Cortico-Hippocampal Communication by Way of Parallel Parahippocampal-Subicular Pathways Menno P. Witter, 1,2 * Pieterke A. Naber, 1–3 Theo van Haeften, 1,2 Willem C.M. Machielsen, 1,2 Serge A.R.B. Rombouts, 1,4 Frederik Barkhof, 1,5 Philip Scheltens, 1,6 and Fernando H. Lopes da Silva 1,3 1 Graduate School Neurosciences Amsterdam, Amsterdam, The Netherlands 2 Department of Anatomy, Research Institute Neurosciences, Faculty of Medicine, Vrije Universiteit, Amsterdam, The Netherlands 3 Institute for Neurobiology, University of Amsterdam, 1098 SM Amsterdam, The Netherlands 4 Department of Clinical Physics, Research Institute Neurosciences, Faculty of Medicine, Vrije Universiteit, Amsterdam, The Netherlands 5 Department of Radiology, Research Institute Neurosciences, Faculty of Medicine, Vrije Universiteit, Amsterdam, The Netherlands 6 Department of Neurology, Research Institute Neurosciences, Faculty of Medicine, Vrije Universiteit, Amsterdam, The Netherlands ABSTRACT: The hippocampal memory system, consisting of the hippocampal formation and the adjacent parahippocampal region, is known to play an important role in learning and memory pro- cesses. In recent years, evidence from a variety of experimental approaches indicates that each of the constituting fields of the hippocampal memory system may serve functionally different, yet complementary roles. Understanding the anatomical organization of cortico-parahippocampal-hippocampal connectivity may lead to a further understanding of these potential functional differences. In the present paper we present the two main conclusions of experi- ments in which we studied the anatomical organization of the hippocampal memory system of the rat in detail, with a focus on the pivotal position of the entorhinal cortex. We first conclude that the simple traditional view of the entorhinal cortex as simply the input and output structure of the hippocampal formation needs to be modified. Second, our data indicate the existence of two parallel pathways through the hippocampal memory system, arising from the perirhinal and postrhinal cortex. These two parallel pathways may be involved in separately processing functionally different types of sensory information. This second proposition will be sub- sequently evaluated on the basis of series of electrophysiological studies we carried out in rats and some preliminary functional brain imaging studies in humans. Hippocampus 2000;10:398 – 410. © 2000 Wiley-Liss, Inc. KEY WORDS: parahippocampal region; entorhinal cortex; perirhinal cortex; postrhinal cortex; hippocampus; learning and memory; subiculum INTRODUCTION It is widely accepted that the hippocampal formation and the intimately interconnected surrounding cortices of the parahip- pocampal region contribute critically to learning and memory. A prominent current hypothesis is that the hippocampal formation and parahippocampal region together form the “medial temporal lobe or hippocampal memory system” that is primarily involved in declarative or explicit memory. The anatomical framework for this conception is that the parahippocampal region mediates the recip- rocal transfer of information between a variety of multimodal as- sociation cortices and the hippocampal formation. The suspected role played by the cortico-parahippocampal-hippocampal circuitry in normal memory functions has led to a wealth of neuroanatomi- Grant sponsor: Netherlands Organization for Scientific Research; Grant numbers: 903-47-008, 903-47-051, 903-47-069, 970-10- 039; Grant sponsor: Human Frontier Science Foundation Organi- sation. *Correspondence to: M.P. Witter, Ph.D., Department of Anatomy, Faculty of Medicine, Vrije Universiteit, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands. E-mail: mp.witter.anat@med.vu.nl Accepted for publication 1 May 2000 HIPPOCAMPUS 10:398 – 410 (2000) © 2000 WILEY-LISS, INC.