Rachel Doser, a Biomedical Sciences Ph.D. student whose research is featured on the latest cover of the Journal of Neuroscience, recalls members of her family experiencing chronic migraines and epileptic seizures when she was growing up.

“We didn’t know why our family experienced these neurological issues and I wondered, ‘why haven’t neurologists figured this out?’” Doser said. Upon realizing how little is actually known about the vast complexities of the brain and nervous system, “I immersed myself in neuroscience and never looked back.”

In a neighboring lab, Abdunaser Eadaim, a Biomedical Sciences Ph.D. student from Libya whose research is featured in the latest issue of Cell Reports, has a similar story. “We have Alzheimer’s disease in my family, and I became very interested in understanding how this disease works and how it effects memory, and in how other neurodegenerative diseases work.”

From thinking to moving, everything we do each moment of our lives depends upon billions of cells and neural pathways correctly doing their job. In order to fully understand what goes awry in cases of neurological disorders and diseases, it is important to better understand what happens when things are going right. Doser’s and Eadaim’s recent prestigious publications represent distinct approaches to better understanding how this activity occurs and is regulated in real time. In their respective labs, meticulous discoveries are being made that seek to uncover the innerworkings of what makes our complicated nervous systems tick.

Cover story

Doser conducted research on autism and how the support cells of the nervous system change in other neurodevelopmental disorders at the University of Arizona before coming to CSU and joining Fred Hoerndli’s lab.

Hoerndli, an assistant professor in the Department of Biomedical Sciences, was also inspired in part by personal experience to pursue the field of neuroscience after witnessing a family member suffer from Parkinson’s disease. “I wondered, why do you start losing yourself as your synapses go away?” Hoerndli said. “Those answers take a long time.” His lab focuses on understanding how cells maintain their excitability, and how that’s lost in neurodegenerative diseases and aging.

Doser’s paper was written with Hoerndli and Greg Amberg, a professor in the Department of Biomedical Sciences. The study looked at the transport of glutamate receptors, which are essential for normal cognition, learning, and memory, and found it was regulated by chemically reactive molecules produced during energy production.

This process impacts the excitability of neurons and other processes underlying learning and memory and provides the first evidence of a mechanistic link between metabolism, glutamate receptor transport, and neurons’ excitability. It’s also an important finding to help better understand the development of several neurodegenerative disorders, including Alzheimer’s disease and Parkinson’s disease, as they involve the disruption of these processes.

“Our brains need a lot of energy to work,” Hoerndli said. “And linking why we need that energy with how we think is fascinating. Is there a link between the amount of energy we need and how many memories we have or how we form memories?” Hoerndli hopes that as his lab helps unravel such big questions, more light will be shed on what happens when neurons no longer work well.

Doser’s next steps are to zoom in further, to the teeny-tiny single synapse level, to try and understand the big black box of what’s occurring here. “We know a lot about how the transport is initiated and how regulation occurs at the destination, but everything in the middle is completely unknown right now,” she said. “It’s something no one has done before.”

Puzzle pieces

Eadaim’s research featured in Cell Reports began in 2015 when he joined Susan Tsunoda’s lab. “We are very excited about it as a line of discoveries in the lab led to this,” said Tsunoda, a professor in the Department of Biomedical Sciences. By using the model Drosophila, a type of fruit fly, her lab studies protective mechanisms that maintain and regulate the signaling of neurons amidst changes that occur during disease, development, and learning and memory.

In 2011, Tsunoda’s lab was featured in Nature Neuroscience as first to discover that a particular set of neurons, cholinergic neurons, were able to adapt to changes in activity via a process called synaptic homeostasis. This process helps keeps the activity of neurons from becoming too low, such as during a stroke, or too high, such as during a seizure. Given that cholinergic neurons are known to degenerate during Alzheimer’s disease, and that synaptic homeostasis plays a key role in the development of the disease, this was an important finding.

In 2018, in another Cell Reports paper, Tsunoda’s lab found in a Drosophila Alzheimer’s model that early hyperactivity in these cholinergic neurons later caused synaptic silencing, a phenomenon seen but not understood in Alzheimer’s disease. This showed that while synaptic homeostasis likely evolved to be protective, it could also get out of whack and cause damage and disease.

“This process plays a role whenever there’s a change in brain activity, such as during development, learning and memory formation, or in pathological conditions that can lead to disease,” Tsunoda said. “We wanted to better understand how the brain tries to protect itself and keep things in an optimal range.”

Eadaim’s paper, written with Tsunoda and lab members Eu-Teum Hahm, a senior scientist, and Elizabeth Justice, a research associate, shows a novel approach to studying this process in real time and identified key receptors and mechanisms involved.

“Synaptic homeostasis is similar to how the thermostat in your house adjusts to keep the temperature just right,” Eadaim said. “And it’s amazing that we can watch this process as it’s occurring in flies and relate that to our own nervous systems.”

Eadaim graduates this fall and hopes to have the chance to continue working in this line of research in the future. “Each discovery opens more doors,” he said. “Before we can get to the point of having good treatments for neurological disorders and diseases, we have to understand how it all works—and we found an important piece of the puzzle.”