The role of brain-derived neurotrophic factor (BDNF) on gonadotropin-releasing hormone (GnRH) neurons during ageing in female rats

Gonadotropin-releasing hormone (GnRH) is a driving force in the hypothalamic-pituitary-gonadal (HPG) axis that controls mammalian reproductive system. GnRH expression and function are strictly regulated by gonadal hormones, neurotransmitters, cytokines and growth factors. Brain-derived neurotrophic factor (BDNF) is a growth factor that regulates the growth, maintenance, survival and plasticity in the brain. The first part of the study in chapter 2 was aimed to, 1) determine the expression of GnRH, BDNF and BDNF-associated receptors in the preoptic area (POA), as well as 2) to localize the BDNF-associated receptors; tropomyosin receptor kinase (Trk) C, TrkB (FL or T1), tumor necrosis factor receptor superfamily p75(NTR) and Sortilin (Sort1) in GnRH neurons of estrus adult and ageing adult female rats. There was an age-dependent decrease of GnRH mRNA expression but there were no changes in the expressions of BDNF and BDNF-associated receptors in the POA. Laser-dissected GnRH neurons revealed the presence of BDNF, TrkB.FL and TrkB.T1 in the estrus adult female rats whereas the ageing adult female rats expressed only BDNF and TrkB.FL receptor. Chapter 3 focused on the role of BDNF in modulating the fine morphology of GnRH neurons in the hypothalamic slice culture containing the organum vasculosum of lamina terminalis (OVLT). BDNF exposure to estrus adult GnRH neurons increased the number or density of filopodia, thin and mushroom type somatic spines and thin type dendritic spines of the proximal dendrite. Whereas, BDNF seemed to only affect the number of mushroom type dendritic spines in the ageing adult GnRH neurons. In Chapter 4, the objectives were to investigate the effect of chronic BDNF infusion on, 1) the morphology of GnRH neurons in the POA, OVLT and anterior hypothalamic area (AHA), as well as 2) the sexual and anxiety-like behavior in ovariectomized (OVX) adults and intact ageing adult female rats.Confocal images revealed that intracerebroventricular (icv) infusion of BDNF (12 µg/day X 14 days) increased the number of thin dendritic spines in the proximal dendrite of OVX adult GnRH neurons and somatic mushroom spines in ageing adult GnRH neurons in the OVLT. In the AHA, the ageing adult female rats showed more somatic and dendritic spines in GnRH neurons, compared with OVX adult GnRH neurons. There was no effect of BDNF treatment on spines and protrusions in GnRH neurons in OVX adult and intact ageing adult female rats in the POA. BDNF-treated OVX adult females showed high locomotor activity in the open arms in elevated plus maze (EPM), whereas the intact ageing adults did not respond to BDNF in anxiety test. BDNF treatment decreased rejection quotient (RQ) of OVX adult but not the intact ageing adult female rats against an intact male in the sexual behavior test. Taken together, the evidence provided in the current study suggest that there were age-related differences in, 1) the GnRH mRNA expression, 2) expression of TrkB.T1 receptors, 3) the effect of BDNF on spines density in vivo, and, 4) the effect of BDNF on anxiety and sexual behavior. The differences in the expression of BDNF receptors most probably influence the density and proportion of spine subtypes upon BDNF exposure that consequently affect the afferent synaptic events in GnRH neuronal circuits resulting in age-associated reproductive decline as well as reproductive-associated mood disorders in ageing.