Visual Abstract

Naturally occurring hormone cycles in adult female humans and rodents create a dynamic neuroendocrine environment. These cycles include the menstrual cycle in humans and its counterpart in rodents, the estrous cycle. These hormone fluctuations induce sex differences in the phenotypes of many behaviors, including those related to motivation, and associated disorders such as depression and addiction. This suggests that the neural substrate instrumental for these behaviors, including the nucleus accumbens core (AcbC), likewise differs between estrous cycle phases. It is unknown whether the electrophysiological properties of AcbC output neurons, medium spiny neurons (MSNs), change between estrous cycle phases. This is a critical knowledge gap given that MSN electrophysiological properties are instrumental for determining AcbC output to efferent targets. Here we test whether the intrinsic electrophysiological properties of adult rat AcbC MSNs differ across female estrous cycle phases and from males. We recorded MSNs with whole cell patch-clamp technique in two experiments, the first using gonad-intact adult males and females in differing phases of the estrous cycle and the second using gonadectomized males and females in which the estrous cycle was eliminated. MSN intrinsic electrophysiological and excitatory synaptic input properties robustly changed between female estrous cycle phases and males. Sex differences in MSN electrophysiology disappeared when the estrous cycle was eliminated. These novel findings indicate that AcbC MSN electrophysiological properties change across the estrous cycle, providing a new framework for understanding how biological sex and hormone cyclicity regulate motivated behaviors and other AcbC functions and disorders. NEW & NOTEWORTHY This research is the first demonstration that medium spiny neuron electrophysiological properties change across adult female hormone cycle phases in any striatal region. This influence of estrous cycle engenders sex differences in electrophysiological properties that are eliminated by gonadectomy. Broadly, these findings indicate that adult female hormone cycles are an important factor for neurophysiology.

This research indicates that estradiol and progesterone act both differentially and synergistically to modulate neuron physiology in the nucleus accumbens core. These actions by specific hormones provide key data indicating the endocrine mechanisms underlying how the estrous cycle modulates neuron physiology in this region. Overall, these data reinforce that hormones are an important influence on neural physiology.

The present study shows, for the first time, that an estrous cycle-relevant estradiol exposure modulates nucleus accumbens neuron excitability. This evidence provides insight into the neuroendocrine mechanisms by which estradiol cyclically alters neuron properties during the estrous cycle. Overall, these data emphasize the significant influence of hormone action in the brain and especially individual neuron physiology.

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The nucleus accumbens core is a key nexus within the mammalian brain for integrating the premotor and limbic systems and regulating important cognitive functions such as motivated behaviors. Nucleus accumbens core functions show sex differences and are sensitive to the presence of hormones such as 17β-estradiol (estradiol) in normal and pathological contexts. The primary neuron type of the nucleus accumbens core, the medium spiny neuron (MSN), exhibits sex differences in both intrinsic excitability and glutamatergic excitatory synapse electrophysiological properties. Here, we provide a review of recent literature showing how estradiol modulates rat nucleus accumbens core MSN electrophysiology within the context of the estrous cycle. We review the changes in MSN electrophysiological properties across the estrous cycle and how these changes can be mimicked in response to exogenous estradiol exposure. We discuss in detail recent findings regarding how acute estradiol exposure rapidly modulates excitatory synapse properties in nucleus accumbens core but not caudate-putamen MSNs, which mirror the natural changes seen across estrous cycle phases. These recent insights demonstrate the strong impact of sex-specific estradiol action upon nucleus accumbens core neuron electrophysiology.

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