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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, and related cognitive processes, 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. 

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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.

We recently identified a novel orphan receptor as potent modifier of short term memory. This has led to new molecular and neural circuit models of short-term memory that we are actively testing.

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 on the time scale of days-to-weeks. 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 and retrieval. 

We recently traced and identified brain-wide inputs to the hippocampus of the mouse brain. One prominent input originated from the prefrontal cortex. To characterize these projections, we developed optical methods to study plasticity at these prefrontal to hippocampus synapses in the behaving animal. Using this approach, we demonstrated preferential targeting of this frontal projection to a sparse, highly connected, hub-like network in the hippocampus that guides memory retrieval. Overall, these findings identified a new memory retrieval circuit in the mammalian brain and suggested a novel brain topology for patterning and retrieving salient memory representations.

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We aim to connect behavior to underlying circuit computation, anatomy, cell types and molecules. We use virtual-reality based behaviors to tightly control and readout animal experiences, while observing brain activity at high resolution, with overlay of anatomy and gene-expression. 

We recently identified a prefrontal cortex - to - hippocampus memory retrieval circuit in the mammalian brain. We are now building on these findings to identify unique prefrontal computations that support memory and cognition.

Several technical limitations have hindered the ability to perform chronic neural recordings and manipulations of prefrontal circuits at cellular resolution in behaving animals. To overcome these limitations, we have focused on developing surgical preparations and virtual-reality based behavioral paradigms, which together enable chronic optical access to prefrontal neurons during goal-directed behavior. We have also invested significant effort in developing methods to record not only the functional activity but also, concurrently, the anatomy and cell type of the recorded neurons. Finally, we are implementing emerging methods for activation and inhibition of projection-defined neurons during imaging and behavior to identify causal roles of network activity on behavioral performance. 

While these studies are currently focused on understanding prefrontal cortex contribution to memory, we are concurrently studying and evaluating the involvement of other circuits, with the ultimate goal of contributing to more complete models of longer-term memory.

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 funding sources including NIH, Robertson Therapeutic Development Fund, Klingenstein-Simons, Mathers, Pershing Square, Searle, and Vallee Foundations, without whom this work would not be possible.

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