Two pharmacology researchers from the University of Colorado School of Medicine have been granted Klingenstein Fellowship Awards in Neuroscience, typically given to high-risk, high-reward projects from early career investigators conducting groundbreaking neuroscience research.
Assistant professors Debosmita Sardar, PhD, and Justin O’Hare, PhD, were each awarded $450,000 over the next three years for their individual projects.
Sardar’s research focuses on how non-neuronal glial cells contribute to behavior through epigenetic mechanisms. Using next-generation sequencing and functional studies in animal models, Sardar’s lab will explore how glial epigenetics shape sense of smell.
Next door, O’Hare’s lab is working on understanding how the brain strengthens or weakens specific synapses during learning. The lab uses unique imaging technology to observe how calcium, which is a key molecule for learning and memory, links synapses in real time as an animal model learns to navigate virtual environments.
Two faculty members earning the distinguished fellowship is a nod to the Department of Pharmacology’s scientific culture, the two researchers say.
“This fellowship gives us the confidence to be bold,” Sardar says. “We can work on gathering preliminary data in areas where there isn’t a lot of research. This allows us to build proof-of-concept and tools for additional funding down the road.”
Studying the sense of smell
Neurons in the brain have received a lot of fanfare over the course of neuroscience history, but Sardar and her lab are more interested in the cells that make up the other half of the brain: glial cells, which until the last few decades were thought of as playing only a supportive role and acting as a sort of glue in the brain.
“We want to understand the role glial cells play in the process of sensory perception. Within glial cells, we focus on how genes are responsible for controlling sense of smell, so we are taking an integrated behavioral, cellular, and molecular approach to this work,” Sardar explains.
Sardar uses epigenetics, a way of regulating the genome, to understand this mechanism. Previously, Sardar discovered that serotonin, the chemical messenger often associated with happiness, can enter glial cells and then attach to DNA packaging histone proteins to become an epigenetic modification.
“Basically, the chemical serotonin can go all the way to the genome, attach to components of the genome, and regulate the genome,” she says. “It’s an interesting phenomenon where serotonin released from a neuron is being taken up by a glial cell and, in this process, is regulating genes, and ultimately behaviors”
Now, the lab is trying to understand how this novel mechanism of cell-cell communication between neurons and glial cells is driving sense of smell.
Glial function is an important part of studying neurological disorders. Sardar explains that most neurological conditions have some aspect of glial dysfunction. Smells play a part here, too.
“One of the first symptoms in people who are diagnosed with neurodegenerative disorders like Alzheimer's, Parkinson's disease, and many others is loss of smell, or reduced odor sensing,” Sardar says. “It's a classic early symptom, and we know absolutely nothing about the role of glia in this smell phenotype that is observed in these patients. In our work, we are coming in with not only the role of glial cells but also looking at the genome code level of how sensory processing is affected, opening doors to our understanding of what this means for disease.”
The work has big implications for human health, but few if any investigations on the role of glial epigenetics in olfactory sensory processing are happening beyond Sardar’s lab – which means the Klingenstein Fellowship is a big boost for the work.
“A lot of our work is venturing into unknown territories,” Sardar says. “This funding gives the lab a lot of courage to be bold and fearless and ask important questions about fundamental biology.”
Investigating calcium’s role in memory
The O’Hare lab sits between cellular neuroscience, which focuses on structure and function of individual brain cells, and systems neuroscience, which studies how the brain operates as a machine of interacting systems.
Typically, scientific labs are dedicated to one discipline or the other, as they require extensive technical and conceptual expertise, but O’Hare and his team of researchers see a major opportunity in bridging them together, especially as they seek to understand how individual neurons contribute to memory formation and storage.
“We’re approaching important questions about normal biological processes affected by diseases, such as Alzheimer’s disease, from a pretty unique angle,” O’Hare says. “Instead of coming at it from that mile-high level of, ‘How do all these neurons create a picture of something in your brain?’ we ask, 'How does a single neuron, a single brain cell, actually learn to participate in these broader patterns of activity?'”
Specifically, the O’Hare lab is interested in how calcium is tied to synaptic plasticity.
“Calcium is considered the starting point for forming new memories,” O’Hare explains. “For the last several decades, neuroscientists have thought about how calcium comes from outside the neuron because there’s a lot of calcium just floating around in your brain. But it so happens that neurons have an internal tank or reservoir of calcium that is concentrated in the endoplasmic reticulum.”
“If you accept that calcium is important for forming new memories, for synaptic plasticity, and you have this gigantic internal source of it that is activated at exactly the time where you'd want it to be active for forming new memories, then you could see why a lot of people thought it was a promising candidate for regulating learning and memory,” he adds.
Historically, those questions could only be pondered in a dish in a lab, but the O’Hare lab’s novel approach uses a live animal model in a virtual reality setting to study what’s happening in a neuron as a memory is being formed.
“Our goal is to use these approaches and the support from the Klingenstein Foundation to figure out exactly how this previously mysterious bag of calcium inside brain cells helps us form new memories,” O’Hare says.
The fellowship funds and resources, including scientific meetings and mentorship, give O’Hare and Sardar — who both opened their labs on the CU Anschutz Medical Campus in 2024 — a chance to quickly scale their work and grow in ways that are much more difficult without dedicated funding.
“I’ve been so well-supported here at CU,” O’Hare says. “We are getting the best possible resources to move science forward. Help from the Klingenstein Foundation means we can continue to recruit top talent to our labs and continue focusing on exciting and impactful work.”
