Accumbens Research Articles

Possible Potentiating Effects of Combined Administration of Alcohol, Caffeine, and Nicotine on In Vivo Dopamine Release in Addiction-Related Circuits Within the CNS of Rats

Background: Studies that assess the effects of the interaction of psychoactive substances on dopamine release, the key neurotransmitter in the neurochemical and behavioral effects related to drug consumption, are crucial to understand both their roles and the dysfunctions they produce in the central nervous system. Objective: We evaluated the effects of individual and combined administration of the three most widely consumed psychoactive substances in the world, ethanol, caffeine, and nicotine, on dopaminergic neurotransmission in three brain regions of rats related to addiction: the prefrontal cortex (PFC), the nucleus accumbens (NAcc), and the dorsal striatum. Methods: The dopamine levels were measured in vivo by cerebral microdialysis associated with HPLC-ED. Results: We observed that local administration of a single concentration of caffeine (5 mM) or nicotine (5 mM) significantly increased the dopamine levels in all three areas studied, while ethanol (300 mM) increased them in the NAcc and striatum. Perfusion of nicotine + caffeine produced a synergistic effect in both the NAcc and striatum, with increases in the in vivo dopamine release greater than the sum of the effects of both substances. When administering the combination of nicotine + caffeine + ethanol, we observed an additive effect in the NAcc, while in the PFC we observed a synergistic effect. Conclusions: Our results support the stimulating effects of caffeine, nicotine, and ethanol on the brain reward system. In addition, we also observed that the administration of different mixtures of these substances produces synergistic and additive effects on the release of dopamine in the mesocortical and nigrostriatal systems.

Possible Mechanisms of the Influence of Oxytocin and Vazopressin on Perception and Memory of Odors and on Social Behavior

A possible mechanism is proposed for the influence of oxytocin and vasopressin on the functioning of the neural network in the CNS, in which olfactory information is processed and stored, and which plays an important role in social behavior. The effect of these neuropeptides on postsynaptic receptors associated with Gq/11 proteins contributes to the induction of LTP of the efficacy of excitatory synaptic inputs to the main projection cells and to inhibitory interneurons in the prefrontal cortex, hippocampus, piriform cortex, anterior olfactory nucleus, olfactory bulb and nucleus accumbens, including the olfactory tubercle. As a result of disynaptic inhibition in each of the structures, the signal-to-noise ratio is improved and the transmission of strong signals through projection neurons to their target cells is facilitated. Due to the fact, that oxytocin promotes the release of dopamine by the neurons of the ventral tegmental area, the conditions for processing and memorizing olfactory information in the interconnected olfactory and hippocampal neural networks, including cortical and subcortical structures, are improved, and attention is also included in this processing. Long-term modification of the effectiveness of interneuronal connections in these networks under the influence of oxytocin and dopamine contributes to the formation and stabilization of contrasting neuronal representation of odors formed in cortical areas. Orientation of attention increases the significance of socially important olfactory stimuli and improves the conditions for the functioning of the reinforcement system necessary for adequate social behavior. Taking into account the known data on the correlation between social behavior and the density of oxytocin and vasopressin receptors on neurons of different structures, understanding the mechanisms of the influence of these neuropeptides on the functioning of the olfactory system can be useful for finding ways to correct behavior if necessary.

Mapping of c-Fos Expression in Rat Brain Sub/Regions Following Chronic Social Isolation: Effective Treatments of Olanzapine, Clozapine or Fluoxetine

The c-Fos as a marker of cell activation is used to identify brain regions involved in stimuli processing. This review summarizes a pattern of c-Fos immunoreactivity and the overlapping brain sub/regions which may provide hints for the identification of neural circuits that underlie depressive- and anxiety-like behaviors of adult male rats following three and six weeks of chronic social isolation (CSIS), relative to controls, as well as the antipsychotic-like effects of olanzapine (Olz), and clozapine (Clz), and the antidepressant-like effect of fluoxetine (Flx) in CSIS relative to CSIS alone. Additionally, drug-treated controls relative to control rats were also characterized. The overlapping rat brain sub/regions with increased expression of c-Fos immunoreactivity following three or six weeks of CSIS were the retrosplenial granular cortex, c subregion, retrosplenial dysgranular cortex, dorsal dentate gyrus, paraventricular nucleus of the thalamus (posterior part, PVP), lateral/basolateral (LA/BL) complex of the amygdala, caudate putamen, and nucleus accumbens shell. Increased activity of the nucleus accumbens core following exposure of CSIS rats either to Olz, Clz, and Flx treatments was found, whereas these treatments in controls activated the LA/BL complex of the amygdala and PVP. We also outline sub/regions that might represent potential neuroanatomical targets for the aforementioned antipsychotics or antidepressant treatments.

Hypocretin modulation of behavioral coping strategies for social stress.

Best known for promoting wakefulness and arousal, the neuropeptide hypocretin (Hcrt) also plays an important role in mediating stress responses, including social stress. However, central and systemic manipulation of the Hcrt system has produced diverse behavioral outcomes in animal models. In this review, we first focus on studies where similar manipulations of the Hcrt system led to divergent coping behaviors. We hypothesize that Hcrt differentially facilitates active and passive coping behaviors in response to social stress by acting in different brain regions and on different cell types. We then focus on region and cell type-specific effects of Hcrt in the ventral pallidum, lateral habenula, ventral tegmental area, nucleus accumbens, amygdala, and bed nucleus of the stria terminalis. Overall, the evidence suggests that rather than enhancing or inhibiting behavioral responses to social stress, Hcrt may signal the heightened arousal associated with stressful contexts. The resulting behavioral effects depend on which circuits Hcrt release occurs in and which receptor types are activated. Further study is needed to determine how and why circuit specific activation of Hcrt neurons occurs.

Age-related volume decrease in subcortical gray matter is a part of healthy brain aging in men.

With the global population aging, the number of individuals over 60 is expected to double by 2050. Brain volume increases until age 13, stabilizes between 18 and 35, then declines by 0.2% annually. Magnetic resonance imaging (MRI) studies highlight significant gray matter atrophy, necessitating differentiation between normal aging and neurodegeneration. This study assessed the impact of aging on subcortical gray matter in healthy males to identify biomarkers of physiological aging. A retrospective study of 106 healthy males who underwent brain MRI from 2012 to 2016, divided into two age groups: younger and older than 35years. MRI scans were performed using a 3T machine, and volumetric analysis was conducted with VolBrain software. Subcortical gray matter volumes were compared between groups. The Shapiro-Wilk test evaluated normality. Student's t-test and Mann-Whitney U test were used for statistical analysis, with significance defined as p < 0.05. Total intracranial volume was comparable between age groups (p = 0.527). Significant volume reductions (p < 0.05) were observed in subcortical gray matter structures, including the nucleus accumbens, caudate nucleus, globus pallidus, putamen, thalamus, and ventral diencephalon, particularly on the right side in the elderly group. Subcortical gray matter volume in healthy males shows significant differences between older and younger individuals (p < 0.05), with asymmetrical reduction and certain structures on the right aging more rapidly. These findings are significant for distinguishing healthy aging from neurodegeneration.

Social isolation induces addictive behavior and increases release of dopamine in the &lt;i&gt;nucleus accumbens&lt;/i&gt; in response to stimulation of the positive reinforcing zone

The study of the role of social isolation in the pathogenesis of addictive behavior disorders is an important medical and biological problem. Of particular importance are the limitations of social experience in ontogenesis. This work makes an attempt to find a connection between social isolation in ontogenesis and impulsive-compulsive behavior, as an indicator of the premorbid background for gaming and other forms of behavioral addictions. The mechanisms of addictive behavior in rats reared in isolation (IS) were investigated by analyzing the extracellular release of dopamine in response to stimulation of the positive reinforcing zone. Before the experiments, male rats were kept in individual cages from the 21st day of birth to the 90th day. To study elements of addictive behavior, a variant of the Iowa Gambling Task in a 3-arm maze and a method of developing compulsive overeating using intermittent consumption of high-calorie foods were used. To study compulsive behavior, a marble test was used against the background of withdrawal from a high-calorie diet. Surgeries were performed to implant electrodes into the ventral tegmental area (VTA) and the nucleus accumbens in rats exhibiting elements of addictive behavior in the 3-arm maze. These animals were then trained to respond to VTA self-stimulation. Dopamine release was recorded telemetrically in freely moving rats in response to electrical stimulation of the VTA self-stimulation zone. Fast scan cyclic voltammetry was used to determine changes in dopamine levels in the extracellular environment of the nucleus accumbens. IS entered less into the arm with a high degree of probability but with a low reward, and entered more in the arm with a low degree of probability, but with a high reward, which is associated with the appearance of impulsivity in behavior. In the model of compulsive overeating, the number of approaches to the feeder in IS increased, and against the background of withdrawal of high-calorie food, IS were more active in the marble test. In IS exhibiting elements of addictive behavior in the 3-arm maze, the content of extracellular dopamine in response to electrical stimulation of the VTA self-stimulation zones did not reveal any differences compared to the control group of rats with addictive behavior in the maze. At the same time, IS exhibiting elements of addictive behavior in the maze showed a more pronounced dopamine response to a complex stimulus: a conditioned signal used during maze learning light + VTA stimulation. Thus, rearing in the IS causes an increase in dopamine release in the nucleus accumbens in response to stimulation of the positive reinforcement area associated with addictive behaviors: impulsivity and compulsivity. A conclusion is drawn about the prospects of studying the extracellular release of dopamine and assesses addictive behavior disorders caused by limited social contacts in ontogenesis.

The interhemispheric amygdala-accumbens circuit encodes negative valence in mice.

The structurally symmetric mammalian brain hemispheres are interconnected by commissural axons across the midline. However, the functions of interhemispheric connectivity remain largely unknown. We found that in mice, transection of the anterior commissure (AC), which connects the rostroventral forebrain, impaired avoidant behaviors. The basolateral amygdala (BLA) in the mouse projects to the contralateral nucleus accumbens (NAc) through the AC, independent of its ipsilateral projections. Aversive stimuli activated contralateral BLA-NAc projections. Positive stimuli, however, activated ipsilateral projections. Selective activation of contralateral BLA-NAc projections activated D2-positive medium spiny neurons (D2-MSNs), reduced NAc dopamine levels, and caused aversion, whereas selective activation of ipsilateral BLA-NAc projections activated D1-MSNs, increased NAc dopamine levels, and induced reward. The contralateral BLA-AC-NAc pathway is crucial for encoding negative valence, demonstrating distinct functions of intra- and interhemispheric circuits in brain physiology.

Ventral pallidum neurons are necessary to generalize and express fear-related responding in a minimal threat setting.

Fear generalization is a hallmark of anxiety disorders. Experimentally, fear generalization can be difficult to dissociate from its counterpart, fear discrimination. Here we use minimal threat learning procedures to reveal such a dissociation. We show that in Long Evans rats, an auditory threat cue predicting foot shock on 10% of trials produces a discriminated fear response that does not generalize to a neutral auditory cue. Even slightly higher foot shock probabilities (30% and 20%) produce fear generalization. AAV-mediated, caspase-3 deletion of ventral pallidum neurons abolishes fear generalization and reduces threat cue responding during extinction. The ventral pallidum's contribution to fear generalization and extinction threat responding does not depend on inputs from the nucleus accumbens. The results demonstrate a minimal threat learning approach to dissociate fear discrimination from fear generalization, and a novel role for the ventral pallidum in generalizing and expressing fear.Significance Statement In the laboratory, healthy mice, rats, and people generalize fear responding to a neutral cue before showing fear discrimination. However, in the real world, fear generalization is not nearly as ubiquitous in healthy individuals. Here we show that in rats, minimal threat learning procedures manipulating foot shock probability identify a boundary at which fear discrimination proceeds in the absence of fear generalization. We exploit this boundary to reveal a novel and essential role for the ventral pallidum in fear generalization.

Cortico-limbic volume abnormalities in late life depression are distinct from β amyloid and white matter pathologies.

This study was conducted to clarify patterns of cortico-limbic volume abnormalities in late life depression (LLD) relative to non-depressed (ND) adults matched for amyloid β (Aβ) deposition and to evaluate the relationship of volume abnormalities with cognitive performance. Participants included 116 LLD and 226 ND. Classification accuracy of LLD status was estimated using area under the receiver operator characteristic curve. Twenty-one percent of LLD and ND participants were Aβ positive and the groups did not differ on white matter hyperintensity volume (WMH (logscale); β = 0.12, p = 0.28). Compared to ND, the LLD group exhibited significantly lower bilateral volume in the lateral orbitofrontal cortex, hippocampus, accumbens area, superior temporal lobe, temporal pole, and amygdala after multiple comparison correction (p < 0.009 for all). Cortico-limbic volumes significantly improved classification of LLD beyond demographic characteristics, Aβ status, and WMH (AUCVol = 0.71, AUCWMH, Aβ = 0.62, AUC difference, 0.09 [0.03 to 0.15]). LLD exhibited poorer performance on measures of global cognition, set shifting, and verbal learning and memory relative to ND. Cognitive function was positively associated with cortico-limbic volumes and these relationships did not differ by group. Secondary analyses with an ND sample additionally matched for Mild Cognitive Impairment (MCI) diagnosis showed a similar but attenuated pattern of volume abnormalities. Overall, our results support LLD as being associated with cortico-limbic volume abnormalities that are distinct from Aβ and white matter pathologies and that these volume abnormalities are important factors associated with cognitive dysfunction in LLD.

Multifunctional Neural Probes Enable Bidirectional Electrical, Optical, and Chemical Recording and Stimulation In Vivo.

Recording and modulation of neuronal activity enables the study of brain function in health and disease. While translational neuroscience relies on electrical recording and modulation techniques, mechanistic studies in rodent models leverage genetic precision of optical methods, such as optogenetics and fluorescent indicator imaging. In addition to electrical signal transduction, neurons produce and receive diverse chemical signals which motivate tools to probe and modulate neurochemistry. Although the past decade has delivered a wealth of technologies for electrophysiology, optogenetics, chemical sensing, and optical recording, combining these modalities within a single platform remains challenging. This work leverages materials selection and convergence fiber drawing to permit neural recording, electrical stimulation, optogenetics, fiber photometry, drug and gene delivery, and voltammetric recording of neurotransmitters within individual fibers. Composed of polymers and non-magnetic carbon-based conductors, these fibers are compatible with magnetic resonance imaging, enabling concurrent stimulation and whole-brain monitoring. Their utility is demonstrated in studies of the mesolimbic reward pathway by interfacing with the ventral tegmental area and nucleus accumbens in mice and characterizing the neurophysiological effects of a stimulant drug. This study highlights the potential of these fibers to probe electrical, optical, and chemical signaling across multiple brain regions in both mechanistic and translational studies.

Change in striatal functional connectivity networks across 2 years due to stimulant exposure in childhood ADHD: results from the ABCD sample.

Widely prescribed for Attention-Deficit/Hyperactivity Disorder (ADHD), stimulants (e.g., methylphenidate) have been studied for their chronic effects on the brain in prospective designs controlling dosage and adherence. While controlled approaches are essential, they do not approximate real-world stimulant exposure contexts where medication interruptions, dosage non-compliance, and polypharmacy are common. Brain changes in real-world conditions are largely unexplored. To fill this gap, we capitalized on the observational design of the Adolescent Brain Cognitive Development (ABCD) study to examine effects of stimulants on large-scale bilateral cortical networks' resting-state functional connectivity (rs-FC) with 6 striatal regions (left and right caudate, putamen, and nucleus accumbens) across two years in children with ADHD. Bayesian hierarchical regressions revealed associations between stimulant exposure and change in rs-FC of multiple striatal-cortical networks, affiliated with executive and visuo-motor control, which were not driven by general psychotropic medication. Of these connections, three were selective to stimulants versus stimulant naive: reduced rs-FC between caudate and frontoparietal network, and between putamen and frontoparietal and visual networks. Comparison with typically developing children in the ABCD sample revealed stronger rs-FC reduction in stimulant-exposed children for putamen and frontoparietal and visual networks, suggesting a normalizing effect of stimulants. 14% of stimulant-exposed children demonstrated reliable reduction in ADHD symptoms, and were distinguished by stronger rs-FC reduction between right putamen and visual network. Thus, stimulant exposure for a two-year period under real-world conditions modulated striatal-cortical functional networks broadly, had a normalizing effect on a subset of networks, and was associated with potential therapeutic effects involving visual attentional control.

Structural projections to the nucleus accumbens link to impulsive components of human risk preference

Abstract Functional responses in the Nucleus Accumbens (NAcc) to risk- and reward-related cues can predict real-life risk-taking behavior. Since NAcc activity depends on neurotransmission from connected brain regions, projections to the NAcc may also predict risk preference. To quantify risk preference, we employed latent variables previously derived in a comprehensive, independent study examining the psychometric structure of risk preference, which yielded a general risk preference factor as well as several specific factors, including a factor capturing impulsivity. Informed by previous work, we preregistered a set of hypotheses concerning the association between different risk preference factors and fractional anisotropy (or FA, which is sensitive to fiber coherence) for projections to the NAcc from Medial PreFrontal Cortex (MPFC), Anterior Insula, Amygdala, and an inferior tract from the Ventral Tegmental Area (iVTA). We tested our hypotheses in a community sample of 125 healthy human adults. As predicted, bilateral iVTA-NAcc tract FA showed a negative correlation with a psychometric factor that captured impulsivity, generalizing findings from prior research. Also as predicted, FA of the bilateral Amygdala-NAcc tract was positively associated with the impulsivity factor. Contrary to predictions, however, we observed no robust associations between the general risk preference factor and FA for projections from bilateral MPFC, right Anterior Insula, or bilateral Amygdala to the NAcc. Notably, exploratory unilateral analyses revealed an association between the general risk preference factor and left MPFC-NAcc tract FA. Taken together, these findings suggest that impulse control as a facet of risk preference maps onto specific neurobiological targets, while more general facets of risk preference may be supported by structural properties of lateral fronto-striatal projections. Although the exact associated functional mechanisms remain to be fully clarified, conNAcctomic approaches like the one presented here could pave the way for further research into the physiological foundations of risk preference and related constructs.

Transcriptomic Profile of the Male Rat Hypothalamus and Nucleus Accumbens After Paroxetine Treatment and Withdrawal: Possible Causes of Sexual Dysfunction.

Paroxetine, a selective serotonin reuptake inhibitor (SSRI), may induce sexual dysfunction during treatment and upon discontinuation. The mechanisms involved have been poorly explored so far. We have analyzed, by RNA sequencing, the whole transcriptomic profile in the hypothalamus and nucleus accumbens (NAc) (two brain regions involved in sexual behavior) of male rats daily treated for 2weeks with paroxetine (T0) and at 1month of withdrawal (T1). Data here reported show seven differentially expressed genes (DEGs) at T0 and 1 at T1 in the hypothalamus and 245 at T0 and 6 at T1 in the NAc. In addition, Gene-Set Enrichment, Gene Ontology, and Reactome analyses confirm that inflammatory signature and immune system activation were present at T0 in both brain areas. Considering that inflammation is generally associated with depression and that no paradigms inducing the pathology were here applied, these SSRI pro-depressive effects should be considered in patients without a clear indication of depression. Moreover, DEGs related to neurotransmitters with a role in sexual behavior and the reward system, such as dopamine (e.g., sialyltransferase 8B-ST8SIA3), glutamate (e.g., glutamate receptor ionotropic delta-2-GRID2) and GABA (e.g., glutamate decarboxylase type 2-GAD2) or associated with neurexin and neuroligin pathways and brain-derived neurotrophic factor (BDNF) signaling, were reported to be dysregulated in the NAc, further confirming dysfunction in this brain area. Interestingly, the analysis of DEGs altered at T1 in the NAc confirms the persistence of some of these side effects providing further information for post-SSRI sexual dysfunction (PSSD) etiopathogenesis.

Extracellular signal-regulated protein kinase-2 signaling in the nucleus accumbens facilitates stress-susceptibility and cocaine reinstatement.

BackgroundSecond messenger signaling within the mesolimbic reward circuit plays a key role in the negative effects of stress and the underlying mechanisms that promote drug abuse. Since the nucleus accumbens (NAc) integrates reward valence, we investigated how extracellular signal-regulated protein kinase-2 (ERK2) signaling affects the development of stress-related comorbidities, including negative affect and drug sensitivity. MethodsWe assessed how chronic unpredictable stress (CUS) influenced the phosphorylation of ERK2-signaling proteins within the NAc of male Sprague Dawley rats. Using a herpes-simplex virus, we either upregulated or downregulated NAc ERK2 activation and evaluated behavioral responses to stress-eliciting stimuli (elevated plus maze, open field, forced-swim test) and cocaine-seeking behavior (conditioned place preference, self-administration). We also examined ERK2-mediated modifications in spine morphology of medium spiny neurons (MSNs) within the NAc. ResultsCUS increased the phosphorylation of ERK2-signaling proteins within the NAc. Viral-mediated activation of NAc ERK2 enhanced susceptibility to both depression- and anxiety-related stimuli and increased cocaine-seeking behavior (conditioned place preference and reinstatement). These behavioral changes were associated with an increase in stubby and mushroom spines of NAc MSNs. Conversely, downregulation of ERK2 activation attenuated affect-related behavioral responses in the forced swim test and blunted cocaine’s rewarding effects, without influencing NAc spine morphology. ConclusionsNAc ERK2 contributes to stress-induced behavioral deficits, including anxiety- and depression-like phenotypes, while promoting cocaine-seeking behavior. These findings suggest that ERK2 signaling in the NAc plays a role in the comorbidity of these related syndromes.

Investigation into the biomolecular bases of blunted cocaine-induced glutamate release within the nucleus accumbens elicited by adolescent exposure to phenylpropanolamine

Globally, phenylpropanolamine (PPA) is a prevalent primary active ingredient in over-the-counter cough and cold, as well as weight-loss medications. Previously, we showed that a sensitization of cocaine-induced glutamate release within the nucleus accumbens (NAC) and the expression of cocaine-conditioned reward is not apparent in adult mice with a prior history of repeated PPA exposure during adolescence. As NAC glutamate is a purported driver of cocaine reward and reinforcement, the present study employed in vivo microdialysis and immunoblotting approaches to inform as to the receptor and transporter anomalies that might underpin the disrupted glutamate response to cocaine in adolescent PPA-exposed mice. For this, male and female C57BL/6J mice were pretreated, once daily, with either 0 or 40mg/kg PPA during post-natal days 35-44. Adolescent PPA pretreatment significantly altered the expression of mGlu2/3 and α2 receptors in the NAC, with less robust changes detected for EAAT2, D2 receptors, DAT and NET. However, we detected no overt change in the capacity of these receptors or transporters to affect extracellular glutamate levels in adolescent PPA-pretreated mice. The present findings contrast with the pronounced changes in the capacity of mGlu2/3 receptors, EAAT, DAT and NET to regulate NAC extracellular glutamate reported previously for juvenile PPA-pretreated mice, indicating further that the long-term biochemical consequences of PPA depend on the critical period of neurodevelopment during which an individual is PPA-exposed, although the specific biomolecular changes underpinning the cocaine phenotype produced by adolescent PPA remain to be elucidated.

Mapping punishment avoidance learning deficits in non-suicidal self-injury in young adults with and without borderline personality disorder: An fMRI study

IntroductionNon-suicidal self-injury (NSSI) is a growing public health concern among young adults in both clinical and non-clinical settings. Despite evidence linking NSSI to alterations in learning from reward and punishment, this area remains understudied, especially in non-clinical populations without borderline personality disorder (BPD). MethodsWe employed a modified version of the Probabilistic Stimulus Selection (PSS) task in two groups of young adults with recurrent NSSI, with (NSSI+BPD) and without BPD (NSSI), and an additional group of healthy controls (HC). While undergoing functional magnetic resonance imaging (fMRI), participants were asked to choose between pairs of stimuli with different reward probabilities. In the training phase, they received probabilistic feedback and learned to identify the most rewarding option within fixed pairs. In the test phase, these learned stimuli were recombined into novel pairs, where participants' accuracy in selecting the most rewarding and avoiding the most punishing options reflected their ability to learn from reward and punishment, respectively. ResultsCompared to HC, participants in the NSSI and NSSI+BPD groups were less accurate at avoiding the most punishing options than at choosing the most rewarding options, and showed reduced activity in the nucleus accumbens (NAcc) during punishment avoidance relative to reward selection. LimitationsThe modest sample size, descriptive rather than modeling approach, and absence of ecological momentary assessments may limit the results. ConclusionFindings suggest that reduced activation of the NAcc when avoiding loss may underlie difficulties in learning to avoid punishment in young adults with NSSI, regardless of the presence of BPD.

Separate anterior paraventricular thalamus projections differentially regulate sensory and affective aspects of pain

The experience of pain is complex, involving both sensory and affective components, yet the underlying neural mechanisms remain elusive. Here, we show that formalin-induced pain behaviors coincide with increased responses in glutamatergic neurons within the anterior paraventricular nucleus of the thalamus (PVA). Furthermore, we describe non-overlapping subpopulations of PVAVgluT2 neurons involved in sensory and affective pain processing, whose activity varies across different pain states. Activating PVA glutamatergic neurons is sufficient to induce mechanical hypersensitivity and aversion behaviors, whereas suppression ameliorates formalin-induced pain. Furthermore, we identify the segregation of PVAVgluT2 projections to the bed nucleus of the stria terminalis (BNST) and nucleus accumbens (NAc), each influencing specific aspects of pain-like behavior. This finding provides an important insight into the mechanism of distinct components of pain, highlighting the pivotal role of PVA in mediating different aspects of pain-like behavior with distinct circuits.

Pre- and postsynaptic signatures in the prelimbic cortex associated with "alcohol use disorder" in the rat.

The transition to alcohol use disorder (AUD) involves persistent neuroadaptations in executive control functions primarily regulated by the medial prefrontal cortex. However, the neurophysiological correlates to behavioral manifestations of AUD are not fully defined. The association between cortical neuroadaptations and behavioral manifestations of addiction was studied using a multi-symptomatic operant model based on the DSM-5 diagnostic criteria for AUD. This model aimed to characterize an AUD-vulnerable and AUD-resistant subpopulation of outbred male Wistar rats and was combined with electrophysiological measurements in the prelimbic cortex (PL). Mirroring clinical observations, rats exhibited individual variability in their vulnerability to develop AUD-like behavior, including motivation to seek for alcohol (crit 1), increased effort to obtain the substance (crit 2), and continued drinking despite negative consequences (crit 3). Only a small subset of rats met all the aforementioned AUD criteria (3 crit, AUD-vulnerable), while a larger fraction was considered AUD-resilient (0 crit). The development of AUD-like behavior was characterized by disruptions in glutamatergic synaptic activity, involving decreased frequency of spontaneous excitatory postsynaptic currents (sEPSCs) and heightened intrinsic excitability in layers 2/3 PL pyramidal neurons. These alterations were concomitant with a significant impairment in the ability of mGlu2/3 receptors to negatively regulate glutamate release in the PL but not in downstream regions like the basolateral amygdala or nucleus accumbens core. In conclusion alterations in PL synaptic activity were strongly associated with individual addiction scores, indicating their role as potential markers of the behavioral manifestations linked to AUD psychopathology.

Wireless optogenetic stimulation on the prelimbic to the nucleus accumbens core circuit attenuates cocaine-induced behavioral sensitization

Behavioral sensitization is defined as the heightened and persistent behavioral response to repeated drug exposure as a manifestation of drug craving. Psychomotor stimulants such as cocaine can induce strong behavioral sensitization. In this study, we explored the effects of optogenetic stimulation of the prelimbic (PL) to the nucleus accumbnes (NAc) core on the expression of cocaine-induced behavioral sensitization. Using wireless optogenetics, we selectively stimulated the PL-NAc core circuit, and assessed the effects of this treatment on cocaine-induced locomotor activity and accompanying changes in neuronal activation and dendritic spine density. Our findings revealed that optogenetic stimulation of the PL-NAc core circuit effectively suppressed the cocaine-induced locomotor sensitization, accompanied by a reduction in c-Fos expression within the NAc core. Moreover, optogenetic stimulation led to reduction in dendritic spine density, particularly thin and mushroom spine densities, in the NAc core. This study demonstrates that cocaine-induced locomotor sensitization can be regulated by optogenetic stimulation of the PL-NAc core circuit, providing insights into the crucial role of this circuit in psychomotor stimulant addiction.

Food choice and neural reward systems in adolescents with anorexia nervosa and atypical anorexia nervosa.

Adolescence is a critical developmental period for the study of anorexia nervosa (AN), an illness characterized by extreme restriction of food intake. The maturation of the reward system during adolescence combined with recent neurobiological models of AN led to the hypothesis that early on in illness, restrictive food choices would be associated with activity in nucleus accumbens reward regions, rather than caudate regions identified among adults with AN. Healthy adolescents (HC, n = 41) and adolescents with AN or atypical AN (atypAN, n = 76) completed a Food Choice Task during fMRI scanning. Selection of high-fat foods and choice-related activation in nucleus accumbens and anterior caudate regions-of-interest (ROIs) were compared between individuals with AN/atypAN and HC. Associations were examined between choice-related activation and choice preferences among the AN group. Exploratory analyses examined associations between choice-related activation and psychological assessments among the patient group. Adolescents with AN or atypAN selected fewer high-fat foods than HC (t = -5.92, p < .001). Counter to predictions, there were no significant group differences in choice-related activation in the ROIs. Among individuals with AN or atypAN, choice-related neural activity in the anterior caudate was significantly negatively associated with high-fat food selections in the task (r = -.32, p = .024). In exploratory analyses, choice-related anterior caudate activation was positively associated with psychological measures of illness severity among patients (p's < .05, uncorrected). In this large cohort of adolescents with AN/atypAN, there was no evidence of altered reward system engagement during food choice. While there was no group difference in choice-related caudate activation, the associations with choices and psychological measures continue to suggest that this neural region is implicated in illness. Longitudinal analyses will clarify whether neural variability relates to longer-term course.