Cracking the ‘Ultimate Code’

By Glenn Jeffers

When Northwestern’s Indira Raman talks about the cerebellum, she doesn’t go into the neurotransmitters or electrochemical signals or the fact that it commands and controls the complicated movements humans make every day. That comes later.

“I think of things as, ‘What is the grammar? What is the language? What is the poetry?’” says Raman, the Bill and Gayle Cook Professor of Neurobiology in the Weinberg College of Arts and Sciences. “We really want to get to poetry, but we need to understand the fundamentals to understand the peculiarities that give poetry its nuance.”

That’s more than an analogy, she says. To understand cellular and molecular neuroscience, how a cell signal becomes movement, sensory input, and perception — from the smallest larval fish to the largest vertebrate — requires profound understanding of the brain’s operation.

“I carry it in my head,” Raman says, embracing the pun. “It's very powerful once you understand where something comes from. Then you can see a little variation, and you can say, ‘Oh, yeah, there's an answer there,’ that a more superficial examination might make you miss.”

Solving that complexity has been top of mind for Raman, a member of Northwestern’s Department of Neurobiology in WCAS as well as an affiliate of the Northwestern University Interdepartmental Neuroscience Program (NUIN), an interdisciplinary graduate initiative extending across some 20 departments. She has said that the brain is like the “ultimate code or puzzle” and has aimed to decipher its intricacies. For the last 21 years, she has focused her research on understanding how the brain — the cerebellum in particular — transmits information. In her work, she measures electrical (“action potentials”) and chemical (“synaptic transmissions”) signals and studies the cells that create these complex signals.

Looking at that baseline can provide insight on a host of neurological diseases, Raman says. Though she is not concentrating on a particular disease, her lab has discovered how autism-like mutations in mice differently affect how the cerebellum processes information in male and female mice. Noticing those slight differences in how synapses signal led to this breakthrough, she says.

“It's only when you really know all the subtleties that you can notice some of these surprising changes that happen,” says Raman.

Raman’s focus has been on Purkinje cells, flask-shaped neurons within the cerebellum that regulate and control movements. Part of their role is sending an “inhibitory signal” that stops other cells from firing electrical signals, thereby stopping nerve impulses and movement.

In other words, Purkinje cells help course-correct, Raman says, like catching a glass of water before it spills: “It helps you fix things in sub-second time. You don't have time to say, ‘Oh, pause. It seems like I made a mistake,’ and then the water's all over the place. You catch it right away and correct it in a couple of milliseconds.”

Her work with Purkinje cells has led to others studying various conditions across several systems including epilepsy, paroxysmal extreme pain disorder and paramyotonia congenita, a disorder where the muscular system constantly stiffens.

“That's a very cool example of how the very fundamental research we're doing has been a springboard for a lot of other people who are doing much more clinically oriented research,” she says.

Raman’s work does more than just lay a foundation. With postdoctoral fellow Spencer Brown, Raman published “Sensorimotor integration and amplification of reflexive whisking by well-timed spiking in the cerebellar corticonuclear circuit” in Neuron, one of the primary peer-reviewed scientific journals in the field of neuroscience. The 2018 article highlighted the duo’s work testing Purkinje cell responses in mice whose whiskers were excited by a small puff of air. The experiment found that disrupting cerebellar activity affects even the simplest reflexive movements.

“It may not sound exciting, but we spent years describing a lot of specific and unusual electrical properties present in these Purkinje cells and it's almost like finding out they have a particular accent,” Raman says. “It helped us synthesize how all those biophysical properties — this ‘funny accent’ — gives rise to a code that is very effective at giving you a correction on a sub-second time scale. It was like finally getting to the point where we can see how all these little details come together into a functioning whole,” she says.

The Path to Purkinje
Raman path’s to neurobiology was similarly rather circuitous. As a teen, she wanted to be a linguist or mathematician, but settled on science after speaking with her father, a polymath who spoke more than a dozen languages. She went right into graduate school after earning her bachelor’s at Cornell University, where she discovered Purkinje cells and their inhibitory nature.

“My words aloud were, ‘That’s stupid,’” Raman recalls thinking when initially confronting the mystery of how the cells worked. “It was a naïve way of saying that I couldn’t figure that out, and it bothered me.”

By the time Raman was a postdoctoral student at Harvard University, Purkinje cells had become a full-blown fascination. She landed in the lab of Bruce Bean, an expert on ion channel proteins in Purkinje cells. “The work I did during my post-doc helped me understand what I didn’t understand,” she says, “to have a clear idea of what the variables were, what the puzzle pieces were, and so I could start thinking about how you might assemble it.”

Raman started working on that puzzle, joining Northwestern in 1999 as a Searle Leadership Fund recipient, studying cerebellar physiology and the inner workings of Purkinje cells. These days, her work ranges from “biophysics to behavior,” working with animal models (mice and zebrafish) to understand how the cerebellum distinguishes and responses to different type of stimuli.

Throughout the years, Raman’s work has been heralded. Most notably, she received the Javits Neuroscience Investigator Award from the National Institute of Neurological Disorders and Stroke. In announcing the seven-year grant, the institute cited “the importance and high quality of Dr. Raman’s research findings, and her record of service to the field and the next generation of neuroscientists.”

That last part is important for Raman. If it is research that fuels her curiosity, teaching and mentoring students in her seven-person lab drives her passion. “Working with the students and watching them grow. To me, that itself is very beautiful,” she says.

Grant Zempolich, a 2019 graduate taking a “gap year” as part of Raman’s lab, cannot imagine working anywhere else. He met Raman during his junior year while in a dual-degree program studying the cello and neuroscience. There, Zempolich found a fellow music lover and musician in Raman, who helped develop neuroscience research that incorporated music in her lab.

“I wrote my senior thesis in Indira’s lab,” says Zempolich. “She thinks circles around other people, but personally, the thing I've most enjoyed is that she's completely encouraged me to follow my passions and to do things that interest me.”

The same goes for Mauricio Medina, a brain surgeon, Fulbright scholar and doctoral student working in Raman’s lab. Medina joined  NUIN in 2017 to continue his research on the brain when he met Raman. Since then, the two have worked to understand how the cerebellum integrates sensory and motor information, a question that melds Medina’s interest as a research with his skills as a doctor.

“She was eager to collaborate and very understanding in how I was going to combine both clinical and research areas,” Medina said. “So that was perfect for me.”

For Raman, teaching is just as important as her research since one informs the other. Teaching challenges Raman to perceive her work as new information so that her students better understand it, she says. But it also gives her a different perspective with which to view her work, leading to new discoveries. It’s a connection Raman hopes to continue at Northwestern.

“For me, the two have been extremely synergistic,” she says. “I've derived a great deal of joy, pleasure and intellectual stimulation by working with my students and I'll say that 21 out of 27 students came back for my 20-year lab reunion last October, and the only two grad students who didn't come back had just had babies in the last few months.”