April 2020: Boldrini Lab

Background:

What is the main focus of your lab?

Our lab studies neuroplasticity, most notably adult hippocampal neurogenesis (the creation of new neurons from neural stem cells). Other forms of plasticity we study include pre and post synaptic changes and their molecular regulators. We also study angiogenesis in the context of the stem cell niche, as capillaries have a fundamental role in sustaining the stem cells and their differentiation and maturation. We study these mechanisms in the context of aging and neuropsychiatric diseases like major depression, Alzheimer’s Disease, epilepsy, and the role of medications in these processes.

How long have you had your lab? When did you join Columbia University?

I started my lab in 2008. I joined Columbia University in 2006 as a Janssen Translational Neuroscience Fellow.

How big is your lab currently?

We currently have a small lab consisting of a few Research assistants and Undergraduate students. During the summer months we also mentor high school students interested in science and provide them their first introduction to the wet lab! In the past we had postdocs and PhD students and we are looking forward to having them in the lab again.

Where is your lab located?

Our lab is located on the 3rd floor of the Pardes building of the New York State Psychiatric Institute (NYSPI); Room 3909, 3910, 3913.

Current affairs:

What are the most exciting projects/directions in the lab at this moment?

We are characterizing and quantifying expression of proteins and mRNAs that are found in immature neurons in the human hippocampus. Using these techniques we are studying adult neurogenesis in major depression and investigating its relationship with the clinical functioning of each individual. This has never been studied before in the human brain. We are seeing a relationship between clinical functioning, antidepressasnt treatment and newborn neurons. Using proteomics and RNA sequencing we are building on these results and investigating expression of genes that control adult neurogenesis in the human brain.

We also are starting to perform these studies in hippocampal blocks from Alzheimer’s Disease patients and we are studying dendrites, spines and synaptic markers, to understand how brain circuits’ wiring is disrupted around the new neurons in normal conditions and disease states. We’re hoping that this could provide a deeper insight into the neuropathology of different neuropsychiatric diseases and normal aging.

What are the biggest accomplishments that your lab recently had?

Our study showing persistent neurogenesis into the eighth decade of life and declining angiogenesis, and neuroplasticity in the aging human postmortem dentate gyrus, was unprecedented in its approach, techniques and results (Boldrini et al., 2018). This study has been at the center of a significant controversy because other labs have been unable to detect neurogenesis in the adult postmortem human brain. Our paper was featured in the report “Best of Cell Stem Cell 2018” and in the NIH Director’s blog, and was covered by more than 800 media outlets, including the Los Angeles Times,  TIME,  Reuters, CBS News,  U.S. News & World Report,  Forbes,  Science Friday,  and  The Economist. 

We recently showed that, in the hippocampus dentate gyrus, the number of granule neurons is reduced in suicide decedents with major depressive disorder, while resilient individuals exposed to early life adversity who had no psychiatric illness lifetime, have larger dentate gyrus and more granule neurons than depressed subjects who died by suicide and controls with no adversity history (Boldrini et al., 2019).

Technology:

What are the model systems that your lab is using? 

We use postmortem human brain tissue for our experiments from donors. Our samples include non-psychiatric controls, untreated depressed subjects, depressed subjects taking antidepressants, epilepsy cases and most recently Alzheimer’s dementia brains.

What are the key techniques that your lab is using? 

Our lab employs double immunofluorescence, duplex and multiplex RNAscope in situ hybridization and western blots to identify our proteins and mRNAs of interest. We are also working on proteomics, single cell RNAseq and qPCR, in collaboration with other labs. We are open to training scientists from other labs on how to optimize experiments using postmortem tissue. 

What facilities or equipment does your absolutely lab rely upon? 

We rely heavily on advanced imaging softwares, including high resolution confocal scanning systems, and stereology. We use CSCI cores for iPSC differentiation and cell sorting.

Who shall be contacted with questions about equipment, resources and training?

For questions about equipment, resources and training, please contact Maura Boldrini, MD, PhD at mb928@cumc.columbia.edu.

Training:

What's your best approach to mentoring trainees in the lab?

I like to teach them everyting I know and also let them be autonomous and free to develop their own ideas. I am not a micromanager and I like people who have their own initiative and share their ideas that I can help them develop.

Who were your most influential mentors/role models in science and what did you learn from them?

I had a few mentors that were very significant to my training. One of them has been Rene’ Hen, PhD, a cheerful scientist with lots of ideas, who is always open to a meaningful constructive discussion and encourages collaboration. On the other hand, a person I admire is Maria Oquendo, MD. She is a role model as she is a strong woman, who was able to balance her personal life with research and clinical work, and a successful career.

What would be your career advice for students/postdocs?

Find what you love and follow your heart and instinct. The road does not have to be a straight path, many times it will be more like a maze or a jungle gym.

Are you accepting rotating students at the moment?

Yes we are accepting rotating students.

Lab management:

How do members of your lab celebrate accomplishments?

We usually celebrate accomplishments by having a team lunch! It’s a nice way for us to reflect on our accomplishments and the hard work we put in to reaching our goal.

What is the key to running a successful lab

Fostering young people, letting them develop and carry on their ideas, supporting them with their growth and accomplishments, guiding them, teaching rigorous methods and scientific inquiry.

What was the most exciting part about starting your new lab?

Well, everything was exciting, getting a new space, having my own people and seeing my ideas grow and get somewhere, having many new ideas, one after the other, and ultimately not enough time to explore them all. I just wish we had more people in the lab!

Stem Cell Directions:

What are the most important recent developments in the stem cell field?

In our area of postmortem human stem cell research, the most important recent developments have been rigorously characterizing the stem cell niche and having important discussions regarding how to best determine if there is hippocampal neurogenesis in adulthood. In 2018, after our paper and the paper from Arturo Alvarez-Buylla’s lab from UCSF was published, there was a lot of controversy surrounding if adult neurogenesis occurred in humans. Since then, few other labs have now replicated our original findings (Moreno-Jimenez et al., 2019; Tobin et al., 2019). We further confirmed the presence of doublecortin expression in the human adult hippocampus using RNAscope technology to detect doublecortin mRNA in dentate gyrus cells (Tartt et al., 2018). Following this debate, I had the honor of being an Invited lecturer at the NIA Workshop “Neurogenesis and Aging” held on March 16-17, 2020, in Bethesda, MD.

This controversy, however, did highlight some important claims about apt stem cell markers in the human brain and how to adequately preserve and process human brain tissue. I think that this has made the postmortem neurogenesis community more rigorous in how we characterize this phenomenon and allows us to continue exploring this idea in other contexts such as psychiatric and neurodegenerative illnesses.

CSCI:

What was the main reason of you joining CSCI? What are the beneficial aspects of CSCI membership for your lab?

I joined CSCI because stem cells are regulated by fundamentally the same mechanisms in different tissues of the body, and interacting with scientists from different fields who are interested in understanding these mechanisms can significantly enhance our ability to dissect how stem cells are maintained and work. Exchanging findings and ideas can generate new research directions that benefit from collaborations across several disciplines.

What do you plan to bring to the CSCI community?

We bring to CSCI our expertise in human brain studies, neuropsychiatric diseases, using postmortem human brain and a translational approach that can involve studies on live patints.  To this end, I have been working with Drs. Barbara Corneo, Director of the Columbia Stem Cell Core Facility, on preliminary data and grant applications to generate and characterize induced pluripotent stem cells (iPSC) obtained from patients’ blood cells, and differentiate them into dentate gyrus neurons, following the protocols developed by Dr. Fred Gage, and under his generous guidance.