Tags Posts tagged with "neuroscience"


Christina Joselevitch

By Daniel Dunaief

Children knock on the door of 1313 Gluto Lane, a favorite house for Halloween. The resident, known for providing coveted confections at a rapid rate, immediately comes to the door, asks no questions about the Halloween costumes that might slow the process down and, with almost super-human speed, dumps candy into open bags and closes the door.

Word spreads about the house on Gluto Lane. Soon, the doorbell rings at a furious pace, with children eager to get the best candy of this difficult year and move on to the next house.

At first, with Trick or Treaters coming at a regular pace, the process works, but then, something goes awry, creepy music begins and the door doesn’t open.

That’s what’s happening in bipolar retinal cells in the goldfish Christina Joselevitch, a Postdoctoral Associate in the Neurobiology and Behavior Department at Stony Brook University’s Renaissance School of Medicine, is studying.

Known for their incredible speed at releasing neurotransmitters stored in circular vesicles, these bipolar retinal cells go through a depression in which they can’t release the neurotransmitter glutamate despite repeated signals for the release of the neurotransmitter.

“When you stimulate those cells very strongly, with two stimuli close apart, they suffer depression,” Joselevitch said. “Nobody knew why, if they’re able to signal constantly, they should suffer from depression.

To be sure, Joselevitch was working with extreme stimulation to probe the limits of the system and understand its underpinnings. This is not necessarily how these cells work. She said the researchers don’t know if retinal neurons experience synaptic depression under normal conditions and what function depression would have in bipolar cell physiology, in vision or in signaling processing in general.

In a recent publication in the Journal of Neuroscience, Joselevitch described at least two processes that contribute to this slowdown, which she describes as the rate limiting steps. The vesicles need to get to the membrane and they need to get ready to mature before they are release. Once vesicles move towards the cell membrane, they don’t immediately fuse and send their neurotransmitter into the synapse between cells. In some cells, such as the retinal photoreceptors and bipolar cells and in hair cells of the ear and lateral line in fish and in cells of the pineal gland, they gather in a ribbon close to calcium entry points.

Scientists have two theories of the ribbon function. The first is that it could act as a conveyor belt and speed up vesicle priming and delivery to the membrane and the second is that it could set a constant pace for vesicle delivery.

Joselevitch’s results suggest that the vesicles attach to the ribbon, where they go through a maturation process. These paired-pulse depressions don’t just occur in fish: they also affect the ability of mammalian cells to respond to a second stimulus.

These cellular phenomena show the limits of the system. Indeed, Joselevitch likened the process to a car that has reached its maximum speed. Pushing down harder or more on the accelerator won’t enable further acceleration.

The impact of this work is “broad,” she said. Studying this process could enable a stronger awareness of the steps in fast-acting processes in the nervous system. Such research could also provide an understanding about processes that go awry in various neurological diseases.

In an email, Professor Lonnie Wollmuth, who is the principal investigator for the Stony Brook lab in which Joselevitch works, described Joselevitch as “invaluable to our on-going efforts to study presynaptic mechanisms in the retina.” He wrote that she was an “outstanding and very careful scientist” who is “passionate” about her research and has served as a mentor for others in the lab.  Joselevitch has been working in Wollmuth’s lab for about 16 months.

Synaptic transmission is fundamental to all brain function, Wollmuth explained. “Changes in the strength of synaptic transmission underlie basic higher order brain functions like learning and memory,” the Stony Brook Professor wrote. Joselevitch’s experiments “reveal mechanisms of presynaptic vesicle release at all synapses and provide novel insights into the processing of vesicles at ribbon synapses.”

Based on Joselevitch’s work, Wollmuth’s lab has submitted a large National Institutes of Health grant to the National Eye Institute to study the molecular components of presynaptic release in the retina. She has also started to integrate her work with Alzheimer’s Disease, as proteins found in that disease disrupt the molecular machinery involved in presynaptic release.

A native of Brazil, Joselevitch has been at Stony Brook University since last July. She is on sabbatical with the University of São Paulo. She is hoping to participate in these studies in New York for a few more years.

She said she was “always a nerd,” and liked to study languages. With varying levels of proficiency, she speaks five languages: Portuguese, English, German, Dutch, and Spanish. At one point, she wanted to be an astronaut, but her mother Carmen dissuaded her from pursuing that interest.

Joselevitch had planned to return to Brazil to see her family in April, but had to cancel that plan because of a travel ban from the COVID-19 pandemic. She said her parents have been “good sports” and her father has bought a smartphone so he can talk through Skype or WhatsApp with his scientist daughter.

Joselevitch enjoys biking, hiking, singing and playing guitar and has been productive during the pandemic, writing papers and proposals. Stony Brook is nominating her work for consideration for the Warren Alpert Distinguished Scholar Award.

Wollmuth wrote that Joselevitch’s research forms “the foundation for future experiments to address the molecular components of vesicle dynamics.” Once they are identified, researchers can modulate and protect them in brain diseases.

Citing author James Joyce, Joselevitch explained her focus on neurons in the fish eye, which, she hopes, may lead to a broader understanding of neurology and disease. When asked why he wrote about Dublin when he could describe other places he’s visited, Joyce responded, “In the particular is contained the universal.”

From left, Megan Crow, Associate Professor Jesse Gillis and postdoctoral researcher Sara Ballouz Photo by Gina Motisi/CSHL

By Daniel Dunaief

Diversity has become a buzz word in the workplace, as companies look to bring different perspectives that might represent customers, constituents or business partners. The same holds true for the human brain, which contains a wide assortment of interneurons that have numerous shapes and functions.

Interneurons act like a negative signal or a brake, slowing or stopping the transmission. Like a negative sign in math, though, some interneurons put the brakes on other neurons, performing a double negative role of disinhibiting. These cells of the nervous system, which are in places including the brain, spinal chord and retina, allow for the orderly and coordinated flow of signals.

One of the challenges in the study of these important cells is that scientists can’t agree on the number of types of interneurons.

“In classifying interneurons, everyone argues about them,” said Megan Crow, a postdoctoral researcher in Jesse Gillis’ lab at Cold Spring Harbor Laboratory. “People come to this question with many different techniques, whether they are looking at the shape or the connectivity or the electrophysiological properties.”

Megan Crow. Photo by Constance Brukin

Crow recently received a two-year grant from the National Institutes of Health to try to measure and explain the diversity of interneurons that, down the road, could have implications for neurological diseases or disorders in which an excitatory stimulus lasts too long.

“Understanding interneuron diversity is one of the holy grails of neuroscience,” explained Gillis in an email. “It is central to the broader mission of understanding the neural circuits which underlie all behavior.”

Crow plans to use molecular classifications to understand these subtypes of neurons. Her “specific vision” involves exploiting “expected relationships between genes and across data modalities in a biologically thoughtful way,” said Gillis.

Crow’s earlier research suggests there are 11 subtypes in the mouse brain, but the exact number is a “work in progress,” she said.

Her work studying the interneurons of the neocortex has been “some of the most influential work in our field in the last two to three years,” said Shreejoy Tripathy, an assistant professor in the Department of Psychiatry at the University of Toronto. Tripathy hasn’t collaborated with Crow but has been aware of her work for several years.

The interactivity of a neuron is akin to personalities people demonstrate when they are in a social setting. The goal of a neuronal circuit is to take an input and turn it into an output. Interneurons are at the center of this circuit, and their “personalities” affect the way they influence information flow, Crow suggested.

“If you think of a neuron as a person, there are main personality characteristics,” she explained. Some neurons are the equivalent of extraverted, which suggests that they have a lot of adhesion proteins that will make connections with other cells.

“The way neurons speak to one another is important in determining” their classes or types, she said.

A major advance that enabled this analysis springs from new technology, including single-cell RNA sequencing, which allows scientists to make thousands of measurements from thousands of cells, all at the same time.

“What I specialize in and what gives us a big leg up is that we can compare all of the outputs from all of the labs,” Crow said. She is no longer conducting her own research to produce data and, instead, is putting together the enormous volume of information that comes out of labs around the world.

Megan Crow. Photo by Daniel Katt

Using data from other scientists does introduce an element of variability, but Crow believes she is more of a “lumper than a splitter,” although she would like to try to understand variation where it is statistically possible.

She believes in using data for which she has rigorous quality control, adding, “If we know some research has been validated externally more rigorously than others, we might tend to trust those classifications with more confidence.”

Additionally she plans to collaborate with Josh Huang, the Charles Robertson professor of neuroscience at Cold Spring Harbor Laboratory, who she described as an interneuron expert and suggested she would use his expertise as a “sniff test” on certain experiments.

At this point, Crow is in the process of collecting baseline data. Eventually, she recognizes that some interneurons might change in their role from one group to another, depending on the stimuli.,

Crow hasn’t always pursued a computational approach to research. 

In her graduate work at King’s College London, she produced data and analyzed her own experiments, studying the sensory experience of pain.

One of the challenges scientists are addressing is how pain becomes chronic, like an injury that never heals. The opioid crisis is a problem for numerous reasons, including that people are in chronic pain. Crow was interested in understanding the neurons involved in pain, and to figure out a way to treat it. “The sensory neurons in pain sparked my general interest in how neurons work and what makes them into what they are,” she said.

Crow indicated that two things brought her to the pain field. For starters, she had a fantastic undergraduate mentor at McGill University, Professor of Psychology Jeff Mogil, who “brought the field to life for me by explaining its socio-economic importance, its evolutionary ancient origins, and showed me how mouse behavioral genetic approaches could make inroads into a largely intractable problem.”

Crow also said she had a feeling that there might be room to make an impact on the field by focusing on molecular genetic techniques rather than the more traditional electrophysiological and pharmacological approaches.

As for computational biology, she said she focuses on interpreting data, rather than in other areas of the field, which include building models and simulations or developing algorithms and software.

In the bigger picture, Crow said she’s still very interested in disease and would like to understand the role that interneurons and other cells play. “If we can get the tools to be able to target” some of the cells involved in diseases, “we might find away to treat those conditions.”

The kind of research she is conducting could start to provide an understanding of how cells interact and what can go wrong in their neurodevelopment.

Gillis praises his postdoctoral researcher for the impact of her research.

“Just about any time [Crow] has presented her work — and she has done it a lot — she has ended up convincing members of the audience so strongly that they either want to collaborate, adapt her ideas, or recruit her,” Gillis wrote in an email. 

Crow grew up in Toronto, Canada. She said she loved school, including science and math, but she also enjoyed reading and performing in school plays. She directed a play and was in “The Merchant of Venice.” In high school, she also used to teach skiing.

A resident of Park Slope in Brooklyn, Crow commutes about an hour each way on the train, during which she can do some work and catch up on her reading.

She appreciates the opportunity to work with other researchers at Cold Spring Harbor, which has been “an incredible learning experience.”