Structure and function of the vomeronasal system: an update
Introduction
It has been more than 15 years since the last comprehensive reviews of the structure and function of the vomeronasal system (VNS) Halpern, 1987, Wysocki and Meredith, 1987. At that time, the main interest was testing the dual olfactory hypothesis, i.e. elucidating anatomical, behavioral and physiological differences between the olfactory and the VNS, which still are not completely understood. Since then, and focusing on the VNS, a number of dramatic observations have been reported that have had a major influence on our understanding of this relatively poorly understood sensory system. Among these findings was the observation that, in mammals, the VNS is dichotomous. This duality can be appreciated by the heterogeneous chemoarchitecture of apical and basal cells in the VN epithelium and it is correlated to the projections of these cells to anterior and posterior portions of the accessory olfactory bulb (AOB) (Fig. 1, Fig. 2). These two populations of VN cells express different putative pheromone receptors, which apparently are activated by different ligands and trigger distinct behaviors. The most outstanding question in the field has been, therefore, to try to characterize these two subsystems within the VNS. Apart from anatomical and behavioral approaches, cloning of families of putative VN receptors has allowed the use of a number of molecular techniques which have greatly expanded our insight on the dual perspective of pheromone detection and behavioral responses.
Major advances have been also made in understanding the signal transduction mechanisms in the VN epithelium, indicating that, in contrast to the olfactory system, the principal second messenger system in the vomeronasal organ (VNO) is probably a phospholipase C (PLC)-dependent pathway. New studies, investigating the turnover of VN bipolar neurons, have resulted in a re-evaluation of the accepted dogma that in mammals neurons are generated at the margins of the epithelium and these neurons migrate toward the center of the epithelium as they mature. Finally, recent anatomical studies have caused us to rethink the parcellation of the amygdala and its functional implications.
These new findings have resulted, in recent years, in a remarkable increase in published reports on this system. These studies have advanced our understanding of the functional significance of the VNS as well as raised interesting questions about the functional integrity of the human VNS. The present review takes a broad approach to recent developments concerning the VNS. We have endeavored to include published studies using a variety of approaches: anatomy, electrophysiology, biochemistry, molecular biology and behavior in all vertebrates studied, not just mammals.
Section snippets
General reviews
Broad ranging reviews of the VNS by Døving and Trotier (1998) and Trotier et al. (1996) cover the history of the discovery by Jacobson of the VNO, the structure of the VNO, the distribution of the VNO in vertebrates, functions of the VNO, stimulus access, stimulus composition, cell turnover, subclasses and physiological properties of VN receptor neurons.
Eisthen, 1992, Eisthen, 1997 reviews the literature on the peripheral anatomy of the VN and main olfactory systems from a phylogenetic
Heterogeneity in the VNS
The VNS in mammals is heterogeneous with respect to a number of molecular, anatomical and physiological parameters, e.g. types of receptors, chemoarchitecture (G-protein-expression, NADPH–diaphorase staining, presence of glycoconjugates, expression of olfactory marker protein, lectin staining and other markers), connections and response to stimulating substances (Fig. 1, Fig. 2, Fig. 7). This section tries to emphasize that morphological duality observed in the VNS should have a functional
Discovery of multiple families of putative VN receptors
As a result of the recent identification of two families of putative VN receptors, new physiological issues have emerged and new molecular approaches have been applied to study this system. The cloning of the genes encoding VN receptor proteins, the implication of these findings for the field of chemosensory research and the questions raised by these discoveries have been reviewed extensively Bargmann, 1997, Bargmann, 1999, Buck, 1995, Buck, 2000, Dulac, 1997, Dulac, 2000a, Dulac, 2000b, Dulac
New information on signal transduction in the VNS
The major issues addressed in the many recent studies on signal transduction in the VNO are the role of different receptor protein families, the differential activation of Gi, Go and Gq proteins, the involvement of the PLC and cyclic AMP (cAMP) second messenger cascades and the importance of the transient receptor potential (TRP) ion channel in the initial activation of calcium signaling. These issues have been reviewed recently by Liman, 1996, Liman, 2001, Tirindelli et al., 1998, Zufall and
Developmental issues in the VNS
The heterogeneity in the VNS and issues related to how vomeronasal information is accurately transmitted from the VN epithelium to the AOB raises several questions related to development. How do VN axons locate the appropriate glomeruli in the AOB during ontogeny? Since there is continuous turnover in the VN epithelium, how do newly generated neurons connect with appropriate targets in the AOB. The VN system is known to regenerate following nerve section. How do the axons in the regenerated
New information on the anatomy of the VNS
The functional domains of the VNS include neuroendocrine and behavioral responses to chemosignals, particularly those arising from conspecifics. To understand how different chemical signals are able to generate appropriate responses attention must be directed to the anatomical substrates for VN functions. Integrating information about the heterogeneity of receptors, signal transduction mechanisms, and patterns of stimulus activation in the VNS with the central connections of the system will aid
New functional data on the role of the VNS in species-typical behaviors
Prior to 1987, it was widely accepted that the VNS was importantly involved in chemosensory-mediated pheromonal effects on endocrine regulation and sexual behavior. In addition, it had been demonstrated in snakes that the VNS was critical for response to prey-derived chemicals and conspecific odors used in aggregation and courtship Halpern, 1987, Wysocki and Meredith, 1987. In the ensuing years, few additional functions for the VNS have been described, although there has been important
Reviews
The history of the discovery of the human VNO has recently been revisited Bhatnagar and Reid, 1996, Bhatnagar and Smith, 2003 and the status of the human VNS has been extensively reviewed Greene and Kipen, 2002, Martı́nez-Marcos, 2001, McClintock, 1998, Meredith, 2001, Monti-Bloch et al., 1998a, Preti and Wysocki, 1999, Trotier et al., 2000, Wysocki and Preti, 2000. Interestingly, these reviewers come to very different conclusions on the functionality of the human VNS. Although over the years,
Electrophysiology
The literature prior to 1987 on electrophysiological characterization of the VNS was reviewed previously Halpern, 1987, Mori, 1987b. Since 1987 there have been relatively few studies using electrophysiological techniques to examine the response of neurons to external stimuli or to investigate the interactions of neurons in the VNS. Some of these studies have been discussed elsewhere in this review (see 3 Heterogeneity in the VNS, 5 New information on signal transduction in the VNS, 8 New
Conclusion
During the past 15 years, there have been significant advances in our understanding of the VNS. We now accept that the system is heterogeneous based on a variety of criteria, although we still do not know how its different parts contribute to vomeronasally-mediated behaviors. Multiple families of VN receptors have been identified, and molecular approaches using this information are providing insights into receptor–ligand interactions and connectivity between the VNO and the central nervous
Acknowledgements
During the preparation of this manuscript the authors received support from the following grants: NIH Grant nos. DC02531, DC03735 and DC02745 (M.H.) and Spanish MEC postdoctoral fellowship EX99573688 (A.M.M.). We are grateful to Isabel Ubeda-Bañón, Takisha Galaor and Wei Su for their help with the references and Frank Fasano for help with the illustrations. The following colleagues read portions of earlier drafts of this manuscript for which we are very grateful: Heather Eisthen, Albert
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