HORMONAS DEL CICLO MENSTRUAL Y EMBARAZO ACTÚAN SOBRE SENSORES OLFATIVOS

El estado hormonal durante el ciclo estral o el embarazo produce alteraciones en la percepción olfativa femenina que se acompañan de comportamientos maternos específicos, pero no está claro cómo las hormonas sexuales actúan sobre el sistema olfativo para que estos cambios sensoriales.

 Pregnancy and estrogen enhance neural progenitor-cell proliferation in the vomeronasal sensory epithelium

Livio Oboti¹⁴, Ximena Ibarra-Soria², Anabel Pérez-Gómez¹, Andreas Schmid¹, Martina Pyrski¹, Nicole Paschek¹, Sarah Kircher¹, Darren W. Logan²³, Trese Leinders-Zufall¹, Frank Zufall¹ and Pablo Chamero^15*

• *Corresponding author: Pablo Chamero pablo.chamero@uks.eu

Author Affiliations

¹Department of Physiology, and Center for Integrative Physiology and Molecular Medicine, University of Saarland School of Medicine, Homburg, 66421, Germany

²Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, Cambridge, UK

³Monell Chemical Senses Center, 3500 Market Street, Philadelphia 19104, Pennsylvania, USA

⁴Present address: Center for Neuroscience Research, Children’s National Health System, Washington, DC, 20010, USA

⁵Present address: Laboratoire de Physiologie de la Reproduction & des Comportments, UMR 7247 INRA-CNRS-Université François Rabelais, Nouzilly, F-37380, France

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BMC Biology 2015, 13:104  doi:10.1186/s12915-015-0211-8

The electronic version of this article is the complete one and can be found online at:http://www.biomedcentral.com/1741-7007/13/104

Received:	28 July 2015
Accepted:	16 November 2015
Published:	30 November 2015

© 2015 Oboti et al. 

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Abstract

Background

The hormonal state during the estrus cycle or pregnancy produces alterations on female olfactory perception that are accompanied by specific maternal behaviors, but it is unclear how sex hormones act on the olfactory system to enable these sensory changes.

Results

Herein, we show that the production of neuronal progenitors is stimulated in the vomeronasal organ (VNO) epithelium of female mice during a late phase of pregnancy. Using a wide range of molecular markers that cover the whole VNO cell maturation process in combination with Ca ²⁺imaging in early postmitotic neurons, we show that newly generated VNO cells adopt morphological and functional properties of mature sensory neurons. A fraction of these newly generated cells project their axons to the olfactory forebrain, extend dendrites that contact the VNO lumen, and can detect peptides and urinary proteins shown to contain pheromone activity. High-throughput RNA-sequencing reveals concomitant differences in gene expression in the VNO transcriptomes of pregnant females. These include relative increases in expression of 20 vomeronasal receptors, of which 17 belong to the V1R subfamily, and may therefore be considered as candidate receptors for mediating maternal behaviors. We identify the expression of several hormone receptors in the VNO of which estrogen receptor α (Esr1) is directly localized to neural progenitors. Administration of sustained high levels of estrogen, but not progesterone, is sufficient to stimulate vomeronasal progenitor cell proliferation in the VNO epithelium.

Conclusions

Peripheral olfactory neurogenesis driven by estrogen may contribute to modulate sensory perception and adaptive VNO-dependent behaviors during pregnancy and early motherhood.

Keywords: 

Adult neurogenesis; Esr1; Estrogen; Hormone receptors; Pregnancy; Vomeronasal organ; Vomeronasal receptors

Background

The vertebrate olfactory system is characterized by a distinctive plastic capacity of cell renewal and axon rewiring that continues during adulthood. This represents an exception within the central nervous system where neurogenesis is largely restricted to embryonic development and early postnatal stages. Adult neurogenesis occurs almost exclusively in three specific areas, the hippocampal subgranular zone, the subventricular zone (SVZ) and the olfactory epithelia [1]–[5]. Two of these regions, the SVZ and olfactory epithelia, supply new neurons directly to parts of the olfactory system in form of olfactory bulb interneurons and olfactory sensory neurons, respectively[4]–[6]. Within peripheral olfactory epithelia, the vomeronasal organ (VNO) conveys chemosensory information, such as pheromones and predator odors, that drive social and reproductive behaviors [7]–[9]. Vomeronasal sensory neurons (VSNs) are constantly renewed throughout the life of the animal [10] by neurons generated from stem cells located at the lateral and basal margins of the mature sensory epithelium [11]–[14]. Most of these margin newborn cells differentiate into mature VSNs rarely undergoing apoptosis [15], and project their axons to the accessory olfactory bulb (AOB) [16]. Whether these newly generated cells become functional VSNs and thus are capable of transducing chemosensory cues has not been determined.

In the olfactory epithelia, adult neurogenesis is often seen as a static, merely restorative process, not regarded as a real mechanism for plasticity. However, every aspect of adult-born cell production is carefully regulated and modulated, strongly suggesting that the olfactory system can tailor its production of new neurons to match the demands of its environment. Newborn neurons in the VNO derive from neural progenitors expressing Mash1 and Ngn1 genes [17], [18]. During their proliferation phase, the majority of these progenitors express Ki-67 (antigen identified by monoclonal antibody Ki-67) and proliferating cell nuclear antigen (PCNA) proteins associated with the cell cycle [19]. Postmitotic, immature VSNs express markers associated with cytoskeletal remodeling such as doublecortin (Dcx), β-tubulin III, and GAP43, NCAM/OCAM adhesion molecules, and other lineage-related genes differentially expressed during the maturation process, includingBcl11b/Ctip2, Gnao1, and Gnai2[13], [17], [20]. Dcx is widely expressed in non-mitotic immature VSNs and their axons during the whole VSN maturation period [21]. Immature neurons migrate towards more superficial and central layers of the VNO epithelium and mature into bipolar neurons characterized by the expression of olfactory marker protein (OMP) and vomeronasal receptors (VR) of the V1R and V2R families [17], [22], [23]. Proliferation of VSN precursors can be activated by a number of intrinsic signals, such as growth factors [21], [24], but also by external stimuli including exposure to urinary compounds [20]. However, it is not known whether adult neurogenesis in the VNO operates in response to specific physiological conditions to modulate VNO-dependent sensory function and behavior.

Adult neurogenesis in the brain has been shown to be regulated by a number of physiological, pathological, and environmental factors, including stress, synaptic activity, hormonal status, injury, and odor exposure [25]. Hormonal changes that occur during pregnancy modulate forebrain and olfactory neurogenesis. Prolactin, luteinizing hormone, and estradiol have been shown to promote neurogenesis and cell survival in the brain [26]–[33]. This is important for the display of maternal behavior [28], [29], [34], because olfactory discrimination and memory, both facilitated by adult-born neurons in the brain [35], are critical for offspring recognition and care [36]. With few exceptions [37], hormonal and pregnancy effects on VNO neurogenesis have not been investigated, yet several lines of evidence associate sex hormones with modulatory effects on sensory function. Hormones and hormone derivatives activate subsets of VSNs [38]–[40] and regulate VSN sensory perception in female mice [41]. Modulatory effects of sensory perception by motherhood and lactation have been recently reported in other systems. For example, hormonal changes associated with motherhood and pup care seem to enable plastic changes in sensory perception of the auditory system [42], [43].

Therefore, the aim of the present study was to elucidate the mechanisms controlling adult neurogenesis in the mouse VNO. First, we performed a molecular characterization of the maturation phase of newly generated cells in the vomeronasal sensory epithelium. Second, we evaluated the functional sensory properties of these cells. Third, we found that neurogenesis in the VNO is enhanced at the end of pregnancy. Fourth, we determined that neuroblasts in the VNO express estrogen receptor α (Esr1) and that sustained high levels of the hormone estrogen enable a higher proliferation rate. These results show that neurogenesis in the VNO epithelium can be modulated by an ovarian hormone, offering important insight to understand pregnancy-evoked changes in olfactory perception and behavior. Tomado de envio de bcm , ver completo en: http://www.biomedcentral.com/1741-7007/13/104