appetite Archives - Amazing Health Advances

Gut Microbiome Acts On the Brain to Control Appetite

AHA Publisher — Wed, 22 Jun 2022 07:00:29 +0000

Dr. Priyom Bose, Ph.D. via News-Medical – The brain is the central information center and constantly monitors the state of every organ present in a body. Previous research has shown that the brain also receives signals from the gut microbiota. In a new Immunity journal study, researchers discuss the work of Gabanyi et al. (2022), published in a recent issue of Science, which reveals that hypothalamic gamma-aminobutyric acid (GABAergic) neurons recognize microbial muropeptides through the cytosolic receptor NOD2, which regulates food intake and body temperature. The Brain and the Gut Microbiome Previous research indicates that structural components from intestinal bacteria can elicit pro-inflammatory responses in the body and, as a result, have an indirect effect on the brain. This phenomenon occurs through peripheral neurons or molecules that are released by immune cells after exposure to bacterial cells circulating in the blood. In the 2022 Science study, Gabanyi and colleagues discuss microbiome-brain communication. Herein, the researchers report that some neurons in the brain can directly identify bacterial cell wall components and subsequently initiate altered feeding behavior and temperature regulation. The hypothalamus is a region in the brain that connects the central nervous system (CNS) to the endocrine system through the pituitary gland. Moreover, the hypothalamus regulates various functions such as thirst, hunger, reproduction, sleep, body temperature, and circadian rhythms by inhibiting or stimulating neurons. To date, there is a limited amount of research on how the hypothalamus recognizes the state of the gastrointestinal lumen and perceives the microbes it is harboring. Commensal microorganisms are typically recognized through pattern recognition receptors (PRRs) of the innate immune system. For instance, NOD2 is involved with the identification of muramyl dipeptide (MDP), which is a peptidoglycan fragment of the bacterial cell wall. Previous studies have highlighted the functions of NOD2 beyond those which are related to innate immunity. However, the mechanisms responsible for the connection between bacterial peptidoglycans and neuronal functions of the brain remain largely unknown. What Happens When Microbial Components Reach the Brain? Gabanyi and her team addressed this gap in research by studying the NOD2-GFP reporter gene in mice, which helped them investigate the function of NOD2 in different parts of the CNS. Although microglia and endothelial cells were found to express NOD2 in all areas of the brain, NOD2 expression in neurons occurred only in specific regions, such as the striatum, thalamus, and hypothalamus. The researchers also observed that muropeptides were able to cross the intestinal barrier and reach the systemic circulation system in mice. These peptides were later detected in the brain tissues of all mice. Notably, the extent of their expression was greater in female mice as compared to males. The researchers also generated a novel mouse model that lacked NOD2 in inhibitory GABAergic neurons (VgatDNod2 mice) and excitatory neurons expressing calcium/calmodulin-dependent protein kinase II (CamKIIDNod2 mice). Aged female VgatDNod2 mice gained weight, had altered body temperature, and increased feeding. These phenotypic events were caused by MDP, as mice treated with MDP exhibited a reduction in food intake as compared to mice that received MDP isomer treatment, which cannot activate NOD2. The scientists also identified the regions of the brain that were affected by MDP. In this context, they mapped the expression of the neuronal activity marker Fos across different areas of the brain in both male and female mice of varied age groups and treated them with MDP or the control isomer. The arcuate nucleus of the hypothalamus exhibited reduced Fos expression in older female mice compared to males. Studies have shown that within the arcuate nucleus, the GABAergic population is responsible for food intake, which is constituted by AgRP+ NPY+ neurons. These genes are active during fasting and are silenced upon exposure to food. Interestingly, Gabanyi et al. observed that these neurons express NOD2 and that MDP exposure suppresses their activity. A decreased activity of GABAergic arcuate nucleus neurons was also identified in both mice. How Does NOD2 Expression Regulate Food Intake? The researchers also infected NOD2fl/fl mice with a Cre-expressing virus in their hypothalamus to locally target NOD2+ GABAergic neurons. Altered phenotypes, such as differential food intake and weight gain in both groups of mice, which included one group treated with MDP and the other with control, returned to normal once treated with broad-spectrum antibiotics. This finding implies that a decrease in the gut microbiome occurred after antibiotics treatment. This resulted in a reduction in the number of circulating muropeptides that subsequently altered neuronal sensing through its activity on NOD2. Conclusions In this study, Gabanyi and her research team highlight the possibility that bacterial components could directly regulate the appetite of individuals. These findings have presented the potential of PRR biology in the brain, which could be exploited to fight against the rising global problem of obesity. To read the original article click here.

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Study Pinpoints Specific Areas of the Brain Where Serotonin Promotes Patience

AHA Publisher — Mon, 07 Dec 2020 08:00:01 +0000

Okinawa Institute of Science and Technology (OIST) Graduate University via News-Medical Net – We’ve all been there. Whether we’re stuck in traffic at the end of a long day, or eagerly anticipating the release of a new book, film or album, there are times when we need to be patient. Learning to suppress the impulse for instant gratification is often vital for future success, but how patience is regulated in the brain remains poorly understood. Now, in a study on mice conducted by the Neural Computation Unit at the Okinawa Institute of Science and Technology Graduate University (OIST), the authors, Dr. Katsuhiko Miyazaki and Dr. Kayoko Miyazaki, pinpoint specific areas of the brain that individually promote patience through the action of serotonin. Their findings were published 27thNovember in Science Advances. Serotonin is one of the most famous neuromodulators of behavior, helping to regulate mood, sleep-wake cycles and appetite. Our research shows that release of this chemical messenger also plays a crucial role in promoting patience, increasing the time that mice are willing to wait for a food reward.” Dr. Katsuhiko Miyazaki, Author Their most recent work draws heavily on previous research, where the unit used a powerful technique called optogenetics – using light to stimulate specific neurons in the brain – to establish a causal link between serotonin and patience. The scientists bred genetically engineered mice which had serotonin-releasing neurons that expressed a light-sensitive protein. This meant that the researchers could stimulate these neurons to release serotonin at precise times by shining light, using an optical fiber implanted in the brain. The researchers found that stimulating these neurons while the mice were waiting for food increased their waiting time, with the maximum effect seen when the probability of receiving a reward was high but when the timing of the reward was uncertain. “In other words, for the serotonin to promote patience, the mice had to be confident that a reward would come but uncertain about when it would arrive,” said Dr. Miyazaki. In the previous study, the scientists focused on an area of the brain called the dorsal raphe nucleus – the central hub of serotonin-releasing neurons. Neurons from the dorsal raphe nucleus reach out into other areas of the forebrain and in their most recent study, the scientists explored specifically which of these other brain areas contributed to regulating patience. The team focused on three brain areas that had been shown to increase impulsive behaviors when they were damaged – a deep brain structure called the nucleus accumbens, and two parts of the frontal lobe called the orbitofrontal cortex and the medial prefrontal cortex. “Impulse behaviors are intrinsically linked to patience – the more impulsive an individual is, the less patient – so these brain areas were prime candidates,” explained Dr. Miyazaki. Good things come to those who wait (or not…) In the study, the scientists implanted optical fibers into the dorsal raphe nucleus and also one of either the nucleus accumbens, the orbitofrontal cortex, or the medial prefrontal cortex. The researchers trained mice to perform a waiting task where the mice held with their nose inside a hole, called a “nose poke”, until a food pellet was delivered. The scientists rewarded the mice in 75% of trials. In some test conditions, the timing of the reward was fixed at six or ten seconds after the mice started the nose poke and in other test conditions, the timing of the reward varied. In the remaining 25% of trials, called the omission trials, the scientists did not provide a food reward to the mice. They measured how long the mice continued performing the nose poke during omission trials – in other words, how patient they were – when serotonin-releasing neurons were and were not stimulated. When the researchers stimulated serotonin-releasing neural fibers that reached into the nucleus accumbens, they found no increase in waiting time, suggesting that serotonin in this area of the brain has no role in regulating patience. But when the scientists stimulated serotonin release in the orbitofrontal cortex and the medial prefrontal cortex while the mice were holding the nose poke, they found the mice waited longer, with a few crucial differences. In the orbitofrontal cortex, release of serotonin promoted patience as effectively as serotonin activation in the dorsal raphe nucleus; both when reward timing was fixed and when reward timing was uncertain, with stronger effects in the latter. But in the medial prefrontal cortex, the scientists only saw an increase in patience when the timing of the reward was varied, with no effect observed when the timing was fixed. “The differences seen in how each area of the brain responded to serotonin suggests that each brain area contributes to the overall waiting behavior of the mice in separate ways,” said Dr. Miyazaki. Modeling patience To investigate this further, the scientists constructed a computational model to explain the waiting behavior of the mice. The model assumes that the mice have an internal model of the timing of reward delivery and keep estimating the probability that a reward will be delivered. They can therefore judge over time whether they are in a reward or non-reward trial and decide whether or not to keep waiting. The model also assumes that the orbitofrontal cortex and the medial prefrontal cortex use different internal models of reward timing, with the latter being more sensitive to variations in timing, to calculate reward probabilities individually. The researchers found that the model best fitted the experimental data of waiting time by increasing the expected reward probability from 75% to 94% under serotonin stimulation. Put more simply, serotonin increased the mice’s belief that they were in a reward trial, and so they waited longer. Importantly, the model showed that stimulation of the dorsal raphe nucleus increased the probability from 75% to 94% in both the orbital frontal cortex and the medial prefrontal cortex, whereas stimulation of the brain areas separately only increased the probability in that particular area. “This confirmed the idea that these two brain areas are calculating the probability of a reward independently from each other, and that these independent calculations are then combined to ultimately determine how long the mice will wait,” explained Dr. Miyazaki. “This sort of complementary system allows animals to behave more flexibly to changing environments.” Ultimately, increasing our knowledge of how different areas of the brain are more or less affected by serotonin could have vital implications in future development of drugs. For example, selective serotonin reuptake inhibitors (SSRIs) are drugs that boost levels of serotonin in the brain and are used to treat depression. “This is an area we are keen to explore in the future, by using depression models of mice,” said Dr. Miyazaki. “We may find under certain genetic or environmental conditions that some of these identified brain areas have altered functions. By pinning down these regions, this could open avenues to provide more targeted treatments that act on specific areas of the brain, rather than the whole brain.” To read the original article click here.

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