Progress in Neuro-Psychopharmacology and Biological Psychiatry

Bipolar disorder (BD) is a severe psychiatric condition marked by episodes of mania and depression, with neurotransmitter imbalance in the midbrain believed to play a critical role in its pathophysiology. Despite this, there is currently no validated midbrain model for examining BD-associated molecular changes available. Leveraging recent advances in stem cell technology, we developed a midbrain organoid model using human induced pluripotent stem cells (hiPSCs) from BD patients and healthy controls (CTR). To address issues of variability and enhance the throughput in organoid production, we implemented liquid handling and high-content imaging techniques. Quality control metrics were established to identify organoids unsuitable for further study. Electrophysiological analysis via high-density microelectrode arrays (MEAs) revealed significantly elevated neuronal properties in individual BD organoids, including increased mean amplitude, conduction velocity, and extended axonal and dendritic growth. Transcriptome and proteome analyses indicated significant dysregulation of BD-relevant signaling pathways--such as those involving phosphatidylinositol, glycogen synthase kinase-3 beta, and AKT. Notably, we identified dysregulated casein kinase 2 (CSNK2A1) and calmodulin 3 (CALM3) in BD organoids, which were reversed by lithium treatment, highlighting potential novel targets for therapeutic intervention. This study validates the midbrain organoid model as a valuable tool for exploring the molecular underpinnings of BD and identifying new treatment avenues.

Numerous mouse models have been engineered to carry alterations to the Disrupted in Schizophrenia 1 (Disc1) gene, thought to be involved in neurodevelopmental conditions. However, most Swiss and probably all 129 mouse substrains, which are widely used in biological research, naturally carry a 25 bp deletion in Disc1 exon 6. Despite the prevalence of these strains, little has been done to characterize the extent to which this natural mutation affects behavioral output and may unintentionally impact studies. Here, we report on experiments to test the effects of this deletion on social and exploratory behaviors. To model natural conditions, we designed a seminatural environment to house groups of mice (4 females and 1 male; 3 groups per strain) for prolonged periods and then employed this model to study social behaviors. First, we compared behavioral phenotypes in C57Bl/6Jrj (B6) mice and 129S4 (S4Disc1-/-) natural mutants to validate our setup. Then, to assess the contribution of the naturally mutated Disc1 to social behavior differences, the wild-type (WT) Disc1 allele was crossed into S4 mice (S4Disc1+/+). S4 and B6 lines were drastically different, with S4 mice being hypoactive, less explorative, and less social than B6 mice. However, S4 mice expressing WT Disc1 only marginally differed from S4Disc1-/- mice, showing little to no contribution of Disc1 to their behavioral phenotype. Thus, this mutation holds little significance for natural exploratory and social behaviors in the seminatural environment.

Schizophrenia is a disorder with a higher cognitive decline in early adulthood, causing impaired retention of episodic memories. However, the physiological and behavioral functions that underlie cognitive deficits with a potential mechanism to ameliorate and improve cognitive performance are unknown. In this study, we used the MK-801 neurodevelopmental schizophrenia-like model. Rats were divided into two groups: one received MK-801, and the other received saline for five consecutive days (7-11 postnatal days, PND). Using extracellular field recordings in acute hippocampal slices and the Barnes maze task, we evaluated synaptic plasticity late-LTP and spatial memory in freely moving animals in early adolescence and young adulthood. Next, we examined D1-like activation as a mechanism to ameliorate cognitive impairments. Our results suggest that MK-801 neonatal treatment induces impairment in late-LTP expression and deficits in spatial memory retrieval in early adolescence that is maintained until young adulthood. Furthermore, we found that activation of D1-like dopamine receptors ameliorates the impairments and promotes a robust expression of late-LTP and an improved performance in the Barnes maze task, suggesting a novel and potential therapeutic role in treating cognitive impairments in schizophrenia. Highlights- MK-801 Schizophrenia model induces impairment in Late-LTP at early adolescence and young developmental stage. - Barnes maze recall phase is impaired in the MK-801 Schizophrenia model. - The activation of D1-like receptors promotes recovery and induction of the - Late-LTP in the MK-801 schizophrenia model in adolescent and young adult rats. - Activation of D1-like dopamine receptors improves behavioral performance in the MK-801 schizophrenia model in adolescent and young adult rats. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=127 SRC="FIGDIR/small/599791v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@e258e7org.highwire.dtl.DTLVardef@3ab481org.highwire.dtl.DTLVardef@20aa4dorg.highwire.dtl.DTLVardef@8cc518_HPS_FORMAT_FIGEXP M_FIG C_FIG Disturbances in episodic memories are observed in patients with schizophrenia and rodent models. Still, the hippocampal physiological substrates with a potential rescue mechanism related to consolidation of memories have not been elucidated. Here, in vitro electrophysiology and in vivo Barnes maze task are used at two ages in the MK-801 neurodevelopmental schizophrenia-like model. We observed a loss of hippocampal late-LTP and impaired recall phase, and the activation of dopamine D1-like receptors attenuated the impairments with a rescue of both late-LTP and recall phase, suggesting an important role of D1-like receptors activity for episodic memory in schizophrenia.

Impairments of decision-making and behavioral flexibility in schizophrenia (SCZ) are currently the most investigated features. One convincing hypothesis explaining this cognitive impairment is the excitatory/inhibitory (E/I) ratio imbalance in brain regions such as the medial prefrontal cortex (mPFC) and the ventral hippocampus (vHPC). An increased GLUergic excitatory activity and a decreased GABAergic inhibitory activity induces an mPFC-vHPC {gamma}/{theta} band desynchronization in many tasks testing behavioral flexibility. However, these tasks were carried out using "perceptual" decision-making/flexibility but not navigational decision-making/flexibility. Our study addressed the role of frequency-specific optogenetic stimulations of GABAergic parvalbumin-positive (PV+) interneurons in mPFC (50Hz, {gamma}-like) and vHPC (10Hz, {theta}-like) in an acute-MK801 mouse model of navigational inflexibility. We used the active place avoidance task on a rotating arena. Results showed that frequency-specific optogenetic stimulations of mPFC or vHPC acted differently in restoring navigational flexibility, advancing our knowledge of the pivotal role of PV+ activity in SCZ-like navigational decision-making/flexibility.

Background and ObjectiveTourette Syndrome (TS) and Persistent Motor or Vocal Tic Disorders (PMVT) are more prevalent in males (vs. females). Females with TS may have a delay in diagnosis, and more complex tic features (vs. males). With respect to comorbidities, obsessive-compulsive disorder (OCD) is more prevalent in females; attention-deficit hyperactivity disorder (ADHD) is more prevalent in males. Less is known about sex differences in PMVT. This study analyzes sex differences in outcomes among individuals with TS and PMVT in the Tourette Association of America International Consortium for Genetics dataset (TAAICG). Design/MethodsData from 2403 individuals (N=2109 TS; N=294 PMVT) from the TAAICG were analyzed to explore the relationship between sex and TS or PMVT outcomes: age at tic onset; age at diagnosis; time-to-diagnosis; tic severity; and comorbidity rates. Regression models were adjusted for age and family relationships to examine the impact of sex on outcomes. ResultsFemales with TS (25.5% of the sample) had a later age of symptom onset (6.5{+/-}2.8 vs. 6.0{+/-}2.7; p=0.001), later age at diagnosis (13.3{+/-}11.2 vs. 10.7{+/-}8.1; p=0.0001), and a longer time-to-diagnosis [3 (1,7) vs. 2 (1,5), p=0.01] than males. The total Yale-Global Tic Severity Scale (YGTSS) was lower in females with TS (28.4{+/-}9.1 vs. 30.7{+/-}8.7); p<0.0001); OCD was slightly more prevalent in females (55% vs. 48.7%; p=0.01) although OCD severity did not differ by sex; ADHD was more prevalent in males (55.7% vs 38.9%; p<0.001). Females with TS had 0.46 lower odds of being diagnosed with TS (p<0.00001). Females with PMVT (42.9% of the sample) had an earlier age of symptom onset (7.9{+/-}3.3 vs. 8.9{+/-}3.7; p=0.05). Motor or vocal tic severity (YGTSS) was not significantly different. OCD, but not ADHD, was more prevalent in females (OCD: 41.9% vs. 22.2%; p<0.001: ADHD:16.5% vs 21.0%; p=0.4). ConclusionFemales with TS are less likely to be formally diagnosed and have a later age of symptom onset, later age at diagnosis, longer time-to-diagnosis, higher prevalence of OCD, and lower prevalence of ADHD (vs. males). Females with PMVT have an earlier age of symptom onset, higher prevalence of OCD, but similar ADHD prevalence rates (vs. males). Females with TS and PMVT may be clinically different than males with TS. Future research is needed to understand differences longitudinally in TS and PMVT.

BACKGROUNDObsessive-compulsive disorder (OCD) is a psychiatric disorder characterized by obsessive thoughts and compulsive behavior. While some theories imply that OCD patients have cognitive biases and dysfunctional motivation regarding a potential threat, these views are not adequately supported by neurological evidence. Hypothalamic perifornical (PeF) urocortin-3 (UCN3) neurons are involved in defensive responses to a potential threat, and the activation of these neurons in mice induces repetitive and excessive checking and burying of novel objects. In this study, we evaluated the hypothesis that mice in which PeF UCN3 neurons are activated can serve as an OCD model. METHODSPeF UCN3 neurons were chemogenetically activated with clozapine-N oxide (CNO) in Ucn3-Cre mice. Marble-burying activity, repetitive/stereotypic behaviors in the homecage, and excessive responses to a novel object were measured as OCD-like behaviors. The effects of clinically used drugs for treating OCD on these behaviors were evaluated. The effect of CNO on neural activity in the cortico-striato-thalamo-cortical loop (which is regarded as an OCD circuit) was assessed with c-Fos immunolabeling. RESULTSCNO increased marble-burying activity, evoked homecage-specific repetitive/stereotypic behaviors that probably aimed to seal entrances, and induced repetitive and excessive checking and burying of novel objects. These behaviors were suppressed by selective serotonin-reuptake inhibitors but not by diazepam. CNO increased neural activity in the cortico-striato-thalamo-cortical loop. CONCLUSIONSThese results indicated that mice whose PeF UCN3 neurons are activated can serve as a model of OCD, particularly as a checking model. This supports theories concerning the role of potential threats in the pathophysiology of OCD.

BackgroundThe link between cannabis use and schizophrenia is well-established in epidemiological studies, especially among adolescents with early-onset use. However, this association in rodent models is less clear. This meta-analysis examined the effects of adolescent cannabinoid exposure on distinct schizophrenia-like behaviours in rodents and how experimental variations influence outcomes. MethodsFollowing a pre-registered protocol (CRD42022338761), we searched PubMed, Ovid Medline, Embse and APA PsychInfo for English-language original studies until 2022. We synthesised data from experiments on schizophrenia-like behaviour in rats and mice after repeated peri-pubertal (onset between P23-P45) cannabinoid exposure. Risk of bias was assessed using the SYRCLEs tool. ResultsWe included 291 experiments from 91 articles across 9 behavioural tests. We found meta-analytic evidence supporting that CB1R agonists, both natural and synthetic, elicited broad schizophrenia-like behavioural alterations, including impaired working memory (g =-0.58 [CI: -1.00,-0.16]), novel object recognition (g=-0.63 [CI: -0.97,-0.30]), novel object location recognition (g=-0.70 [CI: -1.22,-0.28]), social motivation (g=-0.40 [CI: -0.63, -0.16]), pre-pulse inhibition (g=-0.48 [CI: -0.89, -0.08]), and sucrose preference (g=-0.92 [CI: -1.87,0.04]). By contrast, effects on novelty-induced locomotion were negligible. Subgroup analyses revealed similar effects across sexes and species. Substantial variance in the protocols and moderate-to-high heterogeneity in behavioural outcomes were observed. We found CBD may attenuate novelty-induced locomotion in an open field and enhance fear memory recall, but data was limited. DiscussionThis is the first meta-analysis to comprehensively assess the link between cannabinoids and schizophrenia-like behaviours in rodents. Our results support epidemiological links between early cannabis use and schizophrenia-like phenotypes, confirming the utility of animal models. Standardising protocols will optimise models to strengthen reproducibility and comparisons, our work provides a framework for refining rodent models to elucidate biological pathways linking cannabis and schizophrenia.

Substantial research on the association between early-life stress and its long-lasting impact on lifetime mental health has been performed revealing that early-life environmental adversity strongly regulates brain function. Alterations of gene expression and behavior in the off-springs of paternally stressed rats were also revealed. However, the precise mechanisms underlying these changes remain poorly understood. Here, an improved characterization of these processes from investigations of the functional metabolism of animal models exposed to peripubertal stress (PS) is proposed. The ultimate goal of this study was to bring forward functional Magnetic Resonance Spectroscopy (fMRS) as a technique of interest for a better understanding of brain areas by endogenous stimulators such as stress. The present study evaluated, compared and classified effects of individual PS (iPS) and paternal PS (pPS) under corticosterone (CORT) challenge in the septal areas of adult rats. Acute stress was simulated by injection of CORT and metabolic concentration changes were analyzed as a function of time. Evaluation of Glucose and Lactate concentration changes allowed the classification of groups of rats using a Glc to Lac index. Moreover, metabolic responses of control rats (CC) and of pPS x iPS rats (SS) were similar while responses in pPS (SC) and iPS (CS) differed, revealing differential adaption of energetic metabolism and of glutamatergic neurotransmission. Findings have crucial interest for understanding the metabolic mechanisms underlying altered functional connectivity and neuronal plasticity in septal areas inducing increased aggressivity in early-life stressed rats.

IntroductionExercise is a promising intervention for clinical high-risk for psychosis (CHR) populations, who have attenuated positive symptoms, but evidence suggests that these youth may require tailored exercise interventions. Presently, the scope of the problem is unknown, as these youth may not be reliable reporters on fitness. This issue is compounded by the fact that there have been no investigations that utilized a formal fitness assessment in this critical population. The present study aims to determine the level of fitness in CHR youth with lab-based measures, test how effectively self-report measures characterize objective fitness indices, and explore clinical factors that may be interrupting reliable self-report-an important tool if these interventions are to be taken to scale. MethodsForty CHR individuals completed an exercise survey and lab-based indices of fitness (i.e., VO2max and BMI). Forty healthy volunteers completed lab indices of fitness and a structured clinical interview ruling out the presence of psychiatric illness. ResultsCHR youth showed greater BMI and lower VO2max compared to healthy volunteers. In the CHR group, abstract self-report items (perceived fitness) did not reflect lab indices of fitness, whereas specific exercise behaviors (intensity of exercise) showed stronger correlations with laboratory-based fitness measurements. Exploratory analyses suggested that positive symptoms involving grandiosity, and negative symptoms such as avolition, correlated with discrepancy between self-perception and laboratory findings of fitness. DiscussionResults suggest that CHR individuals are less objectively fit than matched controls, and that it will be important to consider unique population characteristics when weighing self-report data.

BackgroundRepetitive rituals in OCD patients result from pathological doubt, which has been linked to dysfunction in decision-making. First-line drug treatments for OCD are selective serotonin reuptake inhibitors; however, 40% of OCD patients do not respond to these. As brain activity patterns in OCD resemble those in schizophrenic patients, this suggests a dopaminergic component, supported by data showing that the D2/D3 receptor agonist Quinpirole induces compulsive checking in male rats. OCD has proved difficult to model in rodents and the contribution of decision making to compulsive behaviour in such models has not been studied. The five-choice continuous performance task (5C-CPT) measures both decision making and compulsive behaviour, making it possible to evaluate whether OCD models show correlated changes in these two behaviours. Establishing this would provide a new model approach to help develop therapeutic agents for OCD. AimsThe role of dopaminergic D3 receptors in decision making and compulsive behaviour was determined by testing the effect of the preferential D3 agonist PD 128907 on 5C-CPT performance measures. Oldhams method was used to determine the presence of any rate-dependent effect. MethodsFemale Lister hooded rats were trained to criterion in the 5C-CPT (>70% accuracy, < 30% omission and < 40% false alarms). The effects of PD128907 (0.25-1 mg/kg) were then investigated under challenging task conditions. ResultsOldham method revealed: a moderate positive association between baseline perseverative correct responses and the change at 0.05 mg/kg PD 128907; a strong positive association between baseline perseverative false alarm and the change at 0.2 mg/kg; a positive association between baseline total number of perseverative responses and the change at 0.05 mg/kg or 0.2 mg/kg PD 128907; a positive relationship between baseline accuracy and the change at 0.05 mg/kg PD 128907; and a moderate positive association between baseline correct response latency and the change at 0.05 mg/kg or 0.2 mg/kg PD 128907. The angle measurements and the direction of movement (clockwise or counterclockwise) showed how effective is one dose at increasing compulsive behaviour compared with other doses. ConclusionsPD 128907 effects on compulsive like behaviour and decision making in poor performing female lister hooded rats with long correct response latency and high perseveration at baseline (vulnerable population) in the 5C-CPT task matches two key features of OCD compulsions in humans (perseveration and indecision), this suggests that PD 128907 is more effective than Quinpirole in simulating the brain network conditions that underpin OCD. This model could help to develop more successful pharmacological interventions and to generate data translatable to clinical studies.

Research studies have demonstrated that persons who have Alcohol Use Disorder (AUD) exhibit a more severe progression of psychiatric disorders, indicating potential causal connections between AUD and psychiatric disorders. Identifying underlying risk variables between AUD and psychiatric problems continues to be challenging. To address these issues, we created a bioinformatics pipeline and employed network-based methods to discover genes that exhibit improper expression in both AUD and psychiatric disorders. The objective of our study was to identify common molecular pathways that may elucidate the relationship between AUD and psychiatric disorders. We identified 49 genes that were expressed differently in tissue samples of patients with both AUD and psychiatric disorders. The DAVID online platform was used to discover the most significant Gene Ontology (GO) keywords and metabolic pathways. It detected the involvement of immune response, chemokine activity, TNF signaling, IL-17 signaling, and prostaglandin signaling pathways among the common DEGs. In addition, eleven topological algorithms identified a single hub protein, specifically TTR, from the protein-protein interaction (PPI) network. Through regulatory network analysis, we identified four crucial transcription factors (TFs)--YY1, FOXC1, JUND, and GATA2--and seven miRNAs (e.g., hsa-mir-146a-5p, hsa-mir-20a-5p) that play vital roles in regulating the development of AUD and psychiatric disorders. These miRNAs may serve as potential therapeutic targets. Validation of the hub gene using ROC analysis indicated acceptable predictive performance. Our approach revealed several potential biomarkers and signaling pathways linking AUD with psychiatric disorders, offering new insights for diagnosis and treatment. HighlightsO_LIIntegration of genome-scale transcriptomic datasets with biomolecular networks identified key hub genes (TTR, SOCS3, CXCL10, MMP9, and C4A). C_LIO_LICommon transcription factors, including YY1, FOXC1, JUND, and GATA2, were uncovered as potential regulatory elements. C_LIO_LICritical miRNAs (hsa-miR-146a-5p, hsa-miR-20a-5p, hsa-miR-107, hsa-miR-124-3p, hsa-miR-138-5p, and hsa-miR-330-3p) were identified as key post-transcriptional regulators. C_LIO_LIHistone modification profiling revealed multiple modification sites in hub genes and transcription factors, linking them to Intellectual Disability, Bipolar Disorder, Schizophrenia, and Alcohol Use Disorder. C_LIO_LIProtein-drug interaction analysis highlighted 10 candidate compounds with potential therapeutic relevance for the identified markers across ID, Bipolar Disorder, Schizophrenia, and AUD. C_LI

Behavioral copying is a key process in group actions, but it is challenging for individuals with Autism Spectrum Disorder (ASD). We investigated behavioral contagion, or instinctual replication of behaviors, in Krushinky-Molodkina (KM) rats (n=16), a new rodent model for ASD, compared to control Wistar rats (n=15). A randomly chosen healthy Wistar male ("demonstrator rat") was introduced to the homecage of experimental rats ("observers") 10-14 days before the experiments to become a member of the group. For the implementation of the behavioral contagion experiment, we used the IntelliCage system, where rats can live in a group of 5-6 rats and their water visits can be fully controlled. During the experiment, the demonstrator was taken out of IntelliCage for 24 hours of water deprivation and then placed back. As a result, a drinking behavior of the water-deprived demonstrator rat prompted activated behaviors in the whole group. Unlike the Wistar controls, KM observers showed fewer visits to the drinking bottles, particularly lacking inspection visits. The control group, in contrast, exhibited a dynamic, cascade-like visiting of the water corners. The proportion of activated observers in KM rats was significantly lower, as compared to Wistar ones, and they did not mimic other observer rats. KM rats, therefore, displayed an attenuated pattern of behavioral contagion, highlighting social deficits in this ASD model. This study suggests that measuring group dynamics of behavioral contagion in an automated, non-invasive setup offers valuable insights into social behavior in rodents, particularly for studying social deficits in ASD models. HighlightsO_LIThirsty demonstrators triggered an avalanche of observers visits to the water corners C_LIO_LIThe contaged behavior was attenuated in observer KM rats C_LIO_LIBehavioral contagion test provides a new tool for objective, automated phenotyping in rodent models of social deficits C_LI

Generalization of conditioned fear is adaptive for survival. However, overgeneralization of fear from threat cues to loosely similar yet safe stimuli is a hallmark of anxiety-related disorders. Such overgeneralization may impact other fear learning processes. In particular, broad fear generalization might limit the effectiveness of extinction training, which may further maintain anxiety. Here, we examined if increased generalization of conditioned fear might reduce the later generalization of fear extinction. To this end, we compared rats conditioned with moderate-versus high-intensity footshocks, the latter showing stronger generalization of acquired fear than the former. Within each shock intensity group, we then conducted extinction training using the original conditioned stimulus (CS) for half of the animals and a generalization stimulus (GS) for the others. We found stronger preserved responding to the CS after GS extinction in rats that had initially been conditioned using the high-intensity footshock than in rats conditioned using the moderate-intensity footshock, in line with the notion of reduced generalization of extinction from the GS to the CS in the former group. However, we also found indications for weaker retention of GS extinction in rats conditioned with the high-intensity footshock, which may in part or in whole explain the apparent difference in generalization of GS extinction to the CS. Our results may be important to consider in extinction-based exposure therapy, where patients often present with broadly generalized fears and exposure treatment is usually not conducted using the exact cues or situations for which fear was initially acquired. Highlights- We see greater CS-to-GS fear generalization using a strong (vs moderate) US in rats - Paradoxically, we see more preserved CS fear upon GS extinction in the former group - This may reflect an effect on extinction generalization and/or extinction retention - CS extinction reduced GS fear similarly in both groups - Male rats showed higher freezing during acquisition and extinction than females

The Disrupted-in-schizophrenia 1 (DISC1) signaling pathway is considered to play a key role in schizophrenia, depression, autism and other psychiatric disorders. DISC1 is involved in regulating the dopaminergic neurotransmission in, among others, the mesolimbic reward system. A transgenic rat line tgDISC1 has been introduced as a model system to study behavioral phenotypes associated with abnormal DISC1 pathways. Here, we evaluated the impact of impaired DISC1 signaling on social (social interaction) and non-social (sucrose) reward preferences in the tgDISC1 animal model. In a plus-maze setting, rats chose between the opportunity for social interaction with an unfamiliar juvenile conspecific (social reward) or drinking sweet solutions with variable sucrose concentrations (non-social reward). tgDISC1 rats differed from wild-type rats in their social, but not in their non-social reward preferences. Specifically, DISC1 rats showed a lower interest in interaction with the juvenile conspecific, but did not differ from wild-type rats in their preference for higher sucrose concentrations. These results suggest that disruptions of the DISC1 pathway that is associated with altered dopamine transmission in the brain result in selective deficits in social motivation seen in neuropsychiatric illness.

Schizophrenia is thought to be the most prevalent chronic psychiatric disorder. Numerous proteins have been identified that are associated with the occurrence and development of schizophrenia. This study aimed to identify potential core genes and pathways involved in schizophrenia, through exhaustive bioinformatic and next generation sequencing (NGS) data analyses using GSE20966 NGS data of neural progenitor cells and neurons obtained from healthy controls and patients with schizophrenia. The NGS data were downloaded from the Gene Expression Omnibus database. NGS data was processed by the DESeq2 package in R software and the differentially expressed genes (DEGs) were identified. Gene Ontology (GO) enrichment analysis and REACTOME pathway enrichment analysis were carried out to identify potential biological functions and pathways of the DEGs. Protein-protein interaction (PPI) network, module, miRNA-hub gene regulatory network and TF-hub gene regulatory network analysis were performed to identify the hub genes, miRNA and TFs. Potential hub genes were analyzed using receiver operating characteristic (ROC) curves in the R package (pROC). In this investigation, an overall 955 DEGs were identified: 478 genes were remarkably up regulated and 477 genes were distinctly down regulated. These genes were enriched for GO terms and pathways mainly involved in the multicellular organismal process, GPCR ligand binding, regulation of cellular process and amine ligand-binding receptors. MYC, FN1, CDKN2A, EEF1G, CAV1, ONECUT1, SYK, MAPK13, TFAP2A and BTK were considered the potential hub genes. miRNA-hub gene regulatory network and TF-hub gene regulatory network were constructed successfully. On the whole, the findings of this investigation enhance our understanding of the potential molecular mechanisms of schizophrenia and provide potential targets for further investigation.

The rapid development of research on the therapeutic benefits of medicinal cannabis, in parallel with an increased understanding of the endocannabinoid system, has driven research of Cannabis sativa constituents for managing neurological conditions. While most studies have focused on the therapeutic potential of the major components of cannabis plant extract isolated or combined, limited research has explored the pharmacological benefits of whole cannabis plant extract. In this study, we investigated the potential anti-inflammatory and neuroprotective effects of NTI-164, a novel full-spectrum cannabis extract with negligible {Delta}9-tetrahydrocannabinol (THC), compared with cannabidiol (CBD) alone in BV-2 microglial and SHSY-5Y neuronal cells. The inflammation-induced upregulation of microglial inflammatory mediators, being tumour necrosis factor (TNF), granulocyte-macrophage colony-stimulating factor (GM-CSF), inducible nitric oxide synthase (iNOS), and Arginase-1 (Arg-1), were significantly attenuated by NTI-164. This immunomodulatory effect was not observed upon treatment with isolated CBD. Compared to CBD alone, NTI-164 prevented elevated mitochondrial activity while normalising cell numbers in immune-activated microglia cells. NTI-164 also promoted the proliferation of undifferentiated neurons and the survival of differentiated neurons under excitotoxic conditions. Overall, our work shows that the anti-inflammatory and neuroprotective effects of NTI-164 as a full-spectrum cannabis extract are enhanced relative to that of CBD alone, highlighting the potential therapeutic efficacy of NTI-164 for the treatment of neuropathologies such as autism spectrum disorder (ASD) and related neuropathologies. This study has further shown that understanding the synergistic effect of phytocannabinoids is integral to realising the therapeutic potential of full-spectrum cannabis extract to inform the design of botanical-derived treatments for managing neurological disorders.

BackgroundMethamphetamine (METH) is a highly addictive central nervous system stimulant. Chronic use of METH is associated with multiple neurological and psychiatric disorders. An overdose of METH can cause brain damage and even death. Mounting evidence indicates that epigenetic changes and functional impairment in the brain occur due to addictive drug exposures. However, the responses of different brain regions to a METH overdose remain unclear. ResultsWe investigated the transcriptomic and epigenetic responses to a METH overdose in four regions of the rat brain, including the nucleus accumbens, dentate gyrus, Ammons horn, and subventricular zone. We found that 24 hours after METH overdose, 15.6% of genes showed changes in expression and 27.6% of open chromatin regions exhibited altered chromatin accessibility in all four rat brain regions. Interestingly, only a few of those differentially expressed genes and differentially accessible regions were affected simultaneously. Among four rat brain regions analyzed, 149 transcription factors and 31 epigenetic factors were significantly affected by METH overdose. METH overdose also resulted in opposite-direction changes in regulation patterns of both gene and chromatin accessibility between the dentate gyrus and Ammons horn. Approximately 70% of chromatin-accessible regions with METH-induced alterations in the rat brain are conserved at the sequence level in the human genome, and they are highly enriched in neurological processes. Many of these conserved regions are active brain-specific enhancers and harbor SNPs associated with human neurological functions and diseases. ConclusionOur results indicate strong region-specific transcriptomic and epigenetic responses to a METH overdose in distinct rat brain regions. We describe the conservation of region-specific gene regulatory networks associated with METH overdose. Overall, our study provides clues toward a better understanding of the molecular responses to METH overdose in the human brain.

Psychedelics are new, promising candidate molecules for clinical use in psychiatric disorders such as Treatment-Resistant Depression (TRD) and Post Traumatic Stress Disorder (PTSD). They were recently also proposed as molecules supporting neural tissue repair by anti-inflammatory properties. Here we reported that two classic psychedelics, DMT and psilocin, can influence microglial functions by reducing the level of TLR4, p65, CD80 proteins, which are markers of the immune response, and upregulat TREM2 neuroprotective receptor. Psilocin also secured neuronal survival in the neuron-microglia co-culture model by attenuating the phagocytic function of microglia. We conclude that DMT and psilocin regulate the immunomodulatory potential of microglia. Of note, psychedelics were previously reported as a relatively safe treatment approach. The demonstrated regulation of inflammatory molecules and microglia phagocytosis suggests that psychedelics or their analogs are candidates in the therapy of neurological disorders where microglia and inflammation significantly contribute to pathogenic disease mechanisms.

Domesticated mice and rats have shown to be powerful model systems for biomedical research, but there are cases in which the biology of species is a poor match for the hypotheses under study. The California mouse (Peromyscus californicus) has unique physiological and behavioral traits and has emerged as a powerful model for studying sex differences in the biology of psychiatric disease, which is particularly relevant considering the new NIH guidelines that require the inclusion of sex as a biological variable. Despite its growing role in preclinical research, there is a lack of studies assessing species-specific housing needs, which presents a challenge for research facilities seeking to ensure good welfare and obtaining high-quality experimental data. Indeed, captive California mice present a high prevalence of stereotypic backflipping behavior, a common consequence of suboptimal housing and a potential source of experimental outcome variability. Using three different cage systems, the present studies show that increasing housing space as well as social and environmental complexity can delay the development of stereotypic behavior in male and female California mice. Critically, this reduction in stereotypy is accompanied by increased effect sizes of stress in an established model for social anxiety. These results suggest that increased cage size and enrichment could enhance welfare in California mice while simultaneously increasing the quality of behavioral experiments.

Core symptoms in patients with schizophrenia spectrum disorder (SSD), such as hallucinations or ego-disturbances, have been associated with a failure of the forward model to adequately predict the sensory outcomes of self-generated actions. Importantly, depending on the requirements of the environment, forward model predictions must also be able to recalibrate flexibly, for example to account for additional delays between action and outcome. In this study, we aimed to investigate whether non-invasive brain stimulation via transcranial direct current stimulation (tDCS) can be used to improve these sensorimotor temporal recalibration mechanisms in patients and in healthy subjects. While receiving tDCS on the cerebellum, temporo-parietal junction (TPJ), supplementary motor area (SMA), or sham stimulation, patients with SSD and healthy control subjects were repeatedly exposed to delays between actively elicited or passively performed button press movements and auditory sensory outcomes. Effects of this procedure on temporal perception were assessed with a delay detection task. We found similar sensorimotor temporal recalibration effects in both SSD and healthy subjects. Furthermore, cerebellar tDCS facilitated recalibration effects in both groups. Our findings indicate that sensorimotor recalibration mechanisms may be preserved in SSD and highlight the importance of the cerebellum in both patients and healthy subjects for this process. Our results suggest that cerebellar tDCS could be a promising tool for addressing deficits in action-outcome monitoring and related adaptive sensorimotor processes in SSD, and potentially alleviating associated symptoms.