Profiles

Nagina Mangal, 2023-2025 K. Lisa Yang and Hock E. Tan Center for Molecular Therapeutics

Probing the biology of brain circuitry

For as long as she can remember, Nagina Mangal has loved science. Now she is channeling her skills as a molecular and cellular biologist to understand brain circuitry and, hopefully, open doors to improved therapies for neurologic and neuropsychiatric disorders.

Mangal, a Y. Eva Tan Postdoctoral Fellow, is conducting research in the laboratory of Ann Graybiel, an institute professor at MIT. Mangal and her colleagues are studying the striatal region of the forebrain, which is essential for motor control, emotions, and other behaviors. When dysfunctional, this large region is associated with such disorders as Parkinson’s and Huntington’s disease, autism spectrum disorder, addiction, impulsivity, and depression. The neurotransmitter dopamine plays an important role in these neural circuits.

“We’re trying to work out the circuitry in the striatum, because knowing the fundamental biology leads to therapeutics,” she says.

Mangal is building on her earlier research on the endocannabinoid system, an endogenous signaling system important for regulating learning, memory, mood, sleep, appetite, and other critical bodily functions. For one of her postdoc projects, she’s investigating the role of CB1 receptors — the most highly expressed GPCR (G protein–coupled receptor) — in the brain.

Graybiel’s lab previously discovered that when the CB1 receptor is knocked out in mice, a cell structure that resembles a bouquet of flowers, topped by dopamine “petals,” withers at its stem-like section. Mangal says they’re eager to know, “Why are these bouquet structures withering when CB1 is knocked out?”

“I hope my research will answer the questions: Is CB1 important in the brain? Is it changing dopamine circuitry? How can we take the basic biology that we know from in vivo studies and translate that to therapies for Parkinson’s and other disorders?”

Starting from scratch

Early in her life, Mangal moved from Afghanistan to London; she spoke barely any English, but there were more opportunities for 6-year-old Mangal and her sister. “We had nothing. We started from scratch, and I worked my way up,” she recalls. “I found that the more science I learned, the less I knew — and this got me hooked.”

She earned a bachelor’s degree in biochemistry from the University of London, a master’s of research in stem cells and developmental biology from the University College London, and a PhD in clinical medicine research from Imperial College London in 2023. Her doctorate highlighted the effects of the endocannabinoid system on pancreatic cancer.

Mangal’s research interests led her to a journal paper of Graybiel’s on the CB1 receptor in the striatum, eventually joining Graybiel’s team for her postdoctoral training with critical support from the Y. Eva Tan Postdoctoral Fellowship.

“I am thrilled that this fellowship exists and delighted to be part of the Yang Tan Collective community,” Mangal says. “I’m very grateful to Ms. Yang and Mr. Tan for their immense support.”

 

Sreeparna Pradhan, 2022-2024 K. Lisa Yang Brain-Body Fellow

Investigating gut-brain communication

Anyone who has felt “butterflies in the stomach” from being excited or anxious knows there’s a palpable link between our digestive system and brain. But exactly how these two parts of the body’s nervous system “talk” to each other isn’t fully clear.

Sreeparna Pradhan, a postdoctoral fellow in the K. Lisa Yang Brain-Body Center, is providing more clarity by studying the role of neuropeptides in gut-brain communication in Caenorhabditis elegans, a transparent worm used as a model organism in research. She’s doing so in the lab of Steven Flavell, an associate professor of brain and cognitive sciences.

Understanding this two-way interplay opens the door to potential therapies for conditions with gastrointestinal symptoms, from autism spectrum disorder to Parkinson’s disease to depression and anxiety.

Neuropeptides are small proteins that help neurons communicate. Although neurons typically connect through synapses when they are close together, they can also “talk” from farther away by releasing peptides that act as neurotransmitters, or chemical messengers, Pradhan explains. Scientists have mapped all 302 neurons and thousands of synapses in C. elegans, but its network of neuropeptides is less well-known.

Pradhan’s current research examines how microorganisms in the digestive system affect the brain. This entails feeding the worms pathogenic bacteria, tracking the animals’ behavior as they become ill — including eating less and slowing down — and using genetically engineered strains to locate the signals coordinating communication between gut and brain. The team has identified a number of neuropeptides involved in this process; Pradhan is investigating which neurons are releasing them, as well as changes in the worms’ brain activity.

“I am very excited about this project,” she says. “It contributes to our understanding of the mechanisms by which gut bacterial infections can influence the brain and behavior. We found that neuropeptide systems can be integral to this cross talk.”

Thinking big

Raised in Kolkata, India, Pradhan earned bachelor’s and master’s degrees in biotechnology and pursued her PhD in neuroscience at McGill University, in Montreal. There, she studied how stressful early experiences like starvation can have long-lasting effects.

At McGill, Pradhan imaged individual C. elegans neurons but wanted a bigger-picture understanding of brain-body communication and its impact on disease and health. The Flavell lab, which she joined in November 2020, was an ideal destination because it has developed technology to image the whole nervous system of freely moving C. elegans using a video tracker and machine learning tools.

How can this nematode inform human health? Many of the genetic pathways in both C. elegans and humans have been “conserved” through evolution and uphold the same principles of communication. “Studying simple invertebrate systems,” Pradhan points out, “has yielded foundational discoveries in many areas of biology.”

Pradhan is deeply grateful for the inaugural K. Lisa Yang Brain-Body Postdoctoral Fellowship, especially as an international scientist. Her future plans include investigating bacterial communication in the intestine and neuropeptides’ role in regulating sleep in animals. “I plan on becoming a tenure-track professor and pursuing some of these ideas in my own lab,” she says. •

Maedbh King, 2022-2025 K. Lisa Yang Integrative Computational Neuroscience (ICoN) Center Fellow

Refining mental health diagnoses

Maedbh King came to MIT to make a difference in mental health. As a postdoctoral fellow in the K. Lisa Yang Integrative Computational Neuroscience (ICoN) Center, she is building computer models aimed at helping clinicians improve diagnosis and treatment, especially for young people with neurodevelopmental and psychiatric disorders.

Tapping two large patient-data sources, King is working to analyze critical biological and behavioral information to better categorize patients’ mental health conditions, including autism spectrum disorder, attention-deficit hyperactivity disorder (ADHD), anxiety, and suicidal thoughts — and to provide more predictive approaches to addressing them. Her strategy reflects the center’s commitment to a holistic understanding of human brain function using theoretical and computa-tional neuroscience.

“Today, treatment decisions for psychiatric disorders are derived entirely from symptoms, which leaves clinicians and patients trying one treatment and, if it doesn’t work, trying another,” says King. “I hope to help change that.”

King grew up in Dublin, Ireland, and studied psychology in college; gained neuroimaging and programming skills while earning a master’s degree from Western University in Canada; and received her doctorate from the University of California, Berkeley, where she built maps and models of the human brain. In fall 2022, King joined the lab of Satrajit Ghosh, a McGovern Institute principal research scientist whose team uses neuroimaging, speech communication, and machine learning to improve assessments and treatments for mental health and neurological disorders.

Big-data insights

King is pursuing several projects using the Healthy Brain Network, a landmark mental health study of children and adolescents in New York City. She and lab colleagues are extracting data from cognitive and other assessments — such as language patterns, favorite school subjects, and family mental illness history — from roughly 4,000 participants to provide more-nuanced understanding of their neurodevelopmental disorders, such as autism or ADHD.

“Computational models are powerful. They can identify patterns that can’t be obtained with the human eye through electronic records,” says King.

With this database, one can develop “very rich clinical profiles of these young people,” including their challenges and adaptive strengths, King explains. “We’re interested in placing these participants within a spectrum of symptoms, rather than just providing a binary label of, ‘has this disorder’ or ‘doesn’t have it.’ It’s an effort to subtype based on these phenotypic assessments.”

In other research, King is developing tools to detect risk factors for suicide among adolescents. Working with psychiatrists at Children’s Hospital of Philadelphia, she is using detailed questionnaires from some 20,000 youths who visited the hospital’s emergency department over several years; about one-tenth had tried to take their own lives. The questionnaires collect information about demographics, lifestyle, relationships, and other aspects of patients’ lives.

“One of the big questions the physicians want to answer is, Are there any risk predictors we can identify that can ultimately prevent, or at least mitigate, future suicide attempts?” King says. “Computational models are powerful. They can identify patterns that can’t be obtained with the human eye through electronic records.”

King is passionate about producing findings to help practitioners, whether they’re clinicians, teachers, parents, or policy makers, and the populations they’re studying. “This applied work,” she says, “should be communicated in a way that can be useful.