The timing and duration of estradiol treatment in a rat model of the perimenopause: Influences on social behavior and the neuromolecular phenotype

Abstract

This study tested the effects of timing and duration of estradiol (E) treatment, factors that are clinically relevant to hormone replacement in perimenopausal women, on social behavior and expression of genes in brain regions that regulate these behaviors. Female rats were ovariectomized (OVX) at 1year of age, roughly equivalent to middle-age in women, and given E or vehicle for different durations (3 or 6months) and timing (immediately or after a 3-month delay) relative to OVX. Social and ultrasonic vocalization (USV) behaviors were assessed at the 3 and 6month timepoints, and the rats' brains were then used for gene expression profiling in hypothalamus (supraoptic nucleus, paraventricular nucleus), bed nucleus of the stria terminalis, medial amygdala, and prefrontal cortex using a 48-gene qPCR platform. At the 3-month post-OVX testing period, E treatment significantly decreased the number of frequency-modulated USVs emitted. No effects of hormone were found at the 6-month testing period. There were few effects of timing and duration of E in a test of social preference of a rat given a choice between her same-sex cagemate and a novel conspecific. For gene expression, effects of timing and duration of E were region-specific, with the majority of changes found for genes involved in regulating social behavior such as neuropeptides (Oxt, Oxtr &Avp), neurotransmitters (Drd1, Drd2, Htr2a, Grin2d &Gabbr1), and steroid hormone receptors (Esr2, Ar, Pgr). These data suggest that the mode of E treatment has specific effects on social behavior and expression of target genes involved in the regulation of these behaviors.

Social and neuromolecular phenotypes are programmed by prenatal exposures to endocrine-disrupting chemicals

“…In the current study, we detected 50 kHz but not 20 kHz USVs in our animals, consistent with other work in our lab using the same Sprague-Dawley rat colony (Bell et al, 2016b, Garcia et al, 2017a, Garcia et al, 2017b). Flat calls were sexually dimorphic (females > males), but numbers of rise, step and trill calls were equivalent between the sexes.…”

“…USVs were recorded over 3 consecutive days in a sound-attenuated Plexiglas apparatus, using a chamber (23l × 29w × 40h cm) divided into two equal compartments by a wire mesh, following published protocols (Garcia et al, 2017a, Garcia et al, 2017b). To habituate the rat, on the first two days the experimental rat was placed alone into the apparatus, and baseline USVs were recorded for 10 minutes using a CM16/CMPA microphone (Avisoft, Germany).…”

Total Polysaccharides of Lily Bulb Ameliorate Menopause-Like Behavior in Ovariectomized Mice: Multiple Mechanisms Distinct from Estrogen Therapy

“…The beneficial effects of estradiol on menopause-associated psychiatric symptoms are closely associated with multiple brain neurotransmitters, including serotoninergic, catecholaminergic, GABAergic, and glutamatergic neurons, and their receptors [61–64]. Low GABAergic activity may play a key role in the pathophysiology of mood disorders [65].…”

Endocrine-disrupting chemicals: Effects on neuroendocrine systems and the neurobiology of social behavior

“…High frequency calls, in the range of 50 to 90 kHz, are emitted in general communicative or in hedonic situations. They are induced by the removal of a partner or mate from the home cage, or when placed into a new cage, and are therefore thought to maintain, establish or reestablish social contact (Garcia et al, 2017a;Garcia et al, 2017b;Harding and McGinnis, 2003;Wöhr et al, 2008). High frequency calls are also emitted in rewarding and positive affective situations such as juvenile play (Knutson et al, 1998), mating behavior (Burgdorf et al, 2008;Willadsen et al, 2014) and other social situations (Brudzynski, 2013).…”