without it. This normalized somewhat after weight gain but still remained elevated.

    At the same time, the study showed that those with anorexia had widespread changes to parts of the brain like the insula, which processes taste along with a number of other functions including body self-awareness.

    The more severely altered the brain, the harder it was to treat the illness, or in other words, the more severely altered the brain, the more difficult it was for the patients to gain weight in treatment.

    Generalized sensitization of brain reward responsiveness may last long into recovery,” the study said. “Whether individuals with anorexia nervosa have a genetic predisposition for such sensitization requires further study.”

    Frank said more studies are also needed to determine if the continued elevated brain response is due to a heightened dopamine reaction to starvation and whether it signals a severe form of anorexia among adolescents that is more resistant to treatment.

    In either case, Frank said the biological markers discovered here could be used to help determine the likelihood of treatment success. They could also point the way toward using drugs that target the dopamine reward system.

    “Anorexia nervosa is hard to treat. It is the third most common chronic illness among teenage girls with a mortality rate 12 times higher than the death rate for all causes of death for females 15-24 years old,” Frank said. “But with studies like this we are learning more and more about what is actually happening in the brain. And if we understand the system, we can develop better strategies to treat the disease.”


  7. Precise technique tracks dopamine in the brain

    March 17, 2017 by Ashley

    From the MIT press release:

    brain scansMIT researchers have devised a way to measure dopamine in the brain much more precisely than previously possible, which should allow scientists to gain insight into dopamine’s roles in learning, memory, and emotion.

    Dopamine is one of the many neurotransmitters that neurons in the brain use to communicate with each other. Previous systems for measuring these neurotransmitters have been limited in how long they provide accurate readings and how much of the brain they can cover. The new MIT device, an array of tiny carbon electrodes, overcomes both of those obstacles.

    “Nobody has really measured neurotransmitter behavior at this spatial scale and timescale. Having a tool like this will allow us to explore potentially any neurotransmitter-related disease,” says Michael Cima, the David H. Koch Professor of Engineering in the Department of Materials Science and Engineering, a member of MIT’s Koch Institute for Integrative Cancer Research, and the senior author of the study.

    Furthermore, because the array is so tiny, it has the potential to eventually be adapted for use in humans, to monitor whether therapies aimed at boosting dopamine levels are succeeding. Many human brain disorders, most notably Parkinson’s disease, are linked to dysregulation of dopamine.

    “Right now deep brain stimulation is being used to treat Parkinson’s disease, and we assume that that stimulation is somehow resupplying the brain with dopamine, but no one’s really measured that,” says Helen Schwerdt, a Koch Institute postdoc and the lead author of the paper, which appears in the journal Lab on a Chip.

    Studying the striatum

    For this project, Cima’s lab teamed up with David H. Koch Institute Professor Robert Langer, who has a long history of drug delivery research, and Institute Professor Ann Graybiel, who has been studying dopamine’s role in the brain for decades with a particular focus on a brain region called the striatum. Dopamine-producing cells within the striatum are critical for habit formation and reward-reinforced learning.

    Until now, neuroscientists have used carbon electrodes with a shaft diameter of about 100 microns to measure dopamine in the brain. However, these can only be used reliably for about a day because they produce scar tissue that interferes with the electrodes’ ability to interact with dopamine, and other types of interfering films can also form on the electrode surface over time. Furthermore, there is only about a 50 percent chance that a single electrode will end up in a spot where there is any measurable dopamine, Schwerdt says.

    The MIT team designed electrodes that are only 10 microns in diameter and combined them into arrays of eight electrodes. These delicate electrodes are then wrapped in a rigid polymer called PEG, which protects them and keeps them from deflecting as they enter the brain tissue. However, the PEG is dissolved during the insertion so it does not enter the brain.

    These tiny electrodes measure dopamine in the same way that the larger versions do. The researchers apply an oscillating voltage through the electrodes, and when the voltage is at a certain point, any dopamine in the vicinity undergoes an electrochemical reaction that produces a measurable electric current. Using this technique, dopamine’s presence can be monitored at millisecond timescales.

    Using these arrays, the researchers demonstrated that they could monitor dopamine levels in many parts of the striatum at once.

    “What motivated us to pursue this high-density array was the fact that now we have a better chance to measure dopamine in the striatum, because now we have eight or 16 probes in the striatum, rather than just one,” Schwerdt says.

    The researchers found that dopamine levels vary greatly across the striatum. This was not surprising, because they did not expect the entire region to be continuously bathed in dopamine, but this variation has been difficult to demonstrate because previous methods measured only one area at a time.

    How learning happens

    The researchers are now conducting tests to see how long these electrodes can continue giving a measurable signal, and so far the device has kept working for up to two months. With this kind of long-term sensing, scientists should be able to track dopamine changes over long periods of time, as habits are formed or new skills are learned.

    “We and other people have struggled with getting good long-term readings,” says Graybiel, who is a member of MIT’s McGovern Institute for Brain Research. “We need to be able to find out what happens to dopamine in mouse models of brain disorders, for example, or what happens to dopamine when animals learn something.”

    She also hopes to learn more about the roles of structures in the striatum known as striosomes. These clusters of cells, discovered by Graybiel many years ago, are distributed throughout the striatum. Recent work from her lab suggests that striosomes are involved in making decisions that induce anxiety.

    This study is part of a larger collaboration between Cima’s and Graybiel’s labs that also includes efforts to develop injectable drug-delivery devices to treat brain disorders.

    “What links all these studies together is we’re trying to find a way to chemically interface with the brain,” Schwerdt says. “If we can communicate chemically with the brain, it makes our treatment or our measurement a lot more focused and selective, and we can better understand what’s going on.”


  8. Alcoholism may be caused by dynamical dopamine imbalance

    March 15, 2017 by Ashley

    From the National Research University Higher School of Economics press release:

    Researchers from the Higher School of Economics, Ecole Normale Supérieure, Paris, Indiana University and the Russian Academy of Sciences Nizhny Novgorod Institute of Applied Physics have identified potential alcoholism mechanisms, associated with altered dopaminergic neuron response to complex dynamics of prefrontal cortex neurons affecting dopamine release.

    Interacting neuronal populations in the cerebral cortex generate electrical impulses (called action potentials), that are characterized by specific spatial and temporal patterns of neural firing (or complex neural dynamics). These firing patterns depend on the intrinsic properties of individual neurons, on the neural network connectivity and the inputs to these circuits. Taken as a basis for this computational study is the experimental evidence for a specific population of prefrontal cortex neurons that connects via excitatory synapses to dopaminergic and inhibitory ventral tegmental area (VTA) neurons. Thus, the structure of neural firing in the prefrontal cortex can directly affect dopamine cell response and dopamine release.

    Boris Gutkin leads the Theoretical Neuroscience Group at the HSE Centre for Cognition and Decision Making. One of the group’s research areas focuses on neurobiological processes leading to substance abuse and addiction — specifically, on detecting links between the neurobiological mechanisms of a drug’s action and observable behavioural reactions. In particular, the researchers use mathematical modelling to examine specific characteristics of dopaminergic neuron firing patterns and dynamics which can lead to addiction.

    Dopamine, a neurotransmitter released by dopaminergic neurons in the brain, is a chemical which plays a key role in the internal brain reward system that drives learning of motivated behavior. By acting within the reward systems in the brain (e.g. the ventral tegmental area found deep in the mid-brain; the striatum, responsible for selecting correct actions and the prefrontal cortex that controls voluntary goals and behaviors), it signals either unexpected reward or anticipation of reward resulting from a particular action or event. Thus, dopamine provides positive reinforcement of behaviours that lead to these rewards, causing them to be repeated. Conversely, where a particular action fails to produce the expected positive effect or is followed by an unpleasant event, dopamine release decreases sharply, leading to frustration and an unwillingness to repeat the behaviour in question.

    Many dopamine neurons produce these learning signals by emitting rapid bursts of spikes when the animal receives more reward than expected or pausing when there is less than expected. In order to govern the learning correctly, the number of bursts (and the dopamine released) must be proportional to the discrepancy between the received and the expected reward (for example if one expects to get 50 euros for his work, but gets 100; the dopamine activity should be proportional to 50; when one expects 50 but gets 500; the activity should signal a number proportional to 450). Hence the bigger the mismatch — the stronger the response. Yet another subgroup of dopamine neurons simply signals when stimuli are important for behaviour or not giving binary all or none responses. These binary signals then drive orienting or approach to the important behaviors. So the two dopamine cell populations have different response modes: analogue learning signal or all-or-none important alert.

    Two Modes of neuron Activity

    Recent research by Gutkin’s group conducted jointly with scientists from Indiana University (Alexey Kuznetsov, Mathematics and Christopher Lapish, Neuroscience) and the RAN Institute of Applied Physics (Denis Zakharov) suggests potential mechanisms of alcohol’s effect on dopaminergic neuronal activity. Their paper ‘Dopamine Neurons Change the Type of Excitability in Response to Stimuli’ published in PLOS features a computational model of dopamine (DA) neuron activity, describing its key properties and demonstrating that the DA neuron’s response mode can vary depending on the pattern of the synaptic input (including that from the prefrontal cortex).

    When in the first mode, the amount of dopamine released by the DA neurons reflects the learning signal propotional to the difference between what an animal or human expects and what they actually receive as a result of a certain action. When in the second DA neuron mode, dopamine release serves as a reference binary signal indicating whether or not a certain event is important. Hence the results of the computational study imply that dopamine neurons may not be two distinct populations, but are capable to move flexibly from one response mode to another depending on the nature of the signals they receive.

    In a related study, ‘Contribution of synchronized GABAergic neurons to dopaminergic neuron firing and bursting’, published in the Journal of Neurophysiology the same group suggests that in addition to direct links between DA and prefrontal cortex neurons, indirect neural inputs from the prefrontal cortex via inhibitory (GABAergic) VTA neurons should be considered. In particular, the researchers found that signals from the prefrontal cortex can cause GABAergic neurons to synchronise, producing a strong inhibitory effect on DA neurons. The study found that in some cases, such inhibitory effects can lead to paradoxical results: instead of suppressing DA neuron firing and thus decreasing dopamine release, they can multiply DA firing frequency leading to higher dopamine release and positive reinforcement.

    What It Means for Our Understanding of Alcoholism

    Experimental evidence suggests that alcohol is capable of modifying DA neuron firing patterns, both indirectly via prefrontal cortex and inhibitory VTA neurons, and directly by acting on DA neurons per se. Based on Gutkin and his collaborators findings, one can hypothesise what mechanisms may be involved.

    The VTA has about 20,000 DA neurons, in someone who is not alcoholic, some of these serve to signal that a certain stimulus has importance, while the rest transmit the error signal. A certain balance between the two types of signals is essential for good judgment and proper behaviour. Alcohol disrupts the balance by changing both the pattern of neural activity in the prefrontal cortex and DA neuron properties. This change may bias more neurons to signal importance as opposed to the error. So, under alcohol influence, any stimulus associated with alcohol is treated by DA neurons as having behavioural and motivational importance, regardless of whether or not it matches the anticipated outcome, while in the absence of alcohol, neural firing would normally be consistent with the expected and received reinforcements.

    This effect may be the reason why alcoholics may eventually develop a narrower than normal range of behavioural responses, dooming them to seek to use alcohol. In doing so, they are either unaware of potential consequences of their actions or, even if they can anticipate such consequences, this awareness has little or no effect on their behaviour. According to surveys, most alcoholics understand that they may lose their home and family and even die from binge drinking, but this rarely stops them. To properly assess the consequences of drinking, their prefrontal cortex needs to integrate and learn to properly represent the negative expectations from this behaviour, supported by reinforcement learning signals from DA neurons. This may not happen, however, because alcohol (like other mood-altering substances) can affect both the neural activity in the addict’s prefrontal cortex and their DA neurons directly, blocking the learning.

    Finding a way to balance out the dopamine function in the addicted brain and to elicit adequate neural responses to environmental stimuli even under the influence could offer hope to people with substance abuse problems.


  9. Dopamine neurons factor ambiguity into predictions enabling us to ‘win big and win often’

    by Ashley

    From the Cold Spring Harbor Laboratory press release:

    In the struggle of life, evolution rewards animals that master their circumstances, especially when the environment changes fast. If there is a recipe for success, it is not: savor your victories when you are fortunate to have them. Rather it is: win big, and win often.

    To make winning decisions, animals cannot consult a hard-wired playbook or receive helpful advice. Instead, success depends on their ability to learn, from triumphs and from mistakes.

    Today in the journal Current Biology, a team led by Professor Adam Kepecs of Cold Spring Harbor Laboratory (CSHL) adds an important new dimension to our understanding of how the brain learns, focusing specifically on situations in which perceptually ambiguous information is used to make predictions.

    What if it’s gotten foggy and we can barely see the sign up ahead, or the announcement over the loudspeaker is garbled? In circumstances like these, how does the brain adjust the predictions that inform decisions?

    Kepecs and colleagues describe how dopamine-releasing neurons, which are understood to produce critical teaching signals for the brain, weigh the ambiguity of sensory information when they assess how successfully past experiences have guided a new decision. Their findings indicate that these neurons are even more sophisticated than previously thought.

    “Dopamine neurons are not just any neurons in the brain,” Kepecs says. “They are neurons that sit in the midbrain and send connections to large swaths of the brain. Dopamine neurons compare the predicted outcomes to actual outcomes, and send the discrepancy between these as an error feedback to other parts of the brain. This is exactly what you would want learning signals to do. And we’ve found that what dopamine neurons do is in perfect agreement with what is theoretically required for a powerful learning algorithm.”

    This is such an effective way of learning that the same strategy, called reinforcement learning, has been incorporated into many types of artificial intelligence, allowing computers to figure out how to do things without instructions from a programmer.

    Kepecs and his team added what computer scientists call a belief state (a probability distribution variable) to a mathematical model of reinforcement learning. The previously used model is good at explaining how an animal learns from experience — but only when the sensory stimuli available to the animal are straightforward, easy to interpret. “It’s been unclear whether or how dopamine neurons factor perceptual ambiguity into their teaching signal,” Kepecs says. “Our revised model generates an estimate of the probability that a given choice is correct — this is the degree of confidence about the decision.”

    “If you can evaluate your decision process — the noise and everything else that’s contributed to it — and in addition to making a binary choice assign a graded level of confidence to the decision, it’s essentially a prediction about your accuracy,” he says. “It’s a completely different computation than just using the cues to recall past experiences to make predictions.”

    Armin Lak, a British Iranian postdoctoral researcher working with Kepecs, developed a computer model that predicted how neurons would behave if they were performing this calculation. Then they compared those predictions to the activity of dopamine neurons in the brains of monkeys while they performed a task in which they made a decision informed by visual cues that were sometimes clear, and sometimes not.

    The activity of the neurons was recorded by Kepecs’ collaborators Kensaku Nomoto and Masamichi Sakagami, neuroscientists at Tamagawa University in Tokyo, who were studying how the brain uses sensory information to make decisions. In the task, monkeys watched a screen filled with moving dots, and had to decide whether more dots were moving to the left or to the right, receiving a juice reward when they got the answer right.

    When Kepecs and Lak analyzed the data, they found that the activity of the dopamine neurons closely fit the predictions of their new model — indicating that these neurons were likely evaluating the reliability of the information used during each decision. Applying the computational model was like looking at the data through a new microscope, Kepecs says. “By looking at it this way, you can see things that you couldn’t see before in the data. Suddenly it just made sense. This system is much smarter than we thought before.”

    Surprisingly, Kepecs says, the confidence-signaling neurons became active a fraction of a second before the monkeys’ made a decision. This early activity suggests the neurons may influence the immediate decision making process — a role that the team will explore in future research.


  10. How dopamine governs ongoing decisions

    March 13, 2017 by Ashley

    From the Salk Institute media release:

    Say you’re reaching for the fruit cup at a buffet, but at the last second you switch gears and grab a cupcake instead. Emotionally, your decision is a complex stew of guilt and mouth-watering anticipation. But physically it’s a simple shift: instead of moving left, your hand went right. Such split-second changes interest neuroscientists because they play a major role in diseases that involve problems with selecting an action, like Parkinson’s and drug addiction.

    In the March 9, 2017 online publication of the journal Neuron, scientists at the Salk Institute report that the concentration of a brain chemical called dopamine governs decisions about actions so precisely that measuring the level right before a decision allows researchers to accurately predict the outcome. Additionally, the scientists found that changing the dopamine level is sufficient to alter upcoming choice. The work may open new avenues for treating disorders both in cases where a person cannot select a movement to initiate, like Parkinson’s disease, as well as those in which someone cannot stop repetitive actions, such as obsessive-compulsive disorder (OCD) or drug addiction.

    “Because we cannot do more than one thing at a time, the brain is constantly making decisions about what to do next,” says Xin Jin, an assistant professor in Salk’s Molecular Neurobiology Laboratory and the paper’s senior author. “In most cases our brain controls these decisions at a higher level than talking directly to particular muscles, and that is what my lab mostly wants to understand better.”

    When we decide to perform a voluntary action, like tying our shoelaces, the outer part of our brain (the cortex) sends a signal to a deeper structure called the striatum, which receives dopamine to orchestrate the sequence of events: bending down, grabbing the laces, tying the knots. Neurodegenerative diseases like Parkinson’s damage the dopamine-releasing neurons, impairing a person’s ability to execute a series of commands. For example, if you ask Parkinson’s patients to draw a V shape, they might draw the line going down just fine or the line going up just fine. But they have major difficulty making the switch from one direction to the other, and spend much longer at the transition. Before researchers can develop targeted therapies for such diseases, they need to understand exactly what the function of dopamine is at a fundamental neurological level in normal brains.

    Jin’s team designed a study in which mice chose between pressing one of two levers to get a sugary treat. The levers were on the right and left side of a custom-built chamber, with the treat dispenser in the middle. The levers retracted from the chamber at the start of each trial and reappeared after either two seconds or eight seconds. The mice quickly learned that when the levers reappeared after the shorter time, pressing the left lever yielded a treat. When they reappeared after the longer time, pressing the right lever resulted in a treat. Thus, the two sides represented a simplified two-choice situation for the mice — they moved to the left side of the chamber initially, but if the levers didn’t reappear within a certain amount of time, the mice shifted to the right side based on an internal decision.

    “This particular design allows us to ask a unique question about what happens in the brain during this mental and physical switch from one choice to another,” says Hao Li, a Salk research associate and the paper’s co-first author.

    As the mice performed the trials, the researchers used a technique called fast-scan cyclic voltammetry to measure dopamine concentration in the animals’ brains via embedded electrodes much finer than a human hair. The technique allows for very fine-time-scale measurement (in this study, sampling occurred 10 times per second) and therefore can indicate rapid changes in brain chemistry. The voltammetry results showed that fluctuations in brain dopamine level were tightly associated with the animal’s decision. The scientists were actually able to accurately predict the animal’s upcoming choice of lever based on dopamine concentration alone.

    Interestingly, other mice that got a treat by pressing either lever (so removing the element of choice) experienced a dopamine increase as trials got under way, but in contrast their levels remained above baseline (didn’t fluctuate below baseline) the entire time, indicating dopamine’s evolving role when a choice is involved.

    “We are very excited by these findings because they indicate that dopamine could also be involved in ongoing decision, beyond its well-known role in learning,” adds the paper’s co-first author, Christopher Howard, a Salk research collaborator.

    To verify that dopamine level caused the choice change, rather than just being associated with it, the team used genetic engineering and molecular tools — including activating or inhibiting neurons with light in a technique called optogenetics — to manipulate the animals’ brain dopamine levels in real time. They found they were able to bidirectionally switch mice from one choice of lever to the other by increasing or decreasing dopamine levels.

    Jin says these results suggest that dynamically changing dopamine levels are associated with the ongoing selection of actions. “We think that if we could restore the appropriate dopamine dynamics — in Parkinson’s disease, OCD and drug addiction — people might have better control of their behavior. This is an important step in understanding how to accomplish that.”