The Breadth of the Brain
Have you ever had that sinking feeling that you might have forgotten to turn off the stove? Or felt anxious about an upcoming event, or had bad dreams after a particularly stressful day? You aren’t alone. Our brains, which create our thoughts, memories, and feelings, define who we are. How the collection of cells in our brain, called neurons, performs higher-order tasks is one of the most interesting and complex problems in science.
Despite its importance, we are only beginning to address many open questions about the brain: What components of the brain are responsible for memory, decision-making, perceiving and understanding our environment, and other experiences we consider critical to a life well lived? How do the various cells and parts of the brain work together, and how does the brain change as the body develops and ages? How does this impact our behaviors, emotions, and our risk of disease? And why do we even have these components in the first place? These and myriad other questions fall under the umbrella of neuroscience, a rapidly expanding interdisciplinary field focused on the brain and the rest of the nervous system.
“Neuroscience as we know it is a baby science; it’s quite new,” said Nikki Crowley, Huck Early Career Chair in Neurobiology and Neural Engineering, assistant professor of biology, and director of the Penn State Neuroscience Institute at University Park. “It’s born from a wide range of disciplines like philosophy, psychology, chemistry, physics, and biology, and the best neuroscience lies at the interface of all of them. At Penn State, the Neuroscience Institute, part of the Huck Institutes of the Life Sciences, facilitates thinking outside the box across traditional disciplines, bringing together researchers from a wide variety of departments and colleges to answer the big questions.”
The Penn State Neuroscience Institute facilitates research, training, and education in topics related to the health and flourishing of the brain. Founded in 2003, the institute brings together more than 100 faculty members, 50 graduate students, and many staff and postdoctoral fellows, collectively representing more than 25 departments across the University, including several in the Eberly College of Science.
“Researchers in the institute study the brain using a wide variety of approaches, including molecular, cellular, computational, and translational biology, as well as cognitive and behavioral methods,” Crowley said. “These varied efforts allow us not only to better understand how the brain works but also to make important connections to mental health, aging, and neurodevelopmental and neurodegenerative diseases.”
The institute serves as a hub for researchers by connecting neuroscientists with each other and to other centers within the Huck, such as the Center for Infectious Disease Dynamics and the One Health Microbiome Center. The institute also hosts weekly neuroscience seminars and coffee hours that bring in experts from all over the world. These serve as an informal gathering for members and are also open to others in the Penn State community.
“Undergraduate students attend the weekly seminar, and for many it may be their first exposure to big questions in science and the first time they are able to casually interact with scientists about their work,” Crowley said. “The institute also places a big focus on teaching and training. Currently, more than 300 undergraduates are doing research in labs connected to the institute, which is amazing, and our graduate students have received prestigious fellowships from the National Institutes of Health and the American Heart Association.”
At the graduate level, Penn State offers a doctoral program in Neuroscience, which is administered jointly by the Huck Institutes of the Life Sciences and the Eberly College of Science. The program’s students can tap into resources from both units, and the breadth of research interests and backgrounds among the institute’s members provides an exceptional learning environment for these burgeoning scientists.
Institute members within the Eberly College of Science, for example, are studying everything from memory formation and alcohol addiction to neurodevelopmental disorders and the evolutionary origins of the nervous system.
“What I like about neuroscience is that we don’t even know what the good questions are yet, and those questions will be different in 5 years and in 10 years,” Crowley said. “Penn State is well positioned to answer those questions because we have such breadth in our research and enthusiasm about answering the big questions. The interdisciplinary nature of the Neuroscience Institute, and the Huck, means we can create teams to tackle questions others haven’t even thought of.”
Over the next several pages, we explore how a few researchers in the college are approaching some of these questions and demonstrate how interdisciplinary connections strengthen their research in this crucial area of science.
How Are Memories Stored and Updated?
Thanks to memories, a fleeting experience can affect the way an animal behaves, sometimes for the rest of its life. This concept has always fascinated Janine Kwapis, Paul Berg Early Career Professor in the Biological Sciences, whose research group studies how memories are formed, stored, and updated.
“I took a psychology class in college and just fell in love with it, and my first neuroscience class was mind blowing; to think you can actually tell what’s happening in the brain while an animal is doing something,” Kwapis said. “Now my research group focuses on the genes that are required for memory and how those genes are regulated at various levels. We’re trying to understand the big mechanisms that control memory formation, which occur even after transient experiences.”
Kwapis is particularly interested in the molecular mechanisms that control how genes related to memory are turned on and off, and how the genes are translated into proteins. Although the main lines of her research to date have focused on the initial formation of a memory, she and her research group—including graduate student Chad Brunswick—are currently exploring how memories are updated and how this process changes with age.
“Memories are storied as a physical or biochemical change in the brain,” Kwapis said. “Existing memories can be updated to include new or changed information, and this process is a bit different than the formation of new memories. I would argue that as humans, most of what we are learning are updates. We already have some knowledge, and we’re modifying that with new information to keep it relevant.”
For this project, Kwapis’s research group is using a mouse model, where they can tag neurons that are engaged during memory formation during a training exercise that is unfamiliar to the mouse. Then, when revisiting the exercise, they can see if the same neurons are reengaged or if new neurons are active.
“In older animals, we see much less of an overlap in the neurons that are engaged both times,” Kwapis said. “This suggests that older animals are not faithfully reactivating what they already know. They’re having a hard time pulling memories out of storage, and that’s causing difficulty modifying the memories.”
Kwapis added that younger animals are more adept at updating memories, while adults may be more efficient at recalling the things they already know. As an animal gets older, they become more rigid and inflexible and less able to modify information.
“If we’re lucky, we all have to deal with normal aging, and we are trying to identify potential places to intervene to help prolong healthy cognitive aging,” Kwapis said. “If we can identify mechanisms that are impaired in old age, we may be able to identify targets for therapeutics. And if we can find a mechanism that helps in memory formation, in theory it could help with Alzheimer’s disease and other neurodegenerative conditions that are related to age.”
Kwapis also serves as the director for the Center for Molecular Investigation of Neurological Disorders (CMIND) at Penn State. The center, which is one of several centers under the umbrella of the Neuroscience Institute, serves as a smaller-scale hub for researchers to connect and collaborate on topics related to neurological and neuropsychiatric disorders.
“CMIND brings together a relatively small group of labs,” Kwapis said. “We have regular meetings, which provide an opportunity to get feedback on work in progress, share ideas and techniques, and find opportunities for collaboration. The center really has expanded the research questions my group is capable of asking.”
How Did the Nervous System Originate?
Evolution is often thought of as a linear process with a continual increase in complexity, but that isn’t always how it plays out in the natural world. When it comes to the nervous system, it turns out that many of its components were in place millions of years ago, before the common ancestor of all animals, though they may have been used for different purposes.
“The key evolutionary events that make neuronal signaling possible actually predate the nervous system,” said Timothy Jegla, associate professor of biology. “The nervous system translates sensory information from the environment and outputs a behavior or action, and electrical signals are the currency of neuronal communication.”
Ion channels are located in the membranes of cells and regulate how charged particles called ions move in and out of the cell. This process produces the electrical signals that are so critical to communication in the nervous system. For more than 20 years, Jegla has investigated the genes encoding ion channels in a wide variety of animals—from humans and mice to fruit flies and marine invertebrates—to understand how these critical proteins came about and how they evolved. This research could lend insight into their function and may also have implications for the treatment of disorders related to ion channel dysfunction, such as heart arrhythmias and epilepsy.
One particular type of ion channel Jegla studies, called a voltage-gated potassium channel, opens or closes based on changes in the electrical field. Animals like humans can express eight different types of these channels in one neuron, which allows for complex patterning of electrical signals. Comb jellies — animals with comparatively simple “nerve nets” that are thought to be similar to the very first animal nervous system — have two of these types in common.
“We found that comb jellies have evolved many of their own types of these channels, and the result is that they have almost all the same functional types of current that humans do,” Jegla said. “So the idea that they are simpler because we only have a couple types of ion channels in common is wrong. We see this across the animal kingdom and over evolutionary time—the same types of current are represented, even though the genes that encode them have very different evolutionary histories.”
Although the kinds of questions Jegla is exploring have largely remained the same over the last two decades, advances to DNA sequencing and molecular methods have greatly changed what his research looks like.
“When I was in grad school, we didn’t have genomes available for any of the species we looked at,” he said. “We used some very creative and difficult experimental approaches to find these genes and then to identify similar but nonexact gene sequences in other species. We found a few genes, but we didn’t really know what we were missing. It turns out we were missing a lot! These days, we have huge databases of whole genome sequences, and we can find all the ion-channel genes. The genetic information is there, and now we can use that to figure out how and when the key functional properties of our neuronal channels first evolved.”
Jegla added that many of the ion channels that were thought of as specifically adapted for neuronal signaling may have been around long before even animals made their first appearance. For example, ion channels play key roles in plant physiology. Jegla also collaborates with Sally Assmann, Waller Professor of Biology, to study the diverse and ancient family of ion channels that control how a plant’s leaf pores open and close to control the rate of photosynthesis.
“The breadth of research at Penn State and support for crossing traditional disciplinary boundaries have enabled collaborations on research problems that I would not have considered working on before,” Jegla said. “The intellectual quality and diversity of my fellow faculty members have really influenced my research program in a very positive way.”
Why Does the Severity of Neurodevelopmental Disorders Vary?
A person’s DNA serves as the blueprint for their traits, from their height and hair color to how they learn new information and even their disease risk.
“Although the environment has a considerable influence, it is ultimately our genes that determine who we are and how we behave,” said Santhosh Girirajan, T. Ming Chu Professor and head of the Department of Biochemistry and Molecular Biology and professor of genomics. “When researchers were first starting to sequence the human genome, we thought we would find single genes that were responsible for traits—a gene for height or a gene for heart disease. But the reality is much more complicated, especially when it comes to neurodevelopmental disorders.”
Girirajan was involved in the early discoveries of genes and genetic variants—differences in the letters of the DNA alphabet found across the population—that are associated with autism and neurodevelopmental disorders like developmental delay, but he and his colleagues quickly realized that having one gene or variant doesn’t necessarily dictate how a disorder manifests. Many people with the same genetic variant, for example, may be affected much more severely than others, even among siblings.
“I am particularly interested in understanding how combinations of genes or mutations come together to impact if and how a disorder manifests,” Girirajan said. “Ultimately, we hope our work will shed light on the core mechanisms behind neurodevelopmental disorders that may inspire new treatment options.”
One way Girirajan studies complex gene interactions is by working with families who have rare deletions on chromosome 16, which is known to be associated with developmental delays, cognitive and speech difficulties, and autism. This deletion occurs in approximately 1 in 3000 people and, like most genetic variants, can be passed on from generation to generation.
“The deletion sensitizes the genome for a variety of trajectories,” Girirajan said. “By studying individuals in families where symptoms vary greatly but much of the genetic information is shared, we can try to pinpoint the underlying cause of these differences.”
Improvements to genetic sequencing and molecular technologies over the years have allowed Girirajan to move beyond associations and really investigate the underlying mechanisms of these disorders.
“Beyond improved technology, having access to more and more families who are willing to work with us has improved the statistical rigor and allowed us to really understand the complexity from a mechanistic point of view,” Girirajan said. “Additionally, data from biobanks, where everyday people can share genetic and other information for research use, have been incredibly helpful as a point of comparison.”
The human element of Girirajan’s research has attracted undergraduate and graduate researchers to his research group, many of whom have gone on to pursue medical school and careers in neuroscience and genetics. Although working directly with families as part of his research may be less common within the Eberly College of Science, Girirajan says the wide variety of specialties among his colleagues within the college and the Neuroscience Institute have enriched his research.
“I am a trained physician, though I don’t practice, and one of the reasons I’m at Penn State and not at a medical school is because of the interdisciplinary nature of the questions we can address,” he said. “The questions I am asking have been transitioning from being medical to being biological. And at Penn State we have neuroscientists, biochemists, structural biologists, genomicists, and psychologists. It’s a good group of people to think about these questions in multiple dimensions.”