Estrogens in the bed nucleus of the stria terminalis: State-dependent modulation of inhibitory synaptic transmission in rats

Abstract

Beyond their important role in reproduction, estrogens contribute in various adaptive and maladaptive physiological phenomena including, but not limited to, appetite, stress response, and the development of compulsive behaviours. There are estrogen receptors throughout the brain, including in regions and circuits contributing to maladaptive behaviours. Thus, pharmacological interventions targeting estrogens result in considerable undesirable side effects. Traditionally considered a female steroid hormone, estrogens are also potent neuromodulators in the male vertebrate brain. In comparison to female rats, peripherally administered estrogens have negligible effects as the male rat brain likely relies on brain-derived de novo estrogens synthesis. While the neurophysiological effects of estrogens are well characterized in the hippocampus of both sexes, nothing is known about their effects in the oval nucleus of the bed nucleus of the stria-terminalis (ovBNST), a key region that integrates sensory information within the appetite, anxiety, and compulsion circuits. The ovBNST is rich in estrogen receptors and has the capability of synthesising estrogens in both sexes. Using brain slice voltage-clamp electrophysiology, we characterized the effects of estrogens on inhibitory synaptic transmission within the rat ovBNST. These studies will demonstrate that Estradiol (E2) had a potent, but sexually dimorphic effects on both inhibitory synaptic transmission and plasticity at GABA synapses within the ovBNST. These effects of E2 were sensitive to changes in the rats metabolic-state and intriguingly, a form of compulsive behaviours in rats was associated with a dysfunction in the endogenous estrogenic system within the ovBNST. This dysfunction appears to be caused by a weakening of the paraventricular thalamus circuit with the ovBNST that may cause changes in E2 synthesis. Thus, we discovered that brain-derived estrogens are potent modulators of inhibitory synaptic transmission within the ovBNST and they gate a metabolic-state induced bi-directional plasticity that is associated with the development and maintenance of maladaptive compulsive behaviours in male rats. These studies lay the foundation in understanding how the endogenous estrogenic system within the male brain is integral in influencing state-dependent behaviour.