Association between RMTg Neuropeptide Genes and Negative Effect during Alcohol Withdrawal in Mice.

Alcohol use disorders (AUDs) frequently co-occur with negative mood disorders, such as anxiety and depression, exacerbating relapse through dopaminergic dysfunction. Stress-related neuropeptides play a crucial role in AUD pathophysiology by modulating dopamine (DA) function. The rostromedial tegmental nucleus (RMTg), which inhibits midbrain dopamine neurons and signals aversion, has been shown to increase ethanol consumption and negative emotional states during abstinence. Despite some stress-related neuropeptides acting through the RMTg to affect addiction behaviors, their specific roles in alcohol-induced contexts remain underexplored. This study utilized an intermittent voluntary drinking model in mice to induce negative effect behavior 24 h into ethanol (EtOH) abstinence (post-EtOH). It examined changes in pro-stress (Pnoc, Oxt, Npy) and anti-stress (Crf, Pomc, Avp, Orx, Pdyn) neuropeptide-coding genes and analyzed their correlations with aversive behaviors. We observed that adult male C57BL/6J mice displayed evident anxiety, anhedonia, and depression-like symptoms at 24 h post-EtOH. The laser-capture microdissection technique, coupled with or without retrograde tracing, was used to harvest total ventral tegmental area (VTA)-projecting neurons or the intact RMTg area. The findings revealed that post-EtOH consistently reduced Pnoc and Orx levels while elevating Crf levels in these neuronal populations. Notably, RMTg Pnoc and Npy levels counteracted ethanol consumption and depression severity, while Crf levels were indicative of the mice's anxiety levels. Together, these results underscore the potential role of stress-related neuropeptides in the RMTg in regulating the negative emotions related to AUDs, offering novel insights for future research.

Comorbidity of Post-Traumatic Stress Disorder and Alcohol Use Disorder: Animal Models and Associated Neurocircuitry.

Post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) are prevalent neuropsychiatric disorders and frequently co-occur concomitantly. Individuals suffering from this dual diagnosis often exhibit increased symptom severity and poorer treatment outcomes than those with only one of these diseases. Lacking standard preclinical models limited the exploration of neurobiological mechanisms underlying PTSD and AUD comorbidity. In this review, we summarize well-accepted preclinical model paradigms and criteria for developing successful models of comorbidity. We also outline how PTSD and AUD affect each other bidirectionally in the nervous nuclei have been heatedly discussed recently. We hope to provide potential recommendations for future research.

Inhibition of heat shock protein family A member 8 attenuates spinal cord ischemia-reperfusion injury via astrocyte NF-κB/NLRP3 inflammasome pathway : HSPA8 inhibition protects spinal ischemia-reperfusion injury.

BACKGROUND: Astrocyte over-activation and extensive neuron loss are the main characteristic pathological features of spinal cord ischemia-reperfusion injury (SCII). Prior studies have placed substantial emphasis on the role of heat shock protein family A member 8 (HSPA8) on postischemic myocardial inflammation and cardiac dysfunction. However, it has never been determined whether HSPA8 participates in astrocyte activation and thus mediated neuroinflammation associated with SCII. METHODS: The left renal artery ligation-induced SCII rat models and oxygen-glucose deprivation and reoxygenation (OGD/R)-induced rat primary cultured astrocytes were established. The lentiviral vector encoding short hairpin RNA targeting HSPA8 was delivered to the spinal cord by intrathecal administration or to culture astrocytes. Then, the spinal neuron survival, gliosis, and nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome and its related pro-inflammatory cytokines were analyzed. RESULTS: SCII significantly enhanced the GFAP and HSPA8 expression in the spinal cord, resulting in blood-brain barrier breakdown and the dramatical loss of spinal neuron and motor function. Moreover, injury also increased spinal nuclear factor-kappa B (NF-κB) p65 phosphorylation, NLRP3 inflammasome-mediated caspase-1 activation, and subsequent interleukin (IL)-1ß as well as IL-18 secretion. Silencing the HSPA8 expression efficiently ameliorated the spinal cord tissue damage and promoted motor function recovery after SCII, through blockade of the astrocyte activation and levels of phosphorylated NF-κB, NLRP3, caspase-1, IL-1ß, and IL-18. Further in vitro studies confirmed that HSPA8 knockdown protected astrocytes from OGD/R-induced injury via the blockade of NF-κB and NLRP3 inflammasome activation. CONCLUSION: Our findings indicate that knockdown of HSPA8 inhibits spinal astrocytic damage after SCII, which may provide a promising therapeutic strategy for SCII treatment.

MicroRNA-137-3p Protects PC12 Cells Against Oxidative Stress by Downregulation of Calpain-2 and nNOS.

The imbalance between excess reactive oxygen species (ROS) generation and insufficient antioxidant defenses contribute to a range of neurodegenerative diseases. High ROS levels damage cellular macromolecules such as DNA, proteins and lipids, leading to neuron vulnerability and eventual death. However, the underlying molecular mechanism of the ROS regulation is not fully elucidated. Recently, an increasing number of studies suggest that microRNAs (miRNAs) emerge as the targets in regulating oxidative stress. We recently reported the neuroprotective effect of miR-137-3p for brachial plexus avulsion-induced motoneuron death. The present study is sought to investigate whether miR-137-3p also could protect PC12 cells against hydrogen peroxide (H2O2) induced neurotoxicity. By using cell viability assay, ROS assay, gene and protein expression assay, we found that PC-12 cells exposed to H2O2 exhibited decreased cell viability, increased expression levels of calpain-2 and neuronal nitric oxide synthase (nNOS), whereas a decreased miR-137-3p expression. Importantly, restoring the miR-137-3p levels in H2O2 exposure robustly inhibited the elevated nNOS, calpain-2 and ROS expression levels, which subsequently improved the cell viability. Furthermore, the suppressive effect of miR-137-3p on the elevated ROS level under oxidative stress was considerably blunted when we mutated the binding site of calpain-2 targted by miR-137-3p, suggesting the critical role of calpain-2 involving the neuroprotective effect of miR-137-3p. Collectively, these findings highlight the neuroprotective role of miR-137-3p through down-regulating calpain and NOS activity, suggesting its potential role for combating oxidative stress insults in the neurodegenerative diseases.

[A consensus on the standardization of the next generation sequencing process for the diagnosis of genetic diseases (3) - Data analysis].

Bioinformatic analysis and variant classification are the key components of high-throughput sequencing-based genetic diagnostic approach. This consensus is part of the effort to develop a standardized process for next generation sequencing (NGS)-based test for germline mutations underlying Mendelian disorders in China. The flow-chart, common software, key parameters of bioinformatics pipeline for data processing, annotation, storage and variant classification are reviewed, which is aimed to help improving and maintaining a high-quality process and obtaining consistent outcomes for NGS-based molecular diagnosis.

Neuroticism and extraversion mediate the association between loneliness and the dorsolateral prefrontal cortex.

Loneliness is an unpleasant and distressing feeling that a person experiences when he/she perceives that his/her social relationships are lacking in someway, either quantitatively or qualitatively; this can be linked to anxiety, depression, and suicide risk. Previous studies have found that certain personality traits (which are temporally stable and heritable) are predictors of loneliness. However, little empirical evidence is available on the brain structures associated with loneliness, as well as how personality traits impact the relationship between loneliness and brain structure. Thus, the current study used voxel-based morphometry to identify the brain structures underlying individual differences in loneliness (as measured by the UCLA Loneliness Scale) in a large sample, and then, applied multiple mediation analyses to explore the nature of the influence of personality traits on the relationship between loneliness and brain structure. The results showed that lonely individuals had greater regional gray matter volume in the left dorsolateral prefrontal cortex (DLPFC), which might reflect immature functioning in terms of emotional regulation. More importantly, we found that neuroticism and extraversion partially mediated the relationship between the left DLPFC and loneliness. In summary, through morphometric and multiple mediation analyses, this paper further validates the influence of both neuroticism and extraversion on loneliness.

An illustrated heuristic prototype facilitates scientific inventive problem solving: A functional magnetic resonance imaging study.

Many scientific inventions (SI) throughout history were inspired by heuristic prototypes (HPs). For instance, an event or piece of knowledge similar to displaced water from a tub inspired Archimedes' principle. However, the neural mechanisms underlying this insightful problem solving are not very clear. Thus, the present study explored the neural correlates used to solve SI problems facilitated by HPs. Each HP had two versions: a literal description with an illustration (LDI) and a literal description with no illustration (LDNI). Thirty-two participants were divided randomly into these two groups. Blood oxygenation level-dependent fMRI contrasts between LDI and LDNI groups were measured. Greater activity in the right middle occipital gyrus (RMOG, BA19), right precentral gyrus (RPCG, BA4), and left middle frontal gyrus (LMFG, BA46) were found within the LDI group as compared to the LDNI group. We discuss these results in terms cognitive functions within these regions related to problem solving and memory retrieval.

Association of creative achievement with cognitive flexibility by a combined voxel-based morphometry and resting-state functional connectivity study.

Although researchers generally concur that creativity involves the production of novel and useful products, the neural basis of creativity remains elusive due to the complexity of the cognitive processes involved. Recent studies have shown that highly creative individuals displayed more cognitive flexibility. However, direct evidence supporting the relationship between creativity and cognitive flexibility has rarely been investigated using both structural and functional neuroimaging techniques. We used a combined voxel-based morphometry and resting-state functional connectivity (rsFC) analysis to investigate the relationship between individual creativity ability assessed by the creative achievement questionnaire (CAQ), and regional gray matter volume (GMV), as well as intrinsic functional connectivity. Results showed that CAQ scores negatively correlated with GMV in the rostral anterior cingulate cortex (ACC) and the bilateral dorsal ACC (dACC) extending to supplementary motor area, but positively correlated with GMV in the bilateral superior frontal gyrus and ventral medial prefrontal cortex (vmPFC). Further functional connectivity analysis revealed that higher creative achievement was inversely associated with the strength of rsFC between the dACC and medial superior frontal gyrus (mSFG), right middle frontal gyrus, and left orbito-frontal insula. Moreover, the association between the dACC-mSFG connectivity and CAQ scores was mediated by cognitive flexibility, assessed by a task-switching paradigm. These findings indicate that individual differences in creative achievement are associated with both brain structure and corresponding intrinsic functional connectivity involved in cognitive flexibility and deliberate creative processing. Furthermore, dACC-mSFG connectivity may affect creative achievement through its impact on cognitive flexibility.

Examining brain structures associated with perceived stress in a large sample of young adults via voxel-based morphometry.

Perceived stress reflects the extent to which situations are appraised as stressful at a given point in one's life. Past brain imaging studies have examined activation patterns underlying the stress response, yet focal differences in brain structures related to perceived stress are not well understood, especially when considering gray matter (GM) and white matter (WM) structures simultaneously. In this study, voxel-based morphometry was used to investigate relations between GM/WM volume and perceived stress levels in a large young adult sample. Participants (138 men, 166 women) completed the Perceived Stress Scale (PSS; Cohen et al., 1983) and underwent an anatomical magnetic resonance imaging scan. Higher PSS scores were associated with larger GM volume in a cluster that included regions in the bilateral parahippocampal gyrus, fusiform cortex, and entorhinal cortex and smaller GM volume in a cluster that included regions of the right insular cortex. Higher PSS scores were also related to smaller WM volume in a cluster that included the body of the corpus callosum. This pattern of results remained significant even after controlling for effects of general intelligence, socioeconomic status, and depression. Together, findings suggest a unique structural basis for individual differences in perceived stress, distributed across different GM and WM regions of the brain.

Regional gray matter volume is associated with rejection sensitivity: a voxel-based morphometry study.

Rejection sensitivity (RS) can be defined as the disposition that one tends to anxiously expect, readily perceive, and intensely react to rejection. High-RS individuals are more likely to suffer mental disorders. Previous studies have investigated brain activity during social rejection using different kinds of rejection paradigms and have provided neural evidence of individual differences in response to rejection cues, but the association between individual differences in RS and brain structure has never been investigated. In this study, voxel-based morphometry (VBM) was used to investigate the relationship between gray matter volume (GMV) and RS in a large healthy sample of 150 men and 188 women. The participants completed the RS Questionnaire and underwent an anatomical magnetic resonance imaging scan. Multiple regression was used to analyze the correlation between regional GMV and RS scores, adjusting for age, sex, and total brain GMV. These results showed that GMV in the region of the posterior cingulate cortex/precuneus was negatively associated with RS, and GMV in the region of the inferior temporal gyrus was positively correlated with RS. These findings suggest a relationship between individual differences in RS and GMV in brain regions that are primarily related to social cognition.

The correlation between emotional intelligence and gray matter volume in university students.

A number of recent studies have investigated the neurological substrates of emotional intelligence (EI), but none of them have considered the neural correlates of EI that are measured using the Schutte Self-Report Emotional Intelligence Scale (SSREIS). This scale was developed based on the EI model of Salovey and Mayer (1990). In the present study, SSREIS was adopted to estimate EI. Meanwhile, magnetic resonance imaging (MRI) and voxel-based morphometry (VBM) were used to evaluate the gray matter volume (GMV) of 328 university students. Results found positive correlations between Monitor of Emotions and VBM measurements in the insula and orbitofrontal cortex. In addition, Utilization of Emotions was positively correlated with the GMV in the parahippocampal gyrus, but was negatively correlated with the VBM measurements in the fusiform gyrus and middle temporal gyrus. Furthermore, Social Ability had volume correlates in the vermis. These findings indicate that the neural correlates of the EI model, which primarily focuses on the abilities of individuals to appraise and express emotions, can also regulate and utilize emotions to solve problems.

The effect of justice sensitivity on malevolent creativity: the mediating role of anger and the moderating role of emotion regulation strategies.

BACKGROUND: the AMORAL model emphasizes the close connection of individuals' belief system and malevolent creativity. Belief in a just world theory (BJW) states that people have a basic need to believe that the world they live in is just, and everyone gets what they deserve. Therefore, justice matters to all people. Justice sensitivity, as one of individual trait, has been found associated with negative goals. However, relevant studies have not tested whether justice sensitivity can affect malevolent creativity and its psychological mechanisms. Additionally, researchers have found that both anger and emotion regulation linked with justice sensitivity and malevolent creativity, but their contribution to the relationship between justice sensitivity and malevolent creativity remained unclear. The current study aims to explore the influence of justice sensitivity on malevolent creativity, the mediating effect of trait anger/state anger on the relationship between justice sensitivity and malevolent creativity, and the moderating effect of emotion regulation on this mediating effect. METHODS: A moderated mediating model was constructed to test the relationship between justice sensitivity and malevolent creativity. A sample of 395 Chinese college students were enrolled to complete the questionnaire survey. RESULTS: Justice sensitivity positively correlated with malevolent creativity, both trait anger and state anger partly mediated the connection between justice sensitivity and malevolent creativity. Moreover, emotion regulation moderated the indirect effect of the mediation model. The indirect effect of justice sensitivity on malevolent creativity through trait anger/state anger increased as the level of emotion regulation increased. The results indicated that justice sensitivity can affect malevolent creativity directly and indirectly through the anger. The level of emotion regulation differentiated the indirect paths of justice sensitivity on malevolent creativity. CONCLUSIONS: Justice sensitivity and malevolent creativity was mediated by trait anger/state anger. The higher sensitivity to justice, the higher level of trait anger/state anger, which in turn boosted the tendency of malevolent creativity. This indirect connection was moderated by emotion regulation, individuals with high emotion regulation are better able to buffer anger from justice sensitivity.

Childhood Maltreatment and Creativity among Chinese College Students: A Serial Mediation Model.

Creativity plays a very crucial impact on our cultural life and has also been important to the improvement of human civilization. Numerous studies have indicated that family circumstance plays an important role in the development of individual creativity. However, little is known about the mediating mechanisms underlying the association between childhood maltreatment and creativity. This study intended to explore the serial multiple mediation model in which undergraduates' cognitive flexibility and self-efficacy were proposed to mediate the potential influence of childhood maltreatment on their creativity. Participants were 1069 undergraduates (573 males and 496 females, mean age was 20.57 ± 1.24 years ranging from 17 to 24) from a university in Shandong Province, China. Participants were required to complete an internet survey including the Short Form of Childhood Trauma Questionnaire (CTQ-SF), General Self-Efficacy Scale (GSES), Cognitive Flexibility Inventory (CFI), and Williams Creativity Aptitude Test (WCAT). Serial multiple mediation analysis and the bootstrap method were used to investigate the mediation effects of cognitive flexibility and self-efficacy. The results showed that childhood maltreatment indirectly influenced undergraduates' creativity through three indirect paths: childhood maltreatment→cognitive flexibility→creativity, childhood maltreatment→self-efficacy→creativity, and childhood maltreatment→cognitive flexibility→self-efficacy→creativity. The ratios of the total indirect effects and branch-indirect effects to the total effects were 92.73%, 34.61%, 35.68%, and 22.44%, respectively. These results indicated that cognitive flexibility and self-efficacy could completely mediate the potential impact of childhood maltreatment on individuals creativity.

The mediating effects of dysfunctional attitudes and moderating effect of sex between stressful life events and depressive symptoms among Chinese college students.

Stressful life events (SLEs) closely correlates with depressive symptoms. Although vulnerability-stress model suggests SLEs interacted with dysfunctional attitudes (DA) to predict depression, the mediation role of DA is poorly understood. Therefore, this study intended to investigate the mediating role of DA and the moderating role of sex between SLEs and self-reported depression. A cross-sectional survey was conducted with a sample of 7769 Chinese college students. Participants were assessed in terms of self-reported SLEs, DA and depression variables. Results showed that there were significant sex differences in both SLE and DA. DA mediated the association between SLE and self-reported depression. The moderated mediation model analysis showed that the interaction of SLEs and sex significantly predicted DA in mediator variable model and self-reported depression in dependent variable model. Results indicated that DA partially mediated the association between SLEs and self-reported depression, and sex moderates the association between SLEs and both DA and self-reported depression, which females have bigger changes of DA and depressive symptoms across low and high levels of SLEs than males.

Rostromedial tegmental nucleus nociceptin/orphanin FQ (N/OFQ) signaling regulates anxiety- and depression-like behaviors in alcohol withdrawn rats.

Recent studies indicate that stimulation of the rostromedial tegmental nucleus (RMTg) can drive a negative affective state and that nociceptin/orphanin FQ (N/OFQ) may play a role in affective disorders and drug addiction. The N/OFQ precursor prepronociceptin encoding genes Pnoc are situated in RMTg neurons. To determine whether N/OFQ signaling contributes to the changes in both behavior phenotypes and RMTg activity of alcohol withdrawn (Post-EtOH) rats, we trained adult male Long-Evans rats, randomly assigned into the ethanol and Naïve groups to consume either 20% ethanol or water-only under an intermittent-access procedure. Using the fluorescence in situ hybridization technique combined with retrograde tracing, we show that the ventral tegmental area projecting RMTg neurons express Pnoc and nociceptin opioid peptide (NOP) receptors encoding gene Oprl1. Also, using the laser capture microdissection technique combined with RT-qPCR, we detected a substantial decrease in Pnoc but an increase in Oprl1 mRNA levels in the RMTg of Post-EtOH rats. Moreover, RMTg cFos expression is increased in Post-EtOH rats, which display anxiety- and depression-like behaviors. Intra-RMTg infusion of the endogenous NOP agonist nociceptin attenuates the aversive behaviors in Post-EtOH rats without causing any notable change in Naïve rats. Conversely, intra-RMTg infusion of the NOP selective antagonist [Nphe1]nociceptin(1-13)NH2 elicits anxiety- and depression-like behaviors in Naïve but not Post-EtOH rats. Furthermore, intra-RMTg infusion of nociceptin significantly reduces alcohol consumption. Thus, our results show that the deficiency of RMTg NOP signaling during alcohol withdrawal mediates anxiety- and depression-like behaviors. The intervention of NOP may help those individuals suffering from alcohol use disorders.

LPA1 receptors in the lateral habenula regulate negative affective states associated with alcohol withdrawal.

The role of lysophosphatidic acid (LPA) signaling in psychiatric disorders and drug abuse is significant. LPA receptors are widely expressed in the central nervous system, including the lateral habenula (LHb). Recent studies suggest that LHb is involved in a negative emotional state during alcohol withdrawal, which can lead to relapse. The current study examines the role of LHb LPA signaling in the negative affective state associated with alcohol withdrawal. Adult male Long-Evans rats were trained to consume either alcohol or water for eight weeks. At 48 h of withdrawal, alcohol-drinking rats showed anxiety- and depression-like symptoms, along with a significant increase in LPA signaling and related neuronal activation molecules, including autotaxin (ATX, Enpp2), LPA receptor 1/3 (LPA1/3), ßCaMKII, and c-Fos. However, there was a decrease in lipid phosphate phosphatase-related protein type 4 (LPPR4) in the LHb. Intra-LHb infusion of the LPA1/3 receptor antagonist ki-16425 or PKC-γ inhibitor Go-6983 reduced the abnormal behaviors and elevated relapse-like ethanol drinking. It also normalized high LPA1/3 receptors and enhanced AMPA GluA1 phosphorylation in Ser831 and GluA1/GluA2 ratio. Conversely, selective activation of LPA1/3 receptors by intra-LHb infusion of 18:1 LPA induced negative affective states and upregulated ßCaMKII-AMPA receptor phosphorylation in Naive rats, which were reversed by pretreatment with intra-LHb Go-6983. Our findings suggest that disturbances in LPA signaling contribute to adverse affective disorders during alcohol withdrawal, likely through PKC-γ/ßCaMKII-linked glutamate signaling. Targeting LPA may therefore be beneficial for individuals suffering from alcohol use disorders.

Childhood Trauma and Malevolent Creativity in Chinese College Students: Moderated Mediation by Psychological Resilience and Aggression.

Although a previous study has shown that childhood trauma influences malevolent creativity, aggression and psychological resilience have been linked with childhood trauma and creativity. However, little is known about the complex correlations among these factors in Chinese college students. The present study aimed to investigate the mediating role of aggression and the moderating role of psychological resilience between childhood trauma and malevolent creativity. A total of 389 undergraduates were enrolled in this cross-sectional study. The moderated mediation model was conducted to explore whether aggression mediated the correlation between childhood trauma and malevolent creativity and whether psychological resilience moderated the indirect role of childhood trauma. The results showed that childhood trauma positively correlated with aggression and malevolent creativity and was negatively associated with psychological resilience. Aggression partly mediated the association of childhood trauma with malevolent creativity. Resilience moderated the indirect effect of the mediation model, such that the indirect effect of childhood trauma on malevolent creativity through aggression increased as the level of resilience increased. The study indicated that childhood trauma exposure is associated with malevolent creativity behavior, and aggression mediated this association. The level of psychological resilience differentiates the indirect paths of childhood trauma on malevolent creativity. These results have important implications for preventing and containing expressions of malevolent creativity.

Positive selection on hemagglutinin and neuraminidase genes of H1N1 influenza viruses.

BACKGROUND: Since its emergence in March 2009, the pandemic 2009 H1N1 influenza A virus has posed a serious threat to public health. To trace the evolutionary path of these new pathogens, we performed a selection-pressure analysis of a large number of hemagglutinin (HA) and neuraminidase (NA) gene sequences of H1N1 influenza viruses from different hosts. RESULTS: Phylogenetic analysis revealed that both HA and NA genes have evolved into five distinct clusters, with further analyses indicating that the pandemic 2009 strains have experienced the strongest positive selection. We also found evidence of strong selection acting on the seasonal human H1N1 isolates. However, swine viruses from North America and Eurasia were under weak positive selection, while there was no significant evidence of positive selection acting on the avian isolates. A site-by-site analysis revealed that the positively selected sites were located in both of the cleaved products of HA (HA1 and HA2), as well as NA. In addition, the pandemic 2009 strains were subject to differential selection pressures compared to seasonal human, North American swine and Eurasian swine H1N1 viruses. CONCLUSIONS: Most of these positively and/or differentially selected sites were situated in the B-cell and/or T-cell antigenic regions, suggesting that selection at these sites might be responsible for the antigenic variation of the viruses. Moreover, some sites were also associated with glycosylation and receptor-binding ability. Thus, selection at these positions might have helped the pandemic 2009 H1N1 viruses to adapt to the new hosts after they were introduced from pigs to humans. Positive selection on position 274 of NA protein, associated with drug resistance, might account for the prevalence of drug-resistant variants of seasonal human H1N1 influenza viruses, but there was no evidence that positive selection was responsible for the spread of the drug resistance of the pandemic H1N1 strains.

The time course of breaking mental sets and forming novel associations in insight-like problem solving: an ERP investigation.

In the present study, high-density event-related potentials were recorded to examine the electrophysiological correlates of logogriph problem solving in using a new experimental paradigm (learning-testing model) that was adopted in order to enable subjects to find a solution on their own initiative. For each trial, subjects were given a target logogriph followed by three types of base logogriphs: surface similarity logogriphs (SUSL, the base logogriph and target logogriph share some same words), structural similarity logogriphs (STSL, the base and target logogriphs do not have any words in common), and baseline logogriphs (BSL, the base and target logogriphs are all simple character-generation tasks). The results demonstrated a more negative event-related potential deflection during STSL than during SUSL in both the 300-500 and 1,100-1,300 ms time windows, most likely reflecting the breaking of mental sets during insight-like problem solving. Moreover, SUSL and STSL demonstrated greater positivity than BSL in a time window between 900 and 1,700 ms, possibly reflecting processes such as forming novel associations.

Endocannabinoid signaling in the lateral habenula regulates pain and alcohol consumption.

Hyperalgesia, which often occurs in people suffering from alcohol use disorder, may drive excessive drinking and relapse. Emerging evidence suggests that the lateral habenula (LHb) may play a significant role in this condition. Previous research suggests that endocannabinoid signaling (eCBs) is involved in drug addiction and pain, and that the LHb contains core components of the eCBs machinery. We report here our findings in rats subjected to chronic ethanol vapor exposure. We detected a substantial increase in endocannabinoid-related genes, including Mgll and Daglb mRNA levels, as well as monoacylglycerol lipase (MAGL) protein levels, as well as a decrease in Cnr1 mRNA and type-1 cannabinoid receptor (CB1R) protein levels, in the LHb of ethanol-exposed rats. Also, rats withdrawing from ethanol exposure displayed hypersensitivity to mechanical and thermal nociceptive stimuli. Conversely, intra-LHb injection of the MAGL inhibitor JZL184, the fatty acid amide hydrolase inhibitor URB597, or the CB1R agonist WIN55,212-2 produced an analgesic effect, regardless of ethanol or air exposure history, implying that alcohol exposure does not change eCB pain responses. Intra-LHb infusion of the CB1R inverse agonist rimonabant eliminated the analgesic effect of these chemicals. Rimonabant alone elicited hyperalgesia in the air-, but not ethanol-exposed animals. Moreover, intra-LHb JZL184, URB597, or WIN55,212-2 reduced ethanol consumption in both homecages and operant chambers in rats exposed to ethanol vapor but not air. These findings suggest that LHb eCBs play a pivotal role in nociception and facilitating LHb eCBs may attenuate pain in drinkers.