Behavioral effects of estrogen receptor beta acting locally to regulate the expression of tryptophan hydroxylase 2 (THP2) in serotonergic neurons of the dorsal raphe nuclei
Donner, Nina Caroline
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Handa, Robert J.Affective disorders often involve serotonin (5-HT)-related dysfunctions and are twice as common in women than men. Interactions between estrogen and the brain 5-HT system have long been proposed to contribute to sex differences in mood and anxiety disorders, but the mechanisms underlying this phenomenon have yet to be revealed. Estrogen signaling is mediated by two different receptors termed estrogen receptor alpha and estrogen receptor beta. While estrogen receptor alpha (ERalpha) has mainly reproductive responsibilities, in brain, estrogen receptor beta (ERbeta) has been shown to attenuate anxiety- and despair-like behaviors in rodent models. However, little is known about ERbeta regulation of function in the brainstem raphe nuclei. The raphe nuclei are the main 5-HT system of the brain, and projections from the dorsal raphe nuclei (DRN) innervate many important forebrain and limbic areas. The work presented in this thesis addressed the possibility that ERbeta may be involved in the regulation of 5-HT gene expression specifically in DRN neurons. My studies examined the effects of systemic versus local, intracerebral application of the selective ERbeta agonist diarylpropionitrile (DPN) and the nonselective ERligandestradiol (E) on tryptophan hydroxylase 2 (TPH2) mRNA expression within the DRN of female rats. TPH2 is the brain-specific, rate-limiting enzyme catalyzing 5-HT synthesis, and is expressed in every 5-HT neuron. Thus, it provides an excellent tool to assess the capacity for 5-HT production with the DRN. In these studies, TPH2 mRNA expression was assessed via in situ hybridization. In addition, relevant behavioral parameters were tested in all animals to evaluate each compound’s effect on two closely related, but yet different mental states, anxiety-like and despair-like behavior. Both, chronic systemic and chronic local DPN administration to ovariectomized (OVX) female rats significantly enhanced TPH2 mRNA expression in mid- and caudal subregions of the DRN after 8 days of treatment. Respective controls received systemic vehicle (27% hydroxypropyl-beta-cyclodextrin) or blank control pellets. Local application of DPN caused a stronger effect than systemic drug delivery. Chronic local delivery of E (0.5 μM) increased TPH2 mRNA expression in the same subregions of the DRN as did DPN, but its overall effect was weaker compared to the selective ERbeta agonist. Interestingly, while systemic DPN-administration confirmed the anxiolytic nature of ERbeta in two separate anxiety tests (elevated plus maze and open field test), the effect was lost when DPN was delivered locally. However, local DPN- as well as E-treatment both resulted in attenuated despair-like behavior, as measured in the forced-swim test. Chapter 3 describes the experimental design, results and interpretation of these studies in depth. Taken together, my data indicate that local actions of ERbeta agonist onto DRN neurons are sufficient to decrease despair-like behavior, whereas ERbeta stimulation of other brain regions is necessary to alter anxiety-like behaviors. Correspondingly, ERbeta acts locally to control TPH2 mRNA expression and presumably 5-HT synthesis in the certain subregions of the rat DRN. These results suggest an important role of ERbeta for regulating cellular events in the female DRN, and offer new opportunities for therapeutic treatments of depressive disorders.