Although neuroscience has provided a great deal of information about how neurons work, the fundamental question of how neurons function together in a network to produce cognition has been difficult to address. Our group has been at the forefront of developing methods that allow large scale monitoring of identified neurons, monitoring of voltage signals by optical means and elucidation of subcellular events in dendrites, all of which can now be done in awake behaving animals. We propose to use these methods to provide a deep understanding of how the neurons of the hippocampal region generate the sharp-wave ripple (SPW- R). This remarkable signal has been shown to depend on prior learning and to produce high-speed replay of memory sequences (e.g. a path along a track). The function of this signal is memory consolidation; disruption of SPW-Rs results in strong deficits in memory-guided behavior. Because much is known about the hippocampal cell types involved and their network connections, understanding the SPW-R is a tractable target for the first major effort to elucidate the cellular/network mechanism of a mammalian brain signal at an analytical level comparable to that achieved in the study of simple invertebrate systems. Project 1 is aimed at understanding the external and intra-hippocampal pathways that control the initiation of SPW-Rs. Project 2 deals with the events that occur during the SPW-R, including the timing of activity in identified cell types and understanding the fundamental network architecture by which memory sequences are produced. Project 3 deals with how the information that is replayed during the SPW-R is encoded. We will attempt to create an artificial memory and then determine whether the memory is replayed during a SPW-R; we will also interfere with molecular mechanisms of memory storage to determine whether we can erase the memories that are replayed during the SPW-R. Project 4 builds upon recent work indicating that differentially projecting CA1 pyramidal cells have distinct properties and will test the possibility that SPW- Rs in distinct output channels may carry different information and affect different behaviors. In Project 5 we will develop the first non-reduced computational model of the hippocampus, incorporating information about cell types and connections. This will be a major new resource for our group and the research community that will permit unprecedentedly close interplay between experiment and computation. To the extent that the model can account for the experimental observations, we can use it to understand underlying network principles and design interventional experiments to validate this understanding. To the extent that the model cannot explain results, it will help point us to aspects of network function that require further elucidation. Taken together, Projects 1-5 provide a tractable path to a major breakthrough in understanding how a cognitively important brain signal is generated.

We propose to make the first attempt to fully understand a cognitively important event, called memory replay, in terms of the detailed properties of the brain cells involved. We will use cutting-edge large- scale recording technologies to study and manipulate identified cell types in behaving animals, and we will construct the first full-scale computational of model of the brain area that produces the memory replay in which every cell is explicitly simulated. These powerful new approaches are likely to yield major insights into the principles by which the interactions of neurons gives rise to cognitive function, with important implications for memory disorders.