Research in our laboratory focus on: 1) understanding the molecular and cellular
mechanisms underlying the brain signal for ovulation; 2) determining developmental
mechanisms responsible for sex differences in the brain region that controls ovulation
and 3) determining how exposure to environmental contaminants like dioxins interfere with
the development of this brain region and gonadotoropi release patterns.
The Brain Signal for Ovulation
As ovarian follicles mature, they release increasing amounts of estradiol (E2). This
increase in E2 triggers a number of signals that culminate in activation of
gonadotropin-releasing hormone neurons (GnRH), which activate a surge of luteinizing
hormone (LH) release from the pituitary gland. The LH surge then triggers ovulation. We
previously showed that the anteroventral periventricular nucleus (AVPV) is a brain region
in which E2 must act to trigger the LH surge. More recently we found that the targets of
E2 in the AVPV are unique dual-phenotype GABA/Glutamate neurons. These neurons are more
than twice as abundant in females than in males and they synapse on GnRH neurons. In the
presence of E2, GABAergic vesicles in these synapses are high during the morning, but
then decrease at the time of the LH surge, when glutamatergic neurons predominate in the
dual-phenotype terminals. These findings are consistent with the idea that GABA inhibits
the LH surge and glutamate stimulates it. We are currently using in vivo and in vitro
approaches to determine how daily signals and E2 interact to change the rates of GABA and
glutamatergic release from these dual-phenotype neurons, thereby stimulating GnRH and LH
surge release.
Development of Sex Differences in the AVPV
Only females show activation of GnRH neurons and LH surge release in response to E2;
males show tonic, rather than cyclic patterns of LH release. The sex-specific patterns of
LH release are established during the perinatal period and the resulting pattern is
determined by whether or not animals are exposed to testosterone. If males are
gonadectomized during the perinatal period, they are able to show female-typical LH surge
release. Similarly, if females are exposed to testosterone, or E2 derived from
testosterone, they lose the potential for LH surge release. Our work suggests that
GABA/Glu neurons are more than twice as numerous in females as in males and that
perinatal exposure to testosterone masculinizes the number of GABA/Glu neurons and
abolishes the potential for LH surge release in treated females. These findings together
with our previous findings that GABA/Glu neurons make up most of the AVPV and contain all
the ER in the region, support the idea that these unique dual-phenotype neurons are key
to the sex-specific signal for ovulation. We are currently investigating the
developmental mechanisms underlying sex differences in GABA/Glu neurons of the AVPV.
Dioxins Interfere with Sexual Differentiation of the AVPV
Dioxins are ubiquitous environmental contaminants that are quite potent in disrupting
neural development. Of particular concern are findings that exposure to the prototypic
dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin, prevents defeminization of the LH surge
mechanisms such that exposed males show LH surge release. Dioxins and a number of
dioxin-like compounds act through the arylhydrocarbon receptor (AhR) and often exert
anti-estrogenic effects. We recently found that the AhR is found in GABA/glutamate
neurons of the developing AVPV and that a single exposure to TCDD prevents the
E2-dependent loss of GABA/Glu neurons in the region. Thus, males retain the female AVPV
neuroanatomy and gonadotropin release pattern. We are now using genomics methods to
identify sex-specific genes that are regulated by both E2 and TCDD.
