Eating “junk food” has opposite effects on intrinsic excitability of nucleus accumbens core neurons in obesity-susceptible versus -resistant 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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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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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

Hormones and Behavior ◽

10.1016/j.yhbeh.2019.104583 ◽

2019 ◽

Vol 116 ◽

pp. 104583 ◽

Cited By ~ 7

Author(s):

Yanaira Alonso-Caraballo ◽

Carrie R. Ferrario

Keyword(s):

Nucleus Accumbens ◽

Estrous Cycle ◽

Ovarian Hormones ◽

Female Rats ◽

Intrinsic Excitability ◽

Medium Spiny Neurons ◽

Nucleus Accumbens Core ◽

Spiny Neurons ◽

Accumbens Core

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Cytoarchitectural impairments in the medium spiny neurons of the Nucleus Accumbens core of hyperactive juvenile rats

International Journal of Developmental Neuroscience ◽

10.1016/j.ijdevneu.2010.06.005 ◽

2010 ◽

Vol 28 (6) ◽

pp. 475-480 ◽

Cited By ~ 3

Author(s):

I. González-Burgos ◽

S. García-Martínez ◽

D.A. Velázquez-Zamora ◽

R. Ponce-Rolón

Keyword(s):

Nucleus Accumbens ◽

Medium Spiny Neurons ◽

Nucleus Accumbens Core ◽

Juvenile Rats ◽

Spiny Neurons ◽

Accumbens Core

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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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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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At the limbic-motor interface: disconnection of basolateral amygdala from nucleus accumbens core and shell reveals dissociable components of incentive motivation

European Journal of Neuroscience ◽

10.1111/j.1460-9568.2010.07439.x ◽

2010 ◽

Vol 32 (10) ◽

pp. 1735-1743 ◽

Cited By ~ 92

Author(s):

Michael W. Shiflett ◽

Bernard W. Balleine

Keyword(s):

Nucleus Accumbens ◽

Basolateral Amygdala ◽

Incentive Motivation ◽

Nucleus Accumbens Core ◽

Accumbens Core

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The Sodium Channel β4 Auxiliary Subunit Selectively Controls Long-Term Depression in Core Nucleus Accumbens Medium Spiny Neurons

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2017.00017 ◽

2017 ◽

Vol 11 ◽

Cited By ~ 2

Author(s):

Xincai Ji ◽

Sucharita Saha ◽

Guangping Gao ◽

Amy W. Lasek ◽

Gregg E. Homanics ◽

...

Keyword(s):

Nucleus Accumbens ◽

Sodium Channel ◽

Medium Spiny Neurons ◽

Long Term Depression ◽

Core Nucleus ◽

Auxiliary Subunit ◽

Spiny Neurons

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Microglial NFκB-TNFα hyperactivation induces obsessive–compulsive behavior in mouse models of progranulin-deficient frontotemporal dementia

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1700477114 ◽

2017 ◽

Vol 114 (19) ◽

pp. 5029-5034 ◽

Cited By ~ 45

Author(s):

Grietje Krabbe ◽

S. Sakura Minami ◽

Jon I. Etchegaray ◽

Praveen Taneja ◽

Biljana Djukic ◽

...

Keyword(s):

Nucleus Accumbens ◽

Frontotemporal Dementia ◽

Knockout Mice ◽

Nuclear Factor Κb ◽

Medium Spiny Neurons ◽

Obsessive Compulsive ◽

Compulsive Disorder ◽

Spiny Neurons ◽

Increased Risk ◽

Excessive Grooming

Frontotemporal dementia (FTD) is the second most common dementia before 65 years of age. Haploinsufficiency in the progranulin (GRN) gene accounts for 10% of all cases of familial FTD. GRN mutation carriers have an increased risk of autoimmune disorders, accompanied by elevated levels of tissue necrosis factor (TNF) α. We examined behavioral alterations related to obsessive–compulsive disorder (OCD) and the role of TNFα and related signaling pathways in FTD patients with GRN mutations and in mice lacking progranulin (PGRN). We found that patients and mice with GRN mutations displayed OCD and self-grooming (an OCD-like behavior in mice), respectively. Furthermore, medium spiny neurons in the nucleus accumbens, an area implicated in development of OCD, display hyperexcitability in PGRN knockout mice. Reducing levels of TNFα in PGRN knockout mice abolished excessive self-grooming and the associated hyperexcitability of medium spiny neurons of the nucleus accumbens. In the brain, PGRN is highly expressed in microglia, which are a major source of TNFα. We therefore deleted PGRN specifically in microglia and found that it was sufficient to induce excessive grooming. Importantly, excessive grooming in these mice was prevented by inactivating nuclear factor κB (NF-κB) in microglia/myeloid cells. Our findings suggest that PGRN deficiency leads to excessive NF-κB activation in microglia and elevated TNFα signaling, which in turn lead to hyperexcitability of medium spiny neurons and OCD-like behavior.

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