Analysis of adult neurogenesis in a mice model of impaired GnRH function

After fifty years from the initial description of adult neurogenesis in the mammalian brain (human included), many functional and regulatory aspects still need to be understood. Adult neurogenesis (AN) is restricted to two main areas: the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG) and the subventricular zone (SVZ) of the forebrain, from where neuroblasts migrate along the so-called 'rostral migratory stream' (RMS) to reach the olfactory bulb (OB). It is well known that adult neurogenesis in both DG and OB is regulated by gonadal hormones in a sex- and experience-dependent way in rodents, thus we wanted to determine whether the Gonadotropin releasing hormone (GnRH), which regulates the release of gonadal hormones, through the gonadotropins activation, would also affect the process of AN in the DG and OB. Thanks to a collaboration with the Laboratory of Development and Plasticity of the Postnatal Brain, Jean-Pierre Aubert in Lille, where I performed part of the experiments, we took advantage of a transgenic mouse model developed in this lab, the GnRH::Cre;DicerloxP/loxP, which is unable to produce GnRH across the life span. We performed quantitative analysis for both the proliferating rate of the progenitors in SGZ and SVZ, and for the survival of the neuroblasts in the main olfactory bulb (MOB), accessory olfactory bulb (AOB) and DG. This analysis show that the lack of GnRH increases the number of newly-born neurons integrated in the MOB with no changing in the proliferation rate in the SVZ, suggesting that the effect observed in the MOB is due to enhanced survival of newly-generated neurons. By contrast, in the DG neurogenesis was not modified in null mice. To understand whether GnRH impacts OB neurogenesis in a direct or indirect way (through gonadal hormones), we characterised the OB of adult mice for the expression of GnRH, oestrogen and androgen receptors showing that they are all widely expressed in this region. To further analyse this aspect we combined stereotaxic injection of a fusion protein TATCre with a fluorescence-activated cell sorting (FACS) to separate and analyse the migrating neuroblasts of the MOB for the same profile expression analysis. Although this approach needs to be refined, the results obtained suggest that at least some of the studied receptors are expressed in this cell population.