Retrosplenial and hippocampal brain regions in human navigation: complementary functional contributions to the formation and use of cognitive maps Giuseppe Iaria, 1,2 Jen-Kai Chen, 1 Cecilia Guariglia, 2,3 Alain Ptito 1 and Michael Petrides 1 1 Montreal Neurological Institute, McGill University, 3801 University Street, Montreal, Quebec, Canada, H3A 2B4 2 Dipartimento di Psicologia 39, Universita ` di Roma ‘La Sapienza’, Via Dei Marsi 78, 00185 Roma, Italy 3 Centro Ricerche Neuropsicologia, IRCCS Fondazione Santa Lucia, Via Ardeatina 306, 00179 Roma, Italy Keywords: hippocampus, learning, memory, neuroimaging, topographical orientation, virtual reality Abstract The ability to orientate within familiar environments relies on the formation and use of a mental representation of the environment, namely a cognitive map. Neuropsychological and neuroimaging studies suggest that the retrosplenial and hippocampal brain regions are involved in topographical orientation. We combined functional magnetic resonance imaging with a virtual-reality paradigm to investigate the functional interaction of the hippocampus and retrosplenial cortex during the formation and utilization of cognitive maps by human subjects. We found that the anterior hippocampus is involved during the formation of the cognitive map, while the posterior hippocampus is involved when using it. In conjunction with the hippocampus, the retrosplenial cortex was active during both the formation and the use of the cognitive map. In accordance with earlier studies in non-human animals, these findings suggest that, while navigating within the environment, the retrosplenial cortex complements the hippocampal contribution to topographical orientation by updating the individual’s location as the frame of reference changes. Introduction When moving within familiar surroundings, we are able to reach various locations efficiently by relying on a mental representation of the environment. For example, the mental representation of one’s neighbourhood, which includes the location of one’s home and any other relevant environmental landmark (e.g. the supermarket), allows one to move from one place to another by following correctly a particular route. Such a mental representation, which is built up by exploring the environment and is then used to navigate within the environment, is often referred to as a cognitive map (Tolman, 1948; O’Keefe & Nadel, 1978). The fundamental role of the hippocampus in establishing and maintaining a cognitive map of the environment was first established in rodents (O’Keefe & Dostrovsky, 1971; O’Keefe & Nadel, 1978; Wilson & McNaughton, 1993; White & McDonald, 2002) and was extended to the human brain by several neuropsychological studies (Smith & Milner, 1989; Pigott & Milner, 1993; Maguire et al., 1996; Bohbot et al., 1998, 2004; Ekstrom et al., 2003). More recently, functional neuroimaging, following previous findings in rodents, confirmed the role of the hippocampus (Maguire et al., 1998; Hartley et al., 2003; Iaria et al., 2003) and the parahippocampal cortex (Epstein & Kanwisher, 1998; Epstein et al., 2005) in human topographical orientation. The discovery of head direction cells within the retrosplenial cortex in rodents, i.e. cells that fire when animals are heading towards a certain direction within the environment, suggested that this brain region also plays a critical role in navigation (e.g. Taube, 1998; Cho & Sharp, 2001). Consistent with the rodent research, patients with posterior lesions that include the retrosplenial cortex show a selective topographical disorder referred to as ‘heading disorientation’ (Aguirre & D’Esposito, 1999). These patients are able to remember the landmarks available within the environment, but they are unable to derive directional information from them (Takahashi et al., 1997). In addition, functional neuroimaging studies investigating navigation in human subjects have often reported increased brain activity within the retrosplenial cortex (e.g. Maguire, 2001). Although it appears that both the retrosplenial and the hippocampal brain regions are involved in human topographical orientation (Wolbers & Bu ¨chel, 2005), it is not clear at what point these brain regions interact functionally. Does the interaction take place during the formation of a cognitive map (i.e. while learning about the environment) and ⁄ or while using it to move from one place to another in the same familiar environment? In order to answer these questions, we scanned healthy human subjects with functional magnetic reson- ance imaging (fMRI) in a virtual-reality environment. First, we asked participants to navigate within a virtual city in order to acquire a mental representation of the environment, i.e. the landmarks available within it and their spatial relationships (learning condition). After forming a cognitive map of the environment, the participants were asked to reach various landmarks starting from different locations, i.e. they were required to use their cognitive map of the environment to navigate within the same virtual city (retrieval condition). Correspondence: Dr G. Iaria, 1 Cognitive Neuroscience Unit, Montreal Neurological Institute, as above. E-mail: giuseppe.iaria@mcgill.ca Received 29 July 2006, revised 9 December 2006, accepted 19 December 2006 European Journal of Neuroscience, Vol. 25, pp. 890–899, 2007 doi:10.1111/j.1460-9568.2007.05371.x ª The Authors (2007). Journal Compilation ª Federation of European Neuroscience Societies and Blackwell Publishing Ltd