Research Area: Cellular & Molecular Neuroscience

​synapses, vesicles, electrophysiology, protein complexes, signaling, small molecules, disease-linked genes, dendrites, cell death, brain disorders, neurodevelopment

New research center focused on brain-body relationship established at MIT

by Julie Pryor |

The inextricable link between our brains and our bodies has been gaining increasing recognition among researchers and clinicians over recent years. Studies have shown that the brain-body pathway is bidirectional — meaning that our mental state can influence our physical health and vice versa. But exactly how the two interact is less clear.

A new research center at MIT, funded by a $38 million gift to the McGovern Institute for Brain Research from philanthropist K. Lisa Yang, aims to unlock this mystery by creating and applying novel tools to explore the multidirectional, multilevel interplay between the brain and other body organ systems. This gift expands Yang’s exceptional philanthropic support of human health and basic science research at MIT over the past five years.

“Lisa Yang’s visionary gift enables MIT scientists and engineers to pioneer revolutionary technologies and undertake rigorous investigations into the brain’s complex relationship with other organ systems,” says MIT President L. Rafael Reif.  “Lisa’s tremendous generosity empowers MIT scientists to make pivotal breakthroughs in brain and biomedical research and, collectively, improve human health on a grand scale.”

The K. Lisa Yang Brain-Body Center will be directed by Polina Anikeeva, professor of materials science and engineering and brain and cognitive sciences at MIT and an associate investigator at the McGovern Institute. The center will harness the power of MIT’s collaborative, interdisciplinary life sciences research and engineering community to focus on complex conditions and diseases affecting both the body and brain, with a goal of unearthing knowledge of biological mechanisms that will lead to promising therapeutic options.

“Under Professor Anikeeva’s brilliant leadership, this wellspring of resources will encourage the very best work of MIT faculty, graduate fellows, and research — and ultimately make a real impact on the lives of many,” Reif adds.

microscope image of gut
Mouse small intestine stained to reveal cell nucleii (blue) and peripheral nerve fibers (red).
Image: Polina Anikeeva, Marie Manthey, Kareena Villalobos

Center goals  

Initial projects in the center will focus on four major lines of research:

  • Gut-Brain: Anikeeva’s group will expand a toolbox of new technologies and apply these tools to examine major neurobiological questions about gut-brain pathways and connections in the context of autism spectrum disorders, Parkinson’s disease, and affective disorders.
  • Aging: CRISPR pioneer Feng Zhang, the James and Patricia Poitras Professor of Neuroscience at MIT and investigator at the McGovern Institute, will lead a group in developing molecular tools for precision epigenomic editing and erasing accumulated “errors” of time, injury, or disease in various types of cells and tissues.
  • Pain: The lab of Fan Wang, investigator at the McGovern Institute and professor of brain and cognitive sciences, will design new tools and imaging methods to study autonomic responses, sympathetic-parasympathetic system balance, and brain-autonomic nervous system interactions, including how pain influences these interactions.
  • Acupuncture: Wang will also collaborate with Hilda (“Scooter”) Holcombe, a veterinarian in MIT’s Division of Comparative Medicine, to advance techniques for documenting changes in brain and peripheral tissues induced by acupuncture in mouse models. If successful, these techniques could lay the groundwork for deeper understandings of the mechanisms of acupuncture, specifically how the treatment stimulates the nervous system and restores function.

A key component of the K. Lisa Yang Brain-Body Center will be a focus on educating and training the brightest young minds who aspire to make true breakthroughs for individuals living with complex and often devastating diseases. A portion of center funding will endow the new K. Lisa Yang Brain-Body Fellows Program, which will support four annual fellowships for MIT graduate students and postdocs working to advance understanding of conditions that affect both the body and brain.

Mens sana in corpore sano

“A phrase I remember reading in secondary school has always stuck with me: ‘mens sana in corpore sano’ — ‘a healthy mind in a healthy body,’” says Lisa Yang, a former investment banker committed to advocacy for individuals with visible and invisible disabilities. “When we look at how stress, nutrition, pain, immunity, and other complex factors impact our health, we truly see how inextricably linked our brains and bodies are. I am eager to help MIT scientists and engineers decode these links and make real headway in creating therapeutic strategies that result in longer, healthier lives.”

“This center marks a once-in-a-lifetime opportunity for labs like mine to conduct bold and risky studies into the complexities of brain-body connections,” says Anikeeva, who works at the intersection of materials science, electronics, and neurobiology. “The K. Lisa Yang Brain-Body Center will offer a pathbreaking, holistic approach that bridges multiple fields of study. I have no doubt that the center will result in revolutionary strides in our understanding of the inextricable bonds between the brain and the body’s peripheral organ systems, and a bold new way of thinking in how we approach human health overall.”

Circuit that focuses attention brings in wide array of inputs

by David Orenstein | Picower Institute |

In a new brain-wide circuit tracing study, scientists at MIT’s Picower Institute for Learning and Memory focused selective attention on a circuit that governs, fittingly enough, selective attention. The comprehensive maps they produced illustrate how broadly the mammalian brain incorporates and integrates information to focus its sensory resources on its goals.

Working in mice, the team traced thousands of inputs into the circuit, a communication loop between the anterior cingulate cortex (ACC) and the lateral posterior (LP) thalamus. In primates the LP is called the pulvinar. Studies in humans and nonhuman primates have indicated that the byplay of these two regions is critical for brain functions like being able to focus on an object of interest in a crowded scene, says study co-lead author Yi Ning Leow, a graduate student in the lab of senior author Mriganka Sur, the Newton Professor in MIT’s Department of Brain and Cognitive Sciences. Research has implicated dysfunction in the circuit in attention-affecting disorders such as autism and attention deficit/hyperactivity disorder.

The new study in the Journal of Comparative Neurology extends what’s known about the circuit by detailing it in mice, Leow says, importantly showing that the mouse circuit is closely analogous to the primate version even if the LP is proportionately smaller and less evolved than the pulvinar.

“In these rodent models we were able to find very similar circuits,” Leow says. “So we can possibly study these higher-order functions in mice as well. We have a lot more genetic tools in mice so we are better able to look at this circuit.”

The study, also co-led by former MIT undergraduate Blake Zhou, therefore provides a detailed roadmap in the experimentally accessible mouse model for understanding how the ACC and LP cooperate to produce selective attention. For instance, now that Leow and Zhou have located all the inputs that are wired into the circuit, Leow is tapping into those feeds to eavesdrop on the information they are carrying. Meanwhile, she is correlating that information flow with behavior.

“This study lays the groundwork for understanding one of the most important, yet most elusive, components of brain function, namely our ability to selectively attend to one thing out of several, as well as switch attention,” Sur says.

Using virally mediated circuit-tracing techniques pioneered by co-author Ian Wickersham, principal research scientist in brain and cognitive sciences and the McGovern Institute for Brain Research at MIT, the team found distinct sources of input for the ACC and the LP. Generally speaking, the detailed study finds that the majority of inputs to the ACC were from frontal cortex areas that typically govern goal-directed planning, and from higher visual areas. The bulk of inputs to the LP, meanwhile, were from deeper regions capable of providing context such as the mouse’s needs, location and spatial cues, information about movement, and general information from a mix of senses.

So even though focusing attention might seem like a matter of controlling the senses, Leow says, the circuit pulls in a lot of other information as well.

“We’re seeing that it’s not just sensory — there are so many inputs that are coming from non-sensory areas as well, both sub-cortically and cortically,” she says. “It seems to be integrating a lot of different aspects that might relate to the behavioral state of the animal at a given time. It provides a way to provide a lot of internal and special context for that sensory information.”

Given the distinct sets of inputs to each region, the ACC may be tasked with focusing attention on a desired object, while the LP is modulating how the ACC goes about making those computations, accounting for what’s going on both inside and outside the animal. Decoding just what that incoming contextual information is, and what the LP tells the ACC, are the key next steps, Leow says. Another clear set of questions the study raises are what are the circuit’s outputs. In other words, after it integrates all this information, what does it do with it?

The paper’s other authors are Heather Sullivan and Alexandria Barlowe.

A National Science Scholarship, the National Institutes of Health, and the JPB Foundation provided support for the study.

Aging Brain Initiative awards fund five new ideas to study, fight neurodegeneration

Anne Trafton |

Neurodegenerative diseases are defined by an increasingly widespread and debilitating death of nervous system cells, but they also share other grim characteristics: Their cause is rarely discernible and they have all eluded cures. To spur fresh, promising approaches and to encourage new experts and expertise to join the field, MIT’s Aging Brain Initiative (ABI) this month awarded five seed grants after a competition among labs across the Institute.

Founded in 2015 by nine MIT faculty members, the ABI promotes research, symposia, and related activities to advance fundamental insights that can lead to clinical progress against neurodegenerative conditions, such as Alzheimer’s disease, with an age-related onset. With an emphasis on spurring research at an early stage before it is established enough to earn more traditional funding, the ABI derives support from philanthropic gifts.

“Solving the mysteries of how health declines in the aging brain and turning that knowledge into effective tools, treatments, and technologies is of the utmost urgency given the millions of people around the world who suffer with no meaningful treatment options,” says ABI director and co-founder Li-Huei Tsai, the Picower Professor of Neuroscience in The Picower Institute for Learning and Memory and the Department of Brain and Cognitive Sciences. “We were very pleased that many groups across MIT were eager to contribute their expertise and creativity to that goal. From here, five teams will be able to begin testing their innovative ideas and the impact they could have.”

To address the clinical challenge of accurately assessing cognitive decline during Alzheimer’s disease progression and healthy aging, a team led by Thomas Heldt, associate professor of electrical and biomedical engineering in the Department of Electrical Engineering and Computer Science (EECS) and the Institute for Medical Engineering and Science, proposes to use artificial intelligence tools to bring diagnostics based on eye movements during cognitive tasks to everyday consumer electronics such as smartphones and tablets. By moving these capabilities to common at-home platforms, the team, which also includes EECS Associate Professor Vivian Sze, hopes to increase monitoring beyond what can only be intermittently achieved with high-end specialized equipment and dedicated staffing in specialists’ offices. The team will pilot their technology in a small study at Boston Medical Center in collaboration with neurosurgeon James Holsapple.

Institute Professor Ann Graybiel’s lab in the Department of Brain and Cognitive Sciences (BCS) and the McGovern Institute for Brain Research will test the hypothesis that mutations on a specific gene may lead to the early emergence of Alzheimer’s disease (AD) pathology in the striatum. That’s a a brain region crucial for motivation and movement that is directly and severely impacted by other neurodegenerative disorders including Parkinson’s and Huntington’s diseases, but that has largely been unstudied in Alzheimer’s. By editing the mutations into normal and AD-modeling mice, Research Scientist Ayano Matsushima and Graybiel hope to determine whether and how pathology, such as the accumulation of amyloid proteins, may result. Determining that could provide new insight into the progression of disease and introduce a new biomarker in a region that virtually all other studies have overlooked.

Numerous recent studies have highlighted a potential role for immune inflammation in Alzheimer’s disease. A team led by Gloria Choi, the Mark Hyman Jr. Associate Professor in BCS and The Picower Institute for Learning and Memory, will track one potential source of such activity by determining whether the brain’s meninges, which envelop the brain, becomes a means for immune cells activated by gut bacteria to circulate near the brain, where they may release signaling molecules that promote Alzheimer’s pathology. Working in mice, Choi’s lab will test whether such activity is prone to increase in Alzheimer’s and whether it contributes to disease.

A collaboration led by Peter Dedon, the Singapore Professor in MIT’s Department of Biological Engineering, will explore whether Alzheimer’s pathology is driven by dysregulation of transfer RNAs (tRNAs) and the dozens of natural tRNA modifications in the epitranscriptome, which play a key role in the process by which proteins are assembled based on genetic instructions. With Benjamin Wolozin of Boston University, Sherif Rashad of Tohoku University in Japan, and Thomas Begley of the State University of New York at Albany, Dedon will assess how the tRNA pool and epitranscriptome may differ in Alzheimer’s model mice and whether genetic instructions mistranslated because of tRNA dysregulation play a role in Alzheimer’s disease.

With her seed grant, Ritu Raman, the d’Arbeloff Assistant Professor of Mechanical Engineering, is launching an investigation of possible disruption of intercellular messages in amyotrophic lateral sclerosis (ALS), a terminal condition in which motor neuron causes loss of muscle control. Equipped with a new tool to finely sample interstitial fluid within tissues, Raman’s team will be able to monitor and compare cell-cell signaling in models of the junction between nerve and muscle. These models will be engineered from stem cells derived from patients with ALS. By studying biochemical signaling at the junction the lab hopes to discover new targets that could be therapeutically modified.

Major support for the seed grants, which provide each lab with $100,000, came from generous gifts by David Emmes SM ’76; Kathleen SM ’77, PhD ’86 and Miguel Octavio; the Estate of Margaret A. Ridge-Pappis, wife of the late James Pappis ScD ’59; the Marc Haas Foundation; and the family of former MIT President Paul Gray ’54, SM ’55, ScD ‘60, with additional funding from many annual fund donors to the Aging Brain Initiative Fund.

Developing brain needs cannabinoid receptors after birth

by Jennifer Michalowski |

Doctors warn that marijuana use during pregnancy may have harmful effects on the development of a fetus, in part because the cannabinoid receptors activated by the drug are known be critical for enabling a developing brain to wire up properly. Now, scientists at MIT’s McGovern Institute have learned that cannabinoid receptors’ critical role in brain development does not end at birth.

In today’s online issue of the journal eNeuro, scientists led by McGovern investigator Ann Graybiel report that mice need the cannabinoid receptor CB1R to establish connections within the brain’s dopamine system that take shape soon after birth. The finding raises concern that marijuana use by nursing moms, who pass the CB1R-activating compound THC to their infants when they breastfeed, might interfere with brain development by disrupting cannabinoid signaling.

“This is a real change to one of the truly important systems in the brain—a major controller of our dopamine,” Graybiel says. Dopamine exerts a powerful influence over our motivations and behavior, and changes to the dopamine system contribute to disorders from Parkinson’s disease to addiction. Thus, the researchers say, it is vital to understand whether postnatal drug exposure might put developing dopamine circuits at risk.

Brain bouquets

Cannabinoid receptors in the brain are important mediators of mood, memory, and pain. Graybiel’s lab became interested in CB1R due to their dysregulation in Huntington’s and Parkinson’s diseases, both of which impair the brain’s ability to control movement and other functions. While investigating the receptor’s distribution in the brain, they discovered that in the adult mice, CB1R is abundant within small compartments within the striatum called striosomes. The receptor was particularly concentrated within the neurons that connect striosomes to a dopamine-rich area of the brain called the substantia nigra, via structures that Graybiel’s team has dubbed striosome-dendron bouquets.

Striosome-dendron bouquets are easy to overlook within the densely connected network of the brain. But when the cells that make up the bouquets are labeled with a fluorescent protein, the bouquets become visible—and their appearance is striking, says Jill Crittenden, a research scientist in Graybiel’s lab.

Striosomal neurons form these bouquets by reaching into the substantia nigra, whose cells use dopamine to influence movement, motivation, learning, and habit formation. Clusters of dopamine-producing neurons form dendrites there that intertwine tightly with incoming axons from the striosomal neurons. The resulting structures, whose intimately associated cells resemble the bundled stems of a floral bouquet, establish so many connections that they give striosomal neurons potent control over dopamine signaling.

By tracking the bouquets’ emergence in newborn mice, Graybiel’s team found that they form in the first week after birth, a period during which striosomal neurons are ramping up production of CB1R. Mice genetically engineered to lack CB1R, however, can’t make these elaborate but orderly bouquets. Without the receptor, fibers from striosomes extend into the substantia nigra, but fail to form the tightly intertwined “bouquet stems” that facilitate extensive connections with their targets. This disorganized structure is apparent as soon as bouquets arise in the brains of young pups and persists into adulthood. “There aren’t those beautiful, strong fibers anymore,” Crittenden says. “This suggests that those very strong controllers over the dopamine system function abnormally when you interfere with cannabinoid signaling.”

The finding was a surprise. Without zeroing in on striosome-dendron bouquets, it would be easy to miss CB1R’s impact on the dopamine system, Crittenden says. Plus, she adds, prior studies of the receptor’s role in development largely focused on fetal development. The new findings reveal that the cannabinoid system continues to guide the formation of brain circuits after birth.

Graybiel notes that funds from generous donors, including the Broderick Fund for Phytocannabinoid Research at MIT, the Saks Kavanaugh Foundation, the Kristin R. Pressman and Jessica J. Pourian ‘13 Fund, Mr. Robert Buxton, and the William N. & Bernice E. Bumpus Foundation, enabled her team’s studies of CB1R’s role in shaping striosome-dendron bouquets.

Now that they have shown that CB1R is needed for postnatal brain development, it will be important to determine the consequences of disrupting cannabinoid signaling during this critical period—including whether passing THC to a nursing baby impacts the brain’s dopamine system.

Study finds neurons that encode the outcomes of actions

Anne Trafton |

When we make complex decisions, we have to take many factors into account. Some choices have a high payoff but carry potential risks; others are lower risk but may have a lower reward associated with them.

A new study from MIT sheds light on the part of the brain that helps us make these types of decisions. The research team found a group of neurons in the brain’s striatum that encodes information about the potential outcomes of different decisions. These cells become particularly active when a behavior leads a different outcome than what was expected, which the researchers believe helps the brain adapt to changing circumstances.

“A lot of this brain activity deals with surprising outcomes, because if an outcome is expected, there’s really nothing to be learned. What we see is that there’s a strong encoding of both unexpected rewards and unexpected negative outcomes,” says Bernard Bloem, a former MIT postdoc and one of the lead authors of the new study.

Impairments in this kind of decision-making are a hallmark of many neuropsychiatric disorders, especially anxiety and depression. The new findings suggest that slight disturbances in the activity of these striatal neurons could swing the brain into making impulsive decisions or becoming paralyzed with indecision, the researchers say.

Rafiq Huda, a former MIT postdoc, is also a lead author of the paper, which appears in Nature Communications. Ann Graybiel, an MIT Institute Professor and member of MIT’s McGovern Institute for Brain Research, is the senior author of the study.

Learning from experience

The striatum, located deep within the brain, is known to play a key role in making decisions that require evaluating outcomes of a particular action. In this study, the researchers wanted to learn more about the neural basis of how the brain makes cost-benefit decisions, in which a behavior can have a mixture of positive and negative outcomes.

Striosomes (red) appear and then disappear as the view moves deeper into the striatum. Video courtesy of the researchers

To study this kind of decision-making, the researchers trained mice to spin a wheel to the left or the right. With each turn, they would receive a combination of reward (sugary water) and negative outcome (a small puff of air). As the mice performed the task, they learned to maximize the delivery of rewards and to minimize the delivery of air puffs. However, over hundreds of trials, the researchers frequently changed the probabilities of getting the reward or the puff of air, so the mice would need to adjust their behavior.

As the mice learned to make these adjustments, the researchers recorded the activity of neurons in the striatum. They had expected to find neuronal activity that reflects which actions are good and need to be repeated, or bad and that need to be avoided. While some neurons did this, the researchers also found, to their surprise, that many neurons encoded details about the relationship between the actions and both types of outcomes.

The researchers found that these neurons responded more strongly when a behavior resulted in an unexpected outcome, that is, when turning the wheel in one direction produced the opposite outcome as it had in previous trials. These “error signals” for reward and penalty seem to help the brain figure out that it’s time to change tactics.

Most of the neurons that encode these error signals are found in the striosomes — clusters of neurons located in the striatum. Previous work has shown that striosomes send information to many other parts of the brain, including dopamine-producing regions and regions involved in planning movement.

“The striosomes seem to mostly keep track of what the actual outcomes are,” Bloem says. “The decision whether to do an action or not, which essentially requires integrating multiple outcomes, probably happens somewhere downstream in the brain.”

Making judgments

The findings could be relevant not only to mice learning a task, but also to many decisions that people have to make every day as they weigh the risks and benefits of each choice. Eating a big bowl of ice cream after dinner leads to immediate gratification, but it might contribute to weight gain or poor health. Deciding to have carrots instead will make you feel healthier, but you’ll miss out on the enjoyment of the sweet treat.

“From a value perspective, these can be considered equally good,” Bloem says. “What we find is that the striatum also knows why these are good, and it knows what are the benefits and the cost of each. In a way, the activity there reflects much more about the potential outcome than just how likely you are to choose it.”

This type of complex decision-making is often impaired in people with a variety of neuropsychiatric disorders, including anxiety, depression, schizophrenia, obsessive-compulsive disorder, and posttraumatic stress disorder. Drug abuse can also lead to impaired judgment and impulsivity.

“You can imagine that if things are set up this way, it wouldn’t be all that difficult to get mixed up about what is good and what is bad, because there are some neurons that fire when an outcome is good and they also fire when the outcome is bad,” Graybiel says. “Our ability to make our movements or our thoughts in what we call a normal way depends on those distinctions, and if they get blurred, it’s real trouble.”

The new findings suggest that behavioral therapy targeting the stage at which information about potential outcomes is encoded in the brain may help people who suffer from those disorders, the researchers say.

The research was funded by the National Institutes of Health/National Institute of Mental Health, the Saks Kavanaugh Foundation, the William N. and Bernice E. Bumpus Foundation, the Simons Foundation, the Nancy Lurie Marks Family Foundation, the National Eye Institute, the National Institute of Neurological Disease and Stroke, the National Science Foundation, the Simons Foundation Autism Research Initiative, and JSPS KAKENHI.

David Ginty named winner of 2022 Scolnick Prize

by Jill Crittenden |

Harvard neurobiologist David Ginty, winner of the 2022 Scolnick Prize.

The McGovern Institute for Brain Research announced today that Harvard neurobiologist David D. Ginty has been selected for the 2022 Edward M. Scolnick Prize in Neuroscience. Ginty, who is the Edward R. and Anne G. Lefler Professor of Neurobiology at Harvard Medical School, is being recognized for his fundamental discoveries into the neural mechanisms underlying the sense of touch. The Scolnick Prize is awarded annually by the McGovern Institute for outstanding advances in neuroscience.

“David Ginty has made seminal contributions in basic research that also have important translational implications,” says Robert Desimone, McGovern Institute Director and chair of the selection committee. “His rigorous research has led us to understand how the peripheral nervous system encodes the overall perception of touch, and how molecular mechanisms underlying this can fail in disease states.”

Ginty obtained his PhD in 1989 with Edward Seidel where he studied cell proliferation factors. He went on to a postdoctoral fellowship researching nerve growth factor with John Wagner at the Dana-Farber Cancer Institute and, upon Wagner’s departure to Cornell, transferred to Michael Greenberg’s lab at Harvard Medical School. There, he dissected intracellular signaling pathways for neuronal growth factors and neurotransmitters and developed key antibody reagents to detect activated forms of transcription factors. These antibody tools are now used by labs around the world in the research of neuronal plasticity and brain disorders, including Alzheimer’s disease and schizophrenia.

In 1995, Ginty started his own laboratory at Johns Hopkins University with a focus on the development and functional organization of the peripheral nervous system. Ginty’s group created and applied the latest genetic engineering techniques in mice to uncover how the peripheral nervous system develops and is organized at the molecular, cellular and circuit levels to perceive touch. Most notably, using gene targeting combined with electrophysiological, behavioral and anatomical analyses, the Ginty lab untangled properties and functions of the different types of touch neurons, termed low- and high-threshold mechanoreceptors, that convey distinct aspects of stimulus information from the skin to the central nervous system. Ginty and colleagues also discovered organizational principles of spinal cord and brainstem circuits dedicated to touch information processing, and that integration of signals from the different mechanoreceptor types begins within spinal cord networks before signal transmission to the brain.

In 2013, Ginty joined the faculty of Harvard Medical School where his team applied their genetic tools and techniques to probe the neural basis of touch sensitivity disorders. They discovered properties and functions of peripheral sensory neurons, spinal cord circuits, and ascending pathways that transmit noxious, painful stimuli from the periphery to the brain. They also asked whether abnormalities in peripheral nervous system function lead to touch over-reactivity in cases of autism or in neuropathic pain caused by nerve injury, chemotherapy, or diabetes, where even a soft touch can be aversive or painful. His team found that sensory abnormalities observed in several mouse models of autism spectrum disorder could be traced to peripheral mechanosensory neurons. They also found that reducing the activity of peripheral sensory neurons prevented tactile over-reactivity in these models and even, in some cases, lessened anxiety and abnormal social behaviors. These findings provided a plausible explanation for how sensory dysfunction may contribute to physiological and cognitive impairments in autism. Importantly, this laid the groundwork for a new approach and initiative to identify new potential therapies for disorders of touch and pain.

Ginty was named a Howard Hughes Medical Institute Investigator in 2000 and was elected to the American Academy of Arts and Sciences in 2015 and the National Academy of Sciences in 2017. He shared Columbia University’s Alden W. Spencer Prize with Ardem Patapoutian in 2017 and was awarded the Society for Neuroscience Julius Axelrod Prize in 2021. Ginty is also known for exceptional mentorship. He directed the neuroscience graduate program at Johns Hopkins from 2006 to 2013 and now serves as the associate director of Harvard’s neurobiology graduate program.

The McGovern Institute will award the Scolnick Prize to Ginty on Wednesday, June 1, 2022. At 4:00 pm he will deliver a lecture entitled “The sensory neurons of touch: beauty is skin deep,” to be followed by a reception at the McGovern Institute, 43 Vassar Street (building 46, room 3002) in Cambridge. The event is free and open to the public; registration is required.

Dendrites may help neurons perform complicated calculations

Anne Trafton |

Within the human brain, neurons perform complex calculations on information they receive. Researchers at MIT have now demonstrated how dendrites — branch-like extensions that protrude from neurons — help to perform those computations.

The researchers found that within a single neuron, different types of dendrites receive input from distinct parts of the brain, and process it in different ways. These differences may help neurons to integrate a variety of inputs and generate an appropriate response, the researchers say.

In the neurons that the researchers examined in this study, it appears that this dendritic processing helps cells to take in visual information and combine it with motor feedback, in a circuit that is involved in navigation and planning movement.

“Our hypothesis is that these neurons have the ability to pick out specific features and landmarks in the visual environment, and combine them with information about running speed, where I’m going, and when I’m going to start, to move toward a goal position,” says Mark Harnett, an associate professor of brain and cognitive sciences, a member of MIT’s McGovern Institute for Brain Research, and the senior author of the study.

Mathieu Lafourcade, a former MIT postdoc, is the lead author of the paper, which appears today in Neuron.

Complex calculations

Any given neuron can have dozens of dendrites, which receive synaptic input from other neurons. Neuroscientists have hypothesized that these dendrites can act as compartments that perform their own computations on incoming information before sending the results to the body of the neuron, which integrates all these signals to generate an output.

Previous research has shown that dendrites can amplify incoming signals using specialized proteins called NMDA receptors. These are voltage-sensitive neurotransmitter receptors that are dependent on the activity of other receptors called AMPA receptors. When a dendrite receives many incoming signals through AMPA receptors at the same time, the threshold to activate nearby NMDA receptors is reached, creating an extra burst of current.

This phenomenon, known as supralinearity, is believed to help neurons distinguish between inputs that arrive close together or farther apart in time or space, Harnett says.

In the new study, the MIT researchers wanted to determine whether different types of inputs are targeted specifically to different types of dendrites, and if so, how that would affect the computations performed by those neurons. They focused on a population of neurons called pyramidal cells, the principal output neurons of the cortex, which have several different types of dendrites. Basal dendrites extend below the body of the neuron, apical oblique dendrites extend from a trunk that travels up from the body, and tuft dendrites are located at the top of the trunk.

Harnett and his colleagues chose a part of the brain called the retrosplenial cortex (RSC) for their studies because it is a good model for association cortex — the type of brain cortex used for complex functions such as planning, communication, and social cognition. The RSC integrates information from many parts of the brain to guide navigation, and pyramidal neurons play a key role in that function.

In a study of mice, the researchers first showed that three different types of input come into pyramidal neurons of the RSC: from the visual cortex into basal dendrites, from the motor cortex into apical oblique dendrites, and from the lateral nuclei of the thalamus, a visual processing area, into tuft dendrites.

“Until now, there hasn’t been much mapping of what inputs are going to those dendrites,” Harnett says. “We found that there are some sophisticated wiring rules here, with different inputs going to different dendrites.”

A range of responses

The researchers then measured electrical activity in each of those compartments. They expected that NMDA receptors would show supralinear activity, because this behavior has been demonstrated before in dendrites of pyramidal neurons in both the primary sensory cortex and the hippocampus.

In the basal dendrites, the researchers saw just what they expected: Input coming from the visual cortex provoked supralinear electrical spikes, generated by NMDA receptors. However, just 50 microns away, in the apical oblique dendrites of the same cells, the researchers found no signs of supralinear activity. Instead, input to those dendrites drives a steady linear response. Those dendrites also have a much lower density of NMDA receptors.

“That was shocking, because no one’s ever reported that before,” Harnett says. “What that means is the apical obliques don’t care about the pattern of input. Inputs can be separated in time, or together in time, and it doesn’t matter. It’s just a linear integrator that’s telling the cell how much input it’s getting, without doing any computation on it.”

Those linear inputs likely represent information such as running speed or destination, Harnett says, while the visual information coming into the basal dendrites represents landmarks or other features of the environment. The supralinearity of the basal dendrites allows them to perform more sophisticated types of computation on that visual input, which the researchers hypothesize allows the RSC to flexibly adapt to changes in the visual environment.

In the tuft dendrites, which receive input from the thalamus, it appears that NMDA spikes can be generated, but not very easily. Like the apical oblique dendrites, the tuft dendrites have a low density of NMDA receptors. Harnett’s lab is now studying what happens in all of these different types of dendrites as mice perform navigation tasks.

The research was funded by a Boehringer Ingelheim Fonds PhD Fellowship, the National Institutes of Health, the James W. and Patricia T. Poitras Fund, the Klingenstein-Simons Fellowship Program, a Vallee Scholar Award, and a McKnight Scholar Award.

A new approach to curbing cocaine use

by Jennifer Michalowski |

Cocaine, opioids, and other drugs of abuse disrupt the brain’s reward system, often shifting users’ priorities to obtaining more drug above all else. For people battling addiction, this persistent craving is notoriously difficult to overcome—but new research from scientists at MIT’s McGovern Institute and collaborators points toward a therapeutic strategy that could help.

Researchers in MIT Institute Professor Ann Graybiel’s lab and collaborators at the University of Copenhagen and Vanderbilt University report in a January 25, 2022 online publication in the journal Addiction Biology that activating a signaling molecule in the brain known as muscarinic receptor 4 (M4) causes rodents to reduce cocaine self-administration and simultaneously choose a food treat over cocaine.

M4 receptors are found on the surface of neurons in the brain, where they alter signaling in response to the neurotransmitter acetylcholine. They are plentiful in the striatum, a brain region that Graybiel’s lab has shown is deeply involved in habit formation. They are of interest to addiction researchers because, along with a related receptor called M1, which is also abundant in the striatum, they often seem to act in opposition to the neurotransmitter dopamine.

Drugs of abuse stimulate the brain’s habit circuits by allowing dopamine to build up in the brain. With chronic use, that circuitry can become less sensitive to dopamine, so experiences that were once rewarding become less pleasurable and users are driven to seek higher doses of their drug. Attempts to directly block the dopamine system have not been found to be an effective way of treating addiction and can have unpleasant or dangerous side-effects, so researchers are seeking an alternative strategy to restore balance within the brain’s reward circuitry. “Another way to tweak that system is to activate these muscarinic receptors,” explains Jill Crittenden, a research scientist in the Graybiel lab.

New pathways to treatment

At the University of Copenhagen, neuroscientist Morgane Thomsen has found that activating the M1 receptor causes rodents to choose a food treat over cocaine. In the new work, she showed that a drug that selectively activates the M4 receptor has a similar effect.

When rats that have been trained to self-administer cocaine are given an M4-activating compound, they immediately reduce their drug use, actively choosing food instead. Thomsen found that this effect grew stronger over a seven-day course of treatment, with cocaine use declining day by day. When the M4-activating treatment was stopped, rats quickly resumed their prior cocaine-seeking behavior.

While Thomsen’s experiments have now shown that animals’ cocaine use can be reduced by activating either M1 or M4, it’s clear that the two muscarinic receptors don’t modulate cocaine use in the same way. M1 activation works on a different time scale, taking some time to kick in, but leaving some lasting effects even after the treatment has been discontinued.

Experiments with genetically modified mice developed in Graybiel’s lab confirm that the two receptors influence drug-seeking behavior via different molecular pathways. Previously, the team discovered that activating M1 has no effect on cocaine-seeking in mice that lack a signaling molecule called CalDAG-GEFI. M4 activation, however, reduces cocaine consumption regardless of whether CalDAG-GEFI is present. “The CalDAG-GEFI is completely essential for the M1 effect to happen, but doesn’t appear to play any role in the M4 effect,” Thomsen says. “So that really separates the pathways. In both the behavior and the neurobiology, it’s two different ways that we can modulate the cocaine effects.” The findings suggest that activating M4 could help people with substance abuse disorders overcome their addiction, and that such a strategy might be even more effective if combined with activation of the M1 receptor.

Graybiel’s lab first became interested in CalDAG-GEFI in the late 1990s, when they discovered that it was unusually abundant in the main compartment of the brain’s striatum. Their research revealed the protein to be important for controlling movement and even uncovered an essential role in blood clotting—but CalDAG-GEFI’s impacts on behavior remained elusive for a long time. Graybiel says it’s gratifying that this long-standing interest has now shed light on a potential therapeutic strategy for substance abuse disorder. Her lab will continue investigating the molecular pathways that underlie addiction as part of the McGovern Institute’s new addiction initiative.

Five MIT faculty elected 2021 AAAS Fellows

by MIT News Office |

Five MIT faculty members have been elected as fellows of the American Association for the Advancement of Science (AAAS).

The 2021 class of AAAS Fellows includes 564 scientists, engineers, and innovators spanning 24 scientific disciplines who are being recognized for their scientifically and socially distinguished achievements.

Mircea Dincă is the W. M. Keck Professor of Energy in the Department of Chemistry. His group’s research focuses on addressing challenges related to the storage and consumption of energy, and global environmental concerns. Central to these efforts are the synthesis of novel organic-inorganic hybrid materials and the manipulation of their electrochemical and photophysical properties, with a current emphasis on porous materials and extended one-dimensional van der Waals materials.

Guoping Feng is the James W. and Patricia T. Poitras Professor of Neuroscience in the Department of Brain and Cognitive Sciences, associate director of MIT’s McGovern Institute for Brain Research, director of Model Systems and Neurobiology at the Stanley Center for Psychiatric Research, and an institute member of the Broad Institute of MIT and Harvard. His research is devoted to understanding the development and function of synapses in the brain and how synaptic dysfunction may contribute to neurodevelopmental and psychiatric disorders. By understanding the molecular, cellular, and circuitry mechanisms of these disorders, Feng hopes his work will eventually lead to the development of new and effective treatments for the millions of people suffering from these devastating diseases.

David Shoemaker is a senior research scientist with the MIT Kavli Institute for Astrophysics and Space Research. His work is focused on gravitational-wave observation and includes developing technologies for the detectors (LIGO, LISA), developing proposals for new instruments (Cosmic Explorer), managing the teams to build them and the consortia which exploit the data (LIGO Scientific Collaboration, LISA Consortium), and supporting the overall growth of the field (Gravitational-Wave International Committee).

Ian Hunter is the Hatsopoulos Professor of Mechanical Engineering and runs the Bioinstrumentation Lab at MIT. His main areas of research are instrumentation, microrobotics, medical devices, and biomimetic materials. Over the years he and his students have developed many instruments and devices including: confocal laser microscopes, scanning tunneling electron microscopes, miniature mass spectrometers, new forms of Raman spectroscopy, needle-free drug delivery technologies, nano- and micro-robots, microsurgical robots, robotic endoscopes, high-performance Lorentz force motors, and microarray technologies for massively parallel chemical and biological assays.

Evelyn N. Wang is the Ford Professor of Engineering and head of the Department of Mechanical Engineering. Her research program combines fundamental studies of micro/nanoscale heat and mass transport processes with the development of novel engineered structures to create innovative solutions in thermal management, energy, and water harvesting systems. Her work in thermophotovoltaics was named to Technology Review’s lists of Biggest Clean Energy Advances, in 2016, and Ten Breakthrough Technologies, in 2017, and to the Department of Energy Frontiers Research Center’s Ten of Ten awards. Her work extracting water from air has won her the title of 2017 Foreign Policy’s Global ReThinker and the 2018 Eighth Prince Sultan bin Abdulaziz International Prize for Water.

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.”