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María-Ríos CE, Murphy GG, Morrow JD. Individual Variation in Intrinsic Neuronal Properties of Nucleus Accumbens Core and Shell Medium Spiny Neurons in Animals Prone to Sign- or Goal-Track. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.24.644332. [PMID: 40236090 PMCID: PMC11996421 DOI: 10.1101/2025.03.24.644332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/17/2025]
Abstract
The "sign-tracking" and "goal-tracking" model of individual variation in associative learning permits the identification of rats with different cue-reactivity and predisposition to addiction-like behaviors. Certainly, compared to "goal-trackers" (GTs), "sign-trackers" (STs) show more susceptibility traits such as increased cue-induced 'relapse' of drugs of abuse. Different cue- and reward-evoked patterns of activity in the nucleus accumbens (NAc) have been a hallmark of the ST/GT phenotype. However, it is unknown whether differences in the intrinsic neuronal properties of NAc medium spiny neurons (MSNs) in the core and shell subregions are also a physiological correlate of these phenotypes. We performed whole-cell slice electrophysiology in outbred male rats and found that STs exhibited the lowest excitability in the NAc core, with lower number of action potentials and firing frequency as well as a blunted voltage/current relationship curve in response to hyperpolarized potentials in both the NAc core and shell. Although firing properties of shell MSNs did not differ between STs and GTs, intermediate responders that engage in both behaviors showed greater excitability compared to both STs and GTs. These findings suggest that intrinsic excitability in the NAc may contribute to individual differences in the attribution of incentive salience. Significance Statement During associative learning, cues acquire predictive value, but in some instances, they also acquire incentive salience, meaning they take on some of the motivational properties of the reward. The propensity to attribute cues with incentive salience varies between individuals, and excessive attribution can lead to maladaptive behaviors. The "sign-and goal-tracking" model allows us to isolate these two properties and disambiguate the neurobiological processes that govern them. To our knowledge this is the first study characterizing passive and active membrane properties of MSNs in the NAc core and shell of STs and GTs, as well as IRs. These findings are meant to better inform investigations of the distinct role of the NAc in reward learning, particularly in the attribution of incentive salience and addiction predisposition.
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Brida KL, Jorgensen ET, Phillips RA, Newman CE, Tuscher JJ, Morring EK, Zipperly ME, Ianov L, Montgomery KD, Tippani M, Hyde TM, Maynard KR, Martinowich K, Day JJ. Reelin marks cocaine-activated striatal neurons, promotes neuronal excitability, and regulates cocaine reward. SCIENCE ADVANCES 2025; 11:eads4441. [PMID: 40138397 PMCID: PMC12076537 DOI: 10.1126/sciadv.ads4441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Accepted: 02/20/2025] [Indexed: 03/29/2025]
Abstract
Drugs of abuse activate defined neuronal populations in reward structures such as the nucleus accumbens (NAc), which promote the enduring synaptic, circuit, and behavioral consequences of drug exposure. While the molecular and cellular effects arising from experience with drugs like cocaine are increasingly well understood, mechanisms that dictate NAc neuronal recruitment remain unknown. Here, we leveraged unbiased single-nucleus transcriptional profiling and targeted in situ detection to identify Reln (encoding the secreted glycoprotein, Reelin) as a marker of cocaine-activated neuronal populations within the rat NAc. A CRISPR interference approach enabling selective Reln knockdown in the adult NAc altered expression of calcium signaling genes, promoted a transcriptional trajectory consistent with loss of cocaine sensitivity, and decreased MSN excitability. Behaviorally, Reln knockdown prevented cocaine locomotor sensitization, abolished cocaine place preference memory, and decreased cocaine self-administration behavior. These results identify Reelin as a critical mechanistic link between neuronal activation and cocaine-induced behavioral adaptations.
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Affiliation(s)
- Kasey L. Brida
- Department of Neurobiology, University of
Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Emily T. Jorgensen
- Department of Neurobiology, University of
Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Robert A. Phillips
- Department of Neurobiology, University of
Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Catherine E. Newman
- Department of Neurobiology, University of
Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Jennifer J. Tuscher
- Department of Neurobiology, University of
Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Emily K. Morring
- Department of Neurobiology, University of
Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Morgan E. Zipperly
- Department of Neurobiology, University of
Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Lara Ianov
- Department of Neurobiology, University of
Alabama at Birmingham, Birmingham, AL 35294, USA
- Civitan International Research Center,
University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Kelsey D. Montgomery
- Lieber Institute for Brain Development,
Johns Hopkins Medical Campus, Baltimore, MD 21205, USA
| | - Madhavi Tippani
- Lieber Institute for Brain Development,
Johns Hopkins Medical Campus, Baltimore, MD 21205, USA
| | - Thomas M. Hyde
- Lieber Institute for Brain Development,
Johns Hopkins Medical Campus, Baltimore, MD 21205, USA
- Department of Psychiatry and Behavioral
Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205,
USA
- Department of Neurology, Johns Hopkins
University School of Medicine, Baltimore, MD 21205, USA
| | - Kristen R. Maynard
- Lieber Institute for Brain Development,
Johns Hopkins Medical Campus, Baltimore, MD 21205, USA
- Department of Psychiatry and Behavioral
Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205,
USA
- Department of Neuroscience, Johns Hopkins
University School of Medicine, Baltimore, MD 21205, USA
| | - Keri Martinowich
- Lieber Institute for Brain Development,
Johns Hopkins Medical Campus, Baltimore, MD 21205, USA
- Department of Psychiatry and Behavioral
Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205,
USA
- Department of Neuroscience, Johns Hopkins
University School of Medicine, Baltimore, MD 21205, USA
- The Kavli Neuroscience Discovery
Institute, Johns Hopkins University, Baltimore, MD 21205, USA
| | - Jeremy J. Day
- Department of Neurobiology, University of
Alabama at Birmingham, Birmingham, AL 35294, USA
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Berry EA, Huhulea EN, Ishibashi M, McGregor R, Siegel JM, Leonard CS. Chronic but not acute morphine exposure reversibly impairs spike generation and repetitive firing in a functionally distinct subpopulation of orexin neurons. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.20.644444. [PMID: 40196653 PMCID: PMC11974729 DOI: 10.1101/2025.03.20.644444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 04/09/2025]
Abstract
Orexin (hypocretin) neuropeptides regulate numerous essential functions including sleep/wake state stability and reward processing. Orexin synthesizing neurons respond to drug cues and undergo structural changes following persistent drug exposure. Post-mortem brains from opioid users, and opioid-treated rodents have orexin somata that become ~20 % smaller and ~50% more numerous and are postulated to promote hyper-motivation for drug-seeking though increased orexin release. Biophysical considerations suggest that decreased soma size should increase cellular excitability, however the impact of chronic opioids on firing ability, which drives peptide release, has not been explored. To test this, we assessed the intrinsic electrophysiological properties of orexin neurons by whole-cell recordings in slices from male orexin-EGFP mice treated by daily morphine or saline injections for two weeks. Paradoxically, we found that while daily morphine decreased average soma size, it impaired excitability in a subpopulation of orexin neurons identified by electrophysiological criteria as "H-type", while entirely sparing "D-type" neurons. This impairment was manifest by smaller, broader action potentials, variable firing and a downscaling of firing gain. These adaptations required more than a single morphine dose and recovered, along with soma size, after four weeks of passive withdrawal. Taken together, these observations indicate that daily opioid exposure differentially impacts H-type orexin neurons and predicts that the ability of these neurons to encode synaptic inputs into spike trains and to release neuropeptides becomes impaired in conjunction with opioid dependence.
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Affiliation(s)
| | - Ellen N. Huhulea
- Department of Physiology, New York Medical College, Valhalla, NY, USA
| | - Masaru Ishibashi
- Department of Neurophysiology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Ronald McGregor
- Neuropsychiatric Institute, University of California, Los Angeles, CA and Veterans Administration, Greater Los Angeles Healthcare System, Los Angeles, CA, USA
| | - Jerome M. Siegel
- Neuropsychiatric Institute, University of California, Los Angeles, CA and Veterans Administration, Greater Los Angeles Healthcare System, Los Angeles, CA, USA
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Anderson EM, Tsvetkov E, Wood D, Akiki RM, Al Hasanieh K, McCue LM, Taniguchi M, Lavin A, Cowan CW. Heroin Regulates the Voltage-Gated Sodium Channel Auxiliary Subunit, SCN1b, to Modulate Nucleus Accumbens Medium Spiny Neuron Intrinsic Excitability and Cue-Induced Heroin Seeking. eNeuro 2025; 12:ENEURO.0017-25.2025. [PMID: 39947903 PMCID: PMC11913320 DOI: 10.1523/eneuro.0017-25.2025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Accepted: 01/28/2025] [Indexed: 03/16/2025] Open
Abstract
Self-administration of addictive substances like heroin can couple the rewarding/euphoric effects of the drug with drug-associated cues, and opioid cue reactivity contributes to relapse vulnerability in abstinent individuals recovering from an opioid use disorder (OUD). Opioids are reported to alter the intrinsic excitability of medium spiny neurons (MSNs) in the nucleus accumbens (NAc), a key brain reward region linked to drug seeking, but how opioids alter NAc MSN neuronal excitability and the impact of altered MSN excitability on relapse-like opioid seeking remain unclear. Here, we discovered that self-administered, but not experimenter-administered, heroin reduced NAc protein levels of the voltage-gated sodium channel auxiliary subunit, SCN1b, in male and female rats. Viral-mediated reduction of NAc SCN1b increased the intrinsic excitability of MSNs, but without altering glutamatergic and GABAergic synaptic transmission. While reducing NAc SCN1b levels had no effect on acquisition of heroin self-administration or extinction learning, we observed a significant increase in cue-reinstated heroin seeking, suggesting that NAc SCN1b normally limits cue-reinstated heroin seeking. We also observed that NAc SCN1b protein levels returned to baseline following heroin self-administration, home-cage abstinence, and extinction training, suggesting that the noted reduction of NAc SCN1b during acquisition of heroin self-administration likely enhances MSN excitability and the strength of heroin-cue associations formed during active heroin use. As such, enhancing NAc SCN1b function might mitigate opioid cue reactivity and a return to active drug use in individuals suffering from OUD.
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Affiliation(s)
- Ethan M Anderson
- Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina 29425
- Department of Comparative Biomedical Sciences, Louisiana State University, Baton Rouge, Louisiana 70803
| | - Evgeny Tsvetkov
- Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina 29425
| | - Daniel Wood
- Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina 29425
| | - Rose Marie Akiki
- Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina 29425
| | - Karim Al Hasanieh
- Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina 29425
| | - Lauren M McCue
- Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina 29425
| | - Makoto Taniguchi
- Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina 29425
| | - Antonieta Lavin
- Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina 29425
| | - Christopher W Cowan
- Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina 29425
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Xu Y, Lin Y, Yu M, Zhou K. The nucleus accumbens in reward and aversion processing: insights and implications. Front Behav Neurosci 2024; 18:1420028. [PMID: 39184934 PMCID: PMC11341389 DOI: 10.3389/fnbeh.2024.1420028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Accepted: 07/26/2024] [Indexed: 08/27/2024] Open
Abstract
The nucleus accumbens (NAc), a central component of the brain's reward circuitry, has been implicated in a wide range of behaviors and emotional states. Emerging evidence, primarily drawing from recent rodent studies, suggests that the function of the NAc in reward and aversion processing is multifaceted. Prolonged stress or drug use induces maladaptive neuronal function in the NAc circuitry, which results in pathological conditions. This review aims to provide comprehensive and up-to-date insights on the role of the NAc in motivated behavior regulation and highlights areas that demand further in-depth analysis. It synthesizes the latest findings on how distinct NAc neuronal populations and pathways contribute to the processing of opposite valences. The review examines how a range of neuromodulators, especially monoamines, influence the NAc's control over various motivational states. Furthermore, it delves into the complex underlying mechanisms of psychiatric disorders such as addiction and depression and evaluates prospective interventions to restore NAc functionality.
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Affiliation(s)
| | | | | | - Kuikui Zhou
- School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, China
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Brida KL, Jorgensen ET, Phillips RA, Newman CE, Tuscher JJ, Morring EK, Zipperly ME, Ianov L, Montgomery KD, Tippani M, Hyde TM, Maynard KR, Martinowich K, Day JJ. Reelin marks cocaine-activated striatal ensembles, promotes neuronal excitability, and regulates cocaine reward. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.17.599348. [PMID: 38948801 PMCID: PMC11212904 DOI: 10.1101/2024.06.17.599348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/02/2024]
Abstract
Drugs of abuse activate defined neuronal ensembles in brain reward structures such as the nucleus accumbens (NAc), which are thought to promote the enduring synaptic, circuit, and behavioral consequences of drug exposure. While the molecular and cellular effects arising from experience with drugs like cocaine are increasingly well understood, the mechanisms that sculpt NAc ensemble participation are largely unknown. Here, we leveraged unbiased single-nucleus transcriptional profiling to identify expression of the secreted glycoprotein Reelin (encoded by the Reln gene) as a marker of cocaine-activated neuronal ensembles within the rat NAc. Multiplexed in situ detection confirmed selective expression of the immediate early gene Fos in Reln+ neurons after cocaine experience, and also revealed enrichment of Reln mRNA in Drd1 + medium spiny neurons (MSNs) in both the rat and human brain. Using a novel CRISPR interference strategy enabling selective Reln knockdown in the adult NAc, we observed altered expression of genes linked to calcium signaling, emergence of a transcriptional trajectory consistent with loss of cocaine sensitivity, and a striking decrease in MSN intrinsic excitability. At the behavioral level, loss of Reln prevented cocaine locomotor sensitization, abolished cocaine place preference memory, and decreased cocaine self-administration behavior. Together, these results identify Reelin as a critical mechanistic link between ensemble participation and cocaine-induced behavioral adaptations.
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Chapp AD, Nwakama CA, Jagtap PP, Phan CMH, Thomas MJ, Mermelstein PG. Fundamental Sex Differences in Cocaine-Induced Plasticity of Dopamine D1 Receptor- and D2 Receptor-Expressing Medium Spiny Neurons in the Mouse Nucleus Accumbens Shell. BIOLOGICAL PSYCHIATRY GLOBAL OPEN SCIENCE 2024; 4:100295. [PMID: 38533248 PMCID: PMC10963205 DOI: 10.1016/j.bpsgos.2024.100295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 02/02/2024] [Accepted: 02/11/2024] [Indexed: 03/28/2024] Open
Abstract
Background Cocaine-induced plasticity in the nucleus accumbens shell of males occurs primarily in dopamine D1 receptor-expressing medium spiny neurons (D1R-MSNs), with little if any impact on dopamine D2 receptor-expressing medium spiny neurons (D2R-MSNs). In females, the effect of cocaine on accumbens shell D1R- and D2R-MSN neurophysiology has yet to be reported, nor have estrous cycle effects been accounted for. Methods We used a 5-day locomotor sensitization paradigm followed by a 10- to 14-day drug-free abstinence period. We then obtained ex vivo whole-cell recordings from fluorescently labeled D1R-MSNs and D2R-MSNs in the nucleus accumbens shell of male and female mice during estrus and diestrus. We examined accumbens shell neuronal excitability as well as miniature excitatory postsynaptic currents (mEPSCs). Results In females, we observed alterations in D1R-MSN excitability across the estrous cycle similar in magnitude to the effects of cocaine in males. Furthermore, cocaine shifted estrous cycle-dependent plasticity from intrinsic excitability changes in D1R-MSNs to D2R-MSNs. In males, cocaine treatment produced the anticipated drop in D1R-MSN excitability with no effect on D2R-MSN excitability. Cocaine increased mEPSC frequencies and amplitudes in D2R-MSNs from females in estrus and mEPSC amplitudes of D2R-MSNs from females in diestrus. In males, cocaine increased both D1R- and D2R-MSN mEPSC amplitudes with no effect on mEPSC frequencies. Conclusions Overall, while there are similar cocaine-induced disparities regarding the relative excitability of D1R-MSNs versus D2R-MSNs between the sexes, this is mediated through reduced D1R-MSN excitability in males, whereas it is due to heightened D2R-MSN excitability in females.
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Affiliation(s)
- Andrew D. Chapp
- Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota
- Medical Discovery Team on Addiction, University of Minnesota, Minneapolis, Minnesota
| | - Chinonso A. Nwakama
- Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota
- Medical Discovery Team on Addiction, University of Minnesota, Minneapolis, Minnesota
- Medical Scientist Training Program, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Pramit P. Jagtap
- Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota
| | - Chau-Mi H. Phan
- Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota
| | - Mark J. Thomas
- Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota
- Medical Discovery Team on Addiction, University of Minnesota, Minneapolis, Minnesota
- Center for Neural Circuits in Addiction, University of Minnesota, Minneapolis, Minnesota
| | - Paul G. Mermelstein
- Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota
- Medical Discovery Team on Addiction, University of Minnesota, Minneapolis, Minnesota
- Center for Neural Circuits in Addiction, University of Minnesota, Minneapolis, Minnesota
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He Y, Wang J, Li KL, Wang YQ, Freyberg Z, Dong Y. Membrane excitability of nucleus accumbens neurons gates the incubation of cocaine craving. Neuropsychopharmacology 2023; 48:1318-1327. [PMID: 37041207 PMCID: PMC10354025 DOI: 10.1038/s41386-023-01580-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 03/15/2023] [Accepted: 03/28/2023] [Indexed: 04/13/2023]
Abstract
After drug withdrawal, a key factor triggering relapse is progressively intensified cue-associated drug craving, termed incubation of drug craving. After withdrawal from cocaine self-administration, incubation of cocaine craving develops more reliably in rats compared to mice. This species difference provides an opportunity to determine rat-specific cellular adaptations, which may constitute the critical mechanisms that contribute to incubated cocaine craving in humans. Expression of incubated cocaine seeking is mediated, in part, by cocaine-induced cellular adaptations in medium spiny neurons (MSNs) within the nucleus accumbens (NAc). In rats, decreased membrane excitability in NAc MSNs is a prominent cellular adaptation, which is induced after cocaine self-administration and lasts throughout prolonged drug withdrawal. Here, we show that, similar to rats, mice exhibit decreased membrane excitability of dopamine D1 receptor (D1)-, but not D2 (D2)-, expressing MSNs within the NAc shell (NAcSh) after 1 d withdrawal from cocaine self-administration. However, in contrast to rats, this membrane adaptation does not persist in mice, diminishing after 45-d withdrawal. We also find that restoring the membrane excitability of NAcSh MSNs after cocaine withdrawal decreases cocaine seeking in rats. This suggests that drug-induced membrane adaptations are essential for behavioral expression of incubated cocaine craving. In mice, however, experimentally inducing hypoactivity of D1 NAcSh MSNs after cocaine withdrawal does not alter cocaine seeking, suggesting that MSN hypo-excitability alone is insufficient to increase cocaine seeking. Together, our results demonstrate an overall permissive role of cocaine-induced hypoactivity of NAcSh MSNs in gating increased cocaine seeking after prolonged cocaine withdrawal.
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Affiliation(s)
- Yi He
- Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, 15260, USA
| | - Junshi Wang
- Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, 15260, USA
| | - King-Lun Li
- Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, 15260, USA
| | - Yao Q Wang
- Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, 15260, USA
| | - Zachary Freyberg
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, 15260, USA
- Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA, 15260, USA
| | - Yan Dong
- Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
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Miller CK, Krentzel AA, Meitzen J. ERα Stimulation Rapidly Modulates Excitatory Synapse Properties in Female Rat Nucleus Accumbens Core. Neuroendocrinology 2023; 113:1140-1153. [PMID: 36746131 PMCID: PMC10623399 DOI: 10.1159/000529571] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 01/30/2023] [Indexed: 02/08/2023]
Abstract
INTRODUCTION The nucleus accumbens core (NAcc) is a sexually differentiated brain region that is modulated by steroid hormones such as 17β-estradiol (estradiol), with consequential impacts on relevant motivated behaviors and disorders such as addiction, anxiety, and depression. NAcc estradiol levels naturally fluctuate, including during the estrous cycle in adult female rats, which is analogous to the menstrual cycle in adult humans. Across the estrous cycle, excitatory synapse properties of medium spiny neurons rapidly change, as indicated by analysis of miniature excitatory postsynaptic currents (mEPSCs). mEPSC frequency decreases during estrous cycle phases associated with high estradiol levels. This decrease in mEPSC frequency is mimicked by acute topical exposure to estradiol. The identity of the estrogen receptor (ER) underlying this estradiol action is unknown. Adult rat NAcc expresses three ERs, all extranuclear: membrane ERα, membrane ERβ, and GPER1. METHODS In this brief report, we take a first step toward addressing this challenge by testing whether activation of ERs via acute topical agonist application is sufficient for inducing changes in mEPSC properties recorded via whole-cell patch clamp. RESULTS An agonist of ERα induced large decreases in mEPSC frequency, while agonists of ERβ and GPER1 did not robustly modulate mEPSC properties. CONCLUSIONS These data provide evidence that activation of ERα is sufficient for inducing changes in mEPSC frequency and is a likely candidate underlying the estradiol-induced changes observed during the estrous cycle. Overall, these findings extend our understanding of the neuroendocrinology of the NAcc and implicate ERα as a primary target for future studies.
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Affiliation(s)
- Christiana K. Miller
- Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA
| | - Amanda A. Krentzel
- Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA
| | - John Meitzen
- Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA
- Comparative Medicine Institute, North Carolina State University, Raleigh, NC, USA
- Center for Human Health and the Environment, North Carolina State University, Raleigh, NC, USA
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Domi A, Lucente E, Cadeddu D, Adermark L. Nicotine but not saline self-administering or yoked control conditions produces sustained neuroadaptations in the accumbens shell. Front Mol Neurosci 2023; 16:1105388. [PMID: 36760603 PMCID: PMC9907443 DOI: 10.3389/fnmol.2023.1105388] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 01/09/2023] [Indexed: 01/26/2023] Open
Abstract
Introduction Using yoked animals as the control when monitoring operant drug-self-administration is considered the golden standard. However, instrumental learning per se recruits several neurocircuits that may produce distinct or overlapping neuroadaptations with drugs of abuse. The aim of this project was to assess if contingent responding for nicotine or saline in the presence of a light stimulus as a conditioned reinforcer is associated with sustained neurophysiological adaptations in the nucleus accumbens shell (nAcS), a brain region repeatedly associated with reward related behaviors. Methods To this end, nicotine-or saline-administrating rats and yoked-saline stimulus-unpaired training conditions were assessed in operant boxes over four consecutive weeks. After four additional weeks of home cage forced abstinence and subsequent cue reinforced responding under extinction conditions, ex vivo electrophysiology was performed in the nAcS medium spiny neurons (MSNs). Results Whole cell recordings conducted in voltage and current-clamp mode showed that excitatory synapses in the nAcS were altered after prolonged forced abstinence from nicotine self-administration. We observed an increase in sEPSC amplitude in animals with a history of contingent nicotine SA potentially indicating higher excitability of accumbal MSNs, which was further supported by current clamp recordings. Interestingly no sustained neuroadaptations were elicited in saline exposed rats from nicotine associated visual cues compared to the yoked controls. Conclusion The data presented here indicate that nicotine self-administration produces sustained neuroadaptations in the nAcS while operant responding driven by nicotine visual stimuli has no long-term effects on MSNs in nAcS.
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Affiliation(s)
- Ana Domi
- Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden,Addiction Biology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden,*Correspondence: Ana Domi, ✉
| | - Erika Lucente
- Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Davide Cadeddu
- Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Louise Adermark
- Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden,Addiction Biology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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11
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Differential Patterns of Synaptic Plasticity in the Nucleus Accumbens Caused by Continuous and Interrupted Morphine Exposure. J Neurosci 2023; 43:308-318. [PMID: 36396404 PMCID: PMC9838694 DOI: 10.1523/jneurosci.0595-22.2022] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 10/14/2022] [Accepted: 11/12/2022] [Indexed: 11/18/2022] Open
Abstract
Opioid exposure and withdrawal both cause adaptations in brain circuits that may contribute to abuse liability. These adaptations vary in magnitude and direction following different patterns of opioid exposure, but few studies have systematically manipulated the pattern of opioid administration while measuring neurobiological impact. In this study, we compared cellular and synaptic adaptations in the nucleus accumbens shell caused by morphine exposure that was either continuous or interrupted by daily bouts of naloxone-precipitated withdrawal. At the behavioral level, continuous morphine administration caused psychomotor tolerance, which was reversed when the continuity of morphine action was interrupted by naloxone-precipitated withdrawal. Using ex vivo slice electrophysiology in female and male mice, we investigated how these patterns of morphine administration altered intrinsic excitability and synaptic plasticity of medium spiny neurons (MSNs) expressing the D1 or D2 dopamine receptor. We found that morphine-evoked adaptations at excitatory synapses were predominately conserved between patterns of administration, but there were divergent effects on inhibitory synapses and the subsequent balance between excitatory and inhibitory synaptic input. Overall, our data suggest that continuous morphine administration produces adaptations that dampen the output of D1-MSNs, which are canonically thought to promote reward-related behaviors. Interruption of otherwise continuous morphine exposure does not dampen D1-MSN functional output to the same extent, which may enhance behavioral responses to subsequent opioid exposure. Our findings support the hypothesis that maintaining continuity of opioid administration could be an effective therapeutic strategy to minimize the vulnerability to opioid use disorders.SIGNIFICANCE STATEMENT Withdrawal plays a key role in the cycle of addiction to opioids like morphine. We studied how repeated cycles of naloxone-precipitated withdrawal from otherwise continuous opioid exposure can change brain function of the nucleus accumbens, which is an important brain region for reward and addiction. Different patterns of opioid exposure caused unique changes in communication between neurons in the nucleus accumbens, and the nature of these changes depended on the type of neuron being studied. The specific changes in communication between neurons caused by repeated cycles of withdrawal may increase vulnerability to opioid use disorders. This highlights the importance of reducing or preventing the experience of withdrawal during opioid treatment.
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12
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Miura Y, Shanley MR, Urbaez A, Friedman AK. Electrophysiologically distinct bed nucleus of the stria terminalis projections to the ventral tegmental area in mice. Front Neural Circuits 2023; 16:1081099. [PMID: 36698552 PMCID: PMC9870318 DOI: 10.3389/fncir.2022.1081099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 12/13/2022] [Indexed: 01/11/2023] Open
Abstract
The bed nucleus of the stria terminalis (BNST) is a highly heterogeneous limbic forebrain structure that serves as a relay connecting autonomic, neuroendocrine and behavioral function. It can be divided into over 16 individual subregions with distinct neuronal subpopulations based on receptors, transmitters, and neuropeptides. Specifically, the BNST projection to the ventral tegmental area (VTA), the dopamine hub of the brain, has been shown to have a crucial role in the stress response. However, in mice there is a lack of unbiased data on the functional diversity of this sub-population which serves as an upstream input to the VTA. The dopaminergic neurons in the VTA modify their ion channel activity and intrinsic membrane properties to adapt to stress in part from inputs from BNST projections. Therefore, we aimed to perform a multi-component characterization of the functional diversity of the BNST-VTA pathway. We studied the passive and active electrophysiological properties of virally identified population of BNST neurons that project to the VTA. We used a comprehensive series of in vitro recordings of electrophysiological variables and performed hierarchical clustering to determine the functional diversity of the projection neurons in the BNST-VTA pathway. Our study revealed four subpopulations in the BNST-VTA pathway, all of which differ in their activation profiles and likely have distinct inputs and function in the VTA. Our results will help resolve the discord in interpretation of the various roles of this electrophysiologically diverse projection and builds a foundation for understanding how the different neuronal types integrate signals.
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Affiliation(s)
- Yuka Miura
- Department of Biological Sciences, Hunter College of the City University of New York, New York, NY, United States
- Program in Biology, Graduate Center of the City University of New York, New York, NY, United States
| | - Mary Regis Shanley
- Department of Biological Sciences, Hunter College of the City University of New York, New York, NY, United States
- Program in Biology, Graduate Center of the City University of New York, New York, NY, United States
| | - Ashley Urbaez
- Department of Biological Sciences, Hunter College of the City University of New York, New York, NY, United States
| | - Allyson K. Friedman
- Department of Biological Sciences, Hunter College of the City University of New York, New York, NY, United States
- Program in Biology, Graduate Center of the City University of New York, New York, NY, United States
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13
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Persistent increase of accumbens cocaine ensemble excitability induced by IRK downregulation after withdrawal mediates the incubation of cocaine craving. Mol Psychiatry 2023; 28:448-462. [PMID: 36481931 PMCID: PMC9812793 DOI: 10.1038/s41380-022-01884-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 10/30/2022] [Accepted: 11/10/2022] [Indexed: 12/13/2022]
Abstract
The incubation phenomenon, cue-induced drug craving progressively increasing over prolonged withdrawal, accounts for persistent relapse, leading to a dilemma in the treatment of cocaine addiction. The role of neuronal ensembles activated by initial cocaine experience in the incubation phenomenon was unclear. In this study, with cocaine self-administration (SA) models, we found that neuronal ensembles in the nucleus accumbens shell (NAcSh) showed increasing activation induced by cue-induced drug-seeking after 30-day withdrawal. Inhibition or activation of NAcSh cocaine-ensembles suppressed or promoted craving for cocaine, demonstrating a critical role of NAcSh cocaine-ensembles in incubation for cocaine craving. NAcSh cocaine-ensembles showed a specific increase of membrane excitability and a decrease of inward rectifying channels Kir2.1 currents after 30-day withdrawal. Overexpression of Kir2.1 in NAcSh cocaine-ensembles restored neuronal membrane excitability and suppressed cue-induced drug-seeking after 30-day withdrawal. Expression of dominant-negative Kir2.1 in NAcSh cocaine-ensembles enhanced neuronal membrane excitability and accelerated incubation of cocaine craving. Our results provide a cellular mechanism that the downregulation of Kir2.1 functions in NAcSh cocaine-ensembles induced by prolonged withdrawal mediates the enhancement of ensemble membrane excitability, leading to incubation of cocaine craving.
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Krentzel AA, Proaño SB, Dorris DM, Setzer B, Meitzen J. The estrous cycle and 17β-estradiol modulate the electrophysiological properties of rat nucleus accumbens core medium spiny neurons. J Neuroendocrinol 2022; 34:e13122. [PMID: 35365910 PMCID: PMC9250601 DOI: 10.1111/jne.13122] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 02/02/2022] [Accepted: 02/22/2022] [Indexed: 12/03/2022]
Abstract
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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Affiliation(s)
- Amanda A. Krentzel
- Department of Biological SciencesNorth Carolina State UniversityRaleighNCUSA
| | - Stephanie B. Proaño
- Neurobiology LaboratoryNational Institute of Environmental Health Sciences, NIHResearch Triangle ParkNCUSA
| | - David M. Dorris
- Department of Biological SciencesNorth Carolina State UniversityRaleighNCUSA
| | - Beverly Setzer
- Graduate Program for Neuroscience and Department of Biomedical EngineeringBoston UniversityBostonMAUSA
| | - John Meitzen
- Department of Biological SciencesNorth Carolina State UniversityRaleighNCUSA
- Comparative Medicine InstituteNorth Carolina State UniversityRaleighNCUSA
- Center for Human Health and the EnvironmentNorth Carolina State UniversityRaleighNCUSA
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15
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Fleming W, Lee J, Briones BA, Bolkan SS, Witten IB. Cholinergic interneurons mediate cocaine extinction in male mice through plasticity across medium spiny neuron subtypes. Cell Rep 2022; 39:110874. [PMID: 35649378 PMCID: PMC9196889 DOI: 10.1016/j.celrep.2022.110874] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 03/07/2022] [Accepted: 05/05/2022] [Indexed: 11/28/2022] Open
Abstract
Cholinergic interneurons (ChINs) in the nucleus accumbens (NAc) have been implicated in the extinction of drug associations, as well as related plasticity in medium spiny neurons (MSNs). However, since most previous work relied on artificial manipulations, whether endogenous acetylcholine signaling relates to drug associations is unclear. Moreover, despite great interest in the opposing effects of dopamine on MSN subtypes, whether ChIN-mediated effects vary by MSN subtype is also unclear. Here, we find that high endogenous acetylcholine event frequency correlates with greater extinction of cocaine-context associations across male mice. Additionally, extinction is associated with a weakening of glutamatergic synapses across MSN subtypes. Manipulating ChIN activity bidirectionally controls both the rate of extinction and the associated plasticity at MSNs. Our findings indicate that NAc ChINs mediate drug-context extinction by reducing glutamatergic synaptic strength across MSN subtypes, and that natural variation in acetylcholine signaling may contribute to individual differences in extinction.
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Affiliation(s)
- Weston Fleming
- Princeton Neuroscience Institute, Princeton, NJ 08544, USA
| | - Junuk Lee
- Princeton Neuroscience Institute, Princeton, NJ 08544, USA
| | - Brandy A Briones
- Princeton Neuroscience Institute, Princeton, NJ 08544, USA; Department of Psychology, Princeton University, Princeton, NJ 08544, USA
| | - Scott S Bolkan
- Princeton Neuroscience Institute, Princeton, NJ 08544, USA
| | - Ilana B Witten
- Princeton Neuroscience Institute, Princeton, NJ 08544, USA; Department of Psychology, Princeton University, Princeton, NJ 08544, USA.
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16
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Glycogen Synthase Kinase 3: Ion Channels, Plasticity, and Diseases. Int J Mol Sci 2022; 23:ijms23084413. [PMID: 35457230 PMCID: PMC9028019 DOI: 10.3390/ijms23084413] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 04/13/2022] [Accepted: 04/14/2022] [Indexed: 12/15/2022] Open
Abstract
Glycogen synthase kinase 3β (GSK3) is a multifaceted serine/threonine (S/T) kinase expressed in all eukaryotic cells. GSK3β is highly enriched in neurons in the central nervous system where it acts as a central hub for intracellular signaling downstream of receptors critical for neuronal function. Unlike other kinases, GSK3β is constitutively active, and its modulation mainly involves inhibition via upstream regulatory pathways rather than increased activation. Through an intricate converging signaling system, a fine-tuned balance of active and inactive GSK3β acts as a central point for the phosphorylation of numerous primed and unprimed substrates. Although the full range of molecular targets is still unknown, recent results show that voltage-gated ion channels are among the downstream targets of GSK3β. Here, we discuss the direct and indirect mechanisms by which GSK3β phosphorylates voltage-gated Na+ channels (Nav1.2 and Nav1.6) and voltage-gated K+ channels (Kv4 and Kv7) and their physiological effects on intrinsic excitability, neuronal plasticity, and behavior. We also present evidence for how unbalanced GSK3β activity can lead to maladaptive plasticity that ultimately renders neuronal circuitry more vulnerable, increasing the risk for developing neuropsychiatric disorders. In conclusion, GSK3β-dependent modulation of voltage-gated ion channels may serve as an important pharmacological target for neurotherapeutic development.
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Zinsmaier AK, Dong Y, Huang YH. Cocaine-induced projection-specific and cell type-specific adaptations in the nucleus accumbens. Mol Psychiatry 2022; 27:669-686. [PMID: 33963288 PMCID: PMC8691189 DOI: 10.1038/s41380-021-01112-2] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Revised: 03/29/2021] [Accepted: 04/09/2021] [Indexed: 02/03/2023]
Abstract
Cocaine craving, seeking, and relapse are mediated, in part, by cocaine-induced adaptive changes in the brain reward circuits. The nucleus accumbens (NAc) integrates and prioritizes different emotional and motivational inputs to the reward system by processing convergent glutamatergic projections from the medial prefrontal cortex, basolateral amygdala, ventral hippocampus, and other limbic and paralimbic brain regions. Medium spiny neurons (MSNs) are the principal projection neurons in the NAc, which can be divided into two major subpopulations, namely dopamine receptor D1- versus D2-expressing MSNs, with complementing roles in reward-associated behaviors. After cocaine experience, NAc MSNs exhibit complex and differential adaptations dependent on cocaine regimen, withdrawal time, cell type, location (NAc core versus shell), and related input and output projections, or any combination of these factors. Detailed characterization of these cellular adaptations has been greatly facilitated by the recent development of optogenetic/chemogenetic techniques combined with transgenic tools. In this review, we discuss such cell type- and projection-specific adaptations induced by cocaine experience. Specifically, (1) D1 and D2 NAc MSNs frequently exhibit differential adaptations in spinogenesis, glutamatergic receptor trafficking, and intrinsic membrane excitability, (2) cocaine experience differentially changes the synaptic transmission at different afferent projections onto NAc MSNs, (3) cocaine-induced NAc adaptations exhibit output specificity, e.g., being different at NAc-ventral pallidum versus NAc-ventral tegmental area synapses, and (4) the input, output, subregion, and D1/D2 cell type may together determine cocaine-induced circuit plasticity in the NAc. In light of the projection- and cell-type specificity, we also briefly discuss ensemble and circuit mechanisms contributing to cocaine craving and relapse after drug withdrawal.
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Affiliation(s)
| | - Yan Dong
- Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15219,Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15219
| | - Yanhua H. Huang
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15219
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18
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The role of the nucleus accumbens and ventral pallidum in feeding and obesity. Prog Neuropsychopharmacol Biol Psychiatry 2021; 111:110394. [PMID: 34242717 DOI: 10.1016/j.pnpbp.2021.110394] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 05/31/2021] [Accepted: 06/29/2021] [Indexed: 02/04/2023]
Abstract
Obesity is a growing global epidemic that stems from the increasing availability of highly-palatable foods and the consequent enhanced calorie consumption. Extensive research has shown that brain regions that are central to reward seeking modulate feeding and evidence linking obesity to pathology in such regions have recently started to accumulate. In this review we focus on the contribution of two major interconnected structures central to reward processing, the nucleus accumbens and the ventral pallidum, to obesity. We first review the known literature linking these structures to feeding behavior, then discuss recent advances connecting pathology in the nucleus accumbens and ventral pallidum to obesity, and finally examine the similarities and differences between drug addiction and obesity in the context of these two structures. The understanding of how pathology in brain regions involved in reward seeking and consumption may drive obesity and how mechanistically similar obesity and addiction are, is only now starting to be revealed. We hope that future research will advance knowledge in the field and open new avenues to studying and treating obesity.
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19
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Vadakkan KI. Framework for internal sensation of pleasure using constraints from disparate findings in nucleus accumbens. World J Psychiatry 2021; 11:681-695. [PMID: 34733636 PMCID: PMC8546768 DOI: 10.5498/wjp.v11.i10.681] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 06/27/2021] [Accepted: 09/02/2021] [Indexed: 02/06/2023] Open
Abstract
It is necessary to find a mechanism that generates first-person inner sensation of pleasure to understand what causes addiction and associated behaviour by drugs of abuse. The actual mechanism is expected to explain several disparate findings in nucleus accumbens (NAc), a brain region associated with pleasure, in an interconnected manner. Previously, it was possible to derive a mechanism for natural learning and explain: (1) Generation of inner sensation of memory using changes generated by learning; and (2) Long-term potentiation as an experimental delayed scaled-up change by the same mechanism that occur during natural learning. By extending these findings and by using disparate third person observations in NAc from several studies, present work provides a framework of a mechanism that generates internal sensation of pleasure that can provide interconnected explanations for: (1) Ability to induce robust long-term depression (LTD) in NAc from naïve animals; (2) Impaired ability to induce LTD in “addicted” state; (3) Attenuation of postsynaptic potentials by cocaine; and (4) Reduced firing of medium spiny neurons in response to cocaine or dopamine. Findings made by this work are testable.
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20
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Campbell RR, Chen S, Beardwood JH, López AJ, Pham LV, Keiser AM, Childs JE, Matheos DP, Swarup V, Baldi P, Wood MA. Cocaine induces paradigm-specific changes to the transcriptome within the ventral tegmental area. Neuropsychopharmacology 2021; 46:1768-1779. [PMID: 34155331 PMCID: PMC8357835 DOI: 10.1038/s41386-021-01031-4] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 04/29/2021] [Accepted: 04/29/2021] [Indexed: 12/16/2022]
Abstract
During the initial stages of drug use, cocaine-induced neuroadaptations within the ventral tegmental area (VTA) are critical for drug-associated cue learning and drug reinforcement processes. These neuroadaptations occur, in part, from alterations to the transcriptome. Although cocaine-induced transcriptional mechanisms within the VTA have been examined, various regimens and paradigms have been employed to examine candidate target genes. In order to identify key genes and biological processes regulating cocaine-induced processes, we employed genome-wide RNA-sequencing to analyze transcriptional profiles within the VTA from male mice that underwent one of four commonly used paradigms: acute home cage injections of cocaine, chronic home cage injections of cocaine, cocaine-conditioning, or intravenous-self administration of cocaine. We found that cocaine alters distinct sets of VTA genes within each exposure paradigm. Using behavioral measures from cocaine self-administering mice, we also found several genes whose expression patterns corelate with cocaine intake. In addition to overall gene expression levels, we identified several predicted upstream regulators of cocaine-induced transcription shared across all paradigms. Although distinct gene sets were altered across cocaine exposure paradigms, we found, from Gene Ontology (GO) term analysis, that biological processes important for energy regulation and synaptic plasticity were affected across all cocaine paradigms. Coexpression analysis also identified gene networks that are altered by cocaine. These data indicate that cocaine alters networks enriched with glial cell markers of the VTA that are involved in gene regulation and synaptic processes. Our analyses demonstrate that transcriptional changes within the VTA depend on the route, dose and context of cocaine exposure, and highlight several biological processes affected by cocaine. Overall, these findings provide a unique resource of gene expression data for future studies examining novel cocaine gene targets that regulate drug-associated behaviors.
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Affiliation(s)
- Rianne R Campbell
- Department of Neurobiology and Behavior, School of Biological Sciences University of California, Irvine, CA, USA
- UC Irvine Center for Addiction Neuroscience, School of Biological Sciences, University of California, Irvine, CA, USA
- Center for the Neurobiology of Learning and Memory, School of Biological Sciences, University of California, Irvine, CA, USA
| | - Siwei Chen
- Department of Computer Science, University of California, Irvine, CA, USA
- Institute for Genomics and Bioinformatics, University of California, Irvine, CA, USA
| | - Joy H Beardwood
- Department of Neurobiology and Behavior, School of Biological Sciences University of California, Irvine, CA, USA
- UC Irvine Center for Addiction Neuroscience, School of Biological Sciences, University of California, Irvine, CA, USA
- Center for the Neurobiology of Learning and Memory, School of Biological Sciences, University of California, Irvine, CA, USA
| | - Alberto J López
- Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Lilyana V Pham
- Department of Neurobiology and Behavior, School of Biological Sciences University of California, Irvine, CA, USA
- UC Irvine Center for Addiction Neuroscience, School of Biological Sciences, University of California, Irvine, CA, USA
- Center for the Neurobiology of Learning and Memory, School of Biological Sciences, University of California, Irvine, CA, USA
| | - Ashley M Keiser
- Department of Neurobiology and Behavior, School of Biological Sciences University of California, Irvine, CA, USA
- Center for the Neurobiology of Learning and Memory, School of Biological Sciences, University of California, Irvine, CA, USA
| | - Jessica E Childs
- Department of Neurobiology and Behavior, School of Biological Sciences University of California, Irvine, CA, USA
- UC Irvine Center for Addiction Neuroscience, School of Biological Sciences, University of California, Irvine, CA, USA
- Center for the Neurobiology of Learning and Memory, School of Biological Sciences, University of California, Irvine, CA, USA
| | - Dina P Matheos
- Department of Neurobiology and Behavior, School of Biological Sciences University of California, Irvine, CA, USA
- UC Irvine Center for Addiction Neuroscience, School of Biological Sciences, University of California, Irvine, CA, USA
- Center for the Neurobiology of Learning and Memory, School of Biological Sciences, University of California, Irvine, CA, USA
| | - Vivek Swarup
- Department of Neurobiology and Behavior, School of Biological Sciences University of California, Irvine, CA, USA
| | - Pierre Baldi
- Center for the Neurobiology of Learning and Memory, School of Biological Sciences, University of California, Irvine, CA, USA
- Department of Computer Science, University of California, Irvine, CA, USA
- Institute for Genomics and Bioinformatics, University of California, Irvine, CA, USA
| | - Marcelo A Wood
- Department of Neurobiology and Behavior, School of Biological Sciences University of California, Irvine, CA, USA.
- UC Irvine Center for Addiction Neuroscience, School of Biological Sciences, University of California, Irvine, CA, USA.
- Center for the Neurobiology of Learning and Memory, School of Biological Sciences, University of California, Irvine, CA, USA.
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Krentzel AA, Kimble LC, Dorris DM, Horman BM, Meitzen J, Patisaul HB. FireMaster® 550 (FM 550) exposure during the perinatal period impacts partner preference behavior and nucleus accumbens core medium spiny neuron electrophysiology in adult male and female prairie voles, Microtus ochrogaster. Horm Behav 2021; 134:105019. [PMID: 34182292 PMCID: PMC8403633 DOI: 10.1016/j.yhbeh.2021.105019] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 05/27/2021] [Accepted: 06/11/2021] [Indexed: 11/23/2022]
Abstract
One of the most widely used flame retardant (FR) mixtures in household products is Firemaster 550 (FM 550). FM 550 leaches from items such as foam-based furniture and infant products, resulting in contamination of the household environment and biota. Previous studies indicate sex-specific behavioral deficits in rodents and zebrafish in response to developmental FM 550 exposure. These deficits include impacts on social and attachment behaviors in a prosocial rodent: the prairie vole (Microtus ochrogaster). The prairie vole is a laboratory-acclimated rodent that exhibits spontaneous attachment behaviors including pair bonding. Here we extend previous work by addressing how developmental exposure to FM 550 impacts pair bonding strength via an extended-time partner preference test, as well as neuron electrophysiological properties in a region implicated in pair bond behavior, the nucleus accumbens (NAcc) core. Dams were exposed to vehicle or 1000 μg of FM 550 via subcutaneous injections throughout gestation, and female and male pups were directly exposed beginning the day after birth until weaning. Pair bond behavior of adult female and male offspring was assessed using a three hour-long partner preference test. Afterwards, acute brain slices of the NAcc core were produced and medium spiny neuron electrophysiological attributes recorded via whole cell patch-clamp. Behavioral impacts were sex-specific. Partner preference behavior was increased in exposed females but decreased in exposed males. Electrophysiological impacts were similar between sexes and specific to attributes related to input resistance. Input resistance was decreased in neurons recorded from both sexes exposed to FM 550 compared to vehicle. This study supports the hypothesis that developmental exposure to FM 550 impacts attachment behaviors and demonstrates a novel FM 550 effect on neural electrophysiology.
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Affiliation(s)
- Amanda A Krentzel
- Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695, USA
| | - Laney C Kimble
- Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695, USA
| | - David M Dorris
- Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695, USA
| | - Brian M Horman
- Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695, USA
| | - John Meitzen
- Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695, USA; Center for Human Health and the Environment, North Carolina State University, Raleigh, NC 27695, USA; Comparative Medicine Institute, North Carolina State University, Raleigh, NC 27695, USA.
| | - Heather B Patisaul
- Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695, USA; Center for Human Health and the Environment, North Carolina State University, Raleigh, NC 27695, USA
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22
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Cao J, Meitzen J. Perinatal activation of ER α and ER β but not GPER-1 masculinizes female rat caudate-putamen medium spiny neuron electrophysiological properties. J Neurophysiol 2021; 125:2322-2338. [PMID: 33978486 DOI: 10.1152/jn.00063.2021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Exposure to steroid sex hormones such as 17β-estradiol (estradiol) during early life potentially permanently masculinize neuron electrophysiological phenotype. In rodents, one crucial component of this developmental process occurs in males, with estradiol aromatized in the brain from testes-sourced testosterone. However, it is unknown whether most neuron electrophysiological phenotypes are altered by this early masculinization process, including medium spiny neurons (MSNs) of the rat caudate-putamen. MSNs are the predominant and primary output neurons of the caudate-putamen and exhibit increased intrinsic excitability in females compared to males. Here, we hypothesize that since perinatal estradiol exposure occurs in males, then a comparable exposure in females to estradiol or its receptor agonists would be sufficient to induce masculinization. To test this hypothesis, we injected perinatal female rats with estradiol or its receptor agonists and then later assessed MSN electrophysiology. Female and male rats on postnatal day 0 and 1 were systemically injected with either vehicle, estradiol, the estrogen receptor (ER)α agonist PPT, the ERβ agonist DPN, or the G-protein-coupled receptor 1 (GPER-1) agonist G1. On postnatal days 19 ± 2, MSN electrophysiological properties were assessed using whole cell patch clamp recordings. Estradiol exposure abolished increased intrinsic excitability in female compared to male MSNs. Exposure to either an ERα or ERβ agonist masculinized female MSN evoked action potential firing rate properties, whereas exposure to an ERβ agonist masculinized female MSN inward rectification properties. Exposure to ER agonists minimally impacted male MSN electrophysiological properties. These findings indicate that perinatal estradiol exposure masculinizes MSN electrophysiological phenotype via activation of ERα and ERβ.NEW & NOTEWORTHY This study is the first to demonstrate that estradiol and estrogen receptor α and β stimulation during early development sexually differentiates the electrophysiological properties of caudate-putamen medium spiny neurons, the primary output neuron of the striatal regions. Overall, this evidence provides new insight into the neuroendocrine mechanism by which caudate-putamen neuron electrophysiology is sexually differentiated and demonstrates the powerful action of early hormone exposure upon individual neuron electrophysiology.
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Affiliation(s)
- Jinyan Cao
- Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina
| | - John Meitzen
- Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina.,Center for Human Health and the Environment, North Carolina State University, Raleigh, North Carolina.,Comparative Medicine Institute, North Carolina State University, Raleigh, North Carolina
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Neugornet A, O'Donovan B, Ortinski PI. Comparative Effects of Event Detection Methods on the Analysis and Interpretation of Ca 2+ Imaging Data. Front Neurosci 2021; 15:620869. [PMID: 33841076 PMCID: PMC8032960 DOI: 10.3389/fnins.2021.620869] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Accepted: 01/25/2021] [Indexed: 01/04/2023] Open
Abstract
Calcium imaging has gained substantial popularity as a tool to profile the activity of multiple simultaneously active cells at high spatiotemporal resolution. Among the diverse approaches to processing of Ca2+ imaging data is an often subjective decision of how to quantify baseline fluorescence or F 0. We examine the effect of popular F 0 determination methods on the interpretation of neuronal and astrocyte activity in a single dataset of rats trained to self-administer intravenous infusions of cocaine and compare them with an F 0-independent wavelet ridgewalking event detection approach. We find that the choice of the processing method has a profound impact on the interpretation of widefield imaging results. All of the dF/F 0 thresholding methods tended to introduce spurious events and fragment individual transients, leading to smaller calculated event durations and larger event frequencies. Analysis of simulated datasets confirmed these observations and indicated substantial intermethod variability as to the events classified as significant. Additionally, most dF/F 0 methods on their own were unable to adequately account for bleaching of fluorescence, although the F 0 smooth approach and the wavelet ridgewalking algorithm both did so. In general, the choice of the processing method led to dramatically different quantitative and sometimes opposing qualitative interpretations of the effects of cocaine self-administration both at the level of individual cells and at the level of cell networks. Significantly different distributions of event duration, amplitude, frequency, and network measures were found across the majority of dF/F 0 approaches. The wavelet ridgewalking algorithm broadly outperformed dF/F 0-based methods for both neuron and astrocyte recordings. These results indicate the need for heightened awareness of the limitations and tendencies associated with decisions to use particular Ca2+ image processing pipelines. Both quantification and interpretation of the effects of experimental manipulations are strongly sensitive to such decisions.
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Affiliation(s)
- Austin Neugornet
- Department of Neuroscience, School of Medicine, University of Kentucky, Lexington, KY, United States
| | - Bernadette O'Donovan
- Department of Pharmacology, Physiology and Neuroscience, University of South Carolina School of Medicine, Columbia, SC, United States
| | - Pavel Ivanovich Ortinski
- Department of Neuroscience, School of Medicine, University of Kentucky, Lexington, KY, United States
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24
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Schall TA, Wright WJ, Dong Y. Nucleus accumbens fast-spiking interneurons in motivational and addictive behaviors. Mol Psychiatry 2021; 26:234-246. [PMID: 32071384 PMCID: PMC7431371 DOI: 10.1038/s41380-020-0683-y] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Revised: 01/02/2020] [Accepted: 02/07/2020] [Indexed: 02/07/2023]
Abstract
The development of drug addiction is associated with functional adaptations within the reward circuitry, within which the nucleus accumbens (NAc) is anatomically positioned as an interface between motivational salience and behavioral output. The functional output of NAc is profoundly altered after exposure to drugs of abuse, and some of the functional changes continue to evolve during drug abstinence, contributing to numerous emotional and motivational alterations related drug taking, seeking, and relapse. As in most brain regions, the functional output of NAc is critically dependent on the dynamic interaction between excitation and inhibition. One of the most prominent sources of inhibition within the NAc arises from fast-spiking interneurons (FSIs). Each NAc FSI innervates hundreds of principal neurons, and orchestrates population activity through its powerful and sustained feedforward inhibition. While the role of NAc FSIs in the context of drug addiction remains poorly understood, emerging evidence suggests that FSIs and FSI-mediated local circuits are key targets for drugs of abuse to tilt the functional output of NAc toward a motivational state favoring drug seeking and relapse. In this review, we discuss recent findings and our conceptualization about NAc FSI-mediated regulation of motivated and cocaine-induced behaviors. We hope that the conceptual framework proposed in this review may provide a useful guidance for ongoing and future studies to determine how FSIs influence the function of NAc and related reward circuits, ultimately leading to addictive behaviors.
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Affiliation(s)
- Terra A Schall
- Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, 15260, USA
| | - William J Wright
- Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, 15260, USA
| | - Yan Dong
- Departments of Neuroscience and Psychiatry, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
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25
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Luo YX, Huang D, Guo C, Ma YY. Limited versus extended cocaine intravenous self-administration: Behavioral effects and electrophysiological changes in insular cortex. CNS Neurosci Ther 2020; 27:196-205. [PMID: 33118700 PMCID: PMC7816201 DOI: 10.1111/cns.13469] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 09/19/2020] [Accepted: 09/23/2020] [Indexed: 12/22/2022] Open
Abstract
Aims Limited vs extended drug exposure has been proposed as one of the key factors in determining the risk of relapse, which is the primary characteristic of addiction behaviors. The current studies were designed to explore the related behavioral effects and neuronal alterations in the insular cortex (IC), an important brain region involved in addiction. Methods Experiments started with rats at the age of 35 days, a typical adolescent stage when initial drug exposure occurs often in humans. The drug‐seeking/taking behaviors, and membrane properties and intrinsic excitability of IC pyramidal neurons were measured on withdrawal day (WD) 1 and WD 45‐48 after limited vs extended cocaine intravenous self‐administration (IVSA). Results We found higher cocaine‐taking behaviors at the late withdrawal period after limited vs extended cocaine IVSA. We also found minor but significant effects of limited but not extended cocaine exposure on the kinetics and amplitude of action potentials on WD 45, in IC pyramidal neurons. Conclusion Our results indicate potential high risks of relapse in young rats with limited but not extended drug exposure, although the adaptations detected in the IC may not be sufficient to explain the neural changes of higher drug‐taking behaviors induced by limited cocaine IVSA.
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Affiliation(s)
- Yi-Xiao Luo
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA.,Department of Psychology, Behavioral Neuroscience Program, State University of New York, Binghamton, NY, USA
| | - Donald Huang
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Changyong Guo
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Yao-Ying Ma
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA.,Department of Psychology, Behavioral Neuroscience Program, State University of New York, Binghamton, NY, USA.,Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA
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26
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Luo YX, Galaj E, Ma YY. Differential alterations of insular cortex excitability after adolescent or adult chronic intermittent ethanol administration in male rats. J Neurosci Res 2020; 99:649-661. [PMID: 33094531 DOI: 10.1002/jnr.24737] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 09/19/2020] [Accepted: 09/30/2020] [Indexed: 12/31/2022]
Abstract
Adolescent alcohol drinking, primarily in the form of binge-drinking episodes, is a serious public health concern. Binge drinking in laboratory animals has been modeled by a procedure involving chronic intermittent ethanol (CIE) administration, as compared with chronic intermittent water (CIW). The prolonged effects of adolescent binge alcohol exposure in adults, such as high risk of developing alcohol use disorder, are severe but available treatments in the clinic are limited. One reason is the lack of sufficient understanding about the associated neuronal alterations. The involvement of the insular cortex, particularly the anterior agranular insula (AAI), has emerged as a critical region to explain neuronal mechanisms of substance abuse. This study was designed to evaluate the functional output of the AAI by measuring the intrinsic excitability of pyramidal neurons from male rats 2 or 21 days after adolescent or adult CIE treatment. Decreases in intrinsic excitability in AAI pyramidal neurons were detected 21 days, relative to 2 days, after adolescent CIE. Interestingly, the decreased intrinsic excitability in the AAI pyramidal neurons was observed 2 days after adult CIE, compared to adult CIW, but no difference was found between 2 versus 21 days after adult CIE. These data indicate that, although the AAI is influenced within a limited period after adult but not adolescent CIE, neuronal alterations in AAI are affected during the prolonged period of withdrawal from adolescent but not adult CIE. This may explain the prolonged vulnerability to mental disorders of subjects with an alcohol binge history during their adolescent stage.
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Affiliation(s)
- Yi-Xiao Luo
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA.,Department of Psychology, Behavioral Neuroscience Program, State University of New York, Binghamton, NY, USA
| | - Ewa Galaj
- Department of Psychology, Behavioral Neuroscience Program, State University of New York, Binghamton, NY, USA
| | - Yao-Ying Ma
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA.,Department of Psychology, Behavioral Neuroscience Program, State University of New York, Binghamton, NY, USA.,Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA
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27
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Proaño SB, Meitzen J. Estradiol decreases medium spiny neuron excitability in female rat nucleus accumbens core. J Neurophysiol 2020; 123:2465-2475. [PMID: 32432511 DOI: 10.1152/jn.00210.2020] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
The menstrual cycle in humans and its analogous cycle in rodents, the estrous cycle, modulate brain function and behavior. Both cycles are characterized by the cyclical fluctuation of ovarian hormones including estrogens such as estradiol. Estradiol induces cycle- and sex-dependent differences in the phenotype and incidence of many behaviors, including those related to reward and motivation. The nucleus accumbens core (AcbC), a limbic and premotor system nexus region, directly regulates these behaviors. We previously showed that the estrous cycle modulates intrinsic excitability and excitatory synapse properties of medium spiny neurons (MSNs) in the AcbC. The identity of the underlying hormone mechanism is unknown, with estradiol being a prime candidate. The present study tests the hypothesis that estradiol induces estrous cycle-relevant differences in MSN electrophysiology. To accomplish this goal, a time- and dose-dependent estradiol replacement paradigm designed to simulate the rise of circulating estradiol levels across the estrous cycle was employed in ovariectomized adult female rats as well as a vehicle control group. Estradiol replacement decreased MSN excitability by modulating properties such as resting membrane potential, input resistance in both the linear and rectified ranges, and rheobase compared with vehicle-treated females. These differences in MSN excitability mimic those previously described regarding estrous cycle effects on MSN electrophysiology. Excitatory synapse properties were not modulated in response to this estradiol replacement paradigm. These data are the first to demonstrate that an estrous cycle-relevant estradiol exposure modulates MSN electrophysiology, providing evidence of the fundamental neuroendocrine mechanisms regulating the AcbC.NEW & NOTEWORTHY 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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Affiliation(s)
- Stephanie B Proaño
- Graduate Program in Biology, North Carolina State University, Raleigh, North Carolina.,W. M. Keck Center for Behavioral Biology, North Carolina State University, Raleigh, North Carolina.,Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina
| | - John Meitzen
- W. M. Keck Center for Behavioral Biology, North Carolina State University, Raleigh, North Carolina.,Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina.,Center for Human Health and the Environment, North Carolina State University, Raleigh, North Carolina
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28
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Proaño SB, Krentzel AA, Meitzen J. Differential and synergistic roles of 17β-estradiol and progesterone in modulating adult female rat nucleus accumbens core medium spiny neuron electrophysiology. J Neurophysiol 2020; 123:2390-2405. [PMID: 32401164 DOI: 10.1152/jn.00157.2020] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Naturally occurring cyclical changes in sex steroid hormones such as 17β-estradiol and progesterone can modulate neuron function and behavior in female mammals. One example is the estrous cycle in rats, which is composed of multiple phases. We previously reported evidence of differences between estrous cycle phases in excitatory synapse and intrinsic electrophysiological properties of rat nucleus accumbens core (AcbC) medium spiny neurons (MSNs). The AcbC is a nexus between the limbic and premotor systems and is integral for controlling motivated and reward-associated behaviors and disorders, which are sensitive to the estrous cycle and hormones. The present study expands our prior findings by testing whether circulating levels of estradiol and progesterone correlate with changes in MSN electrophysiology across estrous cycle phases. As part of this project, the excitatory synapse and intrinsic excitability properties of MSNs in late proestrus of adult female rats were assessed. Circulating levels of estradiol correlate with resting membrane potential, the time constant of the membrane, and rheobase. Circulating levels of progesterone correlate with miniature excitatory postsynaptic current (mEPSC) frequency and amplitude. Circulating levels of estradiol and progesterone together correlate with mEPSC amplitude, resting membrane potential, and input resistance. The late proestrus phase features a prominent and unique decrease in mEPSC frequency. These data indicate that circulating levels of estradiol and progesterone alone or in combination interact with specific MSN electrophysiological properties, indicating differential and synergistic roles of these hormones. Broadly, these findings illustrate the underlying endocrine actions regarding how the estrous cycle modulates MSN electrophysiology.NEW & NOTEWORTHY 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.
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Affiliation(s)
- Stephanie B Proaño
- Graduate Program in Biology, North Carolina State University, Raleigh, North Carolina.,W.M. Keck Center for Behavioral Biology, North Carolina State University, Raleigh, North Carolina.,Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina
| | - Amanda A Krentzel
- W.M. Keck Center for Behavioral Biology, North Carolina State University, Raleigh, North Carolina.,Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina
| | - John Meitzen
- W.M. Keck Center for Behavioral Biology, North Carolina State University, Raleigh, North Carolina.,Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina.,Center for Human Health and the Environment, North Carolina State University, Raleigh, North Carolina
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29
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Delint-Ramirez I, Garcia-Oscos F, Segev A, Kourrich S. Cocaine engages a non-canonical, dopamine-independent, mechanism that controls neuronal excitability in the nucleus accumbens. Mol Psychiatry 2020; 25:680-691. [PMID: 29880884 PMCID: PMC7042730 DOI: 10.1038/s41380-018-0092-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Revised: 04/03/2018] [Accepted: 04/13/2018] [Indexed: 11/25/2022]
Abstract
Drug-induced enhanced dopamine (DA) signaling in the brain is a canonical mechanism that initiates addiction processes. However, indirect evidence suggests that cocaine also triggers non-canonical, DA-independent, mechanisms that contribute to behavioral responses to cocaine, including psychomotor sensitization and cocaine self-administration. Identifying these mechanisms and determining how they are initiated is fundamental to further our understanding of addiction processes. Using physiologically relevant in vitro tractable models, we found that cocaine-induced hypoactivity of nucleus accumbens shell (NAcSh) medium spiny neurons (MSNs), one hallmark of cocaine addiction, is independent of DA signaling. Combining brain slice studies and site-directed mutagenesis in HEK293T cells, we found that cocaine binding to intracellular sigma-1 receptor (σ1) initiates this mechanism. Subsequently, σ1 binds to Kv1.2 potassium channels, followed by accumulation of Kv1.2 in the plasma membrane, thereby depressing NAcSh MSNs firing. This mechanism is specific to D1 receptor-expressing MSNs. Our study uncovers a mechanism for cocaine that bypasses DA signaling and leads to addiction-relevant neuroadaptations, thereby providing combinatorial strategies for treating stimulant abuse.
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Affiliation(s)
- Ilse Delint-Ramirez
- 0000 0000 9482 7121grid.267313.2Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390 USA
| | - Francisco Garcia-Oscos
- 0000 0000 9482 7121grid.267313.2Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390 USA
| | - Amir Segev
- 0000 0000 9482 7121grid.267313.2Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390 USA
| | - Saïd Kourrich
- Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
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30
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McDevitt DS, Jonik B, Graziane NM. Morphine Differentially Alters the Synaptic and Intrinsic Properties of D1R- and D2R-Expressing Medium Spiny Neurons in the Nucleus Accumbens. Front Synaptic Neurosci 2019; 11:35. [PMID: 31920618 PMCID: PMC6932971 DOI: 10.3389/fnsyn.2019.00035] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Accepted: 12/06/2019] [Indexed: 12/31/2022] Open
Abstract
Exposure to opioids reshapes future reward and motivated behaviors partially by altering the functional output of medium spiny neurons (MSNs) in the nucleus accumbens shell. Here, we investigated how morphine, a highly addictive opioid, alters synaptic transmission and intrinsic excitability on dopamine D1-receptor (D1R) expressing and dopamine D2-receptor (D2R) expressing MSNs, the two main output neurons in the nucleus accumbens shell. Using whole-cell electrophysiology recordings, we show, that 24 h abstinence following repeated non-contingent administration of morphine (10 mg/kg, i.p.) in mice reduces the miniature excitatory postsynaptic current (mEPSC) frequency and miniature inhibitory postsynaptic current (mIPSC) frequency on D2R-MSNs, with concomitant increases in D2R-MSN intrinsic membrane excitability. We did not observe any changes in synaptic or intrinsic changes on D1R-MSNs. Last, in an attempt to determine the integrated effect of the synaptic and intrinsic alterations on the overall functional output of D2R-MSNs, we measured the input-output efficacy by measuring synaptically-driven action potential firing. We found that both D1R-MSN and D2R-MSN output was unchanged following morphine treatment.
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Affiliation(s)
- Dillon S McDevitt
- Departments of Anesthesiology and Perioperative Medicine, and Pharmacology, Penn State College of Medicine, Hershey, PA, United States.,Neuroscience Graduate Program, Penn State College of Medicine, Hershey, PA, United States
| | - Benjamin Jonik
- Medical Student Research Program, Penn State College of Medicine, Hershey, PA, United States
| | - Nicholas M Graziane
- Departments of Anesthesiology and Perioperative Medicine, and Pharmacology, Penn State College of Medicine, Hershey, PA, United States
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31
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Silent synapses dictate cocaine memory destabilization and reconsolidation. Nat Neurosci 2019; 23:32-46. [PMID: 31792465 PMCID: PMC6930359 DOI: 10.1038/s41593-019-0537-6] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2018] [Accepted: 10/10/2019] [Indexed: 02/04/2023]
Abstract
Cocaine-associated memories are persistent, but, upon retrieval, become temporarily destabilized and vulnerable to disruptions, followed by reconsolidation. To explore the synaptic underpinnings for these memory dynamics, we studied AMPA receptor (AMPAR)-silent excitatory synapses, which are generated in the nucleus accumbens by cocaine self-administration, and subsequently mature after prolonged withdrawal by recruiting AMPARs, echoing acquisition and consolidation of cocaine memories. We show that, upon memory retrieval after prolonged withdrawal, the matured silent synapses become AMPAR-silent again, followed by re-maturation ~6 hr later, defining the onset and termination of a destabilization window of cocaine memories. These synaptic dynamics are controlled by Rac1, with decreased and increased Rac1 activities opening and closing, respectively, the silent synapse-mediated destabilization window. Preventing silent synapse re-maturation within the destabilization window decreases cue-induced cocaine seeking. Thus, cocaine-generated silent synapses constitute a discrete synaptic ensemble dictating the dynamics of cocaine-associated memories and can be targeted for memory disruption.
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32
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Soriani O, Kourrich S. The Sigma-1 Receptor: When Adaptive Regulation of Cell Electrical Activity Contributes to Stimulant Addiction and Cancer. Front Neurosci 2019; 13:1186. [PMID: 31780884 PMCID: PMC6861184 DOI: 10.3389/fnins.2019.01186] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Accepted: 10/21/2019] [Indexed: 12/17/2022] Open
Abstract
The sigma-1 receptor (σ1R) is an endoplasmic reticulum (ER)-resident chaperone protein that acts like an inter-organelle signaling modulator. Among its several functions such as ER lipid metabolisms/transports and indirect regulation of genes transcription, one of its most intriguing feature is the ability to regulate the function and trafficking of a variety of functional proteins. To date, and directly relevant to the present review, σ1R has been found to regulate both voltage-gated ion channels (VGICs) belonging to distinct superfamilies (i.e., sodium, Na+; potassium, K+; and calcium, Ca2+ channels) and non-voltage-gated ion channels. This regulatory function endows σ1R with a powerful capability to fine tune cells’ electrical activity and calcium homeostasis—a regulatory power that appears to favor cell survival in pathological contexts such as stroke or neurodegenerative diseases. In this review, we present the current state of knowledge on σ1R’s role in the regulation of cellular electrical activity, and how this seemingly adaptive function can shift cell homeostasis and contribute to the development of very distinct chronic pathologies such as psychostimulant abuse and tumor cell growth in cancers.
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Affiliation(s)
| | - Saïd Kourrich
- Département des Sciences Biologiques, Université du Québec à Montréal, Montréal, QC, Canada.,Centre d'Excellence en Recherche sur les Maladies Orphelines - Fondation Courtois, Université du Québec à Montréal, Montréal, QC, Canada.,Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, United States.,Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, United States
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33
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Krentzel AA, Barrett LR, Meitzen J. Estradiol rapidly modulates excitatory synapse properties in a sex- and region-specific manner in rat nucleus accumbens core and caudate-putamen. J Neurophysiol 2019; 122:1213-1225. [PMID: 31314648 PMCID: PMC6766735 DOI: 10.1152/jn.00264.2019] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Revised: 07/16/2019] [Accepted: 07/16/2019] [Indexed: 12/26/2022] Open
Abstract
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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Affiliation(s)
- Amanda A Krentzel
- Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina
- W.M. Keck Center for Behavioral Biology, North Carolina State University, Raleigh, North Carolina
| | - Lily R Barrett
- Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina
| | - John Meitzen
- Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina
- W.M. Keck Center for Behavioral Biology, North Carolina State University, Raleigh, North Carolina
- Center for Human Health and the Environment, North Carolina State University, Raleigh, North Carolina
- Comparative Medicine Institute, North Carolina State University, Raleigh, North Carolina
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34
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Oginsky MF, Ferrario CR. Eating "junk food" has opposite effects on intrinsic excitability of nucleus accumbens core neurons in obesity-susceptible versus -resistant rats. J Neurophysiol 2019; 122:1264-1273. [PMID: 31365322 DOI: 10.1152/jn.00361.2019] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
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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Affiliation(s)
- Max F Oginsky
- Department of Pharmacology, University of Michigan, Ann Arbor, Michigan
| | - Carrie R Ferrario
- Department of Pharmacology, University of Michigan, Ann Arbor, Michigan
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35
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Willett JA, Cao J, Johnson A, Patel OH, Dorris DM, Meitzen J. The estrous cycle modulates rat caudate-putamen medium spiny neuron physiology. Eur J Neurosci 2019; 52:2737-2755. [PMID: 31278786 DOI: 10.1111/ejn.14506] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Revised: 05/16/2019] [Accepted: 06/25/2019] [Indexed: 12/27/2022]
Abstract
The neuroendocrine environment in which the brain operates is both dynamic and differs by sex. How differences in neuroendocrine state affect neuron properties has been significantly neglected in neuroscience research. Behavioral data across humans and rodents indicate that natural cyclical changes in steroid sex hormone production affect sensorimotor and cognitive behaviors in both normal and pathological contexts. These behaviors are critically mediated by the caudate-putamen. In the caudate-putamen, medium spiny neurons (MSNs) are the predominant and primary output neurons. MSNs express membrane-associated estrogen receptors and demonstrate estrogen sensitivity. However, how the cyclical hormone changes across the estrous cycle may modulate caudate-putamen MSN electrophysiological properties remains unknown. Here, we performed whole-cell patch-clamp recordings on male, diestrus female, proestrus female, and estrus female caudate-putamen MSNs. Action potential, passive membrane, and miniature excitatory post-synaptic current properties were assessed. Numerous MSN electrical properties robustly differed by cycle state, including resting membrane potential, rheobase, action potential threshold, maximum evoked action potential firing rate, and inward rectification. Strikingly, when considered independent of estrous cycle phase, all but one of these properties do not significantly differ from male MSNs. These data indicate that female caudate-putamen MSNs are sensitive to the estrous cycle, and more broadly, the importance of considering neuroendocrine state in studies of neuron physiology.
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Affiliation(s)
- Jaime A Willett
- Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA.,W.M. Keck Center for Behavioral Biology, North Carolina State University, Raleigh, NC, USA.,Graduate Program in Physiology, North Carolina State University, Raleigh, NC, USA.,Grass Laboratory, Marine Biological Laboratory, Woods Hole, MA, USA
| | - Jinyan Cao
- Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA.,W.M. Keck Center for Behavioral Biology, North Carolina State University, Raleigh, NC, USA
| | - Ashlyn Johnson
- Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA
| | - Opal H Patel
- Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA
| | - David M Dorris
- Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA
| | - John Meitzen
- Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA.,W.M. Keck Center for Behavioral Biology, North Carolina State University, Raleigh, NC, USA.,Center for Human Health and the Environment, North Carolina State University, Raleigh, NC, USA.,Comparative Medicine Institute, North Carolina State University, Raleigh, NC, USA
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36
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Electrophysiological Properties of Medium Spiny Neuron Subtypes in the Caudate-Putamen of Prepubertal Male and Female Drd1a-tdTomato Line 6 BAC Transgenic Mice. eNeuro 2019; 6:eN-CFN-0016-19. [PMID: 30899778 PMCID: PMC6426437 DOI: 10.1523/eneuro.0016-19.2019] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 02/12/2019] [Accepted: 02/24/2019] [Indexed: 12/21/2022] Open
Abstract
The caudate-putamen is a striatal brain region essential for sensorimotor behaviors, habit learning, and other cognitive and premotor functions. The output and predominant neuron of the caudate-putamen is the medium spiny neuron (MSN). MSNs present discrete cellular subtypes that show differences in neurochemistry, dopamine receptor expression, efferent targets, gene expression, functional roles, and most importantly for this study, electrophysiological properties. MSN subtypes include the striatonigral and the striatopallidal groups. Most studies identify the striatopallidal MSN subtype as being more excitable than the striatonigral MSN subtype. However, there is some divergence between studies regarding the exact differences in electrophysiological properties. Furthermore, MSN subtype electrophysiological properties have not been reported disaggregated by biological sex. We addressed these questions using prepubertal male and female Drd1a-tdTomato line 6 BAC transgenic mice, an important transgenic line that has not yet received extensive electrophysiological analysis. We made acute caudate-putamen brain slices and assessed a robust battery of 16 relevant electrophysiological properties using whole-cell patch-clamp recording, including intrinsic membrane, action potential, and miniature EPSC (mEPSC) properties. We found that: (1) MSN subtypes exhibited multiple differential electrophysiological properties in both sexes, including rheobase, action potential threshold and width, input resistance in both the linear and rectified ranges, and mEPSC amplitude; (2) select electrophysiological properties showed interactions between MSN subtype and sex. These findings provide a comprehensive evaluation of mouse caudate-putamen MSN subtype electrophysiological properties across females and males, both confirming and extending previous studies.
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37
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Modelling Differential Vulnerability to Substance Use Disorder in Rodents: Neurobiological Mechanisms. Handb Exp Pharmacol 2019; 258:203-230. [PMID: 31707470 DOI: 10.1007/164_2019_300] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Despite the prevalence of drug use within society, only a subset of individuals actively taking addictive drugs lose control over their intake and develop compulsive drug-seeking and intake that typifies substance use disorder (SUD). Although research in this field continues to be an important and dynamic discipline, the specific neuroadaptations that drive compulsive behaviour in humans addicted to drugs and the neurobiological mechanisms that underlie an individual's innate susceptibility to SUD remain surprisingly poorly understood. Nonetheless, it is clear from research within the clinical domain that some behavioural traits are recurrently co-expressed in individuals with SUD, thereby inviting the hypothesis that certain behavioural endophenotypes may be predictive, or at least act in some way, to modify an individual's probability for developing this disorder. The analysis of such endophenotypes and their catalytic relationship to the expression of addiction-related behaviours has been greatly augmented by experimental approaches in rodents that attempt to capture diagnostically relevant aspects of this progressive brain disorder. This work has evolved from an early focus on aberrant drug reinforcement mechanisms to a now much richer account of the putatively impaired cognitive control processes that ultimately determine individual trajectories to compulsive drug-related behaviours. In this chapter we discuss the utility of experimental approaches in rodents designed to elucidate the neurobiological and genetic underpinnings of so-called risk traits and how these innate vulnerabilities collectively contribute to the pathogenesis of SUD.
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38
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Shi M, Cao L, Cao X, Zhu M, Zhang X, Wu Z, Xiong S, Xie Z, Yang Y, Chen J, Wong PTH, Bian JS. DR-region of Na +/K + ATPase is a target to treat excitotoxicity and stroke. Cell Death Dis 2018; 10:6. [PMID: 30584244 PMCID: PMC6315034 DOI: 10.1038/s41419-018-1230-5] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Revised: 11/20/2018] [Accepted: 11/21/2018] [Indexed: 12/13/2022]
Abstract
Na+/K+ ATPase (NKA) is important in maintaining cellular functions. We found that loss of NKA activities in NKAα1+/− mice is associated with increased susceptibility to ischemic injuries following transient middle cerebral artery occlusion (tMCAO). This is corroborated by the neuroprotective effects of an antibody raised against an extracellular DR region (897DVEDSYGQQWTYEQR911, sequence number as in rat) of NKAα subunit (DR-Ab) in both preventive and therapeutic settings. DR-Ab protects cortical neurons against glutamate-induced toxicity by stimulating activities of NKA and Na+/Ca2+ exchanger (NCX), which resulted in accelerated Ca2+ extrusion. DR-Ab also enhanced the association between NKA and GluR2 and therefore reduced the internalization of both proteins from membrane induced by glutamate toxicity. The mechanism appears to involve suppression of GluR2 phosphorylation through PKCα/PICK pathway. Our data indicate that DR-region of NKA may be a novel therapeutic target for drug development for the treatment of ischemic stroke.
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Affiliation(s)
- Meimei Shi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
| | - Lei Cao
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
| | - Xu Cao
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
| | - Mengyuan Zhu
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
| | - Xingzhou Zhang
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
| | - Zhiyuan Wu
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
| | - Siping Xiong
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
| | - Zhizhong Xie
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
| | - Yong Yang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing, 211198, China
| | - Jingyu Chen
- Lung Transplant Group, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, 214021, Jiangsu, PR China
| | - Peter T H Wong
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
| | - Jin-Song Bian
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore. .,National University of Singapore (Suzhou) Research Institute, Suzhou, 215123, China.
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Parekh PK, Becker-Krail D, Sundaravelu P, Ishigaki S, Okado H, Sobue G, Huang Y, McClung CA. Altered GluA1 (Gria1) Function and Accumbal Synaptic Plasticity in the ClockΔ19 Model of Bipolar Mania. Biol Psychiatry 2018; 84:817-826. [PMID: 28780133 PMCID: PMC5745309 DOI: 10.1016/j.biopsych.2017.06.022] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2016] [Revised: 06/16/2017] [Accepted: 06/19/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND Disruptions in circadian rhythms are associated with an increased risk for bipolar disorder. Moreover, studies show that the circadian protein CLOCK (circadian locomotor output cycles kaput) is involved in regulating monoaminergic systems and mood-related behavior. However, the molecular and synaptic mechanisms underlying this relationship remain poorly understood. METHODS Using ex vivo whole-cell patch-clamp electrophysiology in ClockΔ19 mutant and wild-type mice we characterized alterations in excitatory synaptic transmission, strength, and intrinsic excitability of nucleus accumbens (NAc) neurons. We performed protein crosslinking and Western blot analysis to examine surface and intracellular levels and rhythm of the glutamate receptor subunit, GluA1, in the NAc. Viral-mediated overexpression of Gria1 in the NAc and behavioral assays were also used. RESULTS Compared with wild-type mice, ClockΔ19 mice display reduced alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor-mediated excitatory synaptic responses at NAc medium spiny neurons. These alterations are likely postsynaptic, as presynaptic release of glutamate onto medium spiny neurons is unaltered in mutant mice. Additionally, NAc surface protein levels and the rhythm of GRIA1 are decreased in ClockΔ19 mice diurnally, consistent with reduced functional synaptic response. Furthermore, we observed a significantly hyperpolarized resting membrane potential of ClockΔ19 medium spiny neurons, suggesting lowered intrinsic excitability. Last, overexpression of functional Gria1 in the NAc of mutant mice was able to normalize increased exploratory drive and reward sensitivity behavior when mice are in a manic-like state. CONCLUSIONS Together, our findings demonstrate that NAc excitatory signaling via Gria1 expression is integral to the effects of Clock gene disruption on manic-like behaviors.
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Affiliation(s)
- Puja K. Parekh
- University of Pittsburgh Medical Center, Department of Psychiatry, Pittsburgh, Pennsylvania 15219
| | - Darius Becker-Krail
- University of Pittsburgh Medical Center, Department of Psychiatry, Pittsburgh, Pennsylvania 15219
| | - Poornima Sundaravelu
- University of Pittsburgh Medical Center, Department of Psychiatry, Pittsburgh, Pennsylvania 15219
| | - Shinsuke Ishigaki
- Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Haruo Okado
- Department of Brain Development and Neural Regeneration, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan
| | - Gen Sobue
- Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Yanhua Huang
- University of Pittsburgh Medical Center, Department of Psychiatry, Pittsburgh, Pennsylvania 15219
| | - Colleen A. McClung
- University of Pittsburgh Medical Center, Department of Psychiatry, Pittsburgh, Pennsylvania 15219
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40
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Hearing M. Prefrontal-accumbens opioid plasticity: Implications for relapse and dependence. Pharmacol Res 2018; 139:158-165. [PMID: 30465850 DOI: 10.1016/j.phrs.2018.11.012] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Revised: 11/05/2018] [Accepted: 11/07/2018] [Indexed: 01/12/2023]
Abstract
In addiction, an individual's ability to inhibit drug seeking and drug taking is thought to reflect a pathological strengthening of drug-seeking behaviors or impairments in the capacity to control maladaptive behavior. These processes are not mutually exclusive and reflect drug-induced modifications within prefrontal cortical and nucleus accumbens circuits, however unlike psychostimulants such as cocaine, far less is known about the temporal, anatomical, and cellular dynamics of these changes. We discuss what is known regarding opioid-induced adaptations in intrinsic membrane physiology and pre-/postsynaptic neurotransmission in principle pyramidal and medium spiny neurons in the medial prefrontal cortex and nucleus accumbens from electrophysiological studies and explore how circuit specific adaptations may contribute to unique facets of opioid addiction.
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Affiliation(s)
- Matthew Hearing
- Department of Biomedical Sciences, Marquette University, Milwaukee, WI, 53233, USA.
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41
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Cao J, Dorris DM, Meitzen J. Electrophysiological properties of medium spiny neurons in the nucleus accumbens core of prepubertal male and female Drd1a-tdTomato line 6 BAC transgenic mice. J Neurophysiol 2018; 120:1712-1727. [PMID: 29975170 PMCID: PMC6230806 DOI: 10.1152/jn.00257.2018] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Revised: 06/27/2018] [Accepted: 06/30/2018] [Indexed: 12/12/2022] Open
Abstract
The nucleus accumbens core (AcbC) is a striatal brain region essential for integrating motivated behavior and reward processing with premotor function. In humans and rodents, research has identified sex differences and sex steroid hormone sensitivity in AcbC-mediated behaviors, in disorders, and in rats in the electrophysiological properties of the AcbC output neuron type, the medium spiny neuron (MSN). It is unknown whether the sex differences detected in MSN electrophysiological properties extend to mice. Furthermore, MSNs come in distinct subtypes with subtle differences in electrophysiological properties, and it is unknown whether MSN subtype-specific electrophysiology varies by sex. To address these questions, we used male and female Drd1a-tdTomato line 6 bacterial artificial chromosome transgenic mice. We made acute brain slices of the AcbC, and performed whole cell patch-clamp recordings across MSN subtypes to comprehensively assess AcbC MSN subtype electrophysiological properties. We found that ( 1 mice MSNs did not exhibit the sex differences detected in rat MSNs, and 2) electrophysiological properties differed between MSN subtypes in both sexes, including rheobase, resting membrane potential, action potential properties, intrinsic excitability, input resistance in both the linear and rectified ranges, and miniature excitatory postsynaptic current properties. These findings significantly extend previous studies of MSN subtypes performed in males or animals of undetermined sex and indicate that the influence of sex upon AcbC MSN properties varies between rodent species. NEW & NOTEWORTHY This research provides the most comprehensive assessment of medium spiny neuron subtype electrophysiological properties to date in a critical brain region, the nucleus accumbens core. It additionally represents the first evaluation of whether mouse medium spiny neuron subtype electrophysiological properties differ by sex.
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Affiliation(s)
- Jinyan Cao
- Department of Biological Sciences, North Carolina State University , Raleigh, North Carolina
- W. M. Keck Center for Behavioral Biology, North Carolina State University , Raleigh, North Carolina
| | - David M Dorris
- Department of Biological Sciences, North Carolina State University , Raleigh, North Carolina
| | - John Meitzen
- Department of Biological Sciences, North Carolina State University , Raleigh, North Carolina
- W. M. Keck Center for Behavioral Biology, North Carolina State University , Raleigh, North Carolina
- Center for Human Health and the Environment, North Carolina State University , Raleigh, North Carolina
- Comparative Medicine Institute, North Carolina State University , Raleigh, North Carolina
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42
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Functional Connectivity of Chronic Cocaine Use Reveals Progressive Neuroadaptations in Neocortical, Striatal, and Limbic Networks. eNeuro 2018; 5:eN-NWR-0081-18. [PMID: 30073194 PMCID: PMC6071197 DOI: 10.1523/eneuro.0081-18.2018] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Revised: 06/25/2018] [Accepted: 07/10/2018] [Indexed: 12/21/2022] Open
Abstract
Brain imaging studies indicate that chronic cocaine users display altered functional connectivity between prefrontal cortical, thalamic, striatal, and limbic regions; however, the use of cross-sectional designs in these studies precludes measuring baseline brain activity prior to cocaine use. Animal studies can circumvent this limitation by comparing functional connectivity between baseline and various time points after chronic cocaine use. In the present study, adult male Long–Evans rats were trained to self-administer cocaine intravenously for 6 h sessions daily over 14 consecutive days. Two additional groups serving as controls underwent sucrose self-administration or exposure to the test chambers alone. Functional magnetic resonance imaging was conducted before self-administration and after 1 and 14 d of abstinence (1d and 14d Abs). After 1d Abs from cocaine, there were increased clustering coefficients in brain areas involved in reward seeking, learning, memory, and autonomic and affective processing, including amygdala, hypothalamus, striatum, hippocampus, and thalamus. Similar changes in clustering coefficient after 1d Abs from sucrose were evident in predominantly thalamic brain regions. Notably, there were no changes in strength of functional connectivity at 1 or 14 d after either cocaine or sucrose self-administration. The results suggest that cocaine and sucrose can change the arrangement of functional connectivity of brain regions involved in cognition and emotion, but that these changes dissipate across the early stages of abstinence. The study also emphasizes the importance of including baseline measures in longitudinal functional neuroimaging designs seeking to assess functional connectivity in the context of substance use.
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43
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Kaneda K. Neuroplasticity in cholinergic neurons of the laterodorsal tegmental nucleus contributes to the development of cocaine addiction. Eur J Neurosci 2018; 50:2239-2246. [DOI: 10.1111/ejn.13962] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Revised: 04/20/2018] [Accepted: 05/04/2018] [Indexed: 11/27/2022]
Affiliation(s)
- Katsuyuki Kaneda
- Laboratory of Molecular Pharmacology Institute of Medical, Pharmaceutical and Health Sciences Kanazawa University Kanazawa 920‐1192 Japan
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44
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Proaño SB, Morris HJ, Kunz LM, Dorris DM, Meitzen J. Estrous cycle-induced sex differences in medium spiny neuron excitatory synaptic transmission and intrinsic excitability in adult rat nucleus accumbens core. J Neurophysiol 2018; 120:1356-1373. [PMID: 29947588 DOI: 10.1152/jn.00263.2018] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
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.
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Affiliation(s)
- Stephanie B Proaño
- Graduate Program in Biology, North Carolina State University , Raleigh, North Carolina.,W. M. Keck Center for Behavioral Biology, North Carolina State University , Raleigh, North Carolina.,Department of Biological Sciences, North Carolina State University , Raleigh, North Carolina
| | - Hannah J Morris
- Department of Biological Sciences, North Carolina State University , Raleigh, North Carolina
| | - Lindsey M Kunz
- Department of Biological Sciences, North Carolina State University , Raleigh, North Carolina
| | - David M Dorris
- Department of Biological Sciences, North Carolina State University , Raleigh, North Carolina
| | - John Meitzen
- W. M. Keck Center for Behavioral Biology, North Carolina State University , Raleigh, North Carolina.,Department of Biological Sciences, North Carolina State University , Raleigh, North Carolina.,Center for Human Health and the Environment, North Carolina State University , Raleigh, North Carolina.,Comparative Medicine Institute, North Carolina State University , Raleigh, North Carolina
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45
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Bystrowska B, Frankowska M, Smaga I, Pomierny-Chamioło L, Filip M. Effects of Cocaine Self-Administration and Its Extinction on the Rat Brain Cannabinoid CB1 and CB2 Receptors. Neurotox Res 2018; 34:547-558. [PMID: 29754307 PMCID: PMC6154179 DOI: 10.1007/s12640-018-9910-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2017] [Revised: 04/23/2018] [Accepted: 05/01/2018] [Indexed: 12/18/2022]
Abstract
The aim of this study was to evaluate changes in the expression of cannabinoid type 1 (CB1) and 2 (CB2) receptor proteins in several brain regions in rats undergoing cocaine self-administration and extinction training. We used a triad-yoked procedure to distinguish between the motivational and pharmacological effects of cocaine. Using immunohistochemistry, we observed a significant decrease in CB1 receptor expression in the prefrontal cortex, dorsal striatum, and the basolateral and basomedial amygdala following cocaine (0.5 mg/kg/infusion) self-administration. Increased CB1 receptor expression in the ventral tegmental area in rats with previous cocaine exposure was also found. Following cocaine abstinence after 10 days of extinction training, we detected increases in the expression of CB1 receptors in the substantia nigra in both cocaine groups and in the subregions of the amygdala for only the yoked cocaine controls, while any method of cocaine exposure resulted in a decrease in CB2 receptor expression in the prefrontal cortex (p < 0.01), nucleus accumbens (p < 0.01), and medial globus pallidus (p < 0.01). Our findings further support the idea that the eCB system and CB1 receptors are involved in cocaine-reinforced behaviors. Moreover, we detected a cocaine-evoked adaptation in CB2 receptors in the amygdala, prefrontal cortex, and globus pallidus.
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Affiliation(s)
- Beata Bystrowska
- Department of Toxicology, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland.
| | - Małgorzata Frankowska
- Department of Drug Addiction Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343, Kraków, Poland
| | - Irena Smaga
- Department of Internal Medicine, Jagiellonian University Medical College, Skawińska 8, 31-066, Kraków, Poland
| | - Lucyna Pomierny-Chamioło
- Department of Toxicology, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland
| | - Małgorzata Filip
- Department of Drug Addiction Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343, Kraków, Poland
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46
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Scala F, Nenov MN, Crofton EJ, Singh AK, Folorunso O, Zhang Y, Chesson BC, Wildburger NC, James TF, Alshammari MA, Alshammari TK, Elfrink H, Grassi C, Kasper JM, Smith AE, Hommel JD, Lichti CF, Rudra JS, D'Ascenzo M, Green TA, Laezza F. Environmental Enrichment and Social Isolation Mediate Neuroplasticity of Medium Spiny Neurons through the GSK3 Pathway. Cell Rep 2018; 23:555-567. [PMID: 29642012 PMCID: PMC6150488 DOI: 10.1016/j.celrep.2018.03.062] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2017] [Revised: 02/05/2018] [Accepted: 03/14/2018] [Indexed: 11/29/2022] Open
Abstract
Resilience and vulnerability to neuropsychiatric disorders are linked to molecular changes underlying excitability that are still poorly understood. Here, we identify glycogen-synthase kinase 3β (GSK3β) and voltage-gated Na+ channel Nav1.6 as regulators of neuroplasticity induced by environmentally enriched (EC) or isolated (IC) conditions-models for resilience and vulnerability. Transcriptomic studies in the nucleus accumbens from EC and IC rats predicted low levels of GSK3β and SCN8A mRNA as a protective phenotype associated with reduced excitability in medium spiny neurons (MSNs). In vivo genetic manipulations demonstrate that GSK3β and Nav1.6 are molecular determinants of MSN excitability and that silencing of GSK3β prevents maladaptive plasticity of IC MSNs. In vitro studies reveal direct interaction of GSK3β with Nav1.6 and phosphorylation at Nav1.6T1936 by GSK3β. A GSK3β-Nav1.6T1936 competing peptide reduces MSNs excitability in IC, but not EC rats. These results identify GSK3β regulation of Nav1.6 as a biosignature of MSNs maladaptive plasticity.
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Affiliation(s)
- Federico Scala
- Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX 77550, USA; Biophysics Graduate Program, Institute of Human Physiology, Università Cattolica, Rome, Italy
| | - Miroslav N Nenov
- Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX 77550, USA
| | - Elizabeth J Crofton
- Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX 77550, USA; Neuroscience Graduate Program, The University of Texas Medical Branch, Galveston, TX 77550, USA
| | - Aditya K Singh
- Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX 77550, USA
| | - Oluwarotimi Folorunso
- Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX 77550, USA
| | - Yafang Zhang
- Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX 77550, USA; Pharmacology and Toxicology Graduate Program, The University of Texas Medical Branch, Galveston, TX 77550, USA
| | - Brent C Chesson
- Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX 77550, USA; Pharmacology and Toxicology Graduate Program, The University of Texas Medical Branch, Galveston, TX 77550, USA
| | - Norelle C Wildburger
- Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX 77550, USA
| | - Thomas F James
- Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX 77550, USA; Neuroscience Graduate Program, The University of Texas Medical Branch, Galveston, TX 77550, USA
| | - Musaad A Alshammari
- Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX 77550, USA; Pharmacology and Toxicology Graduate Program, The University of Texas Medical Branch, Galveston, TX 77550, USA; Studies Abroad Program, King Saud University, Riyadh, Saudi Arabia
| | - Tahani K Alshammari
- Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX 77550, USA; Pharmacology and Toxicology Graduate Program, The University of Texas Medical Branch, Galveston, TX 77550, USA; Studies Abroad Program, King Saud University, Riyadh, Saudi Arabia
| | - Hannah Elfrink
- Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX 77550, USA; Bench Tutorials Program: Scientific Research and Design, The University of Texas Medical Branch, Galveston, TX 77550, USA
| | - Claudio Grassi
- Institute of Human Physiology, Università Cattolica, Rome, Italy; Fondazione Policlinico Universitario A. Gemelli, Rome, Italy
| | - James M Kasper
- Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX 77550, USA; Center for Addiction Research, The University of Texas Medical Branch, Galveston, TX 77550, USA
| | - Ashley E Smith
- Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX 77550, USA; Center for Addiction Research, The University of Texas Medical Branch, Galveston, TX 77550, USA; Cell Biology Graduate Program, The University of Texas Medical Branch, Galveston, TX 77550, USA
| | - Jonathan D Hommel
- Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX 77550, USA; Center for Addiction Research, The University of Texas Medical Branch, Galveston, TX 77550, USA
| | - Cheryl F Lichti
- Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX 77550, USA; Mitchell Center for Neurodegenerative Diseases, The University of Texas Medical Branch, Galveston, TX 77550, USA
| | - Jai S Rudra
- Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX 77550, USA
| | | | - Thomas A Green
- Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX 77550, USA; Center for Addiction Research, The University of Texas Medical Branch, Galveston, TX 77550, USA
| | - Fernanda Laezza
- Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX 77550, USA; Mitchell Center for Neurodegenerative Diseases, The University of Texas Medical Branch, Galveston, TX 77550, USA; Center for Addiction Research, The University of Texas Medical Branch, Galveston, TX 77550, USA.
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Cascades of Homeostatic Dysregulation Promote Incubation of Cocaine Craving. J Neurosci 2018; 38:4316-4328. [PMID: 29626166 DOI: 10.1523/jneurosci.3291-17.2018] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Revised: 01/18/2018] [Accepted: 01/22/2018] [Indexed: 01/11/2023] Open
Abstract
In human drug users, cue-induced drug craving progressively intensifies after drug abstinence, promoting drug relapse. This time-dependent progression of drug craving is recapitulated in rodent models, in which rats exhibit progressive intensification of cue-induced drug seeking after withdrawal from drug self-administration, a phenomenon termed incubation of drug craving. Although recent results suggest that functional alterations of the nucleus accumbens (NAc) contribute to incubation of drug craving, it remains poorly understood how NAc function evolves after drug withdrawal to progressively intensify drug seeking. The functional output of NAc relies on how the membrane excitability of its principal medium spiny neurons (MSNs) translates excitatory synaptic inputs into action potential firing. Here, we report a synapse-membrane homeostatic crosstalk (SMHC) in male rats, through which an increase or decrease in the excitatory synaptic strength induces a homeostatic decrease or increase in the intrinsic membrane excitability of NAc MSNs, and vice versa. After short-term withdrawal from cocaine self-administration, despite no actual change in the AMPA receptor-mediated excitatory synaptic strength, GluN2B NMDA receptors, the SMHC sensors of synaptic strength, are upregulated. This may create false SMHC signals, leading to a decrease in the membrane excitability of NAc MSNs. The decreased membrane excitability subsequently induces another round of SMHC, leading to synaptic accumulation of calcium-permeable AMPA receptors and upregulation of excitatory synaptic strength after long-term withdrawal from cocaine. Disrupting SMHC-based dysregulation cascades after cocaine exposure prevents incubation of cocaine craving. Thus, cocaine triggers cascades of SMHC-based dysregulation in NAc MSNs, promoting incubated cocaine seeking after drug withdrawal.SIGNIFICANCE STATEMENT Here, we report a bidirectional homeostatic plasticity between the excitatory synaptic input and membrane excitability of nucleus accumbens (NAc) medium spiny neurons (MSNs), through which an increase or decrease in the excitatory synaptic strength induces a homeostatic decrease or increase in the membrane excitability, and vice versa. Cocaine self-administration creates a false homeostatic signal that engages this synapse-membrane homeostatic crosstalk mechanism, and produces cascades of alterations in excitatory synapses and membrane properties of NAc MSNs after withdrawal from cocaine. Experimentally preventing this homeostatic dysregulation cascade prevents the progressive intensification of cocaine seeking after drug withdrawal. These results provide a novel mechanism through which drug-induced homeostatic dysregulation cascades progressively alter the functional output of NAc MSNs and promote drug relapse.
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Regional Differences in Striatal Neuronal Ensemble Excitability Following Cocaine and Extinction Memory Retrieval in Fos-GFP Mice. Neuropsychopharmacology 2018; 43:718-727. [PMID: 28540927 PMCID: PMC5809776 DOI: 10.1038/npp.2017.101] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2017] [Revised: 05/03/2017] [Accepted: 05/18/2017] [Indexed: 11/08/2022]
Abstract
Learned associations between drugs of abuse and the drug administration environment have an important role in addiction. In rodents, exposure to a drug-associated environment elicits conditioned psychomotor activation, which may be weakened following extinction (EXT) learning. Although widespread drug-induced changes in neuronal excitability have been observed, little is known about specific changes within neuronal ensembles activated during the recall of drug-environment associations. Using a cocaine-conditioned locomotion (CL) procedure, the present study assessed the excitability of neuronal ensembles in the nucleus accumbens core and shell (NAccore and NAcshell), and dorsal striatum (DS) following cocaine conditioning and EXT in Fos-GFP mice that express green fluorescent protein (GFP) in activated neurons (GFP+). During conditioning, mice received repeated cocaine injections (20 mg/kg) paired with a locomotor activity chamber (Paired) or home cage (Unpaired). Seven to 13 days later, both groups were re-exposed to the activity chamber under drug-free conditions and Paired, but not Unpaired, mice exhibited CL. In a separate group of mice, CL was extinguished by repeatedly exposing mice to the activity chamber under drug-free conditions. Following the expression and EXT of CL, GFP+ neurons in the NAccore (but not NAcshell and DS) displayed greater firing capacity compared to surrounding GFP- neurons. This difference in excitability was due to a generalized decrease in GFP- excitability following CL and a selective increase in GFP+ excitability following its EXT. These results suggest a role for both widespread and ensemble-specific changes in neuronal excitability following recall of drug-environment associations.
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Willett JA, Johnson AG, Vogel AR, Patisaul HB, McGraw LA, Meitzen J. Nucleus accumbens core medium spiny neuron electrophysiological properties and partner preference behavior in the adult male prairie vole, Microtus ochrogaster. J Neurophysiol 2018; 119:1576-1588. [PMID: 29361665 DOI: 10.1152/jn.00737.2017] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Medium spiny neurons (MSNs) in the nucleus accumbens have long been implicated in the neurobiological mechanisms that underlie numerous social and motivated behaviors as studied in rodents such as rats. Recently, the prairie vole has emerged as an important model animal for studying social behaviors, particularly regarding monogamy because of its ability to form pair bonds. However, to our knowledge, no study has assessed intrinsic vole MSN electrophysiological properties or tested how these properties vary with the strength of the pair bond between partnered voles. Here we performed whole cell patch-clamp recordings of MSNs in acute brain slices of the nucleus accumbens core (NAc) of adult male voles exhibiting strong and weak preferences for their respective partnered females. We first document vole MSN electrophysiological properties and provide comparison to rat MSNs. Vole MSNs demonstrated many canonical electrophysiological attributes shared across species but exhibited notable differences in excitability compared with rat MSNs. Second, we assessed male vole partner preference behavior and tested whether MSN electrophysiological properties varied with partner preference strength. Male vole partner preference showed extensive variability. We found that decreases in miniature excitatory postsynaptic current amplitude and the slope of the evoked action potential firing rate to depolarizing current injection weakly associated with increased preference for the partnered female. This suggests that excitatory synaptic strength and neuronal excitability may be decreased in MSNs in males exhibiting stronger preference for a partnered female. Overall, these data provide extensive documentation of MSN electrophysiological characteristics and their relationship to social behavior in the prairie vole. NEW & NOTEWORTHY This research represents the first assessment of prairie vole nucleus accumbens core medium spiny neuron intrinsic electrophysiological properties and probes the relationship between cellular excitability and social behavior.
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Affiliation(s)
- Jaime A Willett
- Department of Biological Sciences, North Carolina State University , Raleigh, North Carolina.,W. M. Keck Center for Behavioral Biology, North Carolina State University , Raleigh, North Carolina.,Graduate Program in Physiology, North Carolina State University , Raleigh, North Carolina
| | - Ashlyn G Johnson
- Department of Biological Sciences, North Carolina State University , Raleigh, North Carolina.,W. M. Keck Center for Behavioral Biology, North Carolina State University , Raleigh, North Carolina
| | - Andrea R Vogel
- Department of Biological Sciences, North Carolina State University , Raleigh, North Carolina.,W. M. Keck Center for Behavioral Biology, North Carolina State University , Raleigh, North Carolina.,Graduate Program in Genetics, North Carolina State University , Raleigh, North Carolina
| | - Heather B Patisaul
- Department of Biological Sciences, North Carolina State University , Raleigh, North Carolina.,W. M. Keck Center for Behavioral Biology, North Carolina State University , Raleigh, North Carolina.,Center for Human Health and the Environment, North Carolina State University , Raleigh, North Carolina
| | - Lisa A McGraw
- Department of Biological Sciences, North Carolina State University , Raleigh, North Carolina.,W. M. Keck Center for Behavioral Biology, North Carolina State University , Raleigh, North Carolina.,Graduate Program in Genetics, North Carolina State University , Raleigh, North Carolina
| | - John Meitzen
- Department of Biological Sciences, North Carolina State University , Raleigh, North Carolina.,W. M. Keck Center for Behavioral Biology, North Carolina State University , Raleigh, North Carolina.,Center for Human Health and the Environment, North Carolina State University , Raleigh, North Carolina.,Comparative Medicine Institute, North Carolina State University , Raleigh, North Carolina
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Mapping trait-like socio-affective phenotypes in rats through 50-kHz ultrasonic vocalizations. Psychopharmacology (Berl) 2018; 235:83-98. [PMID: 28971233 DOI: 10.1007/s00213-017-4746-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2017] [Accepted: 09/19/2017] [Indexed: 10/18/2022]
Abstract
RATIONALE Fifty-kilohertz ultrasonic vocalizations (USV) in rats are believed to express inter-individual differences in trait-like positive affective phenotypes. Emission of 50-kHz USV can be induced by amphetamine (AMPH) to model mania-like positive affect, raising the possibility that predispositions for high 50-kHz USV production confer susceptibility to mania-like states. Such 50-kHz USV presumably express the sender's motivation for social contact and elicit social approach behavior in receivers. OBJECTIVES We recently showed that AMPH-induced 50-kHz USV are paralleled by mania-like patterns of enhanced social approach behavior towards playback of 50-kHz USV. Here, we assessed whether these AMPH effects are dependent on trait-like inter-individual differences in 50-kHz USV production. METHODS To this aim, we subdivided juvenile rats into those emitting low (LC) and high (HC) rates of baseline 50-kHz USV and compared them across four AMPH dosage conditions: 0.0, 0.5, 1.0, and 2.5 mg/kg. RESULTS HC rats were considerably more susceptible to AMPH in inducing 50-kHz USV than LC rats, consistently across all examined doses. They further appeared to attribute more incentive salience to signals of rewarding social contact, as evidenced by enhanced social approach behavior towards 50-kHz USV playback, a response pattern also seen in LC rats after receiving AMPH treatment. HC but not LC rats emitted aversive 22-kHz USV following 50-kHz USV playback, indicating increased proneness to experience negative affective states if no actual social consequence followed the incentive signal. CONCLUSION Inter-individual differences in 50-kHz USV map onto a unique trait-like socio-affective phenotype associated with enhanced emotional reactivity towards social and non-social reward, possibly conferring risk to mania-like states.
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