Fred “Rusty” Gage from the Salk Institute and a pioneer in adult neurogenesis research, gave this year’s Konrad Akert Lecture in Zurich. In our interview, he speaks about the brain’s remarkable ability to generate new neurons, his lab’s latest organoid models to study neural disease, and why understanding the aging brain better may hold the key to treating neurodegenerative diseases.
Hi Rusty, welcome to Zurich! You and your team discovered that the human brain can generate new neurons throughout life. Can I – and everyone else – actually do something to enhance the brain’s capacity to produce additional neurons?
Thank you very much, it’s great to be here.
There has been significant research on a variety of activities that enhance what we call “adult hippocampal neurogenesis”, or the birth of new neurons in the adult hippocampus. However, much less work has been done in humans, mainly because it’s currently very difficult to measure neurogenesis in the living human brain. What’s really needed are reliable markers that allow us to measure adult neurogenesis in functioning, living individuals.
Substantial studies have been conducted on postmortem brains from people with various neurological diseases. The consensus is that diseases like Alzheimer’s result in a sharp reduction in adult neurogenesis.
That said, animal studies have shown that a variety of environmental and behavioral experiences can strongly influence adult neurogenesis – particularly regular exercise, environmental enrichment, good nutrition, quality sleep, as well as reduced stress and anxiety. Interestingly, these are many of the same behaviors that support a healthy lifespan, which I believe is no coincidence.
And do these new neurons functionally integrate into existing neural circuits?
Experimental evidence clearly shows that these newly born cells mature into fully developed neurons with extended axons that form appropriate synaptic connections with their target neurons. They are electrophysiologically active and, once fully matured, respond to stimuli in much the same way as their neighboring mature neurons.
Reflecting on the discovery that neurogenesis occurs in the adult human brain, how has our understanding of brain plasticity evolved since then? And what implications does this have for treating neurological conditions?
We have since learned more about the structure that these new neurons mature into: the dentate gyrus, a region of the hippocampus. We now have a deeper understanding of the role this structure plays in the acquisition, storage, and retrieval of new information. The cells in this region are especially important for distinguishing between events, places, and emotions that are quite similar to one another. This process is known as pattern separation. Without adult neurogenesis, it becomes much more difficult to make these subtle distinctions.
More recently, your lab developed advanced brain organoids that include functional astrocytes, enhancing the study of neuroinflammation. Could you elaborate on how this model improves our understanding of diseases like Alzheimer’s – and what new insights it has provided?
Actually, we have developed technology to integrate human microglia and astrocytes into human neural organoids. This allows us to create diseased neural organoids with healthy glial cells, or healthy organoids with diseased glial cells. Our goal is to include all the naturally occurring human cell types in these organoids, such as oligodendrocytes, pericytes, and endothelial cells. By building more complete and realistic models of the human brain, we aim to better understand which cell types are most critical in driving brain diseases.
Looking ahead, what emerging areas of neuroscience research excite you the most, and where do you see the greatest potential for breakthroughs in understanding or treating brain disorders?
I’m particularly interested in the aging brain, as aging is a major risk factor for many neurological diseases. Remarkably, there is still no agreed-upon mechanism that explains what drives brain aging. We hypothesize that it involves an interaction between DNA damage, metabolic or energy dysfunction, and inflammation. I’m looking forward to working with my colleagues here in Zurich to explore how these mechanisms interact in the aging process.
All the best for this research endeavor, thank you for the interview, and enjoy your time in Switzerland!
Useful links:
Images:
Fred “Rusty” Gage, Salk Institute for Biological Studies