Molecular Plasticity of the Nucleus Accumbens Revisited—Astrocytic Waves Shall Rise
Part of the ventral striatal division, the nucleus accumbens (NAc) drives the circuit activity of an entire macrosystem about reward like a “flagship,” signaling and leading diverse conducts. Accordingly, NAc neurons feature complex inhibitory phenotypes that assemble to process circuit inputs and generate outputs by exploiting specific arrays of opposite and/or parallel neurotransmitters, neuromodulatory peptides. The resulting complex combinations enable versatile yet specific forms of accumbal circuit plasticity, including maladaptive behaviors. Although reward signaling and behavior are elaborately linked to neuronal circuit activities, it is plausible to propose whether these neuronal ensembles and synaptic islands can be directly controlled by astrocytes, a powerful modulator of neuronal activity. Pioneering studies showed that astrocytes in the NAc sense citrate cycle metabolites and/or ATP and may induce recurrent activation. We argue that the astrocytic calcium, GABA, and Glu signaling and altered sodium and chloride dynamics fundamentally shape metaplasticity by providing active regulatory roles in the synapse- and network-level flexibility of the NAc.
KeywordsNucleus accumbens macrosystem Motivation-reward metaplasticity Mixed GABAergic and Gluergic synapses Perisynaptic astrocytic processes Astrocytic endfeets Succinate receptor
Astrocytic succinic semialdehyde/aldo-keto reductase enzyme
Succinic semialdehyde/aldo-keto enzyme
Succinic semialdehyde/aldo-keto reductase gene
Mitochondrial succinic semialdehyde/aldo-keto reductase enzyme
Citrate energy cycle
GLT-1, SLC1A2—glial Na+ and H+ ion-dependent excitatory amino acid transporter type 2 with (1Glu:3Na+:1H+)in/(K+)out stoichiometry
Glutamic acid decarboxylase
SLC6A11—glial Na+ and Cl− ion-dependent GABA transporter type 3 with (1GABA:2Na+:1Cl−)in stoichiometry
Glial fibrillary acidic protein
γ-Hydroxy butyric acid
AMPA receptor—alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor
Intrinsic optical signal
Group 1 metabotropic Glu receptor
Perisynaptic astrocytic processes
Sphingomyelin synthase gene
Succinic semialdehyde dehydrogenase enzyme
Succinate receptor 1 gene
Ventral tegmental area
Organization of the Nucleus Accumbens
Nucleus accumbens (NAc) is part of the ventral striatal division where circuit afferents and efferents both unite and segregate [61, 136] in distinctive neuronal ensembles . Discernible NAc sub-territories of rodents, the “chameleon-like” shell and the core [67, 83, 186, 237, 241], are associated with the limbic and the motor systems, respectively . In addition, core and shell sub-regions have many more functions, including incentive-cue responding and behavioral inhibition (see for example ). While rodent shell and core sub-regions and related neuronal circuit connections are clearly distinguishable , sub-region borders of human NAc are less apparent, displaying more diffuse, gradual changes in the topology of afferents and efferents [52, 107, 137]. We suggest that the characteristic differences between rodent and human NAc sub-territories are related to the diverse incentive-cue responding and behavioral inhibition of humans.
The major neuronal type in the nucleus accumbens is the medium spiny neuron (MSN), which comprise about 95% of the cells in the area. Neurochemical phenotypes of MSNs range from “quasi” inhibitory using the major inhibitory neurotransmitter γ-aminobutyric acid (GABA) to mixed inhibitory and excitatory (GABAergic and glutamatergic). Besides, ubiquitous distribution of terminals co-expressing vesicular glutamate (Glu) and GABA transporters in the striatum, hippocampus, thalamus, and cerebellar and cerebral cortices  suggests that the appearance of mixed Glu-GABA phenotypes may possibly be the rule rather than the exception (for a more thorough discussion on the possible significance of the mixed Glu-GABA MSN phenotype in the NAc, see the last paragraph of section “Basic Neurochemistry of Reward Quality and Prediction”). Accumbal MSNs exhibiting both GABA and Glu decarboxylase (GAD) immunoreactivity [5, 7, 227, 238] often co-express modulatory neuropeptides (substance P, dynorphin, enkephalin, and neurotensin) together with various dopamine (DA) receptor subtypes (DR1, DR2, and DR3). The DR1-DR2 receptor heteromer-expressing phenotype also takes up [3H]aspartate ([3H]Asp) [156, 227]. The major DAergic input driving the different DA receptor types originates in the ventral tegmental area (VTA), while Gluergic inputs to the NAc arrive mostly from cortical areas. The latter innervations, however, also terminate on MSNs, raising the idea of “striatal synaptic triad.” This represents a configuration of a Gluergic asymmetric spine head with a DAergic symmetric spine neck [50, 62, 188], although asymmetrical morphology has also been considered [16, 100, 228, 239].
Interneurons (< 5%) in the NAc are mainly GABAergic, and to a lesser extent cholinergic, receiving serotonergic inputs [192, 218, 238] in both the shell and core regions. The GABAergic interneurons exhibit nitric oxide synthase activity and somatostatin (SOM) and neuropeptide Y or parvalbumin (PV) expression. Gluergic input to the accumbal SOM expressing interneurons  may possibly evoke release of SOM specifically signaling to astrocytes . The PV-expressing sub-population of interneurons has recently been noted as a major player in amphetamine sensitization and reward . Also, we conjecture that the GABAergic PV-expressing NAc interneurons control the fast-firing MSNs, thereby shaping accumbal sensitization (for explanation and references cf. the last paragraph of the “Unique Glu-GABA Drives of the NAc” section). The GABAergic interneurons also receive both DAergic input from the VTA and glutamatergic innervation from cortical areas and in turn terminate on MSNs. Recently, Gluergic input from the VTA terminating on both interneurons and MSNs has also been established. This is the only Gluergic input to the NAc, which mediates aversion instead of reward . Another small proportion of NAc neurons are tonically active cholinergic interneurons, which are the only source of acetylcholine (Ach) in the NAc . These cells receive mostly Gluergic but also ascending serotonergic inputs and synapse onto MSNs through nicotinic (nAChR) and muscarinic acetylcholine (mAChR) receptors, which exert opposing effects on DA signaling. Whereas nAChR activation diminishes, mAChR activation increases motivation toward reward-predicting cues ([38, 39] These cells were also identified as central players in the development of depression-like symptoms, because the disruption of cell surface expression of serotonin (5HT) receptors and/or other ion channels on cholinergic interneurons had antidepressant actions with therapeutic potential . As to the molecular mechanisms, the expression and function of the hyperpolarization-activated cyclic nucleotide-gated channel 2 was suggested to be important as its overexpression in cholinergic interneurons was sufficient to rescue depressive phenotypes . Recently, activation of serotonergic innervation from dorsal raphe nucleus to NAc was also found to be a prerequisite for normal social interaction in mice . These findings qualify petite assemblies of accumbal interneurons as governing big networks associated with behavioral regimes. The operational blowup of interneuron activities shall require local and long-range neuro-glia coupling, to keep pace with the extreme energy demand of real-time dynamics of various molecular players and with the remodeling of synaptic morphology and neuronal circuitries.
Basic Neurochemistry of Reward Quality and Prediction
Reward sensitivity critically depends on the DA neurotransmitter system [19, 47, 203]. Incoming DAergic activity from the VTA in the NAc not only affects activity of the neuronal network but also affects astrocytic calcium signals, since they are dynamically modulated by D2R receptor activation . In addition, DAergic stimuli induce the synthesis of modulatory neuropeptides, like dynorphin, enkephalin, neurokinin A/B, neurotensin, and substance P in astrocytes. The action mechanisms of neuropeptides in the NAc are particularly interesting within the framework of the future development of psychiatric drugs . The DAergic VTA input in the NAc can regulate DA level by feedback mechanisms using collaterals to midbrain DA neuron areas. The incoming VTA signal affects neurons in the rostrodorsal and caudal parts of NAc differently (cf. “hotspots” and “coldspots” referenced below) based on separate co-expression patterns of various DA and opiate receptor subtypes. Endogenous ligands of opioid receptors, enkephalins, modulate locomotor activity by the facilitation of presynaptic DA release. D1R-positive MSNs express mu-opioid receptors predominantly, whereas D2R-positive neurons respond to delta and kappa ligands [7, 29]. Mu-opioid receptor agonists induce not only food intake but also food-reinforced operant behavior . In contrast, accumbal DA receptor activation with amphetamine does not bear any feeding motivation component (, but see [194, 217]); nevertheless, it still produces self-stimulation behavior . Opioids/cannabinoids or anandamide evoke their gustatory hedonic reaction by activating receptors distributed in a well-defined anatomical pattern, in the so-called “hotspots” in the NAc shell [29, 78, 102, 119, 148]. Together with mu-opioid receptors, delta- and kappa-opioid receptors are also clustered in the rostrodorsal region of NAc, enhancing gustatory hedonic reaction (“liking”). In contrast, the very same receptors mediating hedonic suppression map to the caudal part of NAc (“negative hedonic coldspot” [29, 30]).
Accumbal instrumental learning [13, 27, 40, 64, 72, 91, 145, 178, 195, 235] is a fundamental capability of an animal to weigh the utility of selected actions against the expected outcomes. This concept involves occurrence-dependent strengthening of response open to different interpretations—that is, putting either “interaction”  or “reward” [18, 19, 180] aspects in the limelight. In this respect, NAc is considered to be the main hub of the brain that—depending on the actual status of the ascending inputs from limbic structures—exercises sharp bivalent control over the operant behavioral output. Various types of in vivo NAc stimulation paradigms consistently yield opposite animal behavior: either reward/appetitive or stress/aversive. The receptive fields of afferent fibers from prefrontal, entorhinal cortex, amygdala, or hippocampus show little spatial overlap, but individual NAc projecting neurons (GABAergic MSNs) demonstrate a high degree of synaptic convergence from the same input regions [142, 143]. MSNs with mixed GABA-Glu phenotypes [156, 227] could well serve this principle. It is conceivable that at mixed GABA-Glu synapses, the ratio of Glu over GABA co-released from these cells depends on the strengths and frequency of varied input stimulations [44, 141, 189]. Activity-dependent shifting of the balance between GABA and glutamate release allows fine-tuning of transmission probability via changing prevalence of the inhibitory component (GABA). This way, accumbal MSNs with mixed GABA-Glu phenotypes predispose NAc to signal and drive positive or negative conducts.
Unique Glu-GABA Drives of the NAc
The medial prefrontal cortex relays taste information from the primary insular cortex, which constitutes the neuronal basis of food intake and energy homeostasis . Local inhibition of ionotropic Glu receptors (or activation of GABAA receptors) in the shell region of NAc evokes strong feeding response (or positive place preference in other experimental paradigms) by inhibiting MSNs that disinhibit upstream targets like the lateral hypothalamus, ventral pallidum (VP), or VTA . Early studies indicated that the major excitatory input from the medial prefrontal cortex to the anterior pole of NAc (cortico-accumbal pathway) uses Glu or Asp as neurotransmitter [36, 37]. Subsequently, it was demonstrated that feeding induces ambient (Glu) increase in the lateral hypothalamus and decrease in the accumbal (Glu) that was detected by microdialysis probes inserted into the NAc . NAc receives Gluergic inputs from the ventral hippocampus [12, 21, 95] suggesting that depression and drug/ethanol reward behaviors are furthered via the strengthening of these synapses. Recently, a chemogenetic approach has been applied to distinguish the contribution of the activation of VTA-GABA neurons from other mesoaccumbal nerve terminals to incentive salience. The results indicate that VTA-GABA neurons, but not GABA projections, disrupt incentive salience processes .
Several lines of evidence support the crucial aspects of NAc in drug reward modulation [10, 60, 103, 157, 243]. Upon chronic exposure to cocaine, the accumbal alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor (GluA2/AMPA receptor) is upregulated , and NMDA receptor–dependent long-term depression in MSNs in the core region of NAc is suppressed . It is to note that extinction and reconsolidation of cocaine seeking behavior monitored by mass spectrometry–based phosphoproteomics disclosed Gluergic basolateral amygdala inputs to NAc as being crucial for cocaine cue exposure . The drug-seeking behavior could be associated with synaptic changes, such as dendritic spine head diameter and AMPA/NMDA receptor ratio . Extracellular Glu in the NAc is modulated by group 2 metabotropic Glu receptors . Group 2 and 3 metabotropic Glu receptors operate at prefrontal cortical axon terminals and modulate DAergic transmission at the same synapse . Although Glu or GABA activation can evoke similar positive/negative motivational patterns, the effect of GABA holds a hedonic component as well. The major source of GABAergic innervation in the NAc arises from local aspiny interneurons [7, 15]. Apparently, these neurons provide the feed-forward inhibition of neighboring MSNs during excitatory stimulation from descending cortical and hippocampal structures. Presynaptic GluK1/2 heterodimer kainate receptors at cortical afferents play a major role in this inhibition of MSN activity, because GluK1/2 receptor activation decreases glutamatergic but increases GABAergic synaptic transmission in the NAc [28, 39].
The “all or none” type of control of fast-spiking MSNs by the GABAergic PV-containing accumbal interneuron ensemble implies unique functional significance [101, 104, 238] such as sensitization . The bivalent nature of NAc output [167, 168, 170] to different basal ganglia and mesencephalic structures is discernible already at the electrophysiological characteristics of the MSNs that also show bistability . MSNs display spontaneous transition of membrane potential between a more hyperpolarized, resting “down state” and a more depolarized, active “up state”—only when barrages of action potentials can be discharged . Similarly, the influence of hippocampal interneurons on the output of cooperating principal cells would serve to induce synaptic enhancement in target structures during behavioral inactivity, consumer behaviors, and slow-wave sleep . Based on findings showing that cortical astrocytes play an indispensable role in cortical state switching  and even in the generation of genuine, physiological slow-wave activity in vivo , it is suggested that astrocytes may trigger the same coordination of neuronal “up” and “down” state oscillations of accumbal MSNs. Consequently, the heavily gap junction–coupled, easily synchronizable astrocyte network may significantly contribute to the coordinated activation of the NAc circuitry, eventually establishing synaptic reinforcement (see also “Rising Astrocyte Waves: New Layers of Accumbal Neuro-Glia Coupling” section).
Modulation of Inhibitory Signaling by Converging Metabolic and Reward Pathways
Emerging themes, like cellular stress, hypoxia, and inflammation, are examples of functional association between signaling molecules and citrate energy cycle (CEC) metabolites , primarily succinate (Sucn) [34, 124, 158, 202]. Fumarate accumulation associated with glutaminolysis also presents a hallmark of cellular defense mechanism . Mutations of the mitochondrial succinic semialdehyde gene (aldo-keto reductase Aldh5A1) cause succinic semialdehyde dehydrogenase (SSADH) deficiency [120, 219]. In this case, the conversion of SSA to Sucn by SSADH is diminished, while the accumulation of γ-hydroxybutyric acid (GHB) from GABA is maintained. Different responses to methadone maintenance treatment have been explained by a deviation of GABA catabolism from the CEC due to altered Aldh5A1 expression in opioid-dependent patients .
Genes repressed in the NAc and the frontal cortex (FC) of cocaine-, morphine-, and ethanol-vulnerable Lewis rats  help to uncover associated signaling and metabolism, underlying the manifestation of addiction, an important behavioral extremity. Higuera-Matas and co-workers  highlighted some genes as being associated with (i) changes in the striatum of cocaine-sensitized rats (parvalbumin/Pvalb) ; (ii) drug addiction (sphingomyelin synthase, Sgms2) ; and (iii) methamphetamine (Meth)–induced psychosis (NAD(P)H dehydrogenase, Nqo2) [79, 146]. Importantly, genes for Sucn receptor 1 (Sucnr1) and aldo-keto reductase AKR1B10 (Akr1b10) involved in Sucn biosynthesis were also repressed in both the FC and the NAc of Lewis rats . Indeed, the significant role for PV-positive accumbal interneurons in drug-related learning is substantiated by recent data demonstrating PV-positive GABAergic interneurons as a prerequisite for psychostimulant (amphetamine)–induced behavioral adaptation [; discussed by ].
Comparison of putative binding sites of potential Sucn targets in the brain
Rising Astrocyte Waves: New Layers of Accumbal Neuro-Glia Coupling
Maintenance of the significant energy demand of balanced Glu-GABA signaling depends on proper neuro-glia metabolic coupling in various physiological and disease conditions [14, 68, 69, 89, 129, 131, 149, 174, 200, 213, 231]; for reviews see [4, 70, 86, 87, 96, 97, 110, 184, 216]. This dependency is highlighted by the observation that complexes between the astrocytic Glu transporter EAAT2 and the α2 isoform of Na+/K+-ATPase are concentrated in the perisynaptic astrocytic processes (PAPs), which also indicates a unique role for Glu homeostasis . Thus, we coin the term tripartite metaplasticity that signifies not only the prior record of the synaptic activity of the neuronal (see for example  and reference herein) but also that of the astrocytic moduls within the synapse, whereby a new level of “plasticity of synaptic plasticity” (metaplasticity [1, 2]) is attained. Accordingly, we suggest astrocytic activation  and tripartite metaplasticity [2, 33, 56, 110], 2011, 2013; [125, 193] as new substrates of behavioral motivation to action driven by the NAc.
Reactive astrogliosis associated with elevated SSA reductase AKR7A2  may serve as a mechanistic clue for the early appearance of both astroglyopathy in cortico-basal degeneration  and modulation of reward/addiction behavior . For example, chronic drug abuse is characterized by astrocytic hypertrophy, astrocytopathy, and astrogliosis [53, 94]. These morphological and pathological changes trigger Glu uptake via EAAT2. The ensuing alteration of Glu and GABA homeostasis and pertinent metabolism [11, 181] cause altered glial fibrillary acidic protein (GFAP) [54, 183] and EAAT2 expressions .
Regarding the astrocytic control over GABAergic actions, tonic inhibition of the extrasynaptic δ-containing GABAA receptors can be induced by GABA release through the astrocytic GABA transporter (GAT3) due to EAAT2 activation. Moreover, the neuronal activity-dependent exchange of GABA for Glu also influences the power of in vivo gamma oscillations as monitored in the rat hippocampus . This mechanism is adjusted by astrocytic GABA production from polyamines by monoamine oxidize B [69, 236]. Several lines of pharmacological evidence suggest that turning excitation into inhibition by astrocytes may also be relevant to NAc. Reportedly, chronic monoamine oxidase B inhibitor treatment diminished cocaine reward in mice . Also, extrasynaptic δ-containing GABAA receptors in the NAc dorsomedial shell played a role in alcohol intake . It is proposed therefore that the astrocytic Glu-GABA exchange mechanism revealed in the hippocampal formation and the striatum [68, 69, 231]; for reviews see [86, 87, 93, 96, 97, 216] may also modulate NAc functions by adapting tonic inhibition. It is tempting to speculate about the likely correlation of connexin 43 (Cx43)–positive astrocytes in the NAc  with the expression of astrocytic GAT3 and EAAT2 in light of the Glu-GABA exchange mechanisms. Also, the induction of EAAT2 expression and trafficking or the motility of the PAPs ( and references cited therein) raises the possibility of excitation-induced co-localization of EAAT2 with GAT3 [71, 110, 135, 144, 152]. It is noteworthy that the “gliocentric” (references cited above, and ) and “neurocentric”  views of inhibitory plasticity corroborate in terms of the chloride gradient shift across the neuronal membrane.
One of the most remarkable manifestations of chloride signaling in the bidirectional communication between neurons and astrocytes in the brain  is the spatiotemporal intrinsic optical signal (IOS). The IOS, generated by action potentials and robustly enhanced by disinhibition via GABAA receptor blockade, progresses by activation of Glu receptors and astrocytic Glu transporters . Alteration of tonic inhibition due to EAAT2-mediated Glu-GABA exchange occurs at the astrocytic leaflets preferentially contacting synapses  of synaptic islands . These findings also point to the significance of EAAT2 activation–induced astrocytic GAT3 reversal not only in terms of extrasynaptic GABAA receptor activation but also as a mechanism to sensitively modulate chloride gradient and neuronal excitability in this way . From a teleological point of view, MSNs with mixed glutamatergic-GABAergic phenotypes fit the mechanistic clue.
Glu receptor pharmacology may also give an insight into the role of astrocyte activation mechanisms. For example, activation of the group 1 metabotropic Glu receptor (mGluR5) expressed by NAc-resident astrocytes results in a prolonged astrocyte-dependent gliotransmission and stimulation of NMDA receptor–dependent slow inward current in MSNs [41, 46]. In addition to its vital role for promoting resilience to chronic stress , accumbal mGluR5s do impact drug-related behaviors. Furthermore, the inhibitory control of astrocyte activation pathways by antagonists of mGluR5 can interfere with cocaine-seeking behavior [111, 204]. Cocaine withdrawal impairs mGluR5-dependent long-term depression in the shell neurons of NAc . It is to note that mGluR1 and mGluR5 modulate distinct excitatory inputs to the NAc shell . The involvement of astrocytic metabotropic Glu receptor is therefore consistent with the positive feedback cell signaling nucleation model of astrocyte dynamics .
The Macrosystem NAc—from Motivation to Action
Below the thunders of the upper deep,
Far far beneath in the abysmal sea,
His ancient, dreamless, uninvaded slee
The Kraken sleepeth:
Tennyson, Alfred Lord: The Kraken
JK participated in the design, coordinated the study, and drafted the manuscript. ÁD evaluated immunohistochemical data and carried out documentation materials. ZsSz helped to draft the manuscript; ÁS considered relevant bioinformatics; GL and MP evaluated anatomical studies. LH participated in the design, helped to draft the manuscript, and carried out documentation materials. All authors read and approved the final manuscript.
Open access funding provided by MTA Research Centre for Natural Sciences (MTA TTK). This work was supported by grants KMR_12-1-2012-0112 TRANSRAT, VEKOP-2.1.1-15-2016-00156 and OTKA K124558.
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The authors declare that they have no competing interests.
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