Research program overview
Cognitive decline is one of the greatest challenges to global health. According to the World Health Organization, more than 55 million people currently live with dementia—a number projected to nearly triple by 2050. While memory loss and other forms of cognitive impairment are most commonly associated with aging, they can also result from a range of neurological diseases, including Alzheimer’s, stroke, and Parkinson’s disease. Risk factors include genetic predisposition, cardiovascular health, poor sleep, chronic stress, depression, and lifestyle choices such as unhealthy diet and physical inactivity.
Despite decades of research, treatment options remain limited. Many cases go undiagnosed or are detected too late, and most available therapies offer only modest benefits. One of the major obstacles is the extraordinary complexity of the brain. The human brain contains more than 80 billion neurons connected by an estimated 100 to 1,000 trillion synapses, forming vast and dynamic networks. We still lack a clear understanding of how memories are acquired, stabilized, and retrieved in this intricate organ—a gap that continues to hinder efforts to identify what goes wrong in disease. Without this foundational knowledge, the development of targeted therapies remains a formidable challenge. It’s like trying to repair a car engine without understanding how it works.
What we do to help
Our mission is to lay the groundwork for effective future treatments for memory loss by advancing basic science. Our research program is guided by two central concepts. First, that the physical substrates of stable memories—also known as engrams—are formed through enduring changes in the brain’s “hardware”: its neural circuits. This principle of long-term information storage extends beyond neuroscience, echoing patterns found in other natural and artificial systems—from gene sequences encoded in DNA to ancient inscriptions carved in stone.
Second, that the core mechanisms by which biological neural networks compute information are evolutionarily conserved. This continuity allows us to gain insight into the human brain by studying simpler, genetically tractable model organisms such as the mouse.
Our strategy
We primarily focus on the hippocampus—a laminated brain region within the limbic system that plays a central role in learning, memory, emotion, and spatial navigation. The importance of the hippocampus for these cognitive functions has been demonstrated across mammalian species, including humans and mice.
Our laboratory employs a broad range of genetic, biophysical, behavioral, and computational approaches to investigate how hippocampal circuits are organized, how they are dynamically reorganized in response to sensory experience, and how they are impacted by aging and neurodegenerative disease. Much of this work is conducted in close collaboration with Dr. Mark Ellisman and colleagues at the National Center for Microscopy and Imaging Research at UC San Diego, using 3-dimensional electron microscopy (3D-EM)—a powerful imaging method that enables comprehensive reconstruction of brain tissue at nanometer resolution.
By combining 3D-EM with contemporary genetic tools and AI, we reverse-engineer memory engrams across scales—ranging from the subcellular architecture of individual synapses and their surrounding microenvironments to connectivity of diverse excitatory and inhibitory neuron subtypes involved in local hippocampal computations and long-range interactions with other brain regions.
As part of this effort, we are also developing new techniques to label and manipulate behaviorally relevant neural ensembles using small molecules, as well as advanced AI-based platforms for image analysis.
Another line of research in our lab focuses on understanding how circuits and synapses are reorganized during learning at the molecular level. To this end, we combine unbiased transcriptional and proteomic profiling of distinct neuronal classes with selective gene perturbation in mouse models.