MAPPING FEAR MEMORY · Identification and selective targeting of neuronal networks underlying memory

Among the most fundamental questions in modern biology is how we learn and remember. Using novel genetic tools, we can now ask fundamental questions not previously possible about how the brain encodes memories. For instance, how many neurons are required for learning? Are the network requirements similar in different brain regions? And, probably most intriguingly, how is a neuron that is part of a memory trace different from its neighboring neurons? In other words, what is the cellular and molecular basis of a memory?Using Pavlovian fear conditioning, decades of elegant experiments have mapped the anatomical location of the engram for learned fear. However, at the cellular and molecular level, little is known about the physiology of individual neurons that encode a memory. Our recent results suggest a path forward, using novel genetic tools in mice that permit targeted manipulations of genes with both spatial and temporal-specificity. In particular, using genetic manipulations of proteins absolutely required for associative learning, we now have the potential to restrict the network space in which neuronal plasticity can occur, permitting the characterization of individual neurons responsible for encoding a specific memory.Our experiments will focus on understanding the fundamental rules by which memories are organized within the brain. Specifically, we will use the immediate-early gene Arc to map neurons active during fear conditioning at single-cell resolution. Next, we plan to define the minimum neural network requirements for establishing a fear memory. Finally, we will investigate the learning-related changes in molecular, structural, and systems-level plasticity of individual neurons of the memory trace.Importantly, the results of these studies will not only expand our mechanistic understanding of the neurobiology of memory, but could also provide opportunities for clinical translation into cognitive neuropsychiatric disorders.