Estrous cycle-induced sex differences in medium spiny neuron excitatory synaptic transmission and intrinsic excitability in adult rat nucleus accumbens core

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.

Effects of the estrous cycle and ovarian hormones on cue-triggered motivation and intrinsic excitability of medium spiny neurons in the Nucleus Accumbens core of female rats

“…Specifically, in obesity-prone rats changes in voltage at positive current injections were significantly greater during metestrus/diestrus vs. proestrus/estrus. This is similar to effects of the cycle on NAc excitability in outbred Sprague-Dawley females ( Proaño et al, 2018 ). To our knowledge this is the only other study to specifically examine effects of the estrous cycle on MSN excitability, and the mechanisms by which ovarian hormones influence NAc excitability have not been determined.…”

“…Furthermore, stimulated dopamine release in the NAc increases during the estrus vs. diestrus phase in female mice ( Calipari et al, 2017 ), suggesting that hormonal regulation of dopamine transmission could contribute to changes in excitability across the cycle. Additionally, NAc glutamatergic transmission increases during proestrus and estrus in female rats ( Proaño et al, 2018 ), and can be influenced by neonatal exposure to estradiol ( Cao et al, 2016 ). Although not well understood, reductions in excitatory transmission often co-occur with increases in intrinsic excitability, and vice versa (see Oginsky and Ferrario, 2019 for additional discussion).…”

Neurochemical organization of the ventral striatum’s olfactory tubercle

“…1978). This is in line with findings from other brain regions displaying an excitatory response to estrogens, including striatal MSNs (Cao, Willett, Dorris, & Meitzen, 2018;Huang & Woolley, 2012;Proaño, Morris, Kunz, Dorris, & Meitzen, 2018).…”

“…17β‐Estradiol augments evoked firing of neurons in the OT upon stimulation of the posterior hypothalamus in cats (Cartas‐Heredia, Guevara‐Aguilar, & Aguilar‐Baturoni, ). This is in line with findings from other brain regions displaying an excitatory response to estrogens, including striatal MSNs (Cao, Willett, Dorris, & Meitzen, ; Huang & Woolley, ; Proaño, Morris, Kunz, Dorris, & Meitzen, ).…”

Neural and Hormonal Control of Sexual Behavior

“…VTA dopaminergic neuron basal firing rate is enhanced and more dopamine released into the NAc during behavioral estrus ( 193-195 ). Several electrophysiological properties of NAc medium spiny neurons have been reported to either vary across the estrous cycle or to be rapidly modulated by estradiol exposure ( 192 , 196 , 197 ). Furthermore, like in many of the regions discussed above, estrogen exposure also regulates spine density in the NAc ( 198 , 199 ).…”