Disturbances of memory significantly diminish quality of life and also contribute to a number of disorders such as Alzheimer’s disease, Schizophrenia, drug addictions and post-traumatic stress disorder, among others. In the lab, we bridge systems genetics and systems neuroscience to provide unique cross disciplinary insights into the biology of memory and cognition. Through dedicated projects focused on memory across multiple time scales, we aim to reveal general principles underlying information storage in the brain.
I. Short Term Memory (seconds to minutes)
Working memory refers to the cognitive process of maintaining and updating task-relevant information, from seconds to minutes, toward goal-directed pursuits. It is a form of short-term memory used pervasively in everyday human life, and is affected in learning disability, aging and mental illness. Remarkably, little is known about the basic genetic or neural circuit mechanisms driving individual variability in working memory performance.
In the past, unbiased genetic mapping approaches have been foundational in linking genes and neurophysiology with complex behavior. Inspired by such approaches, we recently studied a cohort of genetically diverse mice and identified, for the first time, a single genetic locus and causative gene driving substantial variability in short-term memory. Characterization of the causative gene, and in-vivo imaging across neuro-anatomically distributed circuits, is providing an entry point to formulate and test new circuit level models of working memory. Through this work we aim to identify fundamental principles of neural dynamics, computation, and plasticity that govern information storage on short-time scales.
We aim to connect genotype to circuit function to behavior. In one line of work, we use forward genetics in outbred mice to identify novel genes, cell types, and circuits, with prominent functions in memory and cognition.
II. Long Term Memory (days to weeks)
Whereas short-term memory involves transient changes in neural dynamics, long-term memory involves persistent modifications of synaptic weights. Such experience-dependent long-term changes in weights, referred to as synaptic plasticity, was initially thought to be a unique property of hippocampal circuits. Consequently, decades of intense study focused on hippocampal circuits, their plasticity mechanisms, and how they shape memory guided behavior. However, it has since become clear that many other circuits also undergo experience-dependent synaptic plasticity on long time scales, but there is relatively little understanding about their contributions to memory storage, recall, reorganization and stabilization.
Thus, in parallel studies on longer timescale memory, the lab is characterizing how memory representations initially form in the hippocampus over hours to days, and eventually stabilize across the brain over weeks. To form insights into this brain reorganization process, we have developed behavioral tasks to study how multimodal cues are integrated during memory formation and recall, and over time, why some memories are stabilized while others are forgotten. As mice perform these memory-guided tasks, the lab develops and applies methods to longitudinally track neural activity in brain areas that link short- and long-term memory. These and other studies in the lab are identifying a hippocampal-thalamic-cortical pathway as an important component of memory stabilization in the brain. Characterization of this pathway and overlay of molecular annotation is providing an entry point to understand brain mechanisms supporting memory persistence.
Our studies thus far have highlighted a new role for the thalamus in memory maintenance across diverse time scales. The lab continues to combine forward genetics and targeted circuit physiology to contribute organizing principles for memory stabilization over time.
We are grateful to be part of the Rockefeller and Tri-I Community and are particularly thankful to our collaborators, scientific resource centers, and to our current funding sources including NIH, Mathers Foundation, Pershing Square, Helman Family, Halis Family, Vallee Foundation, Black Family Therapeutic Development Fund, Chan Zuckerberg Initiative, without whom this work would not be possible.