Long-term oral administration of a novel estrogen receptor beta agonist enhances memory and alleviates drug-induced vasodilation in young ovariectomized mice

Abstract

Development of estrogen therapies targeting the β (ERβ) but not α (ERα) estrogen receptor is critically needed for the treatment of negative menopausal symptoms, as ERα activation increases health risks like cancer. Here, we determined the effects of long-term oral treatment with EGX358, a novel highly selective ERβ agonist, on memory, vasodilation, and affect in young ovariectomized mice. Mice were orally gavaged daily for 9 weeks with vehicle, 17β-estradiol (E 2 ), the ERβ agonist diarylpropionitrile (DPN), or EGX358 at doses that enhance memory when delivered acutely. Tail skin temperature was recorded as a proxy for vasodilation following injection of vehicle or senktide, a tachykinin receptor 3 agonist used to model hot flashes. Anxiety-like behavior was assessed in the open field (OF) and elevated plus maze (EPM), and depression-like behavior was measured in the tail suspension (TST) and forced swim tests (FST). Finally, memory was assessed in object recognition (OR) and object placement (OP) tasks. E 2 , DPN, and EGX358 reduced senktide-mediated increases in tail skin temperature compared to vehicle. All three treatments also enhanced memory in the OR and OP tasks, whereas vehicle did not. Although E 2 increased time spent in the center of the OF, no other treatment effects were observed in the OF, EPM, TST, or FST. These data suggest that long-term ERβ activation can reduce hot flash-like symptoms and enhance spatial and object recognition memories in ovariectomized mice. Thus, the highly selective ERβ agonist EGX358 may be a promising avenue for reducing menopause-related hot flashes and memory dysfunction.

Chemogenetic inactivation of the nucleus reuniens impairs object placement memory in female mice

“…A minimum of 4 days after arrival, mice were bilaterally ovariectomized as described previously ( Fleischer et al, 2021 ; Koss, Haertel, Philippi, & Frick, 2018 ) and injected with AAV (or saline control) into the RE within the same surgical session. Ovariectomy eliminates the primary source of circulating estrogens, which affect spatial memory in mice ( Frick & Berger-Sweeney, 2001 ).…”

“…Training and testing were conducted in a white open field box (60 × 60 × 47 cm) as described previously ( Fleischer et al, 2021 ). To habituate mice to experimenter handling, they were first handled for 1 min/day for 3 days.…”

A Putative Role for Ubiquitin-Proteasome Signaling in Estrogenic Memory Regulation

“…Although ERα and ERβ are known for exerting genomic effects in the nucleus, they are also abundantly expressed throughout all segments of hippocampal neurons, including axon terminals, dendrites, and dendritic spines (Milner et al, 2000 , 2005 ), where they are positioned near the plasma membrane to interact with metabotropic glutamate receptors (mGluRs) and other receptors to rapidly regulate synaptic signaling (Mitterling et al, 2010 ). Data from our lab and others indicate that activation of ERα or ERβ facilitates the consolidation of object recognition and spatial memories in ovariectomized rats and mice (Jacome et al, 2010 ; Kim and Frick, 2017 ; Hanson et al, 2018 ; Fleischer et al, 2021 ). Additional evidence suggests that glutamate receptors play key roles in mediating these memory-enhancing effects, as ERα and ERβ directly interact with mGluR1a to trigger extracellular signal-regulated kinase (ERK) signaling in the DH to facilitate object placement and object recognition memory consolidation in ovariectomized mice (Boulware et al, 2013 ).…”

The Effects of Estrogens on Neural Circuits That Control Temperature

“…Receptor-selective pharmacological ( 28 ) and genetic manipulations ( 29-31 ) suggest a primary role for ERα in mediating the metabolic effects of estrogens on the hypothalamus, although other receptor(s) are clearly involved in the effects of estrogens on temperature. For example, treating ovariectomized rats or mice with selective ligands for ERβ can mimic the effects of estradiol treatment on lowering tail skin temperature (T tail ) without affecting body or uterine weights ( 32 , 33 ). Similarly, a Gq-coupled estrogen receptor agonist is able to decrease core body temperature similar to E2 in guinea pigs after ovariectomy ( 34 ).…”

“…Nevertheless, this exciting breakthrough demonstrates the power and therapeutic potential of neuroendocrine studies in rodents. Despite the promise of treatments that target NKB signaling, emerging evidence suggests that estrogens modulate vasodilation and heat dissipation responses ( 33 , 50 , 123 ). A full understanding of hot flashes will require a dissection and mechanistic interrogation of the effects of estrogens on the neural circuits that maintain temperature homeostasis.…”