, 1992, Squire and Zola-Morgan, 1991 and Lavenex and Amaral, 2000; Figure 1). On this background, it may come as a surprise that these systems contain a set of representations that perfectly match an attribute

of the external world: the animal’s location in space. In the hippocampus, place cells fire specifically at one or a few locations in the animal’s environment (O’Keefe and Dostrovsky, 1971). In the medial part of the entorhinal cortex, grid cells fire at multiple locations that, for each cell, define a hexagonal array across the entire available space (Hafting et al., 2005 and Moser et al., 2008; Figure 2). Grid cells intermingle with head direction cells, which fire specifically Osimertinib price when the animal faces certain directions, and border cells, which fire specifically when animals move along borders of the local environment (Sargolini et al., 2006, Savelli et al., 2008 and Solstad et al., 2008). Collectively, these cell types form the elements of what we will refer to as the entorhinal-hippocampal space circuit. In this review, we shall take a historical perspective and describe the unfolding of a system of elementary

correlates for representation of space in the hippocampus and the entorhinal cortex. We shall discuss mechanisms that might generate this representation, many synapses away from the specific receptive fields of the sensory cortices, and we shall elaborate on how the evolution of a functional architecture within this system might benefit not only mapping of space, but also the formation of high-capacity memory. The study of spatial representation PKC activation and spatial navigation started long before neuroscientists approached the cortex. The notion of an internal spatial map can be traced back to Edward C. Tolman, who in his cognitive theory of learning suggested that behavior was guided by a map-like representation Calpain of stimulus relationships in the environment, rather than by chains of

stimulus-response sequences of the type envisaged by Thorndike and Hull (Tolman, 1948). The internal map was thought to enable animals to navigate flexibly in the environment, taking shortcuts and making detours when previously traveled routes were less effective. Tolman’s ideas remained controversial for decades, partly because scientists did not have tools to determine if the cognitive entities proposed by Tolman actually existed. Tolman’s ideas were revitalized many years after his death, after the development of microelectrodes for extracellular recording from single neurons in behaving animals. This development led Ranck (1973) and O’Keefe and Dostrovsky (1971) to monitor activity from single neurons in the hippocampus of freely moving rats. Both laboratories found reliable links between neural firing and the animal’s behavior, but it was O’Keefe and Dostrovsky who found that the firing depended on the animal’s location in the environment.