Years of study and theory about the unique role of the hippocampus in storing new memories has led to a general idea that the hippocampus generates a unique output code for every unique experience, that is projected back to the neocortex, where it becomes coupled to attributes of the experience that are widely dispersed over the cortex, thus enabling their coherent retrieval. Hippocampal cellular firing, which is rooted in a self-motion based spatial framework, so-called, 'place cells', is modulated by the attributes of each experience (what actually happens at a given location, including sensory input, motor output, and internal brain states such as plans, and 'working' memory). How these memory 'indexes' impact the representation and storage of memory in cortex, at the neural population level, is not understood. We showed that hippocampal output enables the formation of unique, memory-related codes in superficial neocortex (the main target of hippocampal output). Similar to hippocampal 'place' cells, these codes take the form of position correlated cells (PCCs) that participate in sparse, orthogonal representations, corresponding to position and experience in a virtual reality environment (VRE). We have also shown that, like the behavioral manifestations of episodic memory and its derivative, generalized knowledge, these codes survive subsequent damage to hippocampus, and exhibit pattern completion and error correction in the face of cue deletions and rearrangements. These, and related, findings open up a new domain of cortical memory research, and many important questions arise concerning the origins of PCC spatial tuning, the exact role of top-down (hippocampal) and bottom-up (sensory) convergence of inputs to superficial cortex, including off-line replay, and the plasticity rules governing the creation and stabilization of cortical PCCs and their ability to exhibit pattern completion - a sine qua non of associative memory. We propose to explore these questions in mice in a VR paradigm. We will apply a combination of mesoscopic 2- photon and wide-field Ca2+ imaging, optogenetic and chemogenetic manipulation of hippocampal and cortical activity, multi-neuron electrophysiological recording of hippocampal and cortical neural ensembles and LFP dynamics, and cortical microstimulation of unique subsets of superficial neurons. The latter may enable artificial creation of new PCCs and their insertion into ongoing memory representations. Specific experiments include: 1) Testing, using optogenetic inactivation of hippocampus during replay events (Sharp-Wave-Ripples), whether off-line replay of hippocampal patterns contributes to the emergence of cortical PCCs. 2) Defining the role of bottom-up sensory inputs in the formation and subsequent expression cortical PCCs. 3) Exploration of the synaptic plasticity rules governing emergence of cortical PCCs. These experiments will provide a better understanding how hippocampal outflow to neocortex guides the...