Mice With a Healthy Gut Microbiome Are More Motivated to Exercise

reposted from https://www.the-scientist.com/news-opinion/mice-with-a-healthy-gut-microbiome-are-more-motivated-to-exercise-70845?utm_campaign=TS_DAILY_NEWSLETTER_2022&utm_medium=email&_hsmi=238698979&_hsenc=p2ANqtz-_ymMGFDXk8FwZj9ol6Ge0rVxC-_oiDn4m4ofgcFD6cZlpoxtOelPBFQEdpq6BDv4MMh_wFge2mwPYQOnZ3Dz61bMwgUQ&utm_content=238698979&utm_source=hs_email Mice With a Healthy Gut Microbiome Are More Motivated to Exercise A neural pathway between the gut and the brain led to the release of dopamine when the mice ran on a wheel or treadmill, but only in the presence of a robust microbiome. a white mouse sits on a blue exercise wheel, looking out onto the shavings below A black and white headshot of Katherine Irving Katherine Irving Dec 16, 2022 | 4 min read PDF VERSION ABOVE: © ISTOCK.COM, MARY SWIFT The gut is a jungle teeming with microorganisms that are instrumental to the process of digesting food, regulating metabolism, and defending against infection. However, research now suggests yet another way that the gut microbiome’s influence extends far past the bounds of its abdominal home. In mice, gut bacteria stimulate the production of dopamine during exercise, without which the mice lack the motivation to continue running, scientists at the University of Pennsylvania reported December 14 in Nature. “This is the most comprehensive study I have ever seen,” says Theodore Garland Jr., an evolutionary physiologist studying the gut-brain axis in mice at the University of California, Riverside, who wasn’t involved in the research. “[It’s] pulling together lots of different pieces that we knew before in different contexts or in isolation of other parts in a way that hasn’t been done before.” Exercise is “the single most effective lifestyle intervention that we have that protects us from a very large range of diseases,” says study coauthor Christoph Thaiss, a microbiologist at the University of Pennsylvania Perelman School of Medicine. Yet despite being a very physical activity, he says the success of an individual’s attempts to exercise often depends on their mental state. “If you look at what elite athletes say, many of them will say that they are not necessarily physically better than their competitors, but their mind is very well prepared,” he says. “But when it comes to preparing athletes, mentally or motivationally, for their competitions, there’s very little scientific evidence of how these methods might work.” Previous research had already found that the gut microbiome can influence muscle tissue and cardiovascular fitness as well as brain chemistry. But Thaiss aimed to bring such findings together and examine the broader role of the gut microbiome in exercise performance. So, he and his colleagues set up an experiment using 199 outcrossed mice from eight different genetic backgrounds to ensure that any findings weren’t limited to one strain. Using multiple antibiotics, the researchers altered the mice’s microbiome communities: some mice had fully functioning microbiomes, while the others had their gut microbiomes either partially or entirely removed. See “Tinkering with Gut Microbes Boosts Brain Plasticity in Mice” They then tested each mouse’s performance while running in two different settings: a treadmill, on which the mice were forced to run for an extended period to test their endurance, and a wheel, on which the mice were allowed to run as often and for as long as they wanted. Although all the mice were equally capable of moving around their cages, the mice with reduced microbiomes tired more quickly when exercising on the treadmill than mice with robust microbiomes. They also spent less time on the wheel, which the researchers attributed to reduced motivation to exercise. Thaiss then searched for a neural explanation for the behavioral differences among the groups of mice. He and his team used RNA sequencing to analyze the mice’s striatal spiny neurons, which are involved in producing the behavior-reinforcing neurotransmitter dopamine both before and after exercise, and found that many of the genes normally expressed during exercise were dampened without the microbiome. When he performed an experiment limiting dopamine production during exercise by inhibiting these neurons, it had the same effect that limiting or entirely removing the microbiome had in the previous experiment. From these experiments, Thaiss inferred that the production of dopamine was a significant factor in a mouse’s propensity to exercise, and that a mouse’s gut microbiome composition played some role in the regulation of dopamine in its brain. That led him to conclude that the mice lacking gut bacteria didn’t experience the dopamine rush animals usually get through exercise, known as the “runner’s high.” “If we can remote[ly] control the brain from the perspective of the GI tract, then this becomes a much more accessible problem.” —Christoph Thaiss, University of Pennsylvania Perelman School of Medicine The question then became how microbes in the gut influence dopamine in the brain. To find out, the team inhibited a set of neurons that connects the gastrointestinal tract to the brain using formulated drugs. In the same wheel and treadmill experiments as before, mice with healthy microbiomes but inhibited gut-brain neurons exhibited reduced exercise rates on par with the mice with limited microbiomes, suggesting that it was the stimulation of these neurons that controlled the amount the mice exercised. Finally, the researchers treated mice with specific antibiotics to determine what kinds of microbes were triggering the neurons. They performed a metabolomics analysis to determine which bacterial metabolites triggered the neural response. They found that metabolites known as fatty acid amides (FAAs) made by some microbes found in a healthy mouse gut were the most active during exercise. These FAAs generate neurotransmitters known as endocannabinoids. The scientists performed more experiments using ingestible inhibitors to determine that the endocannabinoids produced by the bacteria’s FAAs were stimulating receptors in the GI tract neurons during exercise, thereby triggering the neurons that subsequently stimulated dopamine production in the brain. “It was really elegant the way they structured the entire story,” says Francesca Ronchi, an immunologist at the Institute of Microbiology, Infectious Diseases and Immunology in Berlin, Germany who wasn’t involved in the study. She adds that she was very impressed by the thoroughness of the paper. “You couldn’t do it better.” Thaiss says that the next step will be to take this research from mice to humans and determine whether the same pathway exists in us. Garland explains that analyzing motivation in humans is more complicated than it is in mice: a person’s incentive to exercise is based on many more factors, including external ones such as their social environment and influence from family or friends, than is a mouse’s. “We don’t go and give our mice pep talks when they run a lot on the wheel,” he observes. In humans, by contrast, those that are naturally talented at some form of exercise may receive more praise, fueling them to exercise more. See “Regular Exercise Helps Patients Combat Cancer” Nonetheless, Ronchi says findings like these could one day reveal ways to stimulate exercise in those who need it, including cancer, Parkinson’s, or Alzheimer’s patients, for whom exercise is a valuable tool in mitigating symptoms. After all, if such a pathway does exist in people, gut microbes may be easier to manipulate or influence than neurons in the brain, Thaiss suggests: Unlike neurons, which are finicky and often inaccessible, gut bacteria could be influenced by an ingestible treatment. “If we can remote[ly] control the brain from the perspective of the GI tract, then this becomes a much more accessible problem,” he says. “But that’s still science fiction for now.” Keywords: bacteriaexercisefitnessgut bacteriagut microbiotaimmunologymicrobiologymicrobiomemicrobiotamouse studyneural activationneuronneurotransmittersNewspathwaysignaling pathwaysstudy story

reposted from https://www.frontiersin.org/articles/10.3389/fneur.2018.00068/full  and it suggests how important circadian rhythms are for life.....

EDITORIAL ARTICLE

Front. Neurol., 16 February 2018 | https://doi.org/10.3389/fneur.2018.00068

Editorial: Intrinsic Clocks

Timo Partonen1* and Daniela D. Pollak2

• 1Department of Public Health Solutions, National Institute for Health and Welfare (THL), Helsinki, Finland
• 2Department of Neurophysiology and Neuropharmacology, Medical University of Vienna, Vienna, Austria

Editorial on the Research Topic

Intrinsic Clocks

The existence of living organisms on our planet has been dependent on and co-evolved with the foreseeable variations in environmental conditions oscillating over recurring periods. All species have responded to these exogenous rhythms by developing endogenous clocks that allow for an approximate, but reliable estimation of the periodic changes and elicit corresponding adaptive processes.

The importance of these mechanisms for health and disease has been highlighted by the 2017 award of the Nobel Prize in Physiology or Medicine to Jeffrey C. Hall, Michael Rosbash, and Michael W. Young for their discoveries of the genetic control of the daily biological rhythm. They explained in molecular terms how the gene named as period contributed to the emergence (eclosion from the pupal case) rhythm of a population and to the locomotor activity of individual flies (Drosophila melanogaster). The key to the explanation was the discovery of transcription-translation feedback loops of the so-called “clock genes.”

This research topic on Intrinsic Clocks which appeared earlier comprises a well-balanced collection of original research and review articles on endogenous rhythms from seasonal and monthly to daily and hourly oscillations in different experimental model systems with analytical approaches from systemic to cellular and molecular levels.

Serchov and Heumann in their review focus on the role of Ras, an enzyme which hydrolyzes guanosine triphosphate and dependent intracellular signaling cascades in the regulation of the circadian rhythm in mice. They elegantly summarize how Ras activity forms a molecular bridge between entrainment of the suprachiasmatic nucleus that is the master clock in the brain and synaptic plasticity in dependent brain regions, such as the hippocampus, and corresponding functions. The extensive study by Chiang et al. specifically investigated rhythmic alterations in the murine hippocampus. They characterized the protein phosphorylation using a mass spectrometry approach with which they provided large-scale quantitative analysis of the daily oscillation of hippocampal phosphorylation events over a range of biological pathways. The hippocampus is a key focus also in the review by Urs Albrecht. It features the role of circadian proteins in the control of adult hippocampal neurogenesis, reciprocally implicated in depression and antidepressant responses. He discusses neurobiological mechanisms implicated in the pathogenesis of mood disorders, such as monoaminergic neurotransmission and stress response by the hypothalamic–pituitary–adrenal axis. The hypothalamus and the pituitary are further involved in seasonal cycles as highlighted in the review by Lewis and Ebling who elaborate in detail on the role of tanycytes, pituitary radial glial cells, in the regulation of circannual clocks in hamsters. They provide evidence supporting their hypothesis that tanycytes serve as central organizers of seasonal rhythms in the adult hypothalamus. Raible et al. present in their review on marine animals the current insight in the cellular mechanisms in molecular detail the monthly or semi-monthly rhythms. They express their worry about light pollution and further review the relevance of circalunar rhythms to mammalian physiology and reproduction in specific. They speculate that these rhythms may be the remnant of evolutionary ancient clocks, which were uncoupled from a natural entrainment mechanism.

Bourguignon and Storch summarize recent findings of the cellular substrate and mechanism, which generate locomotor activity with periods of 2–6 h. Such rhythms are normally integrated with circadian rhythms, but often lack the period stability and expression robustness. They further review the concept of the dopaminergic ultradian oscillator and show that ultradian locomotor rhythms rely on cells in the brain using dopamine for transmission. Intriguingly, Monje et al. report in their study on interleukin-6 knockout mice that the ultradian locomotor rhythm was impaired under both light-entrained and free-running conditions, whereas the circadian period and the level of locomotor activity as well as the phase shift response to light exposure at night remained normal. During the day, Cry1 and Bhlhe41 expression levels were increased whereas those of Nr1d2 were decreased in the hippocampus. Liu and Zhang first created mutants of cryptochrome circadian clock 1 (Cry1) protein at potential phosphorylation sites and conducted thereafter a screen in Cry1/Cry2 double deficient cells. They targeted at identifying mutations that disrupted circadian rhythms. They found that these single amino acid substitutions changed not only the circadian period, but also repression activity, protein stability, or cellular localization of the protein. Concerning the circadian period, Narasimamurthy and Virshup elucidate in their review the molecular mechanisms that regulate an enigma of the clock. Unlike other chemical reactions, the output of the clock as measured with the period remains nearly constant with fluctuations in ambient temperature. This is called as temperature compensation. The key lies especially in the mechanism that controls the stability of period circadian clock 2 protein. Clock-enhancing small molecules have become of particular interest as candidate chronotherapeutics, since there is a close association of circadian amplitude dampening with progression of chronic diseases, especially that of mood disorders. Gloston et al. present in their review an update of the regulatory mechanisms of circadian amplitude and the current status of these small molecules of therapeutic interest. Millius and Ueda introduce the readers to study of biology which takes advantage of engineering and mathematical tools to model and test the behaviors of the intrinsic clocks. It has evolved through the development of both wet lab and in silico work. The goal here is to understand the clocks that are made up of a range of complex properties of cells, tissues, and organisms.

The cross-section of studies comprised in this research topic on Intrinsic Clocks highlights the vibrant scientific activity in the field of the investigation of endogenous biological rhythms and their relevance for physiology and pathology.

Author Contributions

TP and DP planned and wrote the manuscript together.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Keywords: circadian rhythm, depression, marine biology, mouse model, plasticity, seasonality, small-molecule, systems biology

Citation: Partonen T and Pollak DD (2018) Editorial: Intrinsic Clocks. Front. Neurol. 9:68. doi: 10.3389/fneur.2018.00068

Received: 04 December 2017; Accepted: 29 January 2018;
Published: 16 February 2018

Edited and Reviewed by: Yves A. Dauvilliers, Hôpital Gui De Chauliac, France

Copyright: © 2018 Partonen and Pollak. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Timo Partonen, timo.partonen@thl.fi

Oxford researchers offer new insights into the function of neurotransmitter dopamine

http://www.psy.ox.ac.uk/research/walton-laboratory

http://www.psy.ox.ac.uk/news/oxford-researchers-offer-new-insights-into-the-function-of-neurotransmitter-dopamine

Oxford researchers offer new insights into the function of neurotransmitter dopamine 

• 9 December 2015
 
 

Dopamine is known to be an important neurochemical for reward processing and movement. However, the relationship between these two processes is not yet fully understood.  An articlefrom the Walton Lab, published in Nature Neuroscience this week, shows for the first time that dopamine release only increases in anticipation of future benefits if and when an appropriate action is initiated.  

The team, together with researchers in the MRC Brain Network Dynamics Unit and Department of Clinical Neurology, used electrochemistry to measure real-time dopamine release in conditions where rewards could be earned either by making or withholding an action.  While dopamine levels rose rapidly when an action was correctly initiated, no such increase was seen when a movement was correctly inhibited or an inappropriate response was made.  This suggests that dopamine does not just respond to predictions of future reward, but rather acts to promote beneficial actions

The Neuroscience Of Music

reposted from
Wired

The Neuroscience Of Music

• BY JONAH LEHRER  
 
• 01.19.11  |  
 
• 6:08 PM  |  
 
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Why does music make us feel? On the one hand, music is a purely abstract art form, devoid of language or explicit ideas. The stories it tells are all subtlety and subtext. And yet, even though music says little, it still manages to touch us deep, to tickle some universal nerves. When listening to our favorite songs, our body betrays all the symptoms of emotional arousal. The pupils in our eyes dilate, our pulse and blood pressure rise, the electrical conductance of our skin is lowered, and the cerebellum, a brain region associated with bodily movement, becomes strangely active. Blood is even re-directed to the muscles in our legs. (Some speculate that this is why we begin tapping our feet.) In other words, sound stirs us at our biological roots. As Schopenhauer wrote, “It is we ourselves who are tortured by the strings.”

We can now begin to understand where these feelings come from, why a mass of vibrating air hurtling through space can trigger such intense states of excitement. A brand new paper in Nature Neuroscience by a team of Montreal researchers marks an important step in revealing the precise underpinnings of “the potent pleasurable stimulus” that is music. Although the study involves plenty of fancy technology, including fMRI and ligand-based positron emission tomography (PET) scanning, the experiment itself was rather straightforward. After screening 217 individuals who responded to advertisements requesting people that experience “chills to instrumental music,” the scientists narrowed down the subject pool to ten. (These were the lucky few who most reliably got chills.) The scientists then asked the subjects to bring in their playlist of favorite songs – virtually every genre was represented, from techno to tango – and played them the music while their brain activity was monitored.

Because the scientists were combining methodologies (PET and fMRI) they were able to obtain an impressively precise portrait of music in the brain. The first thing they discovered (using ligand-based PET) is that music triggers the release of dopamine in both the dorsal and ventral striatum. This isn’t particularly surprising: these regions have long been associated with the response to pleasurable stimuli. It doesn’t matter if we’re having sex or snorting cocaine or listening to Kanye: These things fill us with bliss because they tickle these cells. Happiness begins here.

The more interesting finding emerged from a close study of the timing of this response, as the scientists looked to see what was happening in the seconds beforethe subjects got the chills. I won’t go into the precise neural correlates – let’s just say that you should thank your right NAcc the next time you listen to your favorite song – but want to instead focus on an interesting distinction observed in the experiment:

In essence, the scientists found that our favorite moments in the music were preceeded by a prolonged increase of activity in the caudate. They call this the “anticipatory phase” and argue that the purpose of this activity is to help us predict the arrival of our favorite part:

Immediately before the climax of emotional responses there was evidence for relatively greater dopamine activity in the caudate. This subregion of the striatum is interconnected with sensory, motor and associative regions of the brain and has been typically implicated in learning of stimulus-response associations and in mediating the reinforcing qualities of rewarding stimuli such as food.

In other words, the abstract pitches have become a primal reward cue, the cultural equivalent of a bell that makes us drool. Here is their summary:

The anticipatory phase, set off by temporal cues signaling that a potentially pleasurable auditory sequence is coming, can trigger expectations of euphoric emotional states and create a sense of wanting and reward prediction. This reward is entirely abstract and may involve such factors as suspended expectations and a sense of resolution. Indeed, composers and performers frequently take advantage of such phenomena, and manipulate emotional arousal by violating expectations in certain ways or by delaying the predicted outcome (for example, by inserting unexpected notes or slowing tempo) before the resolution to heighten the motivation for completion. The peak emotional response evoked by hearing the desired sequence would represent the consummatory or liking phase, representing fulfilled expectations and accurate reward prediction. We propose that each of these phases may involve dopamine release, but in different subcircuits of the striatum, which have different connectivity and functional roles.

The question, of course, is what all these dopamine neurons are up to. What aspects of music are they responding to? And why are they so active fifteen seconds beforethe acoustic climax? After all, we typically associate surges of dopamine with pleasure, with the processing of actual rewards. And yet, this cluster of cells in the caudate is most active when the chills have yet to arrive, when the melodic pattern is still unresolved.

One way to answer these questions is to zoom out, to look at the music and not the neuron. While music can often seem (at least to the outsider) like a labyrinth of intricate patterns – it’s art at its most mathematical – it turns out that the most important part of every song or symphony is when the patterns break down, when the sound becomes unpredictable. If the music is too obvious, it is annoyingly boring, like an alarm clock. (Numerous studies, after all, have demonstrated that dopamine neurons quickly adapt to predictable rewards. If we know what’s going to happen next, then we don’t get excited.) This is why composers introduce the tonic note in the beginning of the song and then studiously avoid it until the end. The longer we are denied the pattern we expect, the greater the emotional release when the pattern returns, safe and sound. That is when we get the chills.

To demonstrate this psychological principle, the musicologist Leonard Meyer, in his classic  book Emotion and Meaning in Music (1956), analyzed the 5^th movement of Beethoven’s String Quartet in C-sharp minor, Op. 131. Meyer wanted to show how music is defined by its flirtation with – but not submission to – our expectations of order. To prove his point, Meyer dissected fifty measures of Beethoven’s masterpiece, showing how Beethoven begins with the clear statement of a rhythmic and harmonic pattern and then, in an intricate tonal dance, carefully avoids repeating it. What Beethoven does instead is suggest variations of the pattern. He is its evasive shadow. If E major is the tonic, Beethoven will play incomplete versions of the E major chord, always careful to avoid its straight expression. He wants to preserve an element of uncertainty in his music, making our brains beg for the one chord he refuses to give us. Beethoven saves that chord for the end.

According to Meyer, it is the suspenseful tension of music (arising out of our unfulfilled expectations) that is the source of the music’s feeling. While earlier theories of music focused on the way a noise can refer to the real world of images and experiences (its “connotative” meaning), Meyer argued that the emotions we find in music come from the unfolding events of the music itself.  This “embodied meaning” arises from the patterns the symphony invokes and then ignores, from the ambiguity it creates inside its own form. “For the human mind,” Meyer writes, “such states of doubt and confusion are abhorrent. When confronted with them, the mind attempts to resolve them into clarity and certainty.” And so we wait, expectantly, for the resolution of E major, for Beethoven’s established pattern to be completed. This nervous anticipation, says Meyer, “is the whole raison d’etre of the passage, for its purpose is precisely to delay the cadence in the tonic.” The uncertainty makes the feeling – it is what triggers that surge of dopamine in the caudate, as we struggle to figure out what will happen next. And so our neurons search for the undulating order, trying to make sense of this flurry of pitches. We can predict some of the notes, but we can’t predict them all, and that is what keeps us listening, waiting expectantly for our reward, for the errant pattern to be completed. Music is a form whose meaning depends upon its violation.

Homepage image: Kashirin Nickolai, Flickr.

reposted from

Scientists use femtosecond lasers to tackle Parkinson's disease

Published on June 26, 2014 at 1:52 AM · No Comments

Scientists are combining physics and neurobiology to tackle Parkinson's disease. The Okinawa Institute of Science and Technology Graduate University's FemtosecondSpectroscopy Unit and Neurobiology Research Unit, along with collaborators at the University of Otago, New Zealand are using lasers, nanotechnology and neuroscience to develop a new, versatile drug delivery system. The researchers describe their work using a laser to release a neurochemical that is dysfunctional in Parkinson's Disease in a controlled and repeatable manner in a new article in Scientific Reports.

An exciting new area of research for a cure or therapy for many diseases is targeted drug delivery.  Currently, we administer drugs in a systemic way and tissues or organs that do not need the drug receive it, leading to unwanted side effects.  A good example of this is in chemotherapy, which is toxic not only to the intended target cancer cells, but also to healthy tissue.  Recent advances in nanotechnology and biology are opening up the possibilities in targeted drug delivery, where researchers can release drugs or compounds in a specific tissue or even individual cells, which would allow the drug to reach only its intended target.  In their recent paper, OIST researchers describe a method to encapsulate a drug in a shell of lipids, or fat, called a liposome, and modulate the release of the drug using a pulse from a laser.

Members of the Neurobiology Research Unit approached the Femtosecond Spectroscopy Unit with the idea to apply laser technology in a possible therapy for Parkinson's Disease. 

In Parkinson's Disease, the neurochemical dopamine does not function properly. The researchers wanted to use the precise timing and intensity of femtosecond lasers to control the release of dopamine in a way that mimicked its natural dynamic mechanism.  Therefore, the researchers encapsulated dopamine in a liposome tethered to a gold nanoparticle.  They used a femtosecond laser pulse as the energy source.  The energy is absorbed by the gold nanoparticle and then transferred to the liposome, causing the liposome to open and release the dopamine.  The length of time and therefore amount of dopamine released can be precisely controlled by the intensity and length of time the laser is on.  The researchers also showed that the liposomes are not destroyed by the laser as in previous similar studies.  Therefore, the release of dopamine, or any chemical contained within the liposome, can be repeated and controlled. 

Takashi Nakano of the OIST Neurobiology Research Unit said, "with this method, we can administer a wide range of drugs with precise timing and duration using laser pulses with sub-second accuracy. We are very excited about the potential this new tool brings to neurobiological research."

The next step is using these laser-activated liposomes in living tissue, and eventually, in a live animal.  The ability to release potentially any type of drug, chemical or naturally occurring compound in the right place at the right time with a controlled dosage will open new possibilities in medicine.  For Dani, it is exciting for him to "be able to utilize a physics technique I learned in graduate school for applications in neuroscience."  Nakano added, "the close collaboration between physicists, chemists, and neuroscientists made this outcome possible.  OIST's interdisciplinary research has truly facilitated smooth understanding of fields outside the collaborators' individual expertise." The future of new technologies and cures for disease may lie at the boundary between different scientific fields, such as physics and neuroscience.  OIST researchers are addressing today's scientific and medical puzzles, like Parkinson's Disease, by developing tomorrow's technologies that straddle those scientific boundaries.  Maybe Parkinson's Disease will be cured by a curious neuroscientist who works across the hall from a willing physicist in Okinawa.

Source:

Okinawa Institute of Science and Technology

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1-May-2014

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Contact: Sarah McDonnell
s_mcd@mit.edu
617-253-8923
Massachusetts Institute of Technology 

Delving deep into the brain

CAMBRIDGE, MA -- Launched in 2013, the national BRAIN Initiative aims to revolutionize our understanding of cognition by mapping the activity of every neuron in the human brain, revealing how brain circuits interact to create memories, learn new skills, and interpret the world around us.

Before that can happen, neuroscientists need new tools that will let them probe the brain more deeply and in greater detail, says Alan Jasanoff, an MIT associate professor of biological engineering. "There's a general recognition that in order to understand the brain's processes in comprehensive detail, we need ways to monitor neural function deep in the brain with spatial, temporal, and functional precision," he says.

Jasanoff and colleagues have now taken a step toward that goal: They have established a technique that allows them to track neural communication in the brain over time, using magnetic resonance imaging (MRI) along with a specialized molecular sensor. This is the first time anyone has been able to map neural signals with high precision over large brain regions in living animals, offering a new window on brain function, says Jasanoff, who is also an associate member of MIT's McGovern Institute for Brain Research.

His team used this molecular imaging approach, described in the May 1 online edition of Science, to study the neurotransmitter dopamine in a region called the ventral striatum, which is involved in motivation, reward, and reinforcement of behavior. In future studies, Jasanoff plans to combine dopamine imaging with functional MRI techniques that measure overall brain activity to gain a better understanding of how dopamine levels influence neural circuitry.

"We want to be able to relate dopamine signaling to other neural processes that are going on," Jasanoff says. "We can look at different types of stimuli and try to understand what dopamine is doing in different brain regions and relate it to other measures of brain function."

Tracking dopamine

Dopamine is one of many neurotransmitters that help neurons to communicate with each other over short distances. Much of the brain's dopamine is produced by a structure called the ventral tegmental area (VTA). This dopamine travels through the mesolimbic pathway to the ventral striatum, where it combines with sensory information from other parts of the brain to reinforce behavior and help the brain learn new tasks and motor functions. This circuit also plays a major role in addiction.

To track dopamine's role in neural communication, the researchers used an MRI sensor they had previously designed, consisting of an iron-containing protein that acts as a weak magnet. When the sensor binds to dopamine, its magnetic interactions with the surrounding tissue weaken, which dims the tissue's MRI signal. This allows the researchers to see where in the brain dopamine is being released. The researchers also developed an algorithm that lets them calculate the precise amount of dopamine present in each fraction of a cubic millimeter of the ventral striatum.

After delivering the MRI sensor to the ventral striatum of rats, Jasanoff's team electrically stimulated the mesolimbic pathway and was able to detect exactly where in the ventral striatum dopamine was released. An area known as the nucleus accumbens core, known to be one of the main targets of dopamine from the VTA, showed the highest levels. The researchers also saw that some dopamine is released in neighboring regions such as the ventral pallidum, which regulates motivation and emotions, and parts of the thalamus, which relays sensory and motor signals in the brain.

Each dopamine stimulation lasted for 16 seconds and the researchers took an MRI image every eight seconds, allowing them to track how dopamine levels changed as the neurotransmitter was released from cells and then disappeared. "We could divide up the map into different regions of interest and determine dynamics separately for each of those regions," Jasanoff says.

He and his colleagues plan to build on this work by expanding their studies to other parts of the brain, including the areas most affected by Parkinson's disease, which is caused by the death of dopamine-generating cells. Jasanoff's lab is also working on sensors to track other neurotransmitters, allowing them to study interactions between neurotransmitters during different tasks.

###

The paper's lead author is postdoc Taekwan Lee. Technical assistant Lili Cai and postdocs Victor Lelyveld and Aviad Hai also contributed to the research, which was funded by the National Institutes of Health and the Defense Advanced Research Projects Agency.

Written by Anne Trafton, MIT News Office

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