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Alfredo Fontanini

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From left, Prerana Shrestha, Sunghoon Kim (Postdoc), Andrew Gallagher (Research Support Specialist), Miura Traficante (SOAR Fellow, Summer undergrad researcher), Keith Yeung (Undergraduate researcher), Matthew Dickinson (PhD student), Saheed Lawal (PhD student), and Olivia Tabaka (MS student)

By Daniel Dunaief

An increasingly complex time filled with extreme stressors such as man-made and natural disasters creates conditions that can lead to post traumatic stress disorder.

PTSD, which can cause anxiety even amid safer conditions, can have adverse effects on the ability to enjoy life.

Prerana Shrestha

Stony Brook University Assistant Professor Prerana Shrestha, who joined the Department of Neurobiology and Behavior at the Renaissance School of Medicine in 2021, recently received a four-year $2.2 million grant from the National Institute of Mental Health to study the molecular mechanisms underlying stabilization of emotional memories in the brain, which is relevant for PTSD.

“Her work will help us understand how the brain stores these traumatic memories,” said Alfredo Fontanini, chair of the Department of Neurobiology and Behavior. “The tools she has developed really are making possible a series of experiments that, before, were impossible to think about.”

Shrestha hopes to develop a druggable target that could “block a key machine inside neurons that are relevant for traumatic emotional memories,” she explained.

Using a mouse model, Shrestha plans to understand the neural signature at the level of molecules, neurons, and neural circuits, exploring the creation and stabilization of these potentially problematic memories and emotional reactions through a multi-disciplinary study.

Shrestha has developed and applied chemogenetic tools to block a key part of the memory process inside neurons that store traumatic emotional memories.

By developing tools to explore neural circuits in particular areas of the brain, Shrestha can help scientists understand the molecular mechanism involved in PTSD, Fontanini said.

‘From the ground up’

In humans, memories from traumatic events are over consolidated, creating an excessive avoidance behavior that can be a debilitating symptom.

“We are trying to understand the neurological basis for why these memories are so robust,” Shrestha said. She is looking at “what can we do to understand the mechanism that supports these memories from the ground up.”

With her chemogenetic tools, Shrestha can block protein synthesis in specific neuron populations in a time period of a few hours. She is developing new tools to improve the precision of blocking the protein synthesis machinery from hours to minutes.

Shrestha is trying to weaken the salient emotional memory while leaving all other processes intact.

The Stony Brook Assistant Professor said she has methods to create a targeted approach that limits or minimizes any off target or collateral damage from inhibiting the synthesis of proteins.

“Up until now, whenever scientists wanted to study the role of the synthesis of new proteins in memory formation” including those involved in the formation of aberrant memories such as those in PTSD, they had to “use drugs which would manipulate and affect protein synthesis everywhere in the brain,” said Fontanini.

The plan over the next four years is to understand and develop molecules to target cells in the prefrontal cortex, which, Shrestha said, is like the “conductor of an orchestra,” providing top-down executive orders for the brain.

She is focusing on neurons that interact specifically with the amygdala, which is the emotional center of the brain, exploring what happens in these streams of information between brain regions.

By increasing or reducing protein synthesis in the prefrontal cortex, Shrestha can see an enhanced or diminished avoidance response in her mouse experiments.

She is interested in how a memory is stabilized, and not as much in what is involved in its retrieval.

Shrestha works with inbred mice that are more or less genetically identical. Her experimental group has the transgenic expression of the chemogenetic tool to block protein synthesis and receive a drug after learning that triggers the tool to block the machinery from making new proteins.

When she introduces the inhibitor of protein synthesis, she found that the wave involved in stabilizing what the animal previously learned is finite in time.

Using a drug to block protein synthesis within an hour alters future behavior, with the animal showing little or no fear. Blocking protein synthesis after that hour, however, doesn’t affect the fear response.

In the first year of the grant, which started in December, Shrestha would like to send out some papers for publication based on the research her team members — postdoctoral researcher  Sunghoon Kim and graduate student Matthew Dickinson —  has already done. She also hopes to use some of the funds from this grant to hire another postdoctoral researcher to join this effort.

She has data on how the regulators of ribosomes are recruited in the prefrontal cortex, which stabilizes memories.

In other preliminary data, she has identified neurons in the prefrontal cortex that project into the amygdala that are selectively storing information for recent parts of emotional memory.

To be sure, while this research offers a potential window into the mechanisms involved in forming emotional memories in a mouse model, it is an early step before even considering any new types of diagnostics or treatment for humans.

Nepal roots

Born and raised in Kathmandu, Nepal, Shrestha received a full scholarship to attend Bates College, in Maine, where she majored in biological chemistry. She received a Howard Hughes Medical Institute fellowship for an internship at Harvard Medical school during her junior year. While preparing for a pre-medical track, she “got spoiled after getting a taste of research in my junior year,” she said. “The idea of trying something new for the first time and seeing how things work was so cool.”

Shrestha lives about eight miles west of Stony Brook and is married to Sameer Maskey, the founder and CEO of an advanced machine learning company called FuseMachines Inc. They have a nine-year old daughter and a two-year-old son.

As for her ongoing work, Shrestha is eager to combine her expertise with those of people from different backgrounds.  “It’s a fascinating time to combine molecular approaches,” she said. 

Fontanini, who helped recruit Shrestha, has been impressed with the work she’s done.

“She’s on an outstanding trajectory,” he said.

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Alfredo Fontanini in front of a poster of a neuron in his office. Photo from Alfredo Fontanini

By Daniel Dunaief

Pull into the parking lot of your favorite restaurant and you can almost taste the onion rings, the fresh baked bread or the steamed clams. The combination of the sign, the smell of the food piped out of the familiar building, and even the familiar voice of the restaurant owner welcoming you back is a hint of the experience of eating. Indeed, when these anticipatory stimuli are a part of the dining experience, they contribute to forming flavor.

Alfredo Fontanini, an associate professor in the Department of Neurobiology & Behavior at Stony Brook University, recently conducted research on rodents in which he explored how other senses — touch, taste, smell and sight — contributed to the part of the brain responsible for taste, the gustatory cortex.

In work published recently in the journal eLife, Fontanini demonstrated that rats who heard particular sounds, smelled odors, felt a puff of air against their whiskers, or saw the flash of an LED light before they ate showed increased activity in the gustatory cortex even before they started eating. If this experiment sounds familiar, it’s because Russian scientist Ivan Pavlov demonstrated the anticipation of food in conditioning experiments with dogs, showing that their digestive systems became active when they heard a tone before they ate, associating the sound with the presentation of food.

Dr. Alfredo Fontanini looks at slides of the gustatory cortex, the part of the brain that mediates the perception of taste. Photo from Stony Brook University
Dr. Alfredo Fontanini looks at slides of the gustatory cortex, the part of the brain that mediates the perception of taste. Photo from Stony Brook University

Fontanini took this research further, however, showing that the brain regions responsible for taste can, and did, show activity prior to eating. “As we paired the stimuli in a Pavlovian task, the animal would produce mouth movements and licks in response,” Fontanini said. These movements were not there right away, but developed after three to seven days of training, suggesting that the animal could infer taste. He recorded the responses of single neurons in the gustatory cortex. Before conditioning, the neuronal response in the gustatory cortex varied according to the sense stimulated. Prior to training, neurons in the gustatory cortex showed a 16 percent response, while that went up to 33 percent after learning. “This suggested that the stimulation was predictive of taste,” Fontanini said. “More neurons were integrating between all the stimuli.”

Donald Katz, a professor of psychology at Brandeis University who oversaw Fontanini’s graduate research for five years, suggested that his former student was one of a few neuroscientists studying how anticipation of an experience, knowing what’s coming, impacts how the brain handles that experience. This study, he explained in an email, “makes perfect sense — while few researchers study how different sensory systems work together, it is well-known that taste is linked to all of the other senses. It is of great evolutionary import that this be so,” because the animal that can recognize something good to eat at the greatest distance will be the one that eats.

Katz described Fontanini’s recent work as a “wonderful finding in that it provides a substantial, natural extension” to work completed in his lab, Katz’s lab and those of other scientists. In exploring which specific senses are most important to the gustatory reflex, Fontanini said olfaction and touch are considered more relevant for food-related decisions. “These are animals that use these senses to navigate their world and explore food,” he said.

In the bigger picture, Fontanini would like to understand how the brain integrates and fuses sensory perceptions with emotions. He explained that one of the tests in animal models of depression is to look at how much a test subject still likes something sweet. “Studying taste allows us to understand how the brain creates pleasure or creates aversion that negates emotions,” he said.

Fontanini plans to extend this study to additional research. He would like to know the neurological pathways that link the visual, auditory, somatosensory and olfaction senses that contribute to forming an expectation about taste. He is also eager to understand how the anticipatory activation influences the way taste is perceived. This, he explained, would be a way to explore how expectations shape perception.

Fontanini, who grew up in the town of Brescia, Italy, which is near Milan, arrived at this particular field of research because of his interest in understanding perception and emotion. He would like to explore how the brain creates emotions. Recognizing the multisensory element to taste and eating, Fontanini suggests that understanding how olfaction and taste can interact may lead to eating sweets where the smell enhances the flavor and taste, even of a lower-calorie dessert, like a piece of chocolate cake. “If you can leverage more of the odor and less” of the taste, “you can find a way of having that richness without the need for overwhelming sweetness.”

A resident of Setauket, Fontanini lives with his wife Arianna Maffei, who is an associate professor in the Department of Neurobiology & Behavior at Stony Brook and their 11-year-old son Carlo. Relying on vocabulary of the gustatory cortex, Fontanini suggested Long Island has a “soothing sweetness” that springs from the quaint and beautiful setting his family enjoys.

As for his work, Fontanini said studying taste in the brain is challenging. “What happens when you taste chocolate: are you activating chocolate neurons or are you activating a complex pattern of activity?” The answer, he said, describing taste while borrowing from another sense, is much more like a musical ensemble during a symphonic experience than like a solo. “Understanding how taste is represented in the cortex is incredibly complex,” he said.

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