scholarly journals Accumbens cholinergic interneurons mediate cue-induced nicotine seeking and associated glutamatergic plasticity

2020 ◽  
Author(s):  
Jonna M. Leyrer-Jackson ◽  
Michael Holter ◽  
Paula F. Overby ◽  
Jason M. Newbern ◽  
Michael D. Scofield ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Glutamate Release ◽  
Neuronal Population ◽  
Medium Spiny Neurons ◽  
Self Administration ◽  
Nucleus Accumbens Core ◽  
Cholinergic Interneurons ◽  
Seeking Behavior ◽  
Underlying Mechanisms

AbstractNicotine, the primary addictive substance in tobacco, is widely abused. Relapse to cues associated with nicotine results in increased glutamate release within nucleus accumbens core (NAcore), modifying synaptic plasticity of medium spiny neurons (MSNs) which contributes to reinstatement of nicotine seeking. However, the role of cholinergic interneurons (ChIs) within the NAcore in mediating these neurobehavioral processes in unknown. ChIs represent less than 1% of the accumbens neuronal population yet are activated during drug seeking and reward-predicting events. Thus, we hypothesized that ChIs may play a significant role in mediating glutamatergic plasticity that underlies nicotine seeking behavior. Using chemogenetics transgenic rats that express Cre under the control of the choline acetyltransferase (ChAT) promoter, ChIs were bi-directionally manipulated prior to cue-induced reinstatement. Following nicotine self-administration and extinction training, ChIs were activated or inhibited prior to a cue reinstatement session. Following reinstatement, whole-cell electrophysiology from NAcore MSNs was used to assess changes in plasticity, measured via α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) / N-Methyl-D-Aspartate (NMDA) (A/N) ratios. Chemogenetic inhibition of ChIs inhibited cued nicotine seeking and resulted in decreased A/N, whereas activation of ChIs had no effect, demonstrating that ChI inhibition prevents transient synaptic potentiation (t-SP) associated with cue-induced nicotine seeking. To assess potential underlying mechanisms, accumbens α4β2- and α7-containing nicotinic ACh receptors (nAChRs) were pharmacologically inhibited and MSN synaptic morphology was assessed following reinstatement. Inhibition of both nAChR subtypes prevented cue-induced nicotine seeking and t-SP (measured via changes in spine head diameter). Together, these results demonstrate that these neurons mediate cue-induced nicotine reinstatement and underlying synaptic plasticity within the NAcore.

scholarly journals BACHD Mice Recapitulate the Striatal Parvalbuminergic Interneuron Loss Found in Huntington’s Disease

2021 ◽  
Vol 15 ◽  
Author(s):  
Vyshnavi Rallapalle ◽  
Annesha C. King ◽  
Michelle Gray
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neuronal Population ◽  
Medium Spiny Neurons ◽  
Cholinergic Interneurons ◽  
Spiny Neurons ◽  
Parvalbumin Interneurons ◽  
Area And Perimeter ◽  
Old Mice ◽  
Disease Grade

Huntington’s disease (HD) is a dominantly inherited, adult-onset neurodegenerative disease characterized by motor, psychiatric, and cognitive abnormalities. Neurodegeneration is prominently observed in the striatum where GABAergic medium spiny neurons (MSN) are the most affected neuronal population. Interestingly, recent reports of pathological changes in HD patient striatal tissue have identified a significant reduction in the number of parvalbumin-expressing interneurons which becomes more robust in tissues of higher disease grade. Analysis of other interneuron populations, including somatostatin, calretinin, and cholinergic, did not reveal significant neurodegeneration. Electrophysiological experiments in BACHD mice have identified significant changes in the properties of parvalbumin and somatostatin expressing interneurons in the striatum. Furthermore, their interactions with MSNs are altered as the mHTT expressing mouse models age with increased input onto MSNs from striatal somatostatin and parvalbumin-expressing neurons. In order to determine whether BACHD mice recapitulate the alterations in striatal interneuron number as observed in HD patients, we analyzed the number of striatal parvalbumin, somatostatin, calretinin, and choline acetyltransferase positive cells in symptomatic 12–14 month-old mice by immunofluorescent labeling. We observed a significant decrease in the number of parvalbumin-expressing interneurons as well as a decrease in the area and perimeter of these cells. No significant changes were observed for somatostatin, calretinin, or cholinergic interneuron numbers while a significant decrease was observed for the area of cholinergic interneurons. Thus, the BACHD mice recapitulate the degenerative phenotype observed in the parvalbumin interneurons in HD patient striata without affecting the number of other interneuron populations in the striatum.

scholarly journals Nucleus accumbens cholinergic interneurons oppose cue-motivated behavior

2019 ◽  
Author(s):  
Anne L. Collins ◽  
Tara J. Aitken ◽  
I-Wen Huang ◽  
Christine Shieh ◽  
Venuz Y. Greenfield ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Female Rats ◽  
Nucleus Accumbens Core ◽  
Cholinergic Interneurons ◽  
Reward Seeking ◽  
Motivated Behavior ◽  
Male And Female Rats ◽  
Seeking Behavior

ABSTRACTBackgroundEnvironmental reward-predictive stimuli provide a major source of motivation for adaptive reward pursuit behavior. This cue-motivated behavior is known to be mediated by the nucleus accumbens core (NAc). The cholinergic interneurons in the NAc are tonically active and densely arborized and, thus, well-suited to modulate NAc function. But their causal contribution to adaptive behavior remains unknown. Here we investigated the function of NAc cholinergic interneurons in cue-motivated behavior.MethodsTo do this, we used chemogenetics, optogenetics, pharmacology, and a translationally analogous Pavlovian-to-instrumental transfer behavioral task designed to assess the motivating influence of a reward-predictive cue over reward-seeking actions in male and female rats.ResultsThe data show that NAc cholinergic interneuron activity is necessary and sufficient to oppose the motivating influence of appetitive cues. Chemogenetic inhibition of NAc cholinergic interneurons augmented cue-motivated behavior. Optical stimulation of acetylcholine release from NAc cholinergic interneurons prevented cues from invigorating reward-seeking behavior, an effect that was mediated by activation of β2-containing nicotinic acetylcholine receptors.ConclusionsThus, NAc cholinergic interneurons provide a critical regulatory influence over adaptive cue-motivated behavior and, therefore, are a potential therapeutic target for the maladaptive cue-motivated behavior that marks many psychiatric conditions, including addiction and depression.

scholarly journals CREST in the Nucleus Accumbens Core Regulates Cocaine Conditioned Place Preference, Cocaine-Seeking Behavior, and Synaptic Plasticity

2018 ◽  
Vol 38 (44) ◽  
pp. 9514-9526 ◽  
Author(s):  
Yasaman Alaghband ◽  
Enikö Kramár ◽  
Janine L. Kwapis ◽  
Earnest S. Kim ◽  
Thekla J. Hemstedt ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Nucleus Accumbens ◽  
Conditioned Place Preference ◽  
Place Preference ◽  
Nucleus Accumbens Core ◽  
Cocaine Seeking ◽  
Seeking Behavior ◽  
Accumbens Core

scholarly journals Electroacupuncture Suppresses Discrete Cue-Evoked Heroin-Seeking and Fos Protein Expression in the Nucleus Accumbens Core in Rats

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Sheng Liu ◽  
Fenglei Zhu ◽  
Miaojun Lai ◽  
Limin Sun ◽  
Yijun Liu ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Therapeutic Benefit ◽  
Sprague Dawley ◽  
Contextual Cues ◽  
Self Administration ◽  
Nucleus Accumbens Core ◽  
Beneficial Effects ◽  
Fos Protein ◽  
Sprague Dawley Rats ◽  
Seeking Behavior

Relapse to drug seeking was studied using a rodent model of reinstatement induced by exposure to drug-related cues. Here, we used intravenous drug self-administration procedures in rats to further investigate the beneficial effects of electroacupuncture (EA) on heroin-seeking behavior in a reinstatement model of relapse. We trained Sprague-Dawley rats to nose-poke for i.v. heroin either daily for 4 h or 25 infusions for 14 consecutive days. Then the rats were abstinent from heroin for two weeks. 2 Hz EA stimulation was conducted once daily for 14 days during heroin abstinence. We tested these animals for contextual and discrete cue-induced reinstatement of active responses. We also applied immunohistochemistry to detect Fos-positive nuclei in the nucleus accumbens (NACc) core and shell after reinstatement test. We found that active responses elicited by both contextual cues and discrete cues were high in the rats trained with heroin than in saline controls. EA treatment significantly reduced active responses elicited by discrete cues. EA stimulation attenuated Fos expression in the core but not the shell of the NACc. Altogether, these results highlight the therapeutic benefit of EA in preventing relapse to drug addiction.

Evidence for the role of dopamine D3receptors in oral operant alcohol self-administration and reinstatement of alcohol-seeking behavior in mice

2007 ◽  
Vol 12 (1) ◽  
pp. 35-50 ◽  
Author(s):  
Christian A. Heidbreder ◽  
Michela Andreoli ◽  
Cristina Marcon ◽  
Daniel M. Hutcheson ◽  
Eliot L. Gardner ◽  
...  
Keyword(s):  
Self Administration ◽  
Seeking Behavior ◽  
Alcohol Seeking

scholarly journals Role of MicroRNA in Governing Synaptic Plasticity

2016 ◽  
Vol 2016 ◽  
pp. 1-13 ◽  
Author(s):  
Yuqin Ye ◽  
Hongyu Xu ◽  
Xinhong Su ◽  
Xiaosheng He
Keyword(s):  
Synaptic Plasticity ◽  
Neurological Disorders ◽  
Therapeutic Strategy ◽  
Target Gene ◽  
Synaptic Function ◽  
The Novel ◽  
Individual Mirnas ◽  
Underlying Mechanisms ◽  
And Function

Although synaptic plasticity in neural circuits is orchestrated by an ocean of genes, molecules, and proteins, the underlying mechanisms remain poorly understood. Recently, it is well acknowledged that miRNA exerts widespread regulation over the translation and degradation of target gene in nervous system. Increasing evidence suggests that quite a few specific miRNAs play important roles in various respects of synaptic plasticity including synaptogenesis, synaptic morphology alteration, and synaptic function modification. More importantly, the miRNA-mediated regulation of synaptic plasticity is not only responsible for synapse development and function but also involved in the pathophysiology of plasticity-related diseases. A review is made here on the function of miRNAs in governing synaptic plasticity, emphasizing the emerging regulatory role of individual miRNAs in synaptic morphological and functional plasticity, as well as their implications in neurological disorders. Understanding of the way in which miRNAs contribute to synaptic plasticity provides rational clues in establishing the novel therapeutic strategy for plasticity-related diseases.

scholarly journals Heroin Cues Reveal Astroglial Heterogeneity in the Nucleus Accumbens Core

2020 ◽  
Author(s):  
Anna Kruyer ◽  
Peter W. Kalivas
Keyword(s):  
Nucleus Accumbens ◽  
Glutamate Uptake ◽  
Glutamate Release ◽  
Surface Expression ◽  
Actin Binding ◽  
Synapsin I ◽  
Self Administration ◽  
Nucleus Accumbens Core ◽  
Distinct Subpopulation ◽  
Accumbens Core

ABSTRACTBACKGROUNDCues predicting heroin delivery induce heroin seeking by initiating synaptic glutamate release in the nucleus accumbens core. The intensity of heroin seeking is negatively modulated by cue-induced increases in synaptic proximity of astrocytes. Glutamate-driven heroin seeking is also negatively regulated by compounds that promote glutamate uptake through the astrocytic transporter GLT-1. We hypothesized that the cue-induced increase in astrocyte synaptic proximity reduces heroin seeking by increasing GLT-1 synaptic proximity.METHODSRats were trained to self-administer heroin or sucrose before undergoing extinction and cued reinstatement of heroin or sucrose seeking. We used confocal microscopy to assess expression and co-registration of GLT-1 with the synaptic marker Synapsin I in the nucleus accumbens core.RESULTSExtinction from heroin, but not sucrose self-administration, downregulated GLT-1. Heroin cues increased surface expression of GLT-1 in parallel with heroin seeking, but counter to expectations, the increase was not proximal to synapses identified by Synapsin I. In fact, astroglia showing cue-induced increased surface expression of GLT-1 constituted a distinct subpopulation of astroglia from those showing increased synaptic proximity. Supporting discrete mechanisms, preventing cue-evoked increases in astrocyte synaptic proximity by knocking down the astroglial-selective actin binding protein ezrin did not impact cue-induced increases in GLT-1 surface expression.CONCLUSIONSOur data demonstrate that heroin-paired cues elicit two transient adaptations in astrocytes in the nucleus accumbens core, restoration of synaptic proximity and increased surface expression of GLT-1. Each adaptation occurs in largely non-overlapping subpopulations of astrocytes, but both adaptations appear to dampen reinstated heroin seeking.

scholarly journals Dynorphin counteracts orexin in the paraventricular nucleus of the thalamus: cellular and behavioral evidence

2017 ◽  
Author(s):  
Alessandra Matzeu ◽  
Marsida Kallupi ◽  
Olivier George ◽  
Paul Schweitzer ◽  
Rémi Martin-Fardon
Keyword(s):  
Paraventricular Nucleus ◽  
Glutamate Release ◽  
Critical Role ◽  
Brain Slices ◽  
Self Administration ◽  
Excitatory Transmission ◽  
Cocaine Seeking ◽  
Seeking Behavior ◽  
Male Wistar Rats ◽  
Behavioral Evidence

ABSTRACTThe orexin (Orx) system is known to play a critical role in drug addiction and reward-related behaviors. The dynorphin (Dyn) system, conversely, promotes depressive-like behavior and plays a key role in the aversive effects of stress. Orexin and Dyn are co-released and have opposing functions in reward and motivation in the ventral tegmental area (VTA). Earlier studies showed that microinjections of OrxA in the posterior paraventricular nucleus of the thalamus (pPVT) exerted priming-like effects and reinstated cocaine-seeking behavior, suggesting that Orx transmission in the pPVT participates in cocaine-seeking behavior. The present study sought to determine whether Orx and Dyn interact in the pPVT. Using a cellular approach, brain slices were prepared for whole-cell recordings and to study excitatory transmission in pPVT neurons. The superfusion of OrxA increased spontaneous glutamatergic transmission by increasing glutamate release onto pPVT neurons, whereas DynA decreased glutamate release. Furthermore, the augmentation of OrxA-induced glutamate release was reversed by DynA. To corroborate the electrophysiological data, separate groups of male Wistar rats were trained to self-administer cocaine or sweetened condensed milk (SCM). After self-administration training, the rats underwent extinction training and were tested with intra-pPVT administration of OrxA±DynA under extinction conditions. OrxA reinstated cocaine-and SCM-seeking behavior, with a greater effect in cocaine animals. DynA selectively blocked OrxA-induced cocaine seeking vs. SCM seeking. The data indicate that DynA in the pPVT prevents OrxA-induced cocaine seeking, perhaps by reversing the OrxA-induced increase in glutamate release, identifying a novel therapeutic target to prevent cocaine relapse.

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