Ventral Striatum Nucleus Accumbens Research Articles

Opposing Spatially Segregated Function of Endogenous GDNF-RET Signaling in Cocaine Addiction.

Cocaine addiction is a serious condition with potentially lethal complications and no current pharmacological approaches towards treatment. Perturbations of the mesolimbic dopamine system are crucial to the establishment of cocaine-induced conditioned place preference and reward. As a potent neurotrophic factor modulating the function of dopamine neurons, glial cell line-derived neurotrophic factor (GDNF) acting through its receptor RET on dopamine neurons may provide a novel therapeutic avenue towards psychostimulant addiction. However, current knowledge on endogenous GDNF and RET function after the onset of addiction is scarce. Here, we utilized a conditional knockout approach to reduce the expression of the GDNF receptor tyrosine kinase RET from dopamine neurons in the ventral tegmental area (VTA) after the onset of cocaine-induced conditioned place preference. Similarly, after establishing cocaine-induced conditioned place preference, we studied the effect of conditionally reducing GDNF in the ventral striatum nucleus accumbens (NAc), the target of mesolimbic dopaminergic innervation. We find that the reduction of RET within the VTA hastens cocaine-induced conditioned place preference extinction and reduces reinstatement, while the reduction of GDNF within the NAc does the opposite: prolongs cocaine-induced conditioned place preference and increases preference during reinstatement. In addition, the brain-derived neurotrophic factor (BDNF) was increased and key dopamine-related genes were reduced in the GDNF cKO mutant animals after cocaine administration. Thus, RET antagonism in the VTA coupled with intact or enhanced accumbal GDNF function may provide a new approach towards cocaine addiction treatment.

Hippocampal and amygdalar increased BDNF expression in the extinction of opioid-induced place preference

The opioid crisis was exacerbated during the COVID-19 pandemic in the United States with alarming statistics about overdose-related deaths (Ahmad et al., 2022). Current treatment options, such as medication assisted treatments, have been unable to prevent relapse in many patients, whereas cue-based exposure therapy have had mixed results in human trials. To improve patient outcomes, it is imperative to develop animal models of addiction to understand molecular mechanisms and identify potential therapeutic targets. We previously found increased brain derived neurotrophic factor (bdnf) transcript in the ventral striatum/nucleus accumbens (VS/NAc) of rats that extinguished morphine-induced place preference. Here, we expand our study to determine whether BDNF protein expression was modulated in mesolimbic brain regions of the reward system in animals exposed to extinction training. Drug conditioning and extinction sessions were followed by Western blots for BDNF in the hippocampus (HPC), amygdala (AMY) and VS/NAc. Rears, as a measure of withdrawal-induced anxiety were also measured to determine their impact on extinction. Results showed that animals who received extinction training and successfully extinguished morphine CPP significantly increased BDNF in the HPC when compared to animals deprived of extinction training (sham-extinction). This increase was not significant in animals who failed to extinguish (extinction-resistant). In AMY, all extinction-trained animals showed increased BDNF, regardless of behavior phenotype. No BDNF modulation was observed in the VS/NAc. Finally, extinction-trained animals showed no difference in rears regardless of extinction outcome, suggesting that anxiety elicited by drug withdrawal did not significantly impact extinction of morphine CPP. Our results suggest that BDNF expression in brain regions of the mesolimbic reward system could play a key role in extinction of opioid-induced maladaptive behaviors and represents a potential therapeutic target for future combined pharmacological and extinction-based therapies.

Two Neural Networks for Laughter: A Tractography Study

Laughter is a complex motor behavior occurring in both emotional and nonemotional contexts. Here, we investigated whether the different functions of laughter are mediated by distinct networks and, if this is the case, which are the white matter tracts sustaining them. We performed a multifiber tractography investigation placing seeds in regions involved in laughter production, as identified by previous intracerebral electrical stimulation studies in humans: the pregenual anterior cingulate (pACC), ventral temporal pole (TPv), frontal operculum (FO), presupplementary motor cortex, and ventral striatum/nucleus accumbens (VS/NAcc). The primary motor cortex (M1) and two subcortical territories were also studied to trace the descending projections. Results provided evidence for the existence of two relatively distinct networks. A first network, including pACC, TPv, and VS/NAcc, is interconnected through the anterior cingulate bundle, the accumbofrontal tract, and the uncinate fasciculus, reaching the brainstem throughout the mamillo-tegmental tract. This network is likely involved in the production of emotional laughter. A second network, anchored to FO and M1, projects to the brainstem motor nuclei through the internal capsule. It is most likely the neural basis of nonemotional and conversational laughter. The two networks interact throughout the pre-SMA that is connected to both pACC and FO.

Ruminative Tendency Relates to Ventral Striatum Functionality: Evidence From Task and Resting-State fMRI.

BackgroundRuminative responding involves repetitive and passive thinking about one’s negative affect. This tendency interferes with initiation of goal-directed rewarding strategies, which could alleviate depressive states. Such reward-directed response selection has been shown to be mediated by ventral striatum/nucleus accumbens (VS/NAcc) function. However, to date, no study has examined whether trait rumination relates to VS/NAcc functionality. Here, we tested whether rumination moderates VS/NAcc function both in response to reward and during a ruminative state.MethodsTrait rumination was considered dimensionally using Rumination Response Scale (RRS) scores. Our sample (N = 80) consisted of individuals from a community sample and from patients diagnosed with major depressive disorder, providing a broad range of RRS scores. Participants underwent fMRI to assess two modes of VS/NAcc functionality: 1) in response to reward, and 2) during resting-state, as a proxy for ruminative state. We then tested for associations between RRS scores and VS/NAcc functional profiles, statistically controlling for overall depressive symptom severity.ResultsRRS scores correlated positively with VS/NAcc response to reward. Furthermore, we noted that higher RRS scores were associated with increased ruminative-dependent resting-state functional connectivity of the VS/NAcc with the left orbitofrontal cortex.ConclusionsThese findings suggest that ruminative tendencies manifest in VS/NAcc reward- and rumination-related functions, providing support for a theoretical-clinical perspective of rumination as a habitual impairment in selection of rewarding, adaptive coping strategies.

Neuroplasticity transcript profile of the ventral striatum in the extinction of opioid-induced conditioned place preference.

Persistent drug-seeking behavior has been associated with deficits in neural circuits that regulate the extinction of addictive behaviors. Although there is extensive data that associates addiction phases with neuroplasticity changes in the reward circuit, little is known about the underlying mechanisms of extinction learning of opioid associated cues. Here, we combined morphine-conditioned place preference (CPP) with real-time polymerase chain reaction (RT-PCR) to identify the effects of extinction training on the expression of genes (mRNAs) associated with synaptic plasticity and opioid receptors in the ventral striatum/nucleus accumbens (VS/NAc). Following morphine extinction training, we identified two animal subgroups showing either extinction (low CPP) or extinction-resistance (high CPP). A third group were conditioned to morphine but did not receive extinction training (sham-extinction; high CPP). RT-PCR results showed that brain derived neurotrophic factor (Bdnf) was upregulated in rats showing successful extinction. Conversely, the lack of extinction training (sham-extinction) upregulated genes associated with kinases (Camk2g), neurotrophins (Ngfr), synaptic connectivity factors (Ephb2), glutamate neurotransmission (Grm8) and opioid receptors (μ1, Δ1). To further identify genes modulated by morphine itself, comparisons with their saline-counterparts were performed. Results revealed that Bdnf was consistently upregulated in the extinction group. Alternatively, widespread gene modulation was observed in the group with lack of extinction training (i.e. Drd2, Cnr1, Creb, μ1, Δ1) and the group showing extinction resistance (i.e. Crem, Rheb, Tnfa). Together, our study builds on the identification of putative genetic markers for the extinction learning of drug-associated cues.

A negative relationship between ventral striatal loss anticipation response and impulsivity in borderline personality disorder.

Patients with borderline personality disorder (BPD) frequently exhibit impulsive behavior, and self-reported impulsivity is typically higher in BPD patients when compared to healthy controls. Previous functional neuroimaging studies have suggested a link between impulsivity, the ventral striatal response to reward anticipation, and prediction errors. Here we investigated the striatal neural response to monetary gain and loss anticipation and their relationship with impulsivity in 21 female BPD patients and 23 age-matched female healthy controls using functional magnetic resonance imaging (fMRI). Participants performed a delayed monetary incentive task in which three categories of objects predicted a potential gain, loss, or neutral outcome. Impulsivity was assessed using the Barratt Impulsiveness Scale (BIS-11). Compared to healthy controls, BPD patients exhibited significantly reduced fMRI responses of the ventral striatum/nucleus accumbens (VS/NAcc) to both reward-predicting and loss-predicting cues. BIS-11 scores showed a significant positive correlation with the VS/NAcc reward anticipation responses in healthy controls, and this correlation, while also nominally positive, failed to reach significance in BPD patients. BPD patients, on the other hand, exhibited a significantly negative correlation between ventral striatal loss anticipation responses and BIS-11 scores, whereas this correlation was significantly positive in healthy controls. Our results suggest that patients with BPD show attenuated anticipation responses in the VS/NAcc and, furthermore, that higher impulsivity in BPD patients might be related to impaired prediction of aversive outcomes.

Age-related striatal BOLD changes without changes in behavioral loss aversion.

Loss aversion (LA), the idea that negative valuations have a higher psychological impact than positive ones, is considered an important variable in consumer research. The literature on aging and behavior suggests older individuals may show more LA, although it is not clear if this is an effect of aging in general (as in the continuum from age 20 and 50 years), or of the state of older age (e.g., past age 65 years). We also have not yet identified the potential biological effects of aging on the neural processing of LA. In the current study we used a cohort of subjects with a 30 year range of ages, and performed whole brain functional MRI (fMRI) to examine the ventral striatum/nucleus accumbens (VS/NAc) response during a passive viewing of affective faces with model-based fMRI analysis incorporating behavioral data from a validated approach/avoidance task with the same stimuli. Our a priori focus on the VS/NAc was based on (1) the VS/NAc being a central region for reward/aversion processing; (2) its activation to both positive and negative stimuli; (3) its reported involvement with tracking LA. LA from approach/avoidance to affective faces showed excellent fidelity to published measures of LA. Imaging results were then compared to the behavioral measure of LA using the same affective faces. Although there was no relationship between age and LA, we observed increasing neural differential sensitivity (NDS) of the VS/NAc to avoidance responses (negative valuations) relative to approach responses (positive valuations) with increasing age. These findings suggest that a central region for reward/aversion processing changes with age, and may require more activation to produce the same LA behavior as in younger individuals, consistent with the idea of neural efficiency observed with high IQ individuals showing less brain activation to complete the same task.

Typical and atypical antipsychotic drugs target dopamine and cyclic AMP-regulated phosphoprotein, 32 kDa and neurotensin-containing neurons, but not GABAergic interneurons in the shell of nucleus accumbens of ventral striatum

Specific neurons in the brain are the primary targets of the action of antipsychotic drugs. Identification and characterization of the nature of these neurons are important for understanding how antipsychotic drugs produce their effects. In previous studies GABAergic/dynorphinergic neurons were identified as a principal cell target of antipsychotic drugs in the shell of nucleus accumbens. In the present study, we further characterized which subpopulations of GABAergic neurons in this area respond after acute administration of antipsychotic drugs. Rats were treated with the typical antipsychotic haloperidol, or the prototype atypical antipsychotic clozapine and killed two hours after treatment. In appropriate sections of brain, double immunofluorescence labeling was performed with antibodies directed against markers specific to candidate cell types and Fos-like proteins (a marker to identify drug-induced cell activation). We reported here that haloperidol- and clozapine-activated neurons showed the following features: 1) approximately 54–57% of them express dopamine and cyclic AMP-regulated phosphoprotein, 32 kDa (a marker for GABAergic medium spiny projection neurons), 2) they appear rarely to be GABAergic interneurons, marked by the calcium binding proteins, parvalbumin, calretinin or calbindin-D28K, 3) about 84–86% of them express the neuropeptide neurotensin (a neurotransmitter most often associated with projection neurons in the site tested). The results suggest that most of the antipsychotic drug–activated neurons in the shell of nucleus accumbens are likely to be neurotensin containing projection neurons.

Ventral Striatum/Nucleus Accumbens Activation to Smoking-Related Pictorial Cues in Smokers and Nonsmokers: A Functional Magnetic Resonance Imaging Study

Converging evidence from several theories of the development of incentive-sensitization to smoking-related environmental stimuli suggests that the ventral striatum plays an important role in the processing of smoking-related cue reactivity. Twenty-six healthy right-handed volunteers (14 smokers and 12 nonsmoking controls) underwent functional magnetic resonance imaging (fMRI) during which neutral and smoking-related images were presented. Region of interest analyses were performed within the ventral striatum/nucleus accumbens (VS/NAc) for the contrast between smoking-related (SR) and nonsmoking related neutral (N) cues. Group activation for SR versus N cues was observed in smokers but not in nonsmokers in medial orbitofrontal cortex, superior frontal gyrus, anterior cingulate cortex, and posterior fusiform gyrus using whole-brain corrected Z thresholds and in the ventral VS/NAc using uncorrected Z-statistics (smokers Z = 3.2). Region of interest analysis of signal change within ventral VS/NAc demonstrated significantly greater activation to SR versus N cues in smokers than controls. This is the first demonstration of greater VS/NAc activation in addicted smokers than nonsmokers presented with smoking-related cues using fMRI. Smokers, but not controls, demonstrated activation to SR versus N cues in a distributed reward signaling network consistent with cue reactivity studies of other drugs of abuse.