Author: Julie Pryor

The craving state

by Jennifer Michalowski |

This story originally appeared in the Winter 2022 issue of BrainScan.

***

For people struggling with substance use disorders — and there are about 35 million of them worldwide — treatment options are limited. Even among those who seek help, relapse is common. In the United States, an epidemic of opioid addiction has been declared a public health emergency.

A 2019 survey found that 1.6 million people nationwide had an opioid use disorder, and the crisis has surged since the start of the COVID-19 pandemic. The Centers for Disease Control and Prevention estimates that more than 100,000 people died of drug overdose between April 2020 and April 2021 — nearly 30 percent more overdose deaths than occurred during the same period the previous year.

In the United States, an epidemic of opioid addiction has been declared a public health emergency.

A deeper understanding of what addiction does to the brain and body is urgently needed to pave the way to interventions that reliably release affected individuals from its grip. At the McGovern Institute, researchers are turning their attention to addiction’s driving force: the deep, recurring craving that makes people prioritize drug use over all other wants and needs.

McGovern Institute co-founder, Lore Harp McGovern.

“When you are in that state, then it seems nothing else matters,” says McGovern Investigator Fan Wang. “At that moment, you can discard everything: your relationship, your house, your job, everything. You only want the drug.”

With a new addiction initiative catalyzed by generous gifts from Institute co-founder Lore Harp McGovern and others, McGovern scientists with diverse expertise have come together to begin clarifying the neurobiology that underlies the craving state. They plan to dissect the neural transformations associated with craving at every level — from the drug-induced chemical changes that alter neuronal connections and activity to how these modifications impact signaling brain-wide. Ultimately, the McGovern team hopes not just to understand the craving state, but to find a way to relieve it — for good.

“If we can understand the craving state and correct it, or at least relieve a little bit of the pressure,” explains Wang, who will help lead the addiction initiative, “then maybe we can at least give people a chance to use their top-down control to not take the drug.”

The craving cycle

For individuals suffering from substance use disorders, craving fuels a cyclical pattern of escalating drug use. Following the euphoria induced by a drug like heroin or cocaine, depression sets in, accompanied by a drug craving motivated by the desire to relieve that suffering. And as addiction progresses, the peaks and valleys of this cycle dip lower: the pleasant feelings evoked by the drug become weaker, while the negative effects a person experiences in its absence worsen. The craving remains, and increasing use of the drug are required to relieve it.

By the time addiction sets in, the brain has been altered in ways that go beyond a drug’s immediate effects on neural signaling.

These insidious changes leave individuals susceptible to craving — and the vulnerable state endures. Long after the physical effects of withdrawal have subsided, people with substance use disorders can find their craving returns, triggered by exposure to a small amount of the drug, physical or social cues associated with previous drug use, or stress. So researchers will need to determine not only how different parts of the brain interact with one another during craving and how individual cells and the molecules within them are affected by the craving state — but also how things change as addiction develops and progresses.

Circuits, chemistry and connectivity

One clear starting point is the circuitry the brain uses to control motivation. Thanks in part to decades of research in the lab of McGovern Investigator Ann Graybiel, neuroscientists know a great deal about how these circuits learn which actions lead to pleasure and which lead to pain, and how they use that information to establish habits and evaluate the costs and benefits of complex decisions.

Graybiel’s work has shown that drugs of abuse strongly activate dopamine-responsive neurons in a part of the brain called the striatum, whose signals promote habit formation. By increasing the amount of dopamine that neurons release, these drugs motivate users to prioritize repeated drug use over other kinds of rewards, and to choose the drug in spite of pain or other negative effects. Her group continues to investigate the naturally occurring molecules that control these circuits, as well as how they are hijacked by drugs of abuse.

Distribution of opioid receptors targeted by morphine (shown in blue) in two regions in the dorsal striatum and nucleus accumbens of the mouse brain. Image: Ann Graybiel

In Fan Wang’s lab, work investigating the neural circuits that mediate the perception of physical pain has led her team to question the role of emotional pain in craving. As they investigated the source of pain sensations in the brain, they identified neurons in an emotion-regulating center called the central amygdala that appear to suppress physical pain in animals. Now, Wang wants to know whether it might be possible to modulate neurons involved in emotional pain to ameliorate the negative state that provokes drug craving.

These animal studies will be key to identifying the cellular and molecular changes that set the brain up for recurring cravings. And as McGovern scientists begin to investigate what happens in the brains of rodents that have been trained to self-administer addictive drugs like fentanyl or cocaine, they expect to encounter tremendous complexity.

McGovern Associate Investigator Polina Anikeeva, whose lab has pioneered new technologies that will help the team investigate the full spectrum of changes that underlie craving, says it will be important to consider impacts on the brain’s chemistry, firing patterns, and connectivity. To that end, multifunctional research probes developed in her lab will be critical to monitoring and manipulating neural circuits in animal models.

Imaging technology developed by investigator Ed Boyden will also enable nanoscale protein visualization brain-wide. An important goal will be to identify a neural signature of the craving state. With such a signal, researchers can begin to explore how to shut off that craving — possibly by directly modulating neural signaling.

Targeted treatments

“One of the reasons to study craving is because it’s a natural treatment point,” says McGovern Associate Investigator Alan Jasanoff. “And the dominant kind of approaches that people in our team think about are approaches that relate to neural circuits — to the specific connections between brain regions and how those could be changed.” The hope, he explains, is that it might be possible to identify a brain region whose activity is disrupted during the craving state, then use clinical brain stimulation methods to restore normal signaling — within that region, as well as in other connected parts of the brain.

To identify the right targets for such a treatment, it will be crucial to understand how the biology uncovered in laboratory animals reflects what’s happens in people with substance use disorders. Functional imaging in John Gabrieli’s lab can help bridge the gap between clinical and animal research by revealing patterns of brain activity associated with the craving state in both humans and rodents. A new technique developed in Jasanoff’s lab makes it possible to focus on the activity between specific regions of an animal’s brain. “By doing that, we hope to build up integrated models of how information passes around the brain in craving states, and of course also in control states where we’re not experiencing craving,” he explains.

In delving into the biology of the craving state, McGovern scientists are embarking on largely unexplored territory — and they do so with both optimism and urgency. “It’s hard to not appreciate just the size of the problem, and just how devastating addiction is,” says Anikeeva. “At this point, it just seems almost irresponsible to not work on it, especially when we do have the tools and we are interested in the general brain regions that are important for that problem. I would say that there’s almost a civic duty.”

Perfecting pitch perception

by Jennifer Michalowski |

New research from MIT neuroscientists suggest that natural soundscapes have shaped our sense of hearing, optimizing it for the kinds of sounds we most often encounter.

Mark Saddler, graduate fellow of the K. Lisa Yang Integrative Computational Neuroscience Center. Photo: Caitlin Cunningham

In a study reported December 14 in the journal Nature Communications, researchers led by McGovern Institute Associate Investigator Josh McDermott used computational modeling to explore factors that influence how humans hear pitch. Their model’s pitch perception closely resembled that of humans—but only when it was trained using music, voices, or other naturalistic sounds.

Humans’ ability to recognize pitch—essentially, the rate at which a sound repeats—gives melody to music and nuance to spoken language. Although this is arguably the best-studied aspect of human hearing, researchers are still debating which factors determine the properties of pitch perception, and why it is more acute for some types of sounds than others. McDermott, who is also an associate professor in MIT’s Department of Brain and Cognitive Sciences and an investigator with the Center for Brains Minds and Machines (CBMM), is particularly interested in understanding how our nervous system perceives pitch because cochlear implants, which send electrical signals about sound to the brain in people with profound deafness, don’t replicate this aspect of human hearing very well.

“Cochlear implants can do a pretty good job of helping people understand speech, especially if they’re in a quiet environment. But they really don’t reproduce the percept of pitch very well,” says Mark Saddler, a CBMM graduate student who co-led the project and an inaugural graduate fellow of the K. Lisa Yang Integrative Computational Neuroscience Center. “One of the reasons it’s important to understand the detailed basis of pitch perception in people with normal hearing is to try to get better insights into how we would reproduce that artificially in a prosthesis.”

Artificial hearing

Pitch perception begins in the cochlea, the snail-shaped structure in the inner ear where vibrations from sounds are transformed into electrical signals and relayed to the brain via the auditory nerve. The cochlea’s structure and function help determine how and what we hear. And although it hasn’t been possible to test this idea experimentally, McDermott’s team suspected our “auditory diet” might shape our hearing as well.

To explore how both our ears and our environment influence pitch perception, McDermott, Saddler and research assistant Ray Gonzalez built a computer model called a deep neural network. Neural networks are a type of machine learning model widely used in automatic speech recognition and other artificial intelligence applications. Although the structure of an artificial neural network coarsely resembles the connectivity of neurons in the brain, the models used in engineering applications don’t actually hear the same way humans do—so the team developed a new model to reproduce human pitch perception. Their approach combined an artificial neural network with an existing model of the mammalian ear, uniting the power of machine learning with insights from biology. “These new machine learning models are really the first that can be trained to do complex auditory tasks and actually do them well, at human levels of performance,” Saddler explains.

The researchers trained the neural network to estimate pitch by asking it to identify the repetition rate of sounds in a training set. This gave them the flexibility to change the parameters under which pitch perception developed. They could manipulate the types of sound they presented to the model, as well as the properties of the ear that processed those sounds before passing them on to the neural network.

When the model was trained using sounds that are important to humans, like speech and music, it learned to estimate pitch much as humans do. “We very nicely replicated many characteristics of human perception…suggesting that it’s using similar cues from the sounds and the cochlear representation to do the task,” Saddler says.

But when the model was trained using more artificial sounds or in the absence of any background noise, its behavior was very different. For example, Saddler says, “If you optimize for this idealized world where there’s never any competing sources of noise, you can learn a pitch strategy that seems to be very different from that of humans, which suggests that perhaps the human pitch system was really optimized to deal with cases where sometimes noise is obscuring parts of the sound.”

The team also found the timing of nerve signals initiated in the cochlea to be critical to pitch perception. In a healthy cochlea, McDermott explains, nerve cells fire precisely in time with the sound vibrations that reach the inner ear. When the researchers skewed this relationship in their model, so that the timing of nerve signals was less tightly correlated to vibrations produced by incoming sounds, pitch perception deviated from normal human hearing. 

McDermott says it will be important to take this into account as researchers work to develop better cochlear implants. “It does very much suggest that for cochlear implants to produce normal pitch perception, there needs to be a way to reproduce the fine-grained timing information in the auditory nerve,” he says. “Right now, they don’t do that, and there are technical challenges to making that happen—but the modeling results really pretty clearly suggest that’s what you’ve got to do.”

MIT response to Wall Street Journal opinion essay

by Robert Desimone, McGovern Institute | Nergis Mavalvala, MIT School of Science | Maria T. Zuber, MIT Office of the Vice President for Research |

Following is an open statement in response to “Is MIT’s Research Helping the Chinese Military?”, an opinion essay by Michelle Bethel posted by the Wall Street Journal on Dec. 10, 2021. This statement is jointly from Prof. Robert Desimone, director of the McGovern Institute for Brain Research at MIT, Prof. Nergis Mavalvala, dean of MIT’s School of Science, and Prof. Maria T. Zuber, vice president for research at MIT.  

Ms. Bethel is absolutely right that research relationships with institutions in China require the most serious care and consideration. MIT brings a thorough and rigorous approach to these matters.

First let us be clear about the work of the MIT McGovern Institute for Brain Research. Of the dozens of research projects currently under way at the McGovern Institute, there is one active research collaboration with China. It involves better identifying and ultimately developing treatments for severe forms of autism or neurological disorders that often render individuals unable to speak and frequently require lifelong care. That project was thoroughly vetted and approved by the U.S. National Institutes of Health in 2019. MIT receives no funding from China for this research, and all findings will be published in peer-reviewed journals, meaning that they are open to medical researchers anywhere in the world. This is the collaboration with the Shenzhen Institute of Advanced Technology that Ms. Bethel referenced in vague terms.

This does not eliminate general concerns about how research may be conducted or used, however. That’s why MIT has strong processes for evaluating and managing the risks of research involving countries, including China, whose behavior affects U.S. national and economic security. Every proposed engagement that involves an organization or funding source from China, once it has been evaluated for compliance with U.S. law and regulation, is further reviewed by committees of senior administrators to consider risks related to national security, economic competitiveness, and civil and human rights. Projects have been variously turned down, modified, or approved under this process.

Ms. Bethel raises important points with respect to U.S.-China relations – but not with respect to the work of the McGovern Institute. We regret that Ms. Bethel felt it necessary to step away from the McGovern, but we respect her views and continue in conversation with her. We note that two other members of the McGovern family, including the McGovern Institute’s co-founder and another daughter, continue to proudly serve on the McGovern board. We are grateful to all three family members.

McGovern Institute Director receives highest honor from the Society for Neuroscience

by Julie Pryor |

The Society for Neuroscience will present its highest honor, the Ralph W. Gerard Prize in Neuroscience, to McGovern Institute Director Robert Desimone at its annual meeting today.

The Gerard Prize is named for neuroscientist Ralph W. Gerard who helped establish the Society for Neuroscience, and honors “outstanding scientists who have made significant contributions to neuroscience throughout their careers.” Desimone will share the $30,000 prize with Vanderbilt University neuroscientist Jon Kaas.

Desimone is being recognized for his career contributions to understanding cortical function in the visual system. His seminal work on attention spans decades, including the discovery of a neural basis for covert attention in the temporal cortex and the creation of the biased competition model, suggesting that attention is biased towards material relevant to the task. More recent work revealed how synchronized brain rhythms help enhance visual processing. Desimone also helped discover both face cells and neural populations that identify objects even when the size or location of the object changes. His long list of contributions includes mapping the extrastriate visual cortex, publishing the first report of columns for motion processing outside the primary visual cortex, and discovering how the temporal cortex retains memories. Desimone’s work has moved the field from broad strokes of input and output to a more nuanced understanding of cortical function that allows the brain to make sense of the environment.

At its annual meeting, beginning today, the Society will honor Desimone and other leading researchers who have made significant contributions to neuroscience — including the understanding of cognitive processes, drug addiction, neuropharmacology, and theoretical models — with this year’s Outstanding Achievement Awards.

“The Society is honored to recognize this year’s awardees, whose groundbreaking research has revolutionized our understanding of the brain, from the level of the synapse to the structure and function of the cortex, shedding light on how vision, memory, perception of touch and pain, and drug
addiction are organized in the brain,” SfN President Barry Everitt, said. “This exceptional group of neuroscientists has made fundamental discoveries, paved the way for new therapeutic approaches, and introduced new tools that will lay the foundation for decades of research to come.”

A connectome for cognition

by Jennifer Michalowski |

The lateral prefrontal cortex is a particularly well-connected part of the brain. Neurons there communicate with processing centers throughout the rest of the brain, gathering information and sending commands to implement executive control over behavior. Now, scientists at MIT’s McGovern Institute have mapped these connections and revealed an unexpected order within them: The lateral prefrontal cortex, they’ve found, contains maps of other major parts of the brain’s cortex.

The researchers, led by postdoctoral researcher Rui Xu and McGovern Institute Director Robert Desimone, report that the lateral prefrontal cortex contains a set of maps that represent the major processing centers in the other parts of the cortex, including the temporal and parietal lobes. Their organization likely supports the lateral prefrontal cortex’s roles managing complex functions such as attention and working memory, which require integrating information from multiple sources and coordinating activity elsewhere in the brain. The findings are published November 4, 2021, in the journal Neuron.

Topographic maps

The layout of the maps, which allows certain regions of the lateral prefrontal cortex to directly interact with multiple areas across the brain, indicates that this part of the brain is particularly well positioned for its role. “This function of integrating and then sending back control signals to appropriate levels in the processing hierarchies of the brain is clearly one of the reasons that prefrontal cortex is so important for cognition and executive control,” says Desimone.

In many parts of the brain, neurons’ physical organization has been found to reflect the information represented there. For example, individual neurons’ positions within the visual cortex mirror the layout of the cells in the retina from which they receive input, such that the spatial pattern of neuronal activity in this part of the brain provides an approximate view of the image seen by the eyes. For example, if you fixate on the first letter of a word, the next letters in the word will map to sequential locations in the visual cortex. Likewise, the arm and hand are mapped to adjacent locations in the somatic cortex, where the brain receives sensory information from the skin.

Topographic maps such as these, which have been found primarily in brain regions involved in sensory and motor processing, offer clues about how information is stored and processed in the brain. Neuroscientists have hoped that topographic maps within the lateral prefrontal cortex will provide insight into the complex cognitive processes that are carried out there—but such maps have been elusive.

Previous anatomical studies had given little indication how different parts of the brain communicate preferentially to specific locations within the prefrontal cortex to give rise to regional specialization of cognitive functions. Recently, however, the Desimone lab identified two areas within the lateral prefrontal cortex of monkeys with specific roles in focusing an animal’s visual attention. Knowing that some spots within the lateral prefrontal cortex were wired for specific functions, they wondered if others were, too. They decided they needed a detailed map of the connections emanating from this part of the brain, and devised a plan to plot connectivity from hundreds of points within the lateral prefrontal cortex.

Cortical connectome

To generate a wiring diagram, or connectome, Xu used functional MRI to monitor activity throughout a monkey’s brain as he stimulated specific points within its lateral prefrontal cortex. He moved systematically through the brain region, stimulating points spaced as close as one millimeter apart, and noting which parts of the brain lit up in response. Ultimately, the team collected data from about 100 sites for each of two monkeys.

As the data accumulated, clear patterns emerged. Different regions within the lateral prefrontal cortex formed orderly connections with each of five processing centers throughout the brain. Points within each of these maps connected to sites with the same relative positions in the distant processing centers. Because some parts of the lateral prefrontal cortex are wired to interact with more than one processing centers, these maps overlap, positioning the prefrontal cortex to integrate information from different sources.

The team found significant overlap, for example, between the maps of the temporal cortex, a part of the brain that uses visual information to recognize objects, and the parietal cortex, which computes the spatial relationships between objects. “It is mapping objects and space together in a way that would integrate the two systems,” explains Desimone. “And then on top of that, it has other maps of other brain systems that are partially overlapping with that—so they’re all sort of coming together.”

Desimone and Xu say the new connectome will help guide further investigations of how the prefrontal cortex orchestrates complex cognitive processes. “I think this really gives us a direction for the future, because we now need to understand the cognitive concepts that are mapped there,” Desimone says.

Already, they say, the connectome offers encouragement that a deeper understanding of complex cognition is within reach. “This topographic connectivity gives the lateral prefrontal some specific advantage to serve its function,” says Xu. “This suggests that lateral prefrontal cortex has a fine organization, just like the more studied parts of the brain, so the approaches that have been used to study these other regions may also benefit the studies of high-level cognition.”

Data transformed

by Jennifer Michalowski |

With the tools of modern neuroscience, data accumulates quickly. Recording devices listen in on the electrical conversations between neurons, picking up the voices of hundreds of cells at a time. Microscopes zoom in to illuminate the brain’s circuitry, capturing thousands of images of cells’ elaborately branched paths. Functional MRIs detect changes in blood flow to map activity within a person’s brain, generating a complete picture by compiling hundreds of scans.

“When I entered neuroscience about 20 years ago, data were extremely precious, and ideas, as the expression went, were cheap. That’s no longer true,” says McGovern Associate Investigator Ila Fiete. “We have an embarrassment of wealth in the data but lack sufficient conceptual and mathematical scaffolds to understand it.”

Fiete will lead the McGovern Institute’s new K. Lisa Yang Integrative Computational Neuroscience (ICoN) Center, whose scientists will create mathematical models and other computational tools to confront the current deluge of data and advance our understanding of the brain and mental health. The center, funded by a $24 million donation from philanthropist Lisa Yang, will take a uniquely collaborative approach to computational neuroscience, integrating data from MIT labs to explain brain function at every level, from the molecular to the behavioral.

“Driven by technologies that generate massive amounts of data, we are entering a new era of translational neuroscience research,” says Yang, whose philanthropic investment in MIT research now exceeds $130 million. “I am confident that the multidisciplinary expertise convened by this center will revolutionize how we synthesize this data and ultimately understand the brain in health and disease.”

Data integration

Fiete says computation is particularly crucial to neuroscience because the brain is so staggeringly complex. Its billions of neurons, which are themselves complicated and diverse, interact with one other through trillions of connections.

“Conceptually, it’s clear that all these interactions are going to lead to pretty complex things. And these are not going to be things that we can explain in stories that we tell,” Fiete says. “We really will need mathematical models. They will allow us to ask about what changes when we perturb one or several components — greatly accelerating the rate of discovery relative to doing those experiments in real brains.”

By representing the interactions between the components of a neural circuit, a model gives researchers the power to explore those interactions, manipulate them, and predict the circuit’s behavior under different conditions.

“You can observe these neurons in the same way that you would observe real neurons. But you can do even more, because you have access to all the neurons and you have access to all the connections and everything in the network,” explains computational neuroscientist and McGovern Associate Investigator Guangyu Robert Yang (no relation to Lisa Yang), who joined MIT as a junior faculty member in July 2021.

Many neuroscience models represent specific functions or parts of the brain. But with advances in computation and machine learning, along with the widespread availability of experimental data with which to test and refine models, “there’s no reason that we should be limited to that,” he says.

Robert Yang’s team at the McGovern Institute is working to develop models that integrate multiple brain areas and functions. “The brain is not just about vision, just about cognition, just about motor control,” he says. “It’s about all of these things. And all these areas, they talk to one another.” Likewise, he notes, it’s impossible to separate the molecules in the brain from their effects on behavior – although those aspects of neuroscience have traditionally been studied independently, by researchers with vastly different expertise.

The ICoN Center will eliminate the divides, bringing together neuroscientists and software engineers to deal with all types of data about the brain. To foster interdisciplinary collaboration, every postdoctoral fellow and engineer at the center will work with multiple faculty mentors. Working in three closely interacting scientific cores, fellows will develop computational technologies for analyzing molecular data, neural circuits, and behavior, such as tools to identify pat-terns in neural recordings or automate the analysis of human behavior to aid psychiatric diagnoses. These technologies will also help researchers model neural circuits, ultimately transforming data into knowledge and understanding.

“Lisa is focused on helping the scientific community realize its goals in translational research,” says Nergis Mavalvala, dean of the School of Science and the Curtis and Kathleen Marble Professor of Astrophysics. “With her generous support, we can accelerate the pace of research by connecting the data to the delivery of tangible results.”

Computational modeling

In its first five years, the ICoN Center will prioritize four areas of investigation: episodic memory and exploration, including functions like navigation and spatial memory; complex or stereotypical behavior, such as the perseverative behaviors associated with autism and obsessive-compulsive disorder; cognition and attention; and sleep. The goal, Fiete says, is to model the neuronal interactions that underlie these functions so that researchers can predict what will happen when something changes — when certain neurons become more active or when a genetic mutation is introduced, for example. When paired with experimental data from MIT labs, the center’s models will help explain not just how these circuits work, but also how they are altered by genes, the environment, aging, and disease.

These focus areas encompass circuits and behaviors often affected by psychiatric disorders and neurodegeneration, and models will give researchers new opportunities to explore their origins and potential treatment strategies. “I really think that the future of treating disorders of the mind is going to run through computational modeling,” says McGovern Associate Investigator Josh McDermott.

In McDermott’s lab, researchers are modeling the brain’s auditory circuits. “If we had a perfect model of the auditory system, we would be able to understand why when somebody loses their hearing, auditory abilities degrade in the very particular ways in which they degrade,” he says. Then, he says, that model could be used to optimize hearing aids by predicting how the brain would interpret sound altered in various ways by the device.

Similar opportunities will arise as researchers model other brain systems, McDermott says, noting that computational models help researchers grapple with a dauntingly vast realm of possibilities. “There’s lots of different ways the brain can be set up, and lots of different potential treatments, but there is a limit to the number of neuroscience or behavioral experiments you can run,” he says. “Doing experiments on a computational system is cheap, so you can explore the dynamics of the system in a very thorough way.”

The ICoN Center will speed the development of the computational tools that neuroscientists need, both for basic understanding of the brain and clinical advances. But Fiete hopes for a culture shift within neuroscience, as well. “There are a lot of brilliant students and postdocs who have skills that are mathematics and computational and modeling based,” she says. “I think once they know that there are these possibilities to collaborate to solve problems related to psychiatric disorders and how we think, they will see that this is an exciting place to apply their skills, and we can bring them in.”

New integrative computational neuroscience center established at MIT’s McGovern Institute

by Jennifer Michalowski |

With the tools of modern neuroscience, researchers can peer into the brain with unprecedented accuracy. Recording devices listen in on the electrical conversations between neurons, picking up the voices of hundreds of cells at a time. Genetic tools allow us to focus on specific types of neurons based on their molecular signatures. Microscopes zoom in to illuminate the brain’s circuitry, capturing thousands of images of elaborately branched dendrites. Functional MRIs detect changes in blood flow to map activity within a person’s brain, generating a complete picture by compiling hundreds of scans.

This deluge of data provides insights into brain function and dynamics at different levels – molecules, cells, circuits, and behavior — but the insights often remain compartmentalized in separate research silos. An innovative new center at MIT’s McGovern Institute aims to leverage them into powerful revelations of the brain’s inner workings.

The K. Lisa Yang Integrative Computational Neuroscience (ICoN) Center will create advanced mathematical models and computational tools to synthesize the deluge of data across scales and advance our understanding of the brain and mental health.

The center, funded by a $24 million donation from philanthropist Lisa Yang and led by McGovern Institute Associate Investigator Ila Fiete, will take a collaborative approach to computational neuroscience, integrating cutting-edge modeling techniques and data from MIT labs to explain brain function at every level, from the molecular to the behavioral.

“Our goal is that sophisticated, truly integrated computational models of the brain will make it possible to identify how ‘control knobs’ such as genes, proteins, chemicals, and environment drive thoughts and behavior, and to make inroads toward urgent unmet needs in understanding and treating brain disorders,” says Fiete, who is also a brain and cognitive sciences professor at MIT.

“Driven by technologies that generate massive amounts of data, we are entering a new era of translational neuroscience research,” says Yang, whose philanthropic investment in MIT research now exceeds $130 million. “I am confident that the multidisciplinary expertise convened by the ICoN center will revolutionize how we synthesize this data and ultimately understand the brain in health and disease.”

Connecting the data

It is impossible to separate the molecules in the brain from their effects on behavior – although those aspects of neuroscience have traditionally been studied independently, by researchers with vastly different expertise. The ICoN Center will eliminate the divides, bringing together neuroscientists and software engineers to deal with all types of data about the brain.

“The center’s highly collaborative structure, which is essential for unifying multiple levels of understanding, will enable us to recruit talented young scientists eager to revolutionize the field of computational neuroscience,” says Robert Desimone, director of the McGovern Institute. “It is our hope that the ICoN Center’s unique research environment will truly demonstrate a new academic research structure that catalyzes bold, creative research.”

To foster interdisciplinary collaboration, every postdoctoral fellow and engineer at the center will work with multiple faculty mentors. In order to attract young scientists and engineers to the field of computational neuroscience, the center will also provide four graduate fellowships to MIT students each year in perpetuity. Interacting closely with three scientific cores, engineers and fellows will develop computational models and technologies for analyzing molecular data, neural circuits, and behavior, such as tools to identify patterns in neural recordings or automate the analysis of human behavior to aid psychiatric diagnoses. These technologies and models will be instrumental in synthesizing data into knowledge and understanding.

Center priorities

In its first five years, the ICoN Center will prioritize four areas of investigation: episodic memory and exploration, including functions like navigation and spatial memory; complex or stereotypical behavior, such as the perseverative behaviors associated with autism and obsessive-compulsive disorder; cognition and attention; and sleep. Models of complex behavior will be created in collaboration with clinicians and researchers at Children’s Hospital of Philadelphia.

The goal, Fiete says, is to model the neuronal interactions that underlie these functions so that researchers can predict what will happen when something changes — when certain neurons become more active or when a genetic mutation is introduced, for example. When paired with experimental data from MIT labs, the center’s models will help explain not just how these circuits work, but also how they are altered by genes, the environment, aging, and disease. These focus areas encompass circuits and behaviors often affected by psychiatric disorders and neurodegeneration, and models will give researchers new opportunities to explore their origins and potential treatment strategies.

“Lisa Yang is focused on helping the scientific community realize its goals in translational research,” says Nergis Mavalvala, dean of the School of Science and the Curtis and Kathleen Marble Professor of Astrophysics. “With her generous support, we can accelerate the pace of research by connecting the data to the delivery of tangible results.”

 

Artificial networks learn to smell like the brain

by Jennifer Michalowski |

Using machine learning, a computer model can teach itself to smell in just a few minutes. When it does, researchers have found, it builds a neural network that closely mimics the olfactory circuits that animal brains use to process odors.

Animals from fruit flies to humans all use essentially the same strategy to process olfactory information in the brain. But neuroscientists who trained an artificial neural network to take on a simple odor classification task were surprised to see it replicate biology’s strategy so faithfully.

“The algorithm we use has no resemblance to the actual process of evolution,” says Guangyu Robert Yang, an associate investigator at MIT’s McGovern Institute, who led the work as a postdoctoral fellow at Columbia University. The similarities between the artificial and biological systems suggest that the brain’s olfactory network is optimally suited to its task.

Yang and his collaborators, who reported their findings October 6, 2021, in the journal Neuron, say their artificial network will help researchers learn more about the brain’s olfactory circuits. The work also helps demonstrate artificial neural networks’ relevance to neuroscience. “By showing that we can match the architecture [of the biological system] very precisely, I think that gives more confidence that these neural networks can continue to be useful tools for modeling the brain,” says Yang, who is also an assistant professor in MIT’s Departments of Brain and Cognitive Sciences and Electrical Engineering and Computer Science and a member of the Center for Brains, Minds and Machines.

Mapping natural olfactory circuits

For fruit flies, the organism in which the brain’s olfactory circuitry has been best mapped, smell begins in the antennae. Sensory neurons there, each equipped with odor receptors specialized to detect specific scents, transform the binding of odor molecules into electrical activity. When an odor is detected, these neurons, which make up the first layer of the olfactory network, signal to the second-layer: a set of neurons that reside in a part of the brain called the antennal lobe. In the antennal lobe, sensory neurons that share the same receptor converge onto the same second-layer neuron. “They’re very choosy,” Yang says. “They don’t receive any input from neurons expressing other receptors.” Because it has fewer neurons than the first layer, this part of the network is considered a compression layer. These second-layer neurons, in turn, signal to a larger set of neurons in the third layer. Puzzlingly, those connections appear to be random.

For Yang, a computational neuroscientist, and Columbia University graduate student Peter Yiliu Wang, this knowledge of the fly’s olfactory system represented a unique opportunity. Few parts of the brain have been mapped as comprehensively, and that has made it difficult to evaluate how well certain computational models represent the true architecture of neural circuits, they say.

Building an artificial smell network

Neural networks, in which artificial neurons rewire themselves to perform specific tasks, are computational tools inspired by the brain. They can be trained to pick out patterns within complex datasets, making them valuable for speech and image recognition and other forms of artificial intelligence. There are hints that the neural networks that do this best replicate the activity of the nervous system. But, says Wang, who is now a postdoctoral researcher at Stanford University, differently structured networks could generate similar results, and neuroscientists still need to know whether artificial neural networks reflect the actual structure of biological circuits. With comprehensive anatomical data about fruit fly olfactory circuits, he says: “We’re able to ask this question: Can artificial neural networks truly be used to study the brain?”

Collaborating closely with Columbia neuroscientists Richard Axel and Larry Abbott, Yang and Wang constructed a network of artificial neurons comprising an input layer, a compression layer, and an expansion layer—just like the fruit fly olfactory system. They gave it the same number of neurons as the fruit fly system, but no inherent structure: connections between neurons would be rewired as the model learned to classify odors.

The scientists asked the network to assign data representing different odors to categories, and to correctly categorize not just single odors, but also mixtures of odors. This is something that the brain’s olfactory system is uniquely good at, Yang says. If you combine the scents of two different apples, he explains, the brain still smells apple. In contrast, if two photographs of cats are blended pixel by pixel, the brain no longer sees a cat. This ability is just one feature of the brain’s odor-processing circuits, but captures the essence of the system, Yang says.

It took the artificial network only minutes to organize itself. The structure that emerged was stunningly similar to that found in the fruit fly brain. Each neuron in the compression layer received inputs from a particular type of input neuron and connected, seemingly randomly, to multiple neurons in the expansion layer. What’s more, each neuron in the expansion layer receives connections, on average, from six compression-layer neurons—exactly as occurs in the fruit fly brain.

“It could have been one, it could have been 50. It could have been anywhere in between,” Yang says. “Biology finds six, and our network finds about six as well.” Evolution found this organization through random mutation and natural selection; the artificial network found it through standard machine learning algorithms.

The surprising convergence provides strong support that the brain circuits that interpret olfactory information are optimally organized for their task, he says. Now, researchers can use the model to further explore that structure, exploring how the network evolves under different conditions and manipulating the circuitry in ways that cannot be done experimentally.

Dealing with uncertainty

by Jennifer Michalowski |

As we interact with the world, we are constantly presented with information that is unreliable or incomplete – from jumbled voices in a crowded room to solicitous strangers with unknown motivations. Fortunately, our brains are well equipped to evaluate the quality of the evidence we use to make decisions, usually allowing us to act deliberately, without jumping to conclusions.

Now, neuroscientists at MIT’s McGovern Institute have homed in on key brain circuits that help guide decision-making under conditions of uncertainty. By studying how mice interpret ambiguous sensory cues, they’ve found neurons that stop the brain from using unreliable information.

“One area cares about the content of the message—that’s the prefrontal cortex—and the thalamus seems to care about how certain the input is.” – Michael Halassa

The findings, published October 6, 2021, in the journal Nature, could help researchers develop treatments for schizophrenia and related conditions, whose symptoms may be at least partly due to affected individuals’ inability to effectively gauge uncertainty.

Decoding ambiguity

“A lot of cognition is really about handling different types of uncertainty,” says McGovern Associate Investigator Michael Halassa, explaining that we all must use ambiguous information to make inferences about what’s happening in the world. Part of dealing with this ambiguity involves recognizing how confident we can be in our conclusions. And when this process fails, it can dramatically skew our interpretation of the world around us.

“In my mind, schizophrenia spectrum disorders are really disorders of appropriately inferring the causes of events in the world and what other people think,” says Halassa, who is a practicing psychiatrist. Patients with these disorders often develop strong beliefs based on events or signals most people would dismiss as meaningless or irrelevant, he says. They may assume hidden messages are embedded in a garbled audio recording, or worry that laughing strangers are plotting against them. Such things are not impossible—but delusions arise when patients fail to recognize that they are highly unlikely.

Halassa and postdoctoral researcher Arghya Mukherjee wanted to know how healthy brains handle uncertainty, and recent research from other labs provided some clues. Functional brain imaging had shown that when people are asked to study a scene but they aren’t sure what to pay attention to, a part of the brain called the mediodorsal thalamus becomes active. The less guidance people are given for this task, the harder the mediodorsal thalamus works.

The thalamus is a sort of crossroads within the brain, made up of cells that connect distant brain regions to one another. Its mediodorsal region sends signals to the prefrontal cortex, where sensory information is integrated with our goals, desires, and knowledge to guide behavior. Previous work in the Halassa lab showed that the mediodorsal thalamus helps the prefrontal cortex tune in to the right signals during decision-making, adjusting signaling as needed when circumstances change. Intriguingly, this brain region has been found to be less active in people with schizophrenia than it is in others.

group photo of study authors
Study authors (from left to right) Michael Halassa, Arghya Mukherjee, Norman Lam and Ralf Wimmer.

Working with postdoctoral researcher Norman Lam and research scientist Ralf Wimmer, Halassa and Mukherjee designed a set of animal experiments to examine the mediodorsal thalamus’s role in handling uncertainty. Mice were trained to respond to sensory signals according to audio cues that alerted them whether to focus on either light or sound. When the animals were given conflicting cues, it was up to them animal to figure out which one was represented most prominently and act accordingly. The experimenters varied the uncertainty of this task by manipulating the numbers and ratio of the cues.

Division of labor

By manipulating and recording activity in the animals’ brains, the researchers found that the prefrontal cortex got involved every time mice completed this task, but the mediodorsal thalamus was only needed when the animals were given signals that left them uncertain how to behave. There was a simple division of labor within the brain, Halassa says. “One area cares about the content of the message—that’s the prefrontal cortex—and the thalamus seems to care about how certain the input is.”

Within the mediodorsal thalamus, Halassa and Mukherjee found a subset of cells that were especially active when the animals were presented with conflicting sound cues. These neurons, which connect directly to the prefrontal cortex, are inhibitory neurons, capable of dampening downstream signaling. So when they fire, Halassa says, they effectively stop the brain from acting on unreliable information. Cells of a different type were focused on the uncertainty that arises when signaling is sparse. “There’s a dedicated circuitry to integrate evidence across time to extract meaning out of this kind of assessment,” Mukherjee explains.

As Halassa and Mukherjee investigate these circuits more deeply, a priority will be determining whether they are disrupted in people with schizophrenia. To that end, they are now exploring the circuitry in animal models of the disorder. The hope, Mukherjee says, is to eventually target dysfunctional circuits in patients, using noninvasive, focused drug delivery methods currently under development. “We have the genetic identity of these circuits. We know they express specific types of receptors, so we can find drugs that target these receptors,” he says. “Then you can specifically release these drugs in the mediodorsal thalamus to modulate the circuits as a potential therapeutic strategy.”

This work was funded by grants from the National Institute of Mental Health (R01MH107680-05 and R01MH120118-02).