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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.

Major depressive disorder (MDD) with childhood trauma represents a heterogeneous clinical subtype of depression. Previous research has observed alterations in the reward circuitry centered around the nucleus accumbens (NAc) in MDD patients. However, limited investigations have focused on aberrant functional connectivity (FC) within NAc subregions among MDD with childhood trauma. Thus, this study adopts analyses of both static FC (sFC) and dynamic FC (dFC) to examine neurobiological changes in MDD with childhood trauma. The bilateral nucleus accumbens shell (NAc-shell) and nucleus accumbens core (NAc-core) were selected as the seeds. Four participant groups were included: MDD with childhood trauma (n = 48), MDD without childhood trauma (n = 30), healthy controls (HCs) with childhood trauma (n = 57), and HCs without childhood trauma (n = 46). Our findings revealed both abnormal sFC and dFC between NAc-shell and NAc-core and regions including the middle occipital gyrus (MOG), anterior cingulate cortex, and inferior frontal gyrus in MDD with childhood trauma. Furthermore, a significant correlation was identified between the dFC of the left NAc-shell and the right MOG in relation to childhood trauma. Additionally, abnormal dFC moderated the link between childhood abuse and depression severity. These outcomes shed light on the neurobiological underpinnings of MDD with childhood trauma.

Listening to music is a promising and accessible intervention for alleviating symptoms of major depressive disorder. However, the neural mechanisms underlying its antidepressant effects remain unclear. In this study on patients with depression, we used auditory entrainment to evaluate intracranial recordings in the bed nucleus of the stria terminalis (BNST) and nucleus accumbens (NAc), along with temporal scalp electroencephalogram (EEG). We highlight music-induced synchronization across this circuit. The synchronization initiates with temporal theta oscillations, subsequently inducing local gamma oscillations in the BNST-NAc circuit. Critically, the incorporated external entrainment induced a modulatory effect from the auditory cortex to the BNST-NAc circuit, activating the antidepressant response and highlighting the causal role of physiological entrainment in enhancing the antidepressant response. Our study explores the pivotal role of the auditory cortex and proposes a neural oscillation triple time-locking model, emphasizing the capacity of the auditory cortex to access the BNST-NAc circuit.

Whilst reward pathologies are major and common in stress-related neuropsychiatric disorders, their neurobiology and treatment are poorly understood. Imaging studies in human reward pathology indicate attenuated BOLD activity in nucleus accumbens (NAc) coincident with reward anticipation but not reinforcement; potentially, this is dopamine (DA) related. In mice, chronic social stress (CSS) leads to reduced reward learning and motivation. Here, DA-sensor fibre photometry is used to investigate whether these behavioural deficits co-occur with altered NAc DA activity during reward anticipation and/or reinforcement. In CSS mice relative to controls: (1) Reduced discriminative learning of the sequence, tone-on + appetitive behaviour = tone-on + sucrose reinforcement, co-occurs with attenuated NAc DA activity throughout tone-on and sucrose reinforcement. (2) Reduced motivation during the sequence, operant behaviour = tone-on + sucrose delivery + sucrose reinforcement, co-occurs with attenuated NAc DA activity at tone-on and typical activity at sucrose reinforcement. (3) Reduced motivation during the sequence, operant behaviour = appetitive behaviour + sociosexual reinforcement, co-occurs with typical NAc DA activity at female reinforcement. Therefore, in CSS mice, low NAc DA activity co-occurs with low reward anticipation and could account for deficits in learning and motivation, with important implications for understanding human reward pathology.

BACKGROUND: The rewarding effect of Methamphetamine (METH) is commonly believed to play an important role in METH use disorder. The altered expression of dopamine D1 receptor (D1R) has been suggested to be essential to the rewarding effect of METH. Notably, D1R could interact with histamine H3 receptors (H3R) by forming a H3R-D1R heteromer (H3R-D1R).
OBJECTIVE: This study was designed to specifically investigate the involvement of H3R-D1R in the rewarding effect of METH.
METHODS: C57BL/6 mice were treated with intraperitoneal injections of a selective H3R antagonist (Thioperamide, THIO; 20 mg/kg), an H1R antagonist (Pyrilamine, PYRI; 10 mg/kg), or microinjections of cytomegalovirus (CMV)-transmembrane domain 5 (TM5) into the nucleus accumbens (NAc). The animal model of Conditioned Place Preference (CPP) was applied to determine the impact of H3R-D1R on the rewarding effect of METH.
RESULTS: METH resulted in a significant preference for the drug-associated chamber, in conjunction with increased H3R and decreased D1R expression in both NAc and the ventral tegmental area (VTA). THIO significantly attenuated the rewarding effect of METH, accompanied by decreased H3R and increased D1R expression. In contrast, pyrilamine failed to produce the similar effects. Moreover, the inhibitory effect of THIO on METH-induced CPP was reversed by SKF38393, a D1R agonist. Furthermore, SCH23390, a D1R antagonist, counteracted the ameliorative effect of SKF38393 on THIO. Co-immunoprecipitation (CO-IP) experiments further demonstrated the specific interaction between H3R and D1R in METH CPP mice. The rewarding effect of METH was also significantly blocked by the interruption of CMV-transmembrane domain 5 (TM5), but not CMV-transmembrane domain 7 (TM7) in NAc.
CONCLUSIONS: These results suggest that modulating the activity of H3R-D1R complex holds promise for regulating METH use disorder and serves as a potential drug target for its treatment.

Electronic cigarettes (e-cigs) use, especially among youngsters, has been on the rise in recent years. However, little is known about the long-term effects of the use of e-cigs on brain functional activity. We acquired the resting-state functional magnetic resonance imaging (rs-fMRI) data from 93 e-cigs users with nicotine dependence and 103 health controls (HC). The local synchronization was analyzed via the regional homogeneity (ReHo) method at voxel-wise level. The functional connectivity (FC) between the nucleus accumbens (NAcc), the ventral tegmental area (VTA), and the insula was calculated at ROI-wise level. The support vector machining classification model based on rs-fMRI measures was used to identify e-cigs users from HC. Compared with HC, nicotine-dependent e-cigs users showed increased ReHo in the right rolandic operculum and the right insula (p < 0.05, FDR corrected). At the ROI-wise level, abnormal FCs between the NAcc, the VTA, and the insula were found in e-cigs users compared to HC (p < 0.05, FDR corrected). Correlation analysis found a significant negative correlation between ReHo in the left NAcc and duration of e-cigs use (r = -0.273, p = 0.008, FDR corrected). The following support vector machine model based on significant results of rs-fMRI successfully differentiates chronic e-cigs users from HC with an accuracy of 73.47%, an AUC of 0.781, a sensitivity of 67.74%, and a specificity of 78.64%. Dysregulated spontaneous activity and FC of addiction-related regions were found in e-cigs users with nicotine dependence, which provides crucial insights into the prevention of its initial use and intervention for quitting e-cigs.

The nucleus accumbens (NAc) plays an important role in various emotional and motivational behaviors that rely on heightened wakefulness. However, the neural mechanisms underlying the relationship between arousal and emotion regulation in NAc remain unclear. Here, we investigated the roles of a specific subset of inhibitory corticotropin-releasing hormone neurons in the NAc (NAcCRH) in regulating arousal and emotional behaviors in mice. We found an increased activity of NAcCRH neurons during wakefulness and rewarding stimulation. Activation of NAcCRH neurons converts NREM or REM sleep to wakefulness, while inhibition of these neurons attenuates wakefulness. Remarkably, activation of NAcCRH neurons induces a place preference response (PPR) and decreased basal anxiety level, whereas their inactivation induces a place aversion response and anxious state. NAcCRH neurons are identified as the major NAc projection neurons to the bed nucleus of the stria terminalis (BNST). Furthermore, activation of the NAcCRH-BNST pathway similarly induced wakefulness and positive emotional behaviors. Taken together, we identified a basal forebrain CRH pathway that promotes the arousal associated with positive affective states.

Clinically, chronic pain and depression often coexist in multiple diseases and reciprocally reinforce each other, which greatly escalates the difficulty of treatment. The neural circuit mechanism underlying the chronic pain/depression comorbidity remains unclear. The present study reports that two distinct subregions in the paraventricular thalamus (PVT) play different roles in this pathological process. In the first subregion PVT posterior (PVP), glutamatergic neurons (PVPGlu) send signals to GABAergic neurons (VLPAGGABA) in the ventrolateral periaqueductal gray (VLPAG), which mediates painful behavior in comorbidity. Meanwhile, in another subregion PVT anterior (PVA), glutamatergic neurons (PVAGlu) send signals to the nucleus accumbens D1-positive neurons and D2-positive neurons (NAcD1→D2), which is involved in depression-like behavior in comorbidity. This study demonstrates that the distinct thalamo-subcortical circuits PVPGlu→VLPAGGABA and PVAGlu→NAcD1→D2 mediated painful behavior and depression-like behavior following spared nerve injury (SNI), respectively, which provides the circuit-based potential targets for preventing and treating comorbidity.

BACKGROUND: Anxiety disorders are one of the most common mental disorders. Ghrelin is a critical orexigenic brain-gut peptide that regulates food intake and metabolism. Recently, the ghrelin system has attracted more attention for its crucial roles in psychiatric disorders, including depression and anxiety. However, the underlying neural mechanisms involved have not been fully investigated.
METHODS: In the present study, the effect and underlying mechanism of ghrelin signaling in the nucleus accumbens (NAc) core on anxiety-like behaviors were examined in normal and acute stress rats, by using immunofluorescence, qRT-PCR, neuropharmacology, molecular manipulation and behavioral tests.
RESULTS: We reported that injection of ghrelin into the NAc core caused significant anxiolytic effects. Ghrelin receptor growth hormone secretagogue receptor (GHSR) is highly localized and expressed in the NAc core neurons. Antagonism of GHSR blocked the ghrelin-induced anxiolytic effects. Moreover, molecular knockdown of GHSR induced anxiogenic effects. Furthermore, injection of ghrelin or overexpression of GHSR in the NAc core reduced acute restraint stress-induced anxiogenic effects.
CONCLUSIONS: This study demonstrates that ghrelin and its receptor GHSR in the NAc core are actively involved in modulating anxiety induced by acute stress, and raises an opportunity to treat anxiety disorders by targeting ghrelin signaling system.