Brain Disorder: Schizophrenia

Brain region linked to altered social interactions in autism model

by Sabbi Lall |

Although psychiatric disorders can be linked to particular genes, the brain regions and mechanisms underlying particular disorders are not well-understood. Mutations or deletions of the SHANK3 gene are strongly associated with autism spectrum disorder (ASD) and a related rare disorder called Phelan-McDermid syndrome. Mice with SHANK3 mutations also display some of the traits associated with autism, including avoidance of social interactions, but the brain regions responsible for this behavior have not been identified.

A new study by neuroscientists at MIT and colleagues in China provides clues to the neural circuits underlying social deficits associated with ASD. The paper, published in Nature Neuroscience, found that structural and functional impairments in the anterior cingulate cortex (ACC) of SHANK3 mutant mice are linked to altered social interactions.

“Neurobiological mechanisms of social deficits are very complex and involve many brain regions, even in a mouse model,” explains Guoping Feng, the James W. and Patricia T. Poitras Professor at MIT and one of the senior authors of the study. “These findings add another piece of the puzzle to mapping the neural circuits responsible for this social deficit in ASD models.”

The Nature Neuroscience paper is the result of a collaboration between Feng, who is also an investigator at MIT’s McGovern Institute and a senior scientist in the Broad Institute’s Stanley Center for Psychiatric Research, and Wenting Wang and Shengxi Wu at the Fourth Military Medical University, Xi’an, China.

A number of brain regions have been implicated in social interactions, including the prefrontal cortex (PFC) and its projections to brain regions including the nucleus accumbens and habenula, but these studies failed to definitively link the PFC to altered social interactions seen in SHANK3 knockout mice.

In the new study, the authors instead focused on the ACC, a brain region noted for its role in social functions in humans and animal models. The ACC is also known to play a role in fundamental cognitive processes, including cost-benefit calculation, motivation, and decision making.

In mice lacking SHANK3, the researchers found structural and functional disruptions at the synapses, or connections, between excitatory neurons in the ACC. The researchers went on to show that the loss of SHANK3 in excitatory ACC neurons alone was enough to disrupt communication between these neurons and led to unusually reduced activity of these neurons during behavioral tasks reflecting social interaction.

Having implicated these ACC neurons in social preferences and interactions in SHANK3 knockout mice, the authors then tested whether activating these same neurons could rescue these behaviors. Using optogenetics and specfic drugs, the researchers activated the ACC neurons and found improved social behavior in the SHANK3 mutant mice.

“Next, we are planning to explore brain regions downstream of the ACC that modulate social behavior in normal mice and models of autism,” explains Wenting Wang, co-corresponding author on the study. “This will help us to better understand the neural mechanisms of social behavior, as well as social deficits in neurodevelopmental disorders.”

Previous clinical studies reported that anatomical structures in the ACC were altered and/or dysfunctional in people with ASD, an initial indication that the findings from SHANK3 mice may also hold true in these individuals.

The research was funded, in part, by the Natural Science Foundation of China. Guoping Feng was supported by NIMH grant no. MH097104, the  Poitras Center for Psychiatric Disorders Research at the McGovern Institute at MIT, and the Hock E. Tan and K. Lisa Yang Center for Autism Research at the McGovern Institute at MIT.

Alumnus gives MIT $4.5 million to study effects of cannabis on the brain

by MIT School of Science |

The following news is adapted from a press release issued in conjunction with Harvard Medical School.

Charles R. Broderick, an alumnus of MIT and Harvard University, has made gifts to both alma maters to support fundamental research into the effects of cannabis on the brain and behavior.

The gifts, totaling $9 million, represent the largest donation to date to support independent research on the science of cannabinoids. The donation will allow experts in the fields of neuroscience and biomedicine at MIT and Harvard Medical School to conduct research that may ultimately help unravel the biology of cannabinoids, illuminate their effects on the human brain, catalyze treatments, and inform evidence-based clinical guidelines, societal policies, and regulation of cannabis.

Lagging behind legislation

With the increasing use of cannabis both for medicinal and recreational purposes, there is a growing concern about critical gaps in knowledge.

In 2017, the National Academies of Sciences, Engineering, and Medicine issued a report calling upon philanthropic organizations, private companies, public agencies and others to develop a “comprehensive evidence base” on the short- and long-term health effects — both beneficial and harmful — of cannabis use.

“Our desire is to fill the research void that currently exists in the science of cannabis,” says Broderick, who was an early investor in Canada’s medical marijuana market.

Broderick is the founder of Uji Capital LLC, a family office focused on quantitative opportunities in global equity capital markets. Identifying the growth of the Canadian legal cannabis market as a strategic investment opportunity, Broderick took equity positions in Tweed Marijuana Inc. and Aphria Inc., which have since grown into two of North America’s most successful cannabis companies. Subsequently, Broderick made a private investment in and served as a board member for Tokyo Smoke, a cannabis brand portfolio, which merged in 2017 to create Hiku Brands, where he served as chairman. Hiku Brands was acquired by Canopy Growth Corp. in 2018.

Through the Broderick gifts to Harvard Medical School and MIT’s School of Science through the Picower Institute for Learning and Memory and the McGovern Institute for Brain Research, the Broderick funds will support independent studies of the neurobiology of cannabis; its effects on brain development, various organ systems and overall health, including treatment and therapeutic contexts; and cognitive, behavioral and social ramifications.

“I want to destigmatize the conversation around cannabis — and, in part, that means providing facts to the medical community, as well as the general public,” says Broderick, who argues that independent research needs to form the basis for policy discussions, regardless of whether it is good for business. “Then we’re all working from the same information. We need to replace rhetoric with research.”

MIT: Focused on brain health and function

The gift to MIT from Broderick will provide $4.5 million over three years to support independent research for four scientists at the McGovern and Picower institutes.

Two of these researchers — John Gabrieli, the Grover Hermann Professor of Health Sciences and Technology, a professor of brain and cognitive sciences, and a member of MIT’s McGovern Institute for Brain Research; and Myriam Heiman, the Latham Family Associate Professor of Neuroscience at the Picower Institute — will separately explore the relationship between cannabis and schizophrenia.

Gabrieli, who directs the Martinos Imaging Center at MIT, will monitor any potential therapeutic value of cannabis for adults with schizophrenia using fMRI scans and behavioral studies.

“The ultimate goal is to improve brain health and wellbeing,” says Gabrieli. “And we have to make informed decisions on the way to this goal, wherever the science leads us. We need more data.”

Heiman, who is a molecular neuroscientist, will study how chronic exposure to phytocannabinoid molecules THC and CBD may alter the developmental molecular trajectories of cell types implicated in schizophrenia.

“Our lab’s research may provide insight into why several emerging lines of evidence suggest that adolescent cannabis use can be associated with adverse outcomes not seen in adults,” says Heiman.

In addition to these studies, Gabrieli also hopes to investigate whether cannabis can have therapeutic value for autism spectrum disorders, and Heiman plans to look at whether cannabis can have therapeutic value for Huntington’s disease.

MIT Institute Professor Ann Graybiel has proposed to study the cannabinoid 1 (CB1) receptor, which mediates many of the effects of cannabinoids. Her team recently found that CB1 receptors are tightly linked to dopamine — a neurotransmitter that affects both mood and motivation. Graybiel, who is also a member of the McGovern Institute, will examine how CB1 receptors in the striatum, a deep brain structure implicated in learning and habit formation, may influence dopamine release in the brain. These findings will be important for understanding the effects of cannabis on casual users, as well as its relationship to addictive states and neuropsychiatric disorders.

Earl Miller, Picower Professor of Neuroscience at the Picower Institute, will study effects of cannabinoids on both attention and working memory. His lab has recently formulated a model of working memory and unlocked how anesthetics reduce consciousness, showing in both cases a key role in the brain’s frontal cortex for brain rhythms, or the synchronous firing of neurons. He will observe how these rhythms may be affected by cannabis use — findings that may be able to shed light on tasks like driving where maintenance of attention is especially crucial.

Harvard Medical School: Mobilizing basic scientists and clinicians to solve an acute biomedical challenge 

The Broderick gift provides $4.5 million to establish the Charles R. Broderick Phytocannabinoid Research Initiative at Harvard Medical School, funding basic, translational and clinical research across the HMS community to generate fundamental insights about the effects of cannabinoids on brain function, various organ systems, and overall health.

The research initiative will span basic science and clinical disciplines, ranging from neurobiology and immunology to psychiatry and neurology, taking advantage of the combined expertise of some 30 basic scientists and clinicians across the school and its affiliated hospitals.

The epicenter of these research efforts will be the Department of Neurobiology under the leadership of Bruce Bean and Wade Regehr.

“I am excited by Bob’s commitment to cannabinoid science,” says Regehr, professor of neurobiology in the Blavatnik Institute at Harvard Medical School. “The research efforts enabled by Bob’s vision set the stage for unraveling some of the most confounding mysteries of cannabinoids and their effects on the brain and various organ systems.”

Bean, Regehr, and fellow neurobiologists Rachel Wilson and Bernardo Sabatini, for example, focus on understanding the basic biology of the cannabinoid system, which includes hundreds of plant and synthetic compounds as well as naturally occurring cannabinoids made in the brain.

Cannabinoid compounds activate a variety of brain receptors, and the downstream biological effects of this activation are astoundingly complex, varying by age and sex, and complicated by a person’s physiologic condition and overall health. This complexity and high degree of variability in individual biology has hampered scientific understanding of the positive and negative effects of cannabis on the human body. Bean, Regehr, and colleagues have already made critical insights showing how cannabinoids influence cell-to-cell communication in the brain.

“Even though cannabis products are now widely available, and some used clinically, we still understand remarkably little about how they influence brain function and neuronal circuits in the brain,” says Bean, the Robert Winthrop Professor of Neurobiology in the Blavatnik Institute at HMS. “This gift will allow us to conduct critical research into the neurobiology of cannabinoids, which may ultimately inform new approaches for the treatment of pain, epilepsy, sleep and mood disorders, and more.”

To propel research findings from lab to clinic, basic scientists from HMS will partner with clinicians from Harvard-affiliated hospitals, bringing together clinicians and scientists from disciplines including cardiology, vascular medicine, neurology, and immunology in an effort to glean a deeper and more nuanced understanding of cannabinoids’ effects on various organ systems and the body as a whole, rather than just on isolated organs.

For example, Bean and colleague Gary Yellen, who are studying the mechanisms of action of antiepileptic drugs, have become interested in the effects of cannabinoids on epilepsy, an interest they share with Elizabeth Thiele, director of the pediatric epilepsy program at Massachusetts General Hospital. Thiele is a pioneer in the use of cannabidiol for the treatment of drug-resistant forms of epilepsy. Despite proven clinical efficacy and recent FDA approval for rare childhood epilepsies, researchers still do not know exactly how cannabidiol quiets the misfiring brain cells of patients with the seizure disorder. Understanding its mechanism of action could help in developing new agents for treating other forms of epilepsy and other neurologic disorders.

Feng Zhang

Molecular Engineering

Feng Zhang develops tools that are broadly applicable to studying genetic diseases and developing diagnostics and therapeutics. These molecular engineering tools are useful for understanding nervous system function and diseases with genetic links such as autism spectrum disorder. Zhang pioneered the development of CRISPR-cas9 as a genome editing tool and its use in eukaryotic cells –including human cells– from a natural CRISPR immune system found in prokaryotes. He has substantially expanded this toolbox through discovery and harnessing of new CRISPRs. These new tools not only include DNA-targeting CRISPR systems, but also CRISPR systems that can target RNA. Through rational engineering he is improving specificity of CRISPR systems, and is expanding their window of opportunity. He has now engineered systems that can cleave within a specific, targeted nucleic acid sequence, and others that are designed to edit specific bases on the DNA or RNA target, and yet others that make epigenetic modifications. These tools, which he has made widely available, are accelerating research, particularly biomedical research, around the world.

Guoping Feng

Listening to Synapses

Guoping Feng studies the development and function of synapses – the interconnections between neurons – and their disruption in brain disorders. He uses molecular genetics combined with behavioral and electrophysiological methods to study the molecular components of the synapse and to understand how disruptions in these components can lead to neurodevelopmental and psychiatric disease. By understanding the molecular, cellular, and circuit changes underlying brain disorders, the Feng lab hopes one day to help develop new and effective treatments for brain disorders.

Virtual Tour of Feng Lab

 

Ann Graybiel

Probing the Deep Brain

Ann Graybiel studies the basal ganglia, forebrain structures that are profoundly important for normal brain function. Dysfunction in these regions is implicated in neurologic and neuropsychiatric disorders ranging from Parkinson’s disease and Huntington’s disease to obsessive-compulsive disorder, anxiety and depression, and addiction. Graybiel’s laboratory is uncovering circuits underlying both the neural deficits related to these disorders, as well as the role that the basal ganglia play in guiding normal learning, motivation, and behavior.

John Gabrieli

Images of Mind

John Gabrieli’s goal is to understand the organization of memory, thought, and emotion in the human brain, and to use that understanding to help people live happier, more productive lives. By combining brain imaging with behavioral tests, he studies the neural basis of these abilities in human subjects. One important research theme is to understand the neural basis of learning in children and to identify ways that neuroscience could help to improve learning in the classroom. In collaboration with clinical colleagues, Gabrieli also seeks to use brain imaging to better understand, diagnose, and select treatments for neurological and psychiatric diseases.

What is CRISPR?

by The Brain |

CRISPR (which stands for Clustered Regularly Interspaced Short Palindromic Repeats) is not actually a single entity, but shorthand for a set of bacterial systems that are found with a hallmarked arrangement in the bacterial genome.

When CRISPR is mentioned, most people are likely thinking of CRISPR-Cas9, now widely known for its capacity to be re-deployed to target sequences of interest in eukaryotic cells, including human cells. Cas9 can be programmed to target specific stretches of DNA, but other enzymes have since been discovered that are able to edit DNA, including Cpf1 and Cas12b. Other CRISPR enzymes, Cas13 family members, can be programmed to target RNA and even edit and change its sequence.

The common theme that makes CRISPR enzymes so powerful, is that scientists can supply them with a guide RNA for a chosen sequence. Since the guide RNA can pair very specifically with DNA, or for Cas13 family members, RNA, researchers can basically provide a given CRISPR enzyme with a way of homing in on any sequence of interest. Once a CRISPR protein finds its target, it can be used to edit that sequence, perhaps removing a disease-associated mutation.

In addition, CRISPR proteins have been engineered to modulate gene expression and even signal the presence of particular sequences, as in the case of the Cas13-based diagnostic, SHERLOCK.

Do you have a question for The Brain? Ask it here.

Satrajit Ghosh

Personalized Medicine

A fundamental problem in psychiatry is that there are no biological markers for diagnosing mental illness or for indicating how best to treat it. Treatment decisions are based entirely on symptoms, and doctors and their patients will typically try one treatment, then if it does not work, try another, and perhaps another. Satrajit Ghosh hopes to change this picture, and his research suggests that individual brain scans and speaking patterns can hold valuable information for guiding psychiatrists and patients. His research group develops novel analytic platforms that use such information to create robust, predictive models around human health. Current areas include depression, suicide, anxiety disorders, autism, Parkinson’s disease, and brain tumors.

Ed Boyden

Engineering Matter and Mind

Ed Boyden develops new tools for probing, analyzing, and engineering brain circuits. He uses a range of approaches, including synthetic biology, nanotechnology, chemistry, electrical engineering, and optics to develop tools capable of revealing fundamental mechanisms underlying complex brain processes.

Boyden may be best known for pioneering the development of optogenetics, a powerful method that enables neuronal activity to be controlled with light. He also led the team that invented expansion microscopy, in which a specimen is embedded in a gel that swells as it absorbs water, thereby expanding nanoscale features to a size where they can be seen using conventional microscopes. He is now seeking to systematically integrate these technologies to create detailed maps and models of brain circuitry.

Virtual Tour of Boyden Lab

How the brain switches between different sets of rules

Anne Trafton |

Cognitive flexibility — the brain’s ability to switch between different rules or action plans depending on the context — is key to many of our everyday activities. For example, imagine you’re driving on a highway at 65 miles per hour. When you exit onto a local street, you realize that the situation has changed and you need to slow down.

When we move between different contexts like this, our brain holds multiple sets of rules in mind so that it can switch to the appropriate one when necessary. These neural representations of task rules are maintained in the prefrontal cortex, the part of the brain responsible for planning action.

A new study from MIT has found that a region of the thalamus is key to the process of switching between the rules required for different contexts. This region, called the mediodorsal thalamus, suppresses representations that are not currently needed. That suppression also protects the representations as a short-term memory that can be reactivated when needed.

“It seems like a way to toggle between irrelevant and relevant contexts, and one advantage is that it protects the currently irrelevant representations from being overwritten,” says Michael Halassa, an assistant professor of brain and cognitive sciences and a member of MIT’s McGovern Institute for Brain Research.

Halassa is the senior author of the paper, which appears in the Nov. 19 issue of Nature Neuroscience. The paper’s first author is former MIT graduate student Rajeev Rikhye, who is now a postdoc in Halassa’s lab. Aditya Gilra, a postdoc at the University of Bonn, is also an author.

Changing the rules

Previous studies have found that the prefrontal cortex is essential for cognitive flexibility, and that a part of the thalamus called the mediodorsal thalamus also contributes to this ability. In a 2017 study published in Nature, Halassa and his colleagues showed that the mediodorsal thalamus helps the prefrontal cortex to keep a thought in mind by temporarily strengthening the neuronal connections in the prefrontal cortex that encode that particular thought.

In the new study, Halassa wanted to further investigate the relationship between the mediodorsal thalamus and the prefrontal cortex. To do that, he created a task in which mice learn to switch back and forth between two different contexts — one in which they must follow visual instructions and one in which they must follow auditory instructions.

In each trial, the mice are given both a visual target (flash of light to the right or left) and an auditory target (a tone that sweeps from high to low pitch, or vice versa). These targets offer conflicting instructions. One tells the mouse to go to the right to get a reward; the other tells it to go left. Before each trial begins, the mice are given a cue that tells them whether to follow the visual or auditory target.

“The only way for the animal to solve the task is to keep the cue in mind over the entire delay, until the targets are given,” Halassa says.

The researchers found that thalamic input is necessary for the mice to successfully switch from one context to another. When they suppressed the mediodorsal thalamus during the cuing period of a series of trials in which the context did not change, there was no effect on performance. However, if they suppressed the mediodorsal thalamus during the switch to a different context, it took the mice much longer to switch.

By recording from neurons of the prefrontal cortex, the researchers found that when the mediodorsal thalamus was suppressed, the representation of the old context in the prefrontal cortex could not be turned off, making it much harder to switch to the new context.

In addition to helping the brain switch between contexts, this process also appears to help maintain the neural representation of the context that is not currently being used, so that it doesn’t get overwritten, Halassa says. This allows it to be activated again when needed. The mice could maintain these representations over hundreds of trials, but the next day, they had to relearn the rules associated with each context.

Sabine Kastner, a professor of psychology at the Princeton Neuroscience Institute, described the study as a major leap forward in the field of cognitive neuroscience.

“This is a tour-de-force from beginning to end, starting with a sophisticated behavioral design, state-of-the-art methods including causal manipulations, exciting empirical results that point to cell-type specific differences and interactions in functionality between thalamus and cortex, and a computational approach that links the neuroscience results to the field of artificial intelligence,” says Kastner, who was not involved in the research.

Multitasking AI

The findings could help guide the development of better artificial intelligence algorithms, Halassa says. The human brain is very good at learning many different kinds of tasks — singing, walking, talking, etc. However, neural networks (a type of artificial intelligence based on interconnected nodes similar to neurons) usually are good at learning only one thing. These networks are subject to a phenomenon called “catastrophic forgetting” — when they try to learn a new task, previous tasks become overwritten.

Halassa and his colleagues now hope to apply their findings to improve neural networks’ ability to store previously learned tasks while learning to perform new ones.

The research was funded by the National Institutes of Health, the Brain and Behavior Foundation, the Klingenstein Foundation, the Pew Foundation, the Simons Foundation, the Human Frontiers Science Program, and the German Ministry of Education.