To begin, please describe the focus of your research.
We are a cross-species lab in The Lieber Institute, working in two modalities – mouse models of circuits and behavior, and postmortem human tissue. A major component of the lab is molecular work in postmortem human tissue, with the goal to understand molecular associations of disease. We work on that in two ways. First, we perform single cell studies in the postmortem human brain and then spatial transcriptomics. This allows us to see gene expression, the molecular profile of gene expression in individual cells, and then understand where those cells are located within a structure. Second, we look at enrichment of genetic risk using GWA (genome-wide association) studies from neuropsychiatric disorders, neurodegenerative disorders, and really, complex brain disorders overall to understand where genetic risk for those disorders lies in the brain – basically asking, in which cell types and where are those cell types.
What led you into this field of research?
I completed a postdoctoral fellowship at the National Institute of Mental Health (NIMH). When I was interviewing for faculty positions, the Lieber Institute was just getting to start. Our institute director, Danny Weinberger, encouraged me to apply because I was interested in extending my research program into more human tissue work. At the NIMH, I had started doing some of these early cell type molecular profiling experiments in human tissue when those techniques were just starting to emerge but weren’t mature yet. At that time, you could see the possibility, but the techniques were not at all close to where they are now. Yet even then I was interested in being able to do this type of work where we could bridge experimental studies in the mouse to better understand the human brain and associated disorders.
Did you always want to be a scientist?
Actually, I was not a science major as an undergrad, and I never took a science class until later. I majored in international affairs with concentrations in Russian studies and business.
As an undergrad, I was very sure that I wanted to work for a big multinational company in the international business space. I took a year off of school and worked for Coca-Cola in Moscow, and thought I would return later. Then, I read a more pop science book about the search for genes underlying bipolar disorder, and I was fascinated with this. So, I went back to school to take the required
undergraduate classes for my new interests and attended grad school after that.
What is an exciting and challenging project you’re working on right now in the lab?
We are interested in an area of the brainstem called the locus coeruleus. That is the brain’s noradrenergic control center – it synthesizes norepinephrine, and those neurons in the locus coeruleus project widely across the brain, and release norepinephrine to target regions. The released norepinephrine controls many behaviors such as arousal, attention, sleep, and many forms of cognition. Importantly, they also are the first neurons in the brain to die in Alzheimer’s disease. The neurons in that area begin degenerating and showing Alzheimer’s-like pathology long before neurons in other regions.
Neurons in the locus coeruleus (LC) influence behavior through connections to other brain regions, including the dorsal anterior cingulate cortex (dACC). While we can study the molecular composition of both regions in the human brain, we cannot directly trace their connectivity. In mice, however, we can label LC neurons that project to the cingulate cortex using fluorescent markers, allowing us to isolate and sequence them to determine their molecular profiles. Although this direct labeling isn’t possible in postmortem human brains, we can sequence both regions separately and use computational methods to integrate human and mouse data. This approach helps infer which human cell populations may be projection neurons, leveraging the strengths of both systems despite limitations in direct validation. Of particular interest to us are neuropsychiatric disorders and neurodegenerative disorders, and there are limitations to studying them in mouse models because there are many human-specific aspects related to these disorders.
Who are your collaborators in this research?
Lieber is a very collaborative environment, and we work closely with many teams across the Institute. At Hopkins, Dr. Stephanie Hicks, an associate professor in the Department of Biostatistics in the Bloomberg School of Public Health, who is a statistician and data scientist, is our closest collaborator. We work very closely with her lab to generate new methods and approaches for analyzing this data.
What do you enjoy doing in your spare time?
I have two young children, and I enjoy doing many things with them. We live on a tributary of the Chesapeake Bay – I am a huge native plant enthusiast, love paddleboarding, and I am very interested in projects and initiatives related to Chesapeake Bay restoration like oyster and wetland restoration. In fact, a portion of our property is a dedicated natural wetland that we helped restore many years ago.
My children are just becoming interested in science and why things are the way they are. You can get caught up in the day-to-day things, the emails, the endless to-do lists, and their questions always bring back the natural wonder that I feel in the research I do and keep me grounded in what I do.
Images: Keri Martinowich, Chesapeake Bay Restoration
Image Credit: Keri Martinowich / Fluorescent micrograph of an anterior brain slice containing the mouse prefrontal cortex (PFC) at 2.5X magnification. Animals were injected with a retrograde viral vector encoding the recombinase Cre associated with the green fluorescent protein (GFP) in the locus coeruleus (LC) and a Cre-dependent viral vector encoding the chemogenetic receptor hMD3q associated with mCherry (red) fluorescent protein within the PFC. GFP+ neurons represent cortical neurons, broadly that project to the LC while GFP+/mCherry+ (yellow) represent PFC neurons projecting to the LC.