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We investigated the effect of low-intensity focused ultrasound (LIFU) on gene expression related to alcohol dependence and histological effects on brain tissue. We also aimed at determining the miRNA-mRNA relationship and their pathways in alcohol dependence-induced expression changes after focused ultrasound therapy. We designed a case-control study for 100 days of observation to investigate differences in gene expression in the short-term stimulation group (STS) and long-term stimulation group (LTS) compared with the control sham group (SG). The study was performed in our Experimental Research Laboratory. 24 male high alcohol-preferring rats 63 to 79 days old, weighing 270 to 300 g, were included in the experiment. LTS received 50-day LIFU and STS received 10-day LIFU and 40-day sham stimulation, while the SG received 50-day sham stimulation. In miRNA expression analysis, it was found that LIFU caused gene expression differences in NAc. Significant differences were found between the groups for gene expression. Compared to the SG, the expression of 454 genes in the NAc region was changed in the STS while the expression of 382 genes was changed in the LTS. In the LTS, the expression of 32 genes was changed in total compared to STS. Our data suggest that LIFU targeted on NAc may assist in the treatment of alcohol dependence, especially in the long term possibly through altering gene expression. Our immunohistochemical studies verified that LIFU does not cause any tissue damage. These findings may lead to new studies in investigating the efficacy of LIFU for the treatment of alcohol dependence and also for other psychiatric disorders.

The persistence of drug taking despite its adverse consequences plays a central role in the presentation, diagnosis, and impacts of addiction. Eventual recognition and appraisal of these adverse consequences is central to decisions to reduce or cease use. However, the most appropriate ways of conceptualizing persistence in the face of adverse consequences remain unclear. Here we review evidence that there are at least three pathways to persistent use despite the negative consequences of that use. A cognitive pathway for recognition of adverse consequences, a motivational pathway for valuation of these consequences, and a behavioral pathway for responding to these adverse consequences. These pathways are dynamic, not linear, with multiple possible trajectories between them, and each is sufficient to produce persistence. We describe these pathways, their characteristics, brain cellular and circuit substrates, and we highlight their relevance to different pathways to self- and treatment-guided behavior change.

Original Mediterranean Diet and Altered Mediterranean Diet were associated with positive mood when adjusted for sex and age in healthy people. Plant-based Diet Index was only associated with children’s positive mood.

Persistent alcohol use despite negative consequences is a key feature of alcohol use disorder (AUD) and is typically assessed using punishment in animal models. This study examined relapse-like behavior in male and female alcohol-preferring iP rats following punishment-imposed voluntary abstinence to alcohol seeking. We focused on alcohol seeking in the punishment-associated environment after prolonged abstinence. Finally, we sought to understand the predictability of relapse-like behavior by examining AUD comorbidities, namely, anxiety-like behavior and the response to repeated, moderate punishment. We found no sex differences in operant self-administration of alcohol. However, we did find a reduced propensity to relapse in the punishment-associated environment in female rats following prolonged abstinence. Relapse propensity was associated with the response to punishment during operant training, but not prior anxiety-like behavior. Together these results highlight the importance of studying sex differences in relapse to alcohol seeking. In addition, the behavioral response to a negative consequence may be a predictor of relapse, particularly in females. Improving our understanding of the sexually dimorphic responses in alcohol seeking may be a powerful tool for designing personalized, or at least sex-specific, approaches to treatment and rehabilitation programs. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Introduction: More than 1 in 10 people are thought to experience a mental health problem during adolescence, with most adult psychopathology beginning during this time. Experiences of stress or adversity during childhood are important risk factors for poorer mental health outcomes and are also associated with alterations in neurodevelopment. There is evidence to suggest that this relationship is mediated by inflammation and the immune system. The eBRAIN study (The Impact of Early Adversity on Trajectories of Brain Maturation and Mental Health in Young Adolescents) will assess how early life adversity might affect trajectories of brain development throughout adolescence, whether these neurobiological changes are associated with psychopathology, and if they can potentially be explained by an activation of the immune system.Methods: A cohort of 220 adolescents between the ages of 11-14 will be recruited into this study. Each participant will complete three study visits, each one year apart, at the Institute of Psychiatry, Psychology and Neuroscience, King's College London, London (UK). At each study visit, they will be assessed with structural and functional MRI scans, biological sample collection as well as questionnaires and interviews to collect demographic information, assess experiences of adversity, and details of psychopathology. The study will also collect information about factors such as diet and nutrition, physical exercise, and cognition.Ethics and dissemination: Ethical approval for this study has been received by King's College London Research Ethics Committee (REC reference: HR-18/19-9033). Findings from the study will be published in peer-reviewed journals and disseminated at national and international conferences. Patient and public involvement (PPI) is an important component of the study, 'Study Champions' recruited from participants, their parents and teachers at collaborating schools have been invited to take an active role in study governance and dissemination.

Background Recombinant protein-based vaccines targeting serogroup B meningococci protect against invasive disease but impacts on carriage are uncertain. This study assessed carriage prevalence of disease-associated meningococci in 2018–2020 as the proportion of vaccinated adolescents increased following introduction of a school-based 4CMenB immunization program. Methods Eligible participants who completed high school (aged 17–25) in South Australia in the previous year had an oropharyngeal swab taken and completed a risk factor questionnaire. Disease-associated meningococci (genogroups A, B, C, W, X, Y) were detected by meningococcal and genogroup-specific polymerase chain reaction. Results The analysis included 4104 participants in 2018, 2690 in 2019, and 1338 in 2020. The proportion vaccinated with 4CMenB increased from 43% in 2018, to 78% in 2019, and 76% in 2020. Carriage prevalence of disease-associated meningococci in 2018 was 225/4104 (5.5%). There was little difference between carriage prevalence in 2019 (134/2690, 5.0%; adjusted odds ratio [aOR], 0.82; 95% confidence interval [CI], .64–1.05) and 2020 (68/1338, 5.1%; aOR, 0.82; 95% CI, .57–1.17) compared to 2018. Conclusions Increased 4CMenB uptake in adolescents was not associated with decline in carriage of disease-associated meningococci. 4CMenB immunization programs should focus on direct (individual) protection for groups at greatest risk of disease. Clinical Trials Registration NCT03419533.

ImportanceStratification of depression for personalised treatment is urgently needed to improve poor outcomes. Excessive self-blame-related motivations such as self-punishing tendencies have been proposed to play a key role in the onset and maintenance of depression. Their prognostic role, however, remains elusive.ObjectiveUse Virtual Reality (VR) to determine whether maladaptive self-blame-related action tendencies are associated with a poor prognosis for depression when treated as usual in primary care (pre-registered: NCT04593537).DesignRemote prospective cohort study (6/2020-6/2021) with four months follow-up.SettingsOnline recruitment from primary care and self-report.Participantsn=879 pre-screened, n=164 eligible, n=101 completed baseline (age:18-66 years, mean=32.05±12.32, n=89 female), n=98 the VR-task, and n=93 the follow-up. Main inclusion criteria: at least one antidepressant medication trial and Patient Health Questionnaire-9≥15 at screening; main exclusion criteria: screening above threshold on validated self-report instruments for bipolar or alcohol/substance use disorders.Exposure(s)All participants completed a VR assessment via headsets sent to their homes, as well as online questionnaires to measure their clinical characteristics.Main outcomes and MeasuresPrimary: Quick Inventory of Depressive Symptomatology self-reported-16 score after four months. Hypotheses in the study were formulated before the data collection and pre-registered.ResultsContrary to our specific prediction, neither feeling like hiding nor creating a distance from oneself was associated with prognosis of depression during the follow-up period in the pre-registered regression model. Using a data-driven principal components analysis of all pre-registered continuous measures, a factor most strongly loading on punishing oneself for other people’s wrongdoings (β=.23, p=.01), a baseline symptom factor (β=.30, p=.006) and Maudsley Staging Method treatment-resistance scores (β=.28, p=.009) at baseline predicted higher depressive symptoms after four months. This relationship was confirmed by a significant interaction between feeling like punishing oneself for others’ wrongdoings and time of monthly follow-up which was driven by higher depressive symptoms at last follow-up [F(1,84)=6.45, p=.01, partial Eta Squared=0.07] in the subgroup who had reported feeling like punishing themselves at baseline. Our pre-registered statistical learning model prospectively predicted a cross-validated 19% of variance in depressive symptoms.Conclusions and RelevanceFeeling like punishing oneself is a relevant prognostic factor and should therefore be assessed and tackled in personalised care pathways for difficult-to-treat depression.Key pointsQuestionCan remote virtual-reality (VR)-based measures of social interactions be used to identify risk factors of poor prognosis in depression?FindingsIn this pre-registered remote prospective cohort study in 101 participants with depression and follow-up over four months, the VR-assessed feeling like punishing oneself for other people’s wrongdoing was the sole prognostic risk factor apart from known clinical variables such as symptom severity and previous treatment-resistance.MeaningFeeling like punishing oneself is a relevant prognostic factor and should therefore be assessed and targeted in difficult-to-treat depression.

Compulsive forms of eating displayed by some obese individuals share similarities with compulsive drug taking behaviour, a hallmark feature of substance use disorder. This raises the possibility that drug addiction treatments may show utility in the treatment of compulsive overeating. N-Acetylcysteine (NAC) is a cysteine pro-drug which has experienced some success in clinical trials, reducing cocaine, marijuana and cigarette use, as well as compulsive behaviours such as gambling and trichotillomania. We assessed the impact of NAC on addiction-like behaviour towards highly palatable food in a rat model of diet-induced obesity. Adult male Sprague-Dawley rats were placed on a high-fat high-sugar diet for eight weeks and then assigned to diet-induced obesity-prone (DIO) or diet-induced obesity-resistant (DR) groups based on weight gain. DIO and DR rats were subjected to an operant conditioning paradigm whereby rats could lever press for high-fat high-sugar food pellets. This alternated with periods of signalled reward unavailability. Before treatment DIO rats ate more in their home cage, earned more food pellets in operant sessions, and responded more during periods that signalled reward unavailability (suggestive of compulsive-like food seeking) compared to DR rats. This persistent responding in the absence of reward displayed by DIO rats was ameliorated by daily injections of NAC (100 mg/kg, i.p.) for 14 days. By the end of the treatment period, lever-pressing by NAC-treated DIO rats resembled that of DR rats. These findings suggest that NAC reduces addiction-like behaviour towards food in rats and supports the potential use of this compound in compulsive overeating.

BACKGROUND AND PURPOSE: Muscarinic acetylcholine receptors mediate alcohol consumption and seeking in rats. While M4 and M5 receptors have recently been implicated to mediate these behaviours in the striatum, their role in other brain regions remain unknown. The ventral tegmental area (VTA) and ventral subiculum (vSub) both densely express M4 and M5 receptors and modulate alcohol-seeking, via their projections to the nucleus accumbens shell (AcbSh). EXPERIMENTAL APPROACH: In Indiana alcohol-preferring (iP) male rats, we examined Chrm4 (M4 ) and Chrm5 (M5 ) expression in the VTA and vSub following long-term alcohol consumption and abstinence using RT-qPCR. Using a combination of retrograde tracing and RNAscope, we examined the localisation of Chrm4 and Chrm5 on vSub cells that project to the AcbSh. Using selective allosteric modulators, we examined the functional role of M4 and M5 receptors within the vSub in alcohol consumption, context-induced alcohol-seeking, locomotor activity, and food/water consumption. KEY RESULTS: Long-term alcohol and abstinence dysregulated the expression of genes for muscarinic receptors in the vSub, not in the VTA. Chrm4 was down-regulated following long-term alcohol and abstinence, while Chrm5 was up-regulated following long-term alcohol consumption. Consistent with these data, a positive allosteric modulator (VU0467154) of intra-vSub M4 receptors reduced context-induced alcohol-seeking, but not motivation for alcohol self-administration, while M5 receptor negative allosteric modulator (ML375) reduced initial motivation for alcohol self-administration, but not context-induced alcohol-seeking. CONCLUSION AND IMPLICATIONS: Collectively, our data highlight alcohol-induced cholinergic dysregulation in the vSub and distinct roles for M4 and M5 receptor allosteric modulators to reduce alcohol consumption or seeking.

The influence of seasonal variation on animal behavior is a critical component of habitat selection analyses. To examine this relationship, we conducted multi-scale analyses of Lesser Prairie-Chicken (Tympanuchus pallidicinctus) habitat selection in relation to anthropogenic infrastructure associated with oil and gas development, mesquite, and trees during the spring and summer at home range and lek area scales. We tracked 159 Lesser Prairie-Chickens using VHF radiotelemetry or PTT-GPS transmitters in the sand shinnery oak prairie region of eastern New Mexico, USA. We used discrete choice models and logistic regression to assess seasonal patterns of habitat selection at home range and lek area scales, respectively. The static habitat features we examined allowed us to observe differential patterns of habitat selection between the two seasons, revealing an overall increase in the degree of avoidance following the spring season. Results of our home range scale analysis indicate that utility pole density, mesquite cover, and proximity to active well pads, private roads, and mesquite have significant negative effects on habitat selection during both seasons. Avoidance of high utility pole densities was significantly greater during the summer compared to spring. Lek area habitat selection results were similar, but differences in sensitivity to features between seasons were stronger. Avoidance of high mesquite cover and utility pole and tree densities, in particular, was significantly greater in the summer. The effects of density and cover of these features, which have previously been understudied in Lesser Prairie-Chicken research, provide critical information for future conservation practices. Furthermore, our study highlights the importance of accounting for potential seasonal patterns of study species to best examine habitat selection.

Background Memory function is at the core of the psychopathology of dissociative identity disorder (DID), but little is known about its psychobiological correlates. Aims This study aims to investigate whether memory function in DID differs between dissociative identity states Method Behavioural data and neural activation patterns were assessed in 92 sessions during an n-back working memory task. Participants were people with genuine diagnosed DID (n = 14), DID-simulating controls (n = 16) and a paired control group (post-traumatic stress disorder (n = 16), healthy controls (n = 16)). Both DID groups participated as authentic or simulated neutral and trauma-related identity states. Reaction times and errors of omission were analysed with repeated measures ANOVA. Working memory neural activation (main working memory and linear load) was investigated for effects of identity state, participant group and their interaction. Results Identity state-dependent behavioural performance and neural activation was found. DID simulators made fewer errors of omission than those with genuine DID. Regarding the prefrontal parietal network, main working memory in the left frontal pole and ventrolateral prefrontal cortex (Brodmann area 44) was activated in all three simulated neutral states, and in trauma-related identity states of DID simulators, but not those with genuine DID or post-traumatic stress disorder; for linear load, trauma-related identity states of those with genuine DID did not engage the parietal regions. Conclusions Behavioural performance and neural activation patterns related to working memory in DID are dependent on the dissociative identities involved. The narrowed consciousness of trauma-related identity states, with a proneness to re-experiencing traumatising events, may relate to poorer working memory functioning.

Psychedelics are a unique class of drug that commonly produce vivid hallucinations as well as profound psychological and mystical experiences. A grouping of interconnected brain regions characterized by increased temporal coherence at rest have been termed the Default Mode Network (DMN). The DMN has been the focus of numerous studies assessing its role in self-referencing, mind wandering, and autobiographical memories. Altered connectivity in the DMN has been associated with a range of neuropsychiatric conditions such as depression, anxiety, post-traumatic stress disorder, attention deficit hyperactive disorder, schizophrenia, and obsessive-compulsive disorder. To date, several studies have investigated how psychedelics modulate this network, but no comprehensive review, to our knowledge, has critically evaluated how major classical psychedelic agents—lysergic acid diethylamide, psilocybin, and ayahuasca—modulate the DMN. Here we present a systematic review of the knowledge base. Across psychedelics there is consistent acute disruption in resting state connectivity within the DMN and increased functional connectivity between canonical resting-state networks. Various models have been proposed to explain the cognitive mechanisms of psychedelics, and in one model DMN modulation is a central axiom. Although the DMN is consistently implicated in psychedelic studies, it is unclear how central the DMN is to the therapeutic potential of classical psychedelic agents. This article aims to provide the field with a comprehensive overview that can propel future research in such a way as to elucidate the neurocognitive mechanisms of psychedelics.

Chronic overeating is a core feature of diet-induced obesity. There is increasing evidence that in vulnerable individuals, such overeating could become compulsive, resembling an addictive disorder. The transition to compulsive substance use has been linked with changes at glutamatergic synapses in the nucleus accumbens. In this study, we investigated a potential link between such glutamatergic dysregulation and compulsive-like eating using a rat model of diet-induced obesity. A conditioned suppression task demonstrated that diet-induced obese rats display eating despite negative consequences, as their consumption was insensitive to an aversive cue. Moreover, nucleus accumbens expression of GluA1 and xCT proteins was upregulated in diet-induced obese animals. Lastly, both a computed 'addiction score' (based on performance across three criteria) and weight gain were positively correlated with changes in GluA1 and xCT expression in the nucleus accumbens. These data demonstrate that the propensity for diet-induced obesity is associated with compulsive-like eating of highly palatable food and is accompanied by 'addiction-like' glutamatergic dysregulation in the nucleus accumbens, thus providing neurobiological evidence of addiction-like pathology in this model of obesity.

Individuals with psychoses have brain alterations, particularly in frontal and temporal cortices, that may be particularly prominent, already at illness onset, in those more likely to have poorer symptom remission following treatment with the first antipsychotic. The identification of strong neuroanatomical markers of symptom remission could thus facilitate stratification and individualized treatment of patients with schizophrenia. We used magnetic resonance imaging at baseline to examine brain regional and network correlates of subsequent symptomatic remission in 167 medication-naïve or minimally treated patients with first-episode schizophrenia, schizophreniform disorder, or schizoaffective disorder entering a three-phase trial, at seven sites. Patients in remission at the end of each phase were randomized to treatment as usual, with or without an adjunctive psycho-social intervention for medication adherence. The final follow-up visit was at 74 weeks. A total of 108 patients (70%) were in remission at Week 4, 85 (55%) at Week 22, and 97 (63%) at Week 74. We found no baseline regional differences in volumes, cortical thickness, surface area, or local gyrification between patients who did or did not achieved remission at any time point. However, patients not in remission at Week 74, at baseline showed reduced structural connectivity across frontal, anterior cingulate, and insular cortices. A similar pattern was evident in patients not in remission at Week 4 and Week 22, although not significantly. Lack of symptom remission in first-episode psychosis is not associated with regional brain alterations at illness onset. Instead, when the illness becomes a stable entity, its association with the altered organization of cortical gyrification becomes more defined.

Genetic susceptibility to methamphetamine use disorder is poorly understood. No twin or adequately powered genome-wide association studies (GWASs) have been conducted. However, there are a large number of hypothesis-driven candidate gene association studies, which were systematically reviewed herein. Seventy-six studies were identified, investigating markers of 75 different genes. Allele frequencies, odds ratios, 95 % confidence intervals and power were calculated. Risk of bias was also assessed as a quality measure. Meta-analyses were conducted for gene markers if three or more studies were available. Eleven markers from adequately powered studies were significantly associated with methamphetamine use disorder, with Fatty Acid Amide Hydrolase (FAAH) and Brain Derived Neurotrophic Factor (BDNF) representing promising targets. Limitations of these studies include unclear rationale for candidate gene selection, low power and high risk of bias. Future research should include replications to enable more meta-analyses, well-powered GWASs or whole exome or genome sequencing, as well as twin and family studies to further complement the findings of this review to uncover genetic contributions toward methamphetamine use disorder.

Compulsive overeating of palatable food is thought to underlie some forms of obesity. Similarities are often observed in the behavioural symptomology and the neuropathophysiology underlying substance use disorder and compulsive overeating. As such, preclinical animal models which assess addiction-like behaviour towards food may assist the understanding of the neurobiology underlying overeating behaviour. Further, the relationship between these behaviours and the propensity for diet-induced obesity warrants examination. In this study we investigated the relationship between the propensity for diet-induced obesity (DIO) and addiction-like behaviour towards highly palatable food in C57BL/6 J mice as measured by a 3-criteria model. We also examined the extent to which performance on this 3-criteria model predicted two key hallmark features of addiction - resistance to extinction and relapse propensity (as measured by reinstatement of lever pressing). C57BL/6 J mice were allowed free access to a palatable diet for 8 weeks then separated by weight gain into DIO-prone and DIO-resistant subgroups. Access to palatable food was then restricted to daily operant self-administration sessions whereby addiction-like behaviour towards a high-fat high-sugar food reward was assessed using a 3-criteria model similar to that used to assess addiction-like behaviour towards drugs of abuse. In contrast to findings in rats, no difference in addiction-like behaviour towards food was observed between obesity prone (OP) and obesity resistant (OR) mice. Similarly, principal components analysis found no distinct patterns in the relationship between addiction-like behaviours across treatment groups. This suggests that the strain and species of rodent may be critical for studying the mechanisms underlying pathological overconsumption. Further analysis revealed that the extent of performance on the 3-criteria model correlated with the propensity for C57BL/6 J mice to both extinguish food seeking behaviour and "relapse" after a period of withdrawal. This finding was evident across all groups, regardless of DIO. Collectively, these data validate the 3-criteria model as a robust model to comprehensively assess food addiction-like behaviour in mice, regardless of prior food intake history.

Background Alcohol use disorder (AUD) is a major socioeconomic burden on society, and current pharmacotherapeutic treatment options are inadequate. Aberrant alcohol use and seeking alters frontostriatal function. Methods We performed genome-wide RNA sequencing and subsequent quantitative polymerase chain reaction and receptor binding validation in the caudate–putamen of human AUD samples to identify potential therapeutic targets. We then back-translated our top candidate targets into a rodent model of long-term alcohol consumption to assess concordance of molecular adaptations in the rat striatum. Finally, we adopted rat behavioral models of alcohol intake and seeking to validate a potential therapeutic target. Results We found that G protein–coupled receptors were the top canonical pathway differentially regulated in individuals with AUD. The M4 muscarinic acetylcholine receptor (mAChR) was downregulated at the gene and protein levels in the putamen, but not in the caudate, of AUD samples. We found concordant downregulation of the M4 mAChR, specifically on dopamine D1 receptor–expressing medium spiny neurons in the rat dorsolateral striatum. Systemic administration of the selective M4 mAChR positive allosteric modulator, VU0467154, reduced home cage and operant alcohol self-administration, motivation to obtain alcohol, and cue-induced reinstatement of alcohol seeking in rats. Local microinjections of VU0467154 in the rat dorsolateral striatum reduced alcohol self-administration and cue-induced reinstatement of alcohol seeking. Conclusions Collectively, these results identify the M4 mAChR as a potential therapeutic target for the treatment of AUD and the D1 receptor–positive medium spiny neurons in the dorsolateral striatum as a key site mediating the actions of M4 mAChR in relation to alcohol consumption and seeking.

Background: The lateral hypothalamic orexin (hypocretin) system has a well-established role in the motivation for reward. This has particular relevance to substance use disorders since orexin-1 receptors play a critical role in alcohol-seeking behavior, acting at multiple nodes in relapse-associated networks. Aims: This study aimed to further our understanding of the role of orexin-1 receptor signaling within the lateral hypothalamus and bed nucleus of the stria terminalis, specifically in context-induced relapse to alcohol-seeking following punishment-imposed abstinence. Methods: We trained inbred male alcohol-preferring rats to self-administer alcohol in one environment or context (Context A) and subsequently punished their alcohol-reinforced lever presses in a different environment (Context B) using contingent foot shock punishment. Finally, we tested rats for relapse-like behavior in either context following systemic, intra-lateral hypothalamus or intra-bed nucleus of the stria terminalis orexin-1 receptor antagonism with SB-334867. Results/outcomes: We found that systemic orexin-1 receptor antagonism significantly reduced alcohol-seeking in both contexts. Intra-lateral hypothalamus orexin-1 receptor antagonism significantly reduced alcohol-seeking in Context A whereas intra-bed nucleus of the stria terminalis orexin-1 receptor antagonism had no effect on alcohol-seeking behavior. Conclusions/interpretation: Our results suggest a role for the orexin-1 receptor system in context-induced relapse to alcohol-seeking. Specifically, intra-lateral hypothalamus orexin microcircuits contribute to alcohol-seeking.

Muscarinic acetylcholine receptors (mAChRs) have been shown to mediate alcohol consumption and seeking. Both M4 and M5 mAChRs have been highlighted as potential novel treatment targets for alcohol use disorders (AUD). Similarly, M1 mAChRs are expressed throughout reward circuitry, and their signaling has been implicated in cocaine consumption. However, whether the same effects are seen for alcohol consumption, or whether natural reward intake is inadvertently impacted is still unknown. To determine the role of M1 mAChRs in alcohol consumption, we tested operant self‐administration of alcohol under both fixed ratio (FR3) and progressive ratio (PR3‐4) schedules. Enhancing M1 mAChR signaling (via the M1 PAM‐Agonist PF‐06767832, 1 mg/kg, i.p.) reduced operant alcohol consumption on a fixed schedule but had no effect on motivation to acquire alcohol. To determine whether these actions were specific to alcohol, we examined the effects of M1 enhancement on natural reward (sucrose) self‐administration. Systemic administration of PF‐06767832 (1 mg/kg, i.p.) also reduced operant sucrose self‐administration, suggesting the actions of the M1 receptor may be non‐selective across drug and natural rewards. Finally, to understand whether this reduction extended to natural consummatory behaviors, we assessed home cage standard chow and water consumption. M1 enhancement via systemic PF‐06767832 administration reduced food and water consumption. Together our results suggest the M1 PAM‐agonist, PF‐06767832, non‐specifically reduces consummatory behaviors that are not associated with motivational strength for the reward. These data highlight the need to further characterize M1 agonists, PAMs, and PAM‐agonists, which may have varying degrees of utility in the treatment of neuropsychiatric disorders including AUD.

No-take reserves (NTRs) have been effective at conserving fish assemblages in tropical systems such as coral reefs, but have rarely been evaluated in turbid tropical estuaries. The present study evaluated the effect of a mangrove NTR on the conservation of juvenile fish abundance, commercial fish biomass and biodiversity at the assemblage level, and the abundance of juveniles, target and non-target adults at the family level. The evaluation incorporated one aspect of seascape connectivity, namely proximity to the sea, or in this case, the Gulf of Paria. Linear mixed models showed that the NTR had a positive effect only on species richness at the assemblage level. However, juvenile fish abundance, commercial fish biomass, taxonomic distinctness and functional diversity were not enhanced in the NTR. The inclusion of connectivity in these models still failed to identify any positive effects of the NTR at the assemblage level. Yet, there were significant benefits to juvenile fish abundance for 5 of 7 families, and for 1 family of non-target adults. Possible explanations for the limited success of the NTR for fish assemblages include failing to account for the ecology of fish species in NTR design, the drawbacks of ‘inside-outside’ (of the NTR) experimental designs and the fact that fishing does not always impact non-target species. It is important to recognise that mangrove NTRs do not necessarily benefit fish assemblages as a whole, but that finer-scale assessments of specific families may reveal some of the proclaimed benefits of NTRs in tropical estuaries.

BACKGROUND: The meningococcal group B vaccine 4CMenB is a new, recombinant protein-based vaccine that is licensed to protect against invasive group B meningococcal disease. However, its role in preventing transmission and, therefore, inducing population (herd) protection is uncertain.METHODS: We used cluster randomization to assign, according to school, students in years 10 to 12 (age, 15 to 18 years) in South Australia to receive 4CMenB vaccination either at baseline (intervention) or at 12 months (control). The primary outcome was oropharyngeal carriage of disease-causing Neisseria meningitidis (group A, B, C, W, X, or Y) in students in years 10 and 11, as identified by polymerase-chain-reaction assays for PorA (encoding porin protein A) and N. meningitidis genogroups. Secondary outcomes included carriage prevalence and acquisition of all N. meningitidis and individual disease-causing genogroups. Risk factors for carriage were assessed at baseline.RESULTS: A total of 237 schools participated. During April through June 2017, a total of 24,269 students in years 10 and 11 and 10,220 students in year 12 were enrolled. At 12 months, there was no difference in the prevalence of carriage of disease-causing N. meningitidis between the vaccination group (2.55%; 326 of 12,746) and the control group (2.52%; 291 of 11,523) (adjusted odds ratio, 1.02; 95% confidence interval [CI], 0.80 to 1.31; P = 0.85). There were no significant differences in the secondary carriage outcomes. At baseline, the risk factors for carriage of disease-causing N. meningitidis included later year of schooling (adjusted odds ratio for year 12 vs. year 10, 2.75; 95% CI, 2.03 to 3.73), current upper respiratory tract infection (adjusted odds ratio, 1.35; 95% CI, 1.12 to 1.63), cigarette smoking (adjusted odds ratio, 1.91; 95% CI, 1.29 to 2.83), water-pipe smoking (adjusted odds ratio, 1.82; 95% CI, 1.30 to 2.54), attending pubs or clubs (adjusted odds ratio, 1.54; 95% CI, 1.28 to 1.86), and intimate kissing (adjusted odds ratio, 1.65; 95% CI, 1.33 to 2.05). No vaccine safety concerns were identified.CONCLUSIONS: Among Australian adolescents, the 4CMenB vaccine had no discernible effect on the carriage of disease-causing meningococci, including group B. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT03089086.).

Chronic alcohol use is associated with cognitive decline that impedes behavioral change during rehabilitation. Despite this, addiction therapy does not address cognitive deficits, and there is poor understanding regarding the mechanisms that underlie this decline. We established a rodent model of chronic voluntary alcohol use to measure ensuing cognitive effects and underlying pathology. Rats had intermittent access to alcohol or an isocaloric solution in their home cage under voluntary 2-bottle choice conditions. In Experiments 1 and 2 cognition was assessed using operant touchscreen chambers. We examined performance in a visual discrimination and reversal task (Experiment 1), and a 5-choice serial reaction time task (Experiment 2). For Experiment 3, rats were perfused immediately after cessation of alcohol access period, and volume, cell density and microglial populations were assessed in the prefrontal cortex and striatum. Volume was assessed using the Cavalieri probe, while cell and microglial counts were estimated using unbiased stereology with an optical fractionator. Alcohol-exposed and control rats showed comparable acquisition of pairwise discrimination; however, performance was impaired when contingencies were reversed indicating reduced behavioral flexibility. When tested in a 5-choice serial reaction time task alcohol-exposed rats showed increased compulsivity and increased attentional bias towards a reward associated cue. Consistent with these changes, we observed decreased cell density in the prefrontal cortex. These findings confirm a detrimental effect of chronic alcohol and establish a model of alcohol-induced cognitive decline following long-term voluntary intake that may be used for future intervention studies.

Supplemental Digital Content is available in the text., Background and Purpose— Cerebral small vessel disease (SVD) is the most common cause of vascular cognitive impairment, with a significant proportion of cases going on to develop dementia. We explore the extent to which diffusion tensor image segmentation technique (DSEG; which characterizes microstructural damage across the cerebrum) predicts both degree of cognitive decline and conversion to dementia, and hence may provide a useful prognostic procedure. Methods— Ninety-nine SVD patients (aged 43–89 years) underwent annual magnetic resonance imaging scanning (for 3 years) and cognitive assessment (for 5 years). DSEG-θ was used as a whole-cerebrum measure of SVD severity. Dementia diagnosis was based Diagnostic and Statistical Manual of Mental Disorders V criteria. Cox regression identified which DSEG measures and vascular risk factors were related to increased risk of dementia. Linear discriminant analysis was used to classify groups of stable versus subsequent dementia diagnosis individuals. Results— DSEG-θ was significantly related to decline in executive function and global cognition (P

BackgroundDespite common dissatisfaction with the syndromic heterogeneity of major depression, investigations into its symptom structure are scarce. Self-worthlessness/inadequacy is a distinctive and consistent symptom of major depression across cultures.AimsWe investigated whether self-worthlessness is associated with self-blaming attribution-related symptoms or is instead an expression of reduced positive feelings overall, as would be implied by reduced positive affect accounts of depression.Methods44,161 undergraduate students in Study 1, and 215 patients with current Major Depressive Disorder (MDD) and 237 age-matched healthy control participants in Study 2 completed the well-validated Symptom Check List-90. Depression-relevant items were used to construct regularized partial correlation networks with bootstrap estimates of network parameter variability.ResultsWorthlessness co-occurred more strongly with other symptoms linked to self-blaming attributions (hopelessness, and self-blame), displaying a combined edge weight with these symptoms which was significantly stronger than the edge weight representing its connection with reduced positive emotion symptoms (such as reduced pleasure/interest/motivation, difference in edge weight sum in Study 1 = 2.95, in Study 2 = 1.64; 95% confidence intervals: Study 1: 2.6–3.4; Study 2: 0.02–3.5; Bonferroni-corrected p < 0.05).ConclusionsThis confirms the prediction of the revised learned helplessness model that worthlessness is most strongly linked to hopelessness and self-blame. In contrast, we did not find a strong and direct link between anhedonia items and a reduction in self-worth in either study. This supports worthlessness as a primary symptom rather than resulting from reduced positive affect.

Muscarinic acetylcholine receptors (mAChRs) have been shown to mediate alcohol consumption and seeking. Both M

Despite decades of research in the field of addiction, relapse rates for substance use disorders remain high. Consequently, there has been growing focus on providing evidence-based treatments for substance use disorders, resulting in the increased development and use of cognitive and psychological interventions. Such treatment approaches, including contingency management, community-reinforcement approach, and cognitive bias modification, have shown promising clinical efficacy in reducing substance use and promoting abstinence during treatment. However, these interventions are still somewhat limited in achieving sustained periods of abstinence post-treatment. The neurobiological mechanisms underpinning these treatment approaches remain largely unknown and under-studied, in part, due to a lack of translational animal models. The adoption of a reverse translational approach may assist in development of more representative models that can facilitate elucidation of the mechanisms behind these clinically relevant interventions. This review examines our current understanding of addiction neurobiology from clinical, preclinical research and existing animal models, and considers how the efficacy of such behavioral-oriented interventions alone, or in combination with pharmacotherapy, may be enhanced to improve treatment outcomes.

The central nucleus of the amygdala (CeA) is a key hub integrating sensory inputs and modulating behavioural outputs. The CeA is a complex structure with discrete subdivisions, high peptidergic heterogeneity and broad CNS afferent and efferent projections. While several neuropeptide systems within the CeA have been examined in detail, less is known about CeA preproenkephalin (ppENK) cells. Here, we used a recently developed transgenic Penk-Cre mouse line to advance our understanding of the efferent and afferent connectivity of ppENK in the CeA. First, to determine the fidelity of Cre expression in Penk-Cre transgenic mice, we conducted RNAscope in the CeA of Penk-Cre mice. Our analysis revealed that 96.6 % of CeA Cre+ neurons co-expressed pENK mRNA, and 99.7 % of CeA pENK+ neurons co-expressed Cre mRNA, indicating faithful recapitulation of Cre expression in CeA ppENK-expressing cells, supporting the fidelity of the Penk-Cre reporter mouse. Anterograde tracing of CeAsupPenk/supcells showed strong efferent projections to the extended amygdala, midbrain and hindbrain PBN and NTS. Retrograde tracing of Penk afferents to the CeA were more restricted, with primary innervation originating within the amygdala complex and bed nucleus of the stria terminalis, and minor innervation from the parabrachial nucleus and nucleus of the solitary tract. Together, our data provide a comprehensive map of ENKergic efferent and afferent connectivity of the CeA in Penk-Cre mice. Further, we highlight both the utility and limitations of the Penk-Cre mice to study the function of CeA, PBN and NTS ppENK cells.

Inflammatory processes in the Central Nervous System (CNS) have been proposed to mediate the association between peripheral inflammation and the development of psychiatric disorders, but we currently lack sensitive measures of CNS inflammation for human studies in vivo. Here we used quantitative MRI (qMRI) to explore the in vivo central response to a peripheral immune challenge in healthy humans, and we assessed whether changes in quantitative relaxometry MRI parameters were associated with changes in peripheral inflammation. Quantitative relaxation times (T1 & T2) and Proton Density (PD) were measured in n ​= ​6 healthy males (mean age ​= ​30.5 ​± ​6.8 years) in two MRI assessments collected before and 24 ​hours after a subcutaneous injection of the proinflammatory cytokine and immune activator, interferon-alpha (IFN-α). Serum levels of immune markers and markers of blood-brain barrier integrity (S100B) were also measured before and after the injection. Region of interest and histogram-based analyses (optimized for the small sample size) showed a statistically significant increase of both T1 (t(5) ​= ​3.78, p ​= 0.013) and PD (t(5) ​= ​2.91, p ​= ​0.033) parameters in the bilateral hippocampus after IFN-α administration. T1 peak values in bilateral hippocampus were positively correlated with serum Tumour Necrosis Factor-alpha levels at 24 ​h after the injection, when this cytokine peaked (Spearman's rho ​= ​0.67, p ​= ​0.018) and negatively correlated with S100B levels (Spearman's rho ​= ​−0.826, p ​= ​0.001). Our data suggest that peripheral administration of IFN-α produces acute changes in brain qMRI which might indicate a brain immune response. This is supported by the association of such changes with low-grade peripheral inflammation.

Projections to the striatum are well-identified. For example, in the ventral striatum, two major inputs to the medial nucleus accumbens shell include the ventral subiculum and basolateral amygdala. However, the chemical phenotype(s) of these projection neurons remain unclear. In this study, we examined amygdalostriatal and corticostriatal connectivity in rats using injections of the retrograde tracer cholera toxin b into the nucleus accumbens shell. To determine the neurotransmitter identity of projection neurons, we combined retrograde tracing with RNAscope in-situ hybridization, using mRNA probes against vesicular transporters associated with glutamatergic (VGluT1 - Slc17a7, VGluT2 - Slc17a6) or GABAergic (VGaT - Slc32a1) neurotransmission. Confocal imaging was used to examine vesicular transporter mRNA expression in the ventral subiculum and basolateral amygdala inputs to the nucleus accumbens shell. Both projections contained mostly VGluT1-expressing neurons. Interestingly, almost a quarter of ventral subiculum to nucleus accumbens shell projections co-expressed VGluT1 and VGluT2 compared to a relatively small number (∼3%) that were co-expressed in basolateral amygdala to nucleus accumbens shell afferents. However, almost a quarter of basolateral amygdala to nucleus accumbens shell projections were VGaT-positive. These findings highlight the diverse proportions of glutamatergic and GABAergic afferents in two major projections to the nucleus accumbens shell and raise important questions for functional studies.