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

The nucleus accumbens (NAc) plays critical roles in motivated behaviors, including food seeking and feeding. Differences in NAc function contribute to overeating that drives obesity, but the underlying mechanisms are poorly understood. In addition, there is a fair degree of variation in individual susceptibility versus resistance to obesity that is due in part to differences in NAc function. For example, using selectively bred obesity-prone and obesity-resistant rats, we have found that excitability of medium spiny neurons (MSNs) within the NAc core is enhanced in obesity-prone versus -resistant populations, before any diet manipulation. However, it is unknown whether consumption of sugary, fatty “junk food” alters MSN excitability. Here whole cell patch-clamp recordings were conducted to examine MSN intrinsic excitability in adult male obesity-prone and obesity-resistant rats with and without exposure to a sugary, fatty junk food diet. We replicated our initial finding that basal excitability is enhanced in obesity-prone versus obesity-resistant rats and determined that this is due to a lower fast transient potassium current ( IA) in prone versus resistant groups. In addition, the junk food diet had opposite effects on excitability in obesity-prone versus obesity-resistant rats. Specifically, junk food enhanced excitability in MSNs of obesity-resistant rats; this was mediated by a reduction in IA. In contrast, junk food reduced excitability in MSNs from obesity-prone rats; this was mediated by an increase in inward-rectifying potassium current. Thus individual differences in obesity susceptibility influence both basal excitability and how MSN excitability adapts to junk food consumption. NEW & NOTEWORTHY Medium spiny neurons (MSNs) in the nucleus accumbens of obesity-prone rats are hyperexcitable compared with MSNs from obesity-resistant rats. We found that 10 days of “junk food” exposure reduces MSN excitability in obesity-prone rats by increasing inward-rectifying potassium current and increases MSN excitability in obesity-resistant rats by decreasing fast transient potassium current. These data show that there are basal and junk food diet-induced differences in MSN excitability in obesity-prone and obesity-resistant individuals; this may contribute to previously observed differences in incentive motivation.

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Estradiol rapidly modulates excitatory synapse properties in a sex- and region-specific manner in rat nucleus accumbens core and caudate-putamen

Journal of Neurophysiology ◽

10.1152/jn.00264.2019 ◽

2019 ◽

Vol 122 (3) ◽

pp. 1213-1225 ◽

Cited By ~ 9

Author(s):

Amanda A. Krentzel ◽

Lily R. Barrett ◽

John Meitzen

Keyword(s):

Sex Differences ◽

Nucleus Accumbens ◽

Excitatory Synapse ◽

Medium Spiny Neurons ◽

Nucleus Accumbens Core ◽

Caudate Putamen ◽

Spiny Neurons ◽

Glutamatergic Signaling ◽

Mepsc Frequency ◽

Accumbens Core

Estradiol acutely facilitates sex differences in striatum-dependent behaviors. However, little is understood regarding the underlying mechanism. In striatal regions in adult rodents, estrogen receptors feature exclusively extranuclear expression, suggesting that estradiol rapidly modulates striatal neurons. We tested the hypothesis that estradiol rapidly modulates excitatory synapse properties onto medium spiny neurons (MSNs) of two striatal regions, the nucleus accumbens core and caudate-putamen in adult female and male rats. We predicted there would be sex-specific differences in pre- and postsynaptic locus and sensitivity. We further analyzed whether MSN intrinsic properties are predictive of estrogen sensitivity. Estradiol exhibited sex-specific acute effects in the nucleus accumbens core: miniature excitatory postsynaptic current (mEPSC) frequency robustly decreased in response to estradiol in female MSNs, and mEPSC amplitude moderately increased in response to estradiol in both male and female MSNs. This increase in mEPSC amplitude is associated with MSNs featuring increased intrinsic excitability. No MSN intrinsic electrical property associated with changes in mEPSC frequency. Estradiol did not acutely modulate mEPSC properties in the caudate-putamen of either sex. This is the first demonstration of acute estradiol action on MSN excitatory synapse function. This demonstration of sex and striatal region-specific acute estradiol neuromodulation revises our understanding of sex hormone action on striatal physiology and resulting behaviors. NEW & NOTEWORTHY This study is the first to demonstrate rapid estradiol neuromodulation of glutamatergic signaling on medium spiny neurons (MSNs), the major output neuron of the striatum. These findings emphasize that sex is a significant biological variable both in MSN sensitivity to estradiol and in pre- and postsynaptic mechanisms of glutamatergic signaling. MSNs in different regions exhibit diverse responses to estradiol. Sex- and region-specific estradiol-induced changes to excitatory signaling on MSNs explain sex differences partially underlying striatum-mediated behaviors and diseases.

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Eating junk-food has opposite effects on intrinsic excitability of nucleus accumbens core medium spiny neurons in obesity-susceptible vs. -resistant rats

10.1101/658971 ◽

2019 ◽

Author(s):

Max F. Oginsky ◽

Carrie R. Ferrario

Keyword(s):

Nucleus Accumbens ◽

Intrinsic Excitability ◽

Medium Spiny Neurons ◽

Junk Food ◽

Nucleus Accumbens Core ◽

Initial Finding ◽

Spiny Neurons ◽

Whole Cell Patch Clamp ◽

Underlying Mechanisms ◽

Food Seeking

AbstractThe nucleus accumbens (NAc) plays critical roles in motivated behaviors, including food-seeking and feeding. Differences in NAc function contribute to over-eating that drives obesity, but the underlying mechanisms are poorly understood. In addition, there is a fair degree of variation in individual susceptibility vs. resistance to obesity that is due in part to differences in NAc function. For example, using selectively bred obesity-prone and obesity-resistant rats, we have found that excitability of medium spiny neurons within the NAc core is enhanced in obesity-prone vs. resistant populations, prior to any diet manipulation. However, it is unknown whether consumption of sugary, fatty junk-food alters MSN excitability. Here, whole-cell patch clamp recordings were conducted to examine MSN intrinsic excitability in adult male obesity-prone and obesity-resistant rats with and without exposure to a sugary, fatty junk-food diet. We replicated our initial finding that basal excitability is enhanced in obesity-prone vs. obesity-resistant rats and determined that this is due to a lower IA in prone vs. resistant groups. In addition, the junk-food diet had opposite effects on excitability in obesity-prone vs. obesity-resistant rats. Specifically, junk-food enhanced excitability in MSNs of obesity-resistant rats; this was mediated by a reduction in IA. In contrast, junk-food reduced excitability in MSNs from obesity-prone rats; this was mediated by an increase in IKIR. Thus, individual differences in obesity-susceptibility influence both basal excitability and how MSN excitability adapts to junk-food consumption.

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Erbb4 Deletion from Medium Spiny Neurons of the Nucleus Accumbens Core Induces Schizophrenia-Like Behaviors via Elevated GABAA Receptor α1 Subunit Expression

Journal of Neuroscience ◽

10.1523/jneurosci.3948-16.2017 ◽

2017 ◽

Vol 37 (31) ◽

pp. 7450-7464 ◽

Cited By ~ 7

Author(s):

Hong-Yan Geng ◽

Jing Zhang ◽

Jian-Ming Yang ◽

Yue Li ◽

Ning Wang ◽

...

Keyword(s):

Nucleus Accumbens ◽

Gabaa Receptor ◽

Medium Spiny Neurons ◽

Nucleus Accumbens Core ◽

Spiny Neurons ◽

Subunit Expression ◽

Α1 Subunit ◽

Accumbens Core

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Metformin in nucleus accumbens core reduces cue-induced cocaine seeking in male and female rats

10.1101/2021.09.05.458975 ◽

2021 ◽

Author(s):

Amy Chan ◽

Alexis Willard ◽

Sarah Mulloy ◽

Noor Ibrahim ◽

Allegra Sciaccotta ◽

...

Keyword(s):

Nucleus Accumbens ◽

Female Rats ◽

Therapeutic Effects ◽

Self Administration ◽

Nucleus Accumbens Core ◽

Male And Female ◽

Male And Female Rats ◽

Cocaine Seeking ◽

Ampk Activity ◽

Accumbens Core

This study investigated the potential therapeutic effects of the FDA-approved drug metformin on cue-induced reinstatement of cocaine seeking. Metformin (dimethyl-biguanide) is a first-line treatment for type II diabetes that, among other mechanisms, is involved in the activation of adenosine monophosphate activated protein kinase (AMPK). Cocaine self-administration and extinction is associated with decreased levels of phosphorylated AMPK within the nucleus accumbens core (NAcore). Previously it was shown that increasing AMPK activity in the NAcore decreased cue-induced reinstatement of cocaine seeking. Decreasing AMPK activity produced the opposite effect. The goal of the present study was to determine if metformin in the NAcore reduces cue-induced cocaine seeking in adult male and female Sprague Dawley rats. Rats were trained to self-administer cocaine followed by extinction prior to cue-induced reinstatement trials. Metformin microinjected in the NAcore attenuated cue-induced reinstatement in male and female rats. Importantly, metformin's effects on cocaine seeking were not due to a general depression of spontaneous locomotor activity. In female rats, metformin's effects did generalize to a reduction in cue-induced reinstatement of sucrose seeking. These data support a potential role for metformin as a pharmacotherapy for cocaine use disorder, but warrant caution given the potential for metformin's effects to generalize to a natural reward in female rats.

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Ceftriaxone and mGlu2/3 interactions in the nucleus accumbens core affect the reinstatement of cocaine-seeking in male and female rats

Psychopharmacology ◽

10.1007/s00213-020-05514-y ◽

2020 ◽

Vol 237 (7) ◽

pp. 2007-2018 ◽

Cited By ~ 1

Author(s):

Carly N. Logan ◽

Allison R. Bechard ◽

Peter U. Hamor ◽

Lizhen Wu ◽

Marek Schwendt ◽

...

Keyword(s):

Nucleus Accumbens ◽

Female Rats ◽

Nucleus Accumbens Core ◽

Male And Female ◽

Male And Female Rats ◽

Cocaine Seeking ◽

Core Affect ◽

Accumbens Core

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

10.1101/669804 ◽

2019 ◽

Author(s):

Yanaira Alonso-Caraballo ◽

Carrie R. Ferrario

Keyword(s):

Food Intake ◽

Estrous Cycle ◽

Ovarian Hormones ◽

Female Rats ◽

Intrinsic Excitability ◽

Sprague Dawley ◽

Food Cues ◽

Approach Behavior ◽

Individual Susceptibility ◽

Conditioned Approach

AbstractNaturally occurring alterations in estradiol influence food intake in females. However, how motivational responses to food cues are affected by the estrous cycle or ovarian hormones is unknown. In addition, while individual susceptibility to obesity is accompanied by enhanced incentive motivational responses to food cues and increased NAc intrinsic excitability in males, studies in females are absent. Here, we examined basal differences in intrinsic NAc excitability of obesity-prone vs. obesity-resistant females and determined how conditioned approach (a measure of cue-triggered motivation), food intake, and motivation for food vary with the cycle in naturally cycling female obesity-prone, obesity-resistant, and outbred Sprague-Dawley rats. Finally, we used ovariectomy followed by hormone treatment to determine the role of ovarian hormones in cue-triggered motivation in selectively-bred and outbred female rats. We found that intrinsic excitability of NAc MSNs and conditioned approach are enhanced in female obesity-prone vs. obesity-resistant rats. These effects were driven by greater MSN excitability and conditioned approach behavior during metestrus/diestrus vs. proestrus/estrus in obesity-prone but not obesity-resistant rats, despite similar regulation of food intake and food motivation by the cycle in these groups. Furthermore, estradiol and progesterone treatment reduced conditioned approach behavior in obesity-prone and outbred Sprague-Dawley females. To our knowledge, these data are the first to demonstrate cycle- and hormone-dependent effects on the motivational response to a food cue, and the only studies to date to determine how individual susceptibility to obesity influences NAc excitability, cue-triggered food-seeking, and differences in the regulation of these neurobehavioral responses by the cycle.

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Distinct threat and valence signals in rat nucleus accumbens core

10.1101/2021.05.27.446063 ◽

2021 ◽

Author(s):

Madelyn H Ray ◽

Mahsa Moaddab ◽

Michael A McDannald

Keyword(s):

Nucleus Accumbens ◽

Single Unit ◽

Female Rats ◽

Single Unit Activity ◽

Nucleus Accumbens Core ◽

Negative Valence ◽

Positive Valence ◽

Rat Nucleus Accumbens ◽

Separate Population ◽

Accumbens Core

Appropriate responding to threat and reward is essential to survival. The nucleus accumbens core (NAcc) is known to support and organize reward behavior. More recently our laboratory has shown the NAcc is necessary to discriminate cues for threat and safety. To directly reveal NAcc threat responding, we recorded single-unit activity from 7 female rats undergoing Pavlovian fear discrimination. Rats fully discriminated cues for danger, uncertainty, and safety. Demonstrating direct threat responding, most NAcc neurons showed greatest firing changes to danger and uncertainty. Heterogeneity in cue and reward firing led to the detection of multiple, functional populations. One NAcc population specifically decreased firing to threat (danger and uncertainty). A separate population bi-directionally signaled valence through firing decreases to negative valence events (danger and uncertainty) and opposing firing increases to positive valence events (reward and safety onset). The findings point to the NAcc as a neural source of threat information and a more general valence hub.

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Ceftriaxone and mGlu2/3 interactions in the nucleus accumbens core affect the reinstatement of cocaine-seeking in male and female rats

10.1101/2020.02.17.952762 ◽

2020 ◽

Author(s):

Carly N. Logan ◽

Allison R. Bechard ◽

Peter U. Hamor ◽

Lizhen Wu ◽

Marek Schwendt ◽

...

Keyword(s):

Nucleus Accumbens ◽

Surface Expression ◽

Receptor Expression ◽

Female Rats ◽

Beta Lactam ◽

Nucleus Accumbens Core ◽

Male And Female ◽

Male And Female Rats ◽

Cocaine Seeking ◽

Accumbens Core

AbstractRationaleThe beta-lactam antibiotic ceftriaxone reliably attenuates the reinstatement of cocaine-seeking. While the restoration of nucleus accumbens core (NA core) GLT-1 expression is necessary for ceftriaxone to attenuate reinstatement, AAV-mediated GLT-1 overexpression is not sufficient to attenuate reinstatement and does not prevent glutamate efflux during reinstatement.AimsHere, we test the hypothesis that ceftriaxone attenuates reinstatement through interactions with glutamate autoreceptors mGlu2 and mGlu3 in the NA core.MethodsMale and female rats self-administered cocaine for 12 days followed by 2-3 weeks of extinction training. During the last 6-10 days of extinction, rats received ceftriaxone (200 mg/kg IP) or vehicle. In experiment 1, rats were killed, and NA core tissue was biotinylated for assessment of total and surface expression of mGlu2 and mGlu3 via western blotting. In experiment 2, we tested the hypothesis that mGlu2/3 signaling is necessary for ceftriaxone to attenuate cue- and cocaine-primed reinstatement by administering bilateral intra-NA core infusion of mGlu2/3 antagonist LY341495 or vehicle immediately prior to reinstatement testing.ResultsmGlu2 expression was reduced by cocaine and restored by ceftriaxone. There were no effects of cocaine or ceftriaxone on mGlu3 expression. We observed no effects of estrus on expression of either protein. The antagonism of mGlu2/3 in the NA core during both cue- and cocaine-primed reinstatement tests prevented ceftriaxone from attenuating reinstatement.ConclusionsThese results indicate that ceftriaxone’s effects depend on mGlu2/3 function and possibly mGlu2 receptor expression. Future work will test this hypothesis by manipulating mGlu2 expression in pathways that project to the NA core.

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