Continuously eating fatty foods perturbs communication between the gut and brain, which in turn perpetuates a bad diet.
A chronic high-fat diet is thought to desensitize the brain to the feeling of satisfaction that one normally gets from a meal, causing a person to overeat in order to achieve the same high again. New research published today (August 15) in Science,however, suggests that this desensitization actually begins in the gut itself, where production of a satiety factor, which normally tells the brain to stop eating, becomes dialed down by the repeated intake of high-fat food.
“It’s really fantastic work,” said Paul Kenny, a professor of molecular therapeutics at The Scripps Research Institute in Jupiter, Florida, who was not involved in the study. “It could be a so-called missing link between gut and brain signaling, which has been something of a mystery.”
While pork belly, ice cream, and other high-fat foods produce an endorphin response in the brain when they hit the taste buds, according to Kenny, the gut also sends signals directly to the brain to control our feeding behavior. Indeed, mice nourished via gastric feeding tubes, which bypass the mouth, exhibit a surge in dopamine—a neurotransmitter promoting reinforcement in the brain’s reward circuitry—similar to that experienced by those eating normally.
This dopamine surge occurs in response to feeding in both mice and humans. But evidence suggests that dopamine signaling in the brain is deficient in obese people. Ivan de Araujo, a professor of psychiatry at the Yale School of Medicine, has now discovered that obese mice on a chronic high-fat diet also have a muted dopamine response when receiving fatty food via a direct tube to their stomachs.
To determine the nature of the dopamine-regulating signal emanating from the gut, Araujo and his team searched for possible candidates. “When you look at animals chronically exposed to high-fat foods, you see high levels of almost every circulating factor—leptin, insulin, triglycerides, glucose, et cetera,” he said. But one class of signaling molecule is suppressed. Of these, Araujo’s primary candidate was oleoylethanolamide. Not only is the factor produced by intestinal cells in response to food, he said, but during chronic high-fat exposure, “the suppression levels seemed to somehow match the suppression that we saw in dopamine release.”
Araujo confirmed oleoylethanol’s dopamine-regulating ability in mice by administering the factor via a catheter to the tissues surrounding their guts. “We discovered that by restoring the baseline level of [oleoylethanolamide] in the gut … the high-fat fed animals started having dopamine responses that were indistinguishable from their lean counterparts.”
The team also found that oleoylethanolamide’s effect on dopamine was transmitted via the vagus nerve, which runs between the brain and abdomen, and was dependent on its interaction with a transcription factor called PPAR-a.
Oleoylethanolamide levels are also reduced in fasting animals and increase in response to eating, communicating with the brain to stop further consumption once the belly is full. Indeed, oleoylethanolamide is a known satiety factor. Therefore, when chronic consumption of high-fat food diminishes its production, the satisfaction signal is not achieved, and the brain is essentially “blind to the presence of calories in the gut,” said Araujo, and thus demands more food.
It is not clear why a chronic high-fat diet suppresses the production of oleoylethanolamide. But once the vicious cycle starts, it is hard to break because the brain is receiving its information subconsciously, said Daniele Piomelli, a professor at the University of California, Irvine, and director of drug discovery and development at the Italian Institute of Technology in Genoa.
“We eat what we like, and we think we are conscious of what we like, but I think what this [paper] and others are indicating is that there is a deeper, darker side to liking—a side that we’re not aware of,” Piomelli said. “Because it is an innate drive, you can not control it.” Put another way, even if you could trick your taste buds into enjoying low-fat yogurt, you’re unlikely to trick your gut.
The good news, however, is that “there is no permanent impairment in the [animals’] dopamine levels,” Araujo said. This suggests that if drugs could be designed to regulate the oleoylethanolamide–to-PPAR-a pathway in the gut, Kenny added, it could have “a huge impact on people’s ability to control their appetite.”
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.
Prof. Hori emphasizes, “The complementary roles of two dopamine receptor subtypes that our study revealed, in the computation of the cost-benefit trade-off to guide action will help us decipher the pathophysiology of psychiatric disorders.” Their research brings the hope of a future when by manipulating the inbuilt reward system and enhancing the motivation levels, lives of many can be improved.
Among the neurotransmitters in the brain, dopamine has gained an almost mythical status. Decades of research have established its contribution to several seemingly unrelated brain functions including learning, motivation, and movement, raising the question of how a single neurotransmitter can play so many different roles.
(Image caption: Researchers record the activity of neurons in the brain’s olfactory learning center (bottom), as the fly receives a drop of sucrose)
Untangling dopamine’s diverse functions has been challenging, in part because the advanced brain of humans and other mammals contain different kinds of dopamine neurons, all embedded in highly complex circuits. In a new study, Rockefeller’s Vanessa Ruta and her team dive deep into the question by looking instead at the much simpler brain of the fruit fly, whose neurons and their connections have been mapped in detail.
As in humans, a fly’s dopamine neurons provide a signal for learning, helping them to link a particular odor to a particular outcome. Learning that, for example, apple cider vinegar contains sugar serves to shape the animals’ future behavior on their next encounter with that odor. But Ruta’s team discovered that the same dopamine neurons also correlate strongly with the animal’s ongoing behavior. The activity of these dopamine neurons does not simply encode the mechanics of movement, but rather appears to reflect the motivation or goal underlying the fly’s actions in real time. In other words, the same dopamine neurons that teach animals long-term lessons also provide moment-to-moment reinforcement, encouraging the flies to continue with a beneficial action.
“There seems to be an intimate connection between learning and motivation, two different facets of what dopamine does,” says Ruta, who published the findings in Nature Neuroscience.
Continuous learning
Smells are important to flies. A brain center for olfactory learning, called the mushroom body, is responsible for teaching them which smells signify tasty sugar. There, three types of neurons come together: Kenyon cells that respond to odors, the output neurons that send signals to the rest of the brain, and the dopamine-producing neurons. When the fly encounters an odor and then gets a sugar reward, a quick release of dopamine alters the strength of connections between neurons of the mushroom body, essentially helping the fly to make new associations and change its future response to that odor.
But Ruta and her colleagues have noticed ongoing dopamine signaling even in the absence of rewards. The same neurons that helped the flies learn associations also fired frequently as the animal moved. “That raised the question, are these neurons representing specific aspects of the movement, like how the animal is moving its legs, or are they related to something else, like the goal of the animal?” Ruta says.
To find out, the team developed a virtual-reality system in which fruit flies can navigate an olfactory environment, walking on a treadmill-like ball while their brain activity is monitored by a microscope over their head. A stream of air delivers odors through a small tube. When the fly gets a whiff of an attractive odor, like apple cider vinegar, it reorients and starts to move upwind, towards the source.
Using this system, the researchers were able to examine the fly’s brain activity under different conditions. They found that the activity of dopamine neurons closely reflects movements as they were happening, but only when the flies engage in purposeful tracking, and not when they are just wandering about.
When the researchers suppressed the activity of the dopamine neurons, the animals diminished their tracking of the odor, even when they were starving and therefore had a heightened interest in food-related smells. In contrast, activating the neurons in food-indifferent, fully fed flies, propelled them into active pursuit of the odor.
Together, the findings reveal how one dopamine pathway can perform two functions: conveying motivational signals to rapidly shape ongoing behaviors while also providing instructive signals to guide future behavior through learning. “It gives us a deeper understanding of how a single pathway can generate different forms of flexible behavior,” Ruta says.
The next step is to understand how the other neurons know what a burst of dopamine means at any given time. One possibility, Ruta says, is that learning is a more continuous, dynamic process than often thought: On short timescales, animals continuously evaluate their behavior at every step, learning not just the final associations, but also the actions that lead them there.
Release of Chemical Dopamine in Infant Brains May Help Control Early Social Development
Changing levels of the chemical dopamine, a chemical most associated with motivation, may help explain why stressful experiences during infancy can lead to lasting behavioral issues, a new study in rodents shows.
Experts have long understood that negative experiences early in life among rodents and other mammals, including humans, can affect later social development. Past studies in rats, for example, have found that limited bedding causes mother rats to roughly handle pups, impacting pups’ social behavior throughout their lives. However, exactly what changes occurred in the brain as a result of such adversity remained unclear.
In a study led by researchers at NYU Grossman School of Medicine, investigators tied repeated stress during infancy to increased dopamine levels in the basolateral amygdala (BLA), a brain region that plays a role in memory formation. When they housed mother rats and their new pups in stressful conditions while rearing their young, the stressed pups had about twice as much BLA activity compared with those raised in a more comfortable nest. In turn, the former group spent at least 90 percent less time near their mothers and more than 30 percent less time near other pups compared with the latter group.
“Our findings suggest that repeated dopamine release in the basolateral amygdala plays a key role in infant social development,” says study lead author Maya Opendak, PhD. “As a result, this region of the brain may be a promising target for understanding or even treating psychiatric disorders that can interfere with social interaction, such as autism,anxiety, and depression.”
As part of the study, the study authors artificially blocked dopamine release in the BLA in the distressed infants and found that social behavior returned to normal. By contrast, increasing dopamine levels in pups raised in non-stressful conditions impaired their social behavior.
Dr. Opendak, a postdoctoral research fellow in the Department of Child and Adolescent Psychiatry at NYU Langone Health, notes that elevated BLA activity and social impairment only occurred in pups that were stressed in their mother’s presence. If they experienced stress alone, they showed no sign of these issues. Dr. Opendak suggests that the repeated activation of the BLA, already known to play a key role in learning about threats, prompts infants to associate their mother with danger.
“Our investigation offered us a clearer look at how specific brain mechanisms link stressful experiences during infancy to lifelong social behavior problems,” says study senior author Regina M. Sullivan, PhD. “We can take this same approach to explore other areas of brain development, such as memory, learning, and threat recognition,” adds Dr. Sullivan, a professor in the Department of Child and Adolescent Psychiatry.
For the study, published online in the journal Neuron, the research team observed the behavior of hundreds of rat pups. Some rodent mothers were provided limited materials with which to build a nest. In a series of social behavior tests, the study authors measured the length of time pups approached their mothers or peers after five days of living in these stressful conditions. According to the findings, the longer the stress exposure went on, the less often the pups would approach their mothers.
To examine the role of dopamine during these early life experiences, researchers used drugs that block the chemical’s release in the brain. They also stimulated dopamine release in individual brain cells using light to test the impact of the chemical on social behavior after distress.
Dr. Sullivan says the research team next plans to expand the investigation to other brain areas involved in processing threat and reward.
She cautions that the study only explored the effect of a single chemical in one brain pathway, noting that social behavior involves an intricate network of cells and other pathways that still needs to be uncovered.
Contrary to common thinking, cocaine triggers an addiction only in 20% of the consumers. But what happens in their brains when they lose control of their consumption? Thanks to a recent experimental method, neuroscientists at the University of Geneva (UNIGE), Switzerland, have revealed a brain mechanism specific to cocaine, which has the particularity of triggering a massive increase in serotonin in addition to the increase in dopamine common to all drugs. Indeed, serotonin acts as an intrinsic brake on the overexcitement of the reward system elicited by dopamine, the neurotransmitter that causes addiction. These results are published in the journal Science.
Addiction is defined as the compulsive search for a substance despite the negative consequences, whereas dependence is characterised as the occurrence of a withdrawal symptom — the physical effects of which vary greatly from one substance to another — when consumption is stopped abruptly. It thus affects everyone, whereas addiction affects only a minority of users, even after prolonged exposure. For example, it is estimated that 20% of cocaine users and 30% of opiate users are addicted. “The same principle applies to all potentially addictive products”, says Christian Lüscher, a professor in the Department of Basic Neurosciences at the UNIGE Faculty of Medicine, who led the research. “Here in Switzerland, for instance, almost all adults consume alcohol from time to time, which is a strong stimulator of the reward system. However, only a small proportion of us will become alcoholics.”
Addiction triples without serotonin
To assess how cocaine addiction arises in the brain, the research team developed a series of experiments. “Most of the time, scientific experiments aim to reproduce a systematic mechanism. Here, the difficulty lies in observing a random phenomenon, which is triggered only once in five times”, explains Yue Li, a researcher in Christian Lüscher’s laboratory and first author of the study.
The scientists first taught a large group of mice to self-administer cocaine voluntarily, and then added a constraint: each time they self-administered cocaine, the mice received a slightly unpleasant stimulus (electric shock or air jet). Two groups then emerged: 80% of the mice stopped their consumption, while 20% continued, despite the unpleasantness. “This compulsive behaviour is precisely what defines addiction, which affects 20% of individuals, in mice as well as in humans”, emphasises Vincent Pascoli, a scientific collaborator in the Geneva group and co-author of this study.
The experiment was repeated with mice in which cocaine was no longer linked to the serotonin transporter, so that only dopamine increased when the substance was taken. 60% of the animals then developed an addiction. The same was found in other animals with a reward system stimulation protocol that did not affect serotonin. “If serotonin is administered to the latter group, the rate of addiction falls to 20%”, says Christian Lüscher. “Cocaine therefore has a kind of natural brake that is effective four times out of five.”
A delicate synaptic balance
When cocaine is consumed, two forces are at work in the brain: dopamine on the one hand, whose sudden increase leads to compulsion, and serotonin on the other, which acts as a brake on compulsion. Addiction therefore occurs when an imbalance is created between these two neuroregulators and dopamine overtakes serotonin.
“Actually, dopamine triggers a phenomenon of synaptic plasticity, through the strengthening of connections between synapses in the cortex and those in the dorsal striatum. This intense stimulation of the reward system then triggers compulsion. Serotonin has the opposite effect by inhibiting the reinforcement induced by dopamine to keep the reward system under control”, explains Christian Lüscher.
What about other drugs?
Apart from the increase in dopamine, each substance has its own specificity and effect on the brain. If the addictive effect of cocaine is naturally reduced by serotonin, what about other drugs? The Geneva neuroscientists will now look at opiates — which are more addictive than cocaine — and ketamine, which is much less so. The aim is to understand in detail how the brain reacts to these drugs and why some people are much more vulnerable to their harmful effects than others.
The key to overcoming addictions and psychiatric disorders lives deep inside the netherworld of our brains and the circuitry that causes us to feel good. Just like space, this region of the brain needs more exploration.
The oldest and most known reward pathway is the mesolimbic dopamine system, which is composed of neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens – a key structure in mediating emotional and motivation processing,
Dopamine is a neurotransmitter that is released when the brain is expecting reward.A spike in dopamine could come be from eating pizza, dancing, shopping and sex. But it can also come from drugs, and lead to substance abuse.
In the search for new therapies to treat addiction and psychiatric illness, researchers are examining pathways beyond dopamine that could play a role in reward and reinforcement.
In a paper published in Nature Neuroscience, researchers from the Bruchas Lab at UW Medicine pushed the science forward on our reward pathways and found another such pathway.
“This study opens new avenues to understanding reward circuitry that might be altered in abuse of nicotine, opiates or other drugs as well as neuropsychiatric diseases that affect reward processing including depression,” said corresponding author Dr. Michael Bruchas, professor of anesthesiology and pain medicine at the University of Washington School of Medicine.
The researchers found that approximately 30% of cells in the VTA – the midbrain – are GABA neurons. Neurons are the fundamental units of the brain and nervous system, the cells responsible for receiving sensory input from the external world, for sending motor commands to our muscles, and for transforming and relaying the electrical signals at every step in between.
VTA GABA neurons have increasingly been recognized as involved in reward and aversion, as well as potential targets for the treatment of addiction, depression and other stress-linked disorders.
“What we found are unique GABAergic cells that project broadly to the nucleus accumbens, but projections only to a specific portion contribute to reward reinforcement,” said co-lead author Raajaram Gowrishankar, a postdoctoral scholar in the Bruchas Lab and the Center for the Neurobiology of Addiction, Pain and Emotion.
In male and female mice, researchers showed that long-range GABA neurons from the VTA to the ventral, but not the dorsal, nucleus accumben shell are engaged in reward and reinforcement behavior. They showed that this GABAergic projection inhibit cholinergic interneurons – key players in reward-related learning.
These findings “further our understanding of neuronal circuits that are directly implicated in neuropsychiatric conditions such as depression and addiction,“ the researchers wrote.
Gowrishankar said the findings are allowing scientists to understand subregions of the brain and to visualize how specific neuromodulators are released during reward processing. In science terms, the researchers were able to highlight heterogeneity, or differences, in the brain.
"It’s really important that we don’t think of structures in the brain as monolithic," said Gowrishankar. "There’s lots of little nuance in brain – how plastic it is, how it’s wired. This finding is showing one way how differences can play out.”
Increased levels of dopamine release in the basolateral amygdala as a result of stressful situations during infancy could lead to lasting behavioral issues and social difficulties, a new study reports.
Exercise increases dopamine signaling in the motor areas of mice, according to research recently published in JNeurosci.
It’s no secret exercise is good for the brain — working out can improve mood, sharpen memory, and stave off cognitive decline. Exercise even improves motor behavior in people with Parkinson’s disease, but the exact mechanism is not known. One possibility is through an increase…
Was anyone going to tell me that neopronouns make my brain release happy chemicals, or was I just supposed to be reading a fanfic where characters were using neopronouns and have an internal crisis myself?
