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Recent genome-wide association studies (GWAS) and whole-exome sequencing of neuropsychiatric disorders, especially schizophrenia, have identified a plethora of common and rare disease risk variants/genes. Translating the mounting human genetic discoveries into novel disease biology and more tailored clinical treatments is tied to our ability to causally connect genetic risk variants to molecular and cellular phenotypes. When combined with the C lustered R egularly I nterspaced S hort P alindromic R epeats (CRISPR)/CRISPR-associated (Cas) nuclease-mediated genome editing system, human induced pluripotent stem cell (hiPSC)-derived neural cultures (both 2D and 3D organoids) provide a promising tractable cellular model for bridging the gap between genetic findings and disease biology. In this review, we first conceptualize the advances in understanding the disease polygenicity and convergence from the past decade of iPSC modeling of different types of genetic risk factors of neuropsychiatric disorders. We then discuss the major cell types and cellular phenotypes that are most relevant to neuropsychiatric disorders in iPSC modeling. Finally, we critically review the limitations of iPSC modeling of neuropsychiatric disorders and outline the need for implementing and developing novel methods to scale up the number of iPSC lines and disease risk variants in a systematic manner. Sufficiently scaled-up iPSC modeling and a better functional interpretation of genetic risk variants, in combination with cutting-edge CRISPR/Cas9 gene editing and single-cell multi-omics methods, will enable the field to identify the specific and convergent molecular and cellular phenotypes in precision for neuropsychiatric disorders. [ABSTRACT FROM AUTHOR]

Microglia play a major role in the immune defense system of the central nervous system and are activated in many neurological diseases. The immunomodulatory cytokine interleukin (IL)-15 is known to be involved in microglia response and inflammatory factors release. Neoprzewaquinone A (NEO) is an active compound isolated from Salvia miltiorrhiza Bunge. Our previous study has shown that NEO significantly inhibit the proliferation of IL-15-treated Mo7e cells. However, the role of NEO in the structure and function of IL-15-treated human microglial cells (HMC3) remains unclear. Thus, our study aimed to quantitatively analyze the beneficial effects of NEO on HMC3 cells following IL-15 treatment. The cell viability, phagocytosis, migration and energy metabolism were evaluated by Cell Counting Kit-8 (CCK8), scratch assay, pHrodo™ Red Zymosan BioParticles™ Conjugate, and Agilent Seahorse XF Cell Mito Test. Cephalothin (CEP) was selected as a positive drug because it has obvious inhibitory effect on IL-15 and IL-15Rɑ. Our results showed that IL-15 stimulated the proliferation, migration and phagocytosis of HMC3 cells in a time-dependent manner. Interestingly, NEO exhibited significant suppressive effects on these IL-15-induced changes, which were even superior to those observed with the CEP. Moreover, IL-15 treatment did not significantly alter energy metabolism, including glycolysis and mitochondrial respiration. NEO and CEP alone effectively reduced glycolysis, non-mitochondrial respiration, basal respiration, ATP turnover, respiration capacity, and H+ leak in HMC3 cells. Furthermore, NEO displayed a partial regulatory effect on mitochondrial function in IL-15-treated HMC3 cells. Our study confirms the effectively inhibition of NEO on IL-15-induced microglial activation and provides valuable insights into the therapeutic prospects of NEO in neuropsychiatric disorders associated with IL-15 and microglia. [Display omitted] • IL-15 can be used as an external activator to participate in the proliferation, migration and phagocytosis of microglia. • Neoprzewaquinone A can be used as a potent candidate for targeting IL-15/IL-15Rɑ and microglia-associated diseases. • We have discovered a novel small molecule inhibitor that has a remarkable effect on the function of microglia. [ABSTRACT FROM AUTHOR]

This study aimed to examine the reliability and validity of a newly developed questionnaire for Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections (PANDAS) and Pediatric Acute-onset Neuropsychiatric Syndrome (PANS). The aim was to contribute to future standardisation of screening methods for symptoms and comorbidity, as well as the measurement of symptom severity, daily life impairment, and treatment effectiveness in individuals diagnosed with PANDAS/PANS. 27 items from the PANDAS/PANS questionnaire concerning symptoms and comorbidities associated with PANDAS/PANS were divided into ten domains. To assess the external validity, 119 PANDAS/PANS questionnaires from a cohort of 65 children with PANDAS/PANS were correlated with three well-known validated questionnaires: the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS), Attention Deficit Hyperactivity Disorder Rating Scale (ADHD-RS), and the Strengths and Difficulties Questionnaire (SDQ). The internal validity of the PANDAS/PANS questionnaire was assessed by correlating the PANDAS/PANS items with the domains. Internal consistency of the PANDAS/PANS questionnaire was high, measuring moderate to very strong correlations. The external correlations for the PANDAS/PANS questionnaire showed a higher correlation with the ADHD-RS and CY-BOCS (r s ≥ 0.60) than with the SDQ (r s < 0.40). The validity and clinical feasibility of the PANDAS/PANS questionnaire were confirmed as an effective tool for screening symptoms, assessing symptom severity, and evaluating comorbidity and daily life impairment in individuals with PANDAS/PANS. These findings can potentially enhance the management of PANDAS/PANS patients in both clinical and research settings. • A new PANDAS/PANS questionnaire is an effective tool for screening symptoms. • Correlated with validated questionnaires with strong external correlations. • High internal consistency across ten PANDAS/PANS domains. • Potentially enhances the management of PANDAS/PANS patients. [ABSTRACT FROM AUTHOR]

Social memory, the ability to recognize and remember individuals within a social group, is crucial for social interactions and relationships. Deficits in social memory have been linked to several neuropsychiatric and neurodegenerative disorders. The hippocampus, especially the circuit that links dorsal CA2 and ventral CA1 neurons, is considered a neural substrate for social memory formation. Recent studies have provided compelling evidence of extrahippocampal contributions to social memory. The septal nuclei, including the medial and lateral septum, make up a basal forebrain region that shares bidirectional neuronal connections with the hippocampus and has recently been identified as critical for social memory. The focus of our review is the neural circuit mechanisms that underlie social memory, with a special emphasis on the septum. We also discuss the social memory dysfunction associated with neuropsychiatric and neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Accumulating evidence suggests that latent infection with Toxoplasma gondii (T. gondii) is associated with a variety of neuropsychiatric and behavioral conditions. This research aims to explore the potential correlation between T. gondii antibody positivity and neuropsychiatric disorders through a comprehensive prospective cohort study. The cohort study utilized the UK Biobank database to recruit 8814 individuals with no prior diagnosis of neuropsychiatric disorders. Cox proportional hazards models were employed to investigate the associations between T. gondii P22 antibody seropositivity (P22+) and the development of various types of neuropsychiatric disorders. Of the population, 14.65 % tested positive for T. gondii P22 antibody. The presence of T. gondii P22 antibody showed a slight inverse association with epilepsy (HR: 0.28; 95 % CI: 0.10–0.77), while it was positively associated with an increased risk of developing anxiety disorders (HR: 1.38; 95 % CI: 1.04–1.83). The study sample consisted mostly of white British individuals aged 40 to 69 years old. Although we adjusted for potential confounders, there may be other unmeasured and residual confounding factors that could have influenced our reported associations. The findings suggested an increased risk of anxiety and potential evidence of epilepsy associated with T. gondii P22+. However, our analysis did not reveal an increased risk of several other neuropsychiatric conditions including Alzheimer's disease, dementia, substance abuse disorders, depression, and neurodegenerative disorders, associated with P22 antibody seropositivity. • In the UKB, 14.65% of the subjects tested were found to be positive for the T. gondii P22 antibody. • A significant association was observed between T. gondii P22+ and anxiety in a prospective cohort study. • T. gondii P22 antibody-positive individuals had a slightly higher incidence density of neuropsychiatric disorders. [ABSTRACT FROM AUTHOR]

Toxoplasma gondii (T. gondii) is an opportunistic pathogen affecting about 1/3 of world population. While often asymptomatic in immunocompetent individuals, it can lead to severe toxoplasmosis in immunocompromised patients. Recent research has unveiled a potential link between T. gondii infection and neuropsychiatric diseases. We implemented both a cohort study and a case control study to further identify this association. In the cohort study, we analyzed data from the UK Biobank database, which included 8814 individuals tested for T. gondii SAG1 antibodies and free of neuropsychiatric disorders at baseline. Among them, 22.52% (n = 1985) tested positive for SAG1 antibody. Over an average follow-up period of 12.26 years, Cox proportional hazards models and logistic regression analysis revealed a significant association between the SAG1 seropositivity at baseline and the incidence of schizophrenia (HR: 5.89; 95% CI: 1.69–20.53). In our case-control study, 239 patients diagnosed with schizophrenia and 455 healthy individuals were involved. Using the modified agglutination test (MAT) to detect T. gondii antibodies, logistic regression analysis showed a higher prevalence of T. gondii infection among schizophrenia patients (10.04%) compared to healthy controls (3.74%). T. gondii infection emerged as a significant risk factor for schizophrenia (OR: 3.33; 95% CI: 1.68–6.61). However, our investigations did not reveal a robust association between T. gondii infection and other neuropsychiatric conditions, including Alzheimer's disease, dementia, anxiety, depression, neurodegenerative disorders, and peripheral neurological disorders such as neurological and plexus disorders. • In the UK Biobank, 22.52% of the subjects tested were found to be positive for the T. gondii SAG1 antibody. • A significant association was observed between T. gondii SAG1 antibody positivity and symptoms of schizophrenia. • Higher neuropsychiatric morbidity was found in T. gondii SAG1 antibody-positive group. [ABSTRACT FROM AUTHOR]

Polygenic scores (PGS) for sleep disturbances and depressive symptoms in an epidemiological cohort were contrasted. The overlap between genes assigned to variants that compose the PGS predictions was tested to explore the shared genetic bases of sleep problems and depressive symptoms. PGS analysis was performed on the São Paulo Epidemiologic Sleep Study (EPISONO, N = 1042), an adult epidemiological sample. A genome wide association study (GWAS) for depression grounded the PGS calculations for Beck Depression Index (BDI), while insomnia GWAS based the PGS for Insomnia Severity Index (ISI) and Pittsburg Sleep Quality Index (PSQI). Pearson's correlation was applied to contrast PGS and clinical scores. Fisher's Exact and Benjamin-Hochberg tests were used to verify the overlaps between PGS-associated genes and the pathways enriched among their intersections. All PGS models were significant when individuals were divided as cases or controls according to BDI (R2 = 1.2%, p = 0.00026), PSQI (R2 = 3.3%, p = 0.007) and ISI (R2 = 3.4%, p = 0.021) scales. When clinical scales were used as continuous variables, the PGS models for BDI (R2 = 1.5%, p = 0.0004) and PSQI scores (R2 = 3.3%, p = 0.0057) reached statistical significance. PSQI and BDI scores were correlated, and the same observation was applied to their PGS. Genes assigned to variants that compose the best-fit PGS predictions for sleep quality and depressive symptoms were significantly overlapped. Pathways enriched among the intersect genes are related to synapse function. The genetic bases of sleep quality and depressive symptoms are correlated; their implicated genes are significantly overlapped and converge on neural pathways. This data suggests that sleep complaints accompanying depressive symptoms are not secondary issues, but part of the core mental illness. • The genetic architectures of sleep disturbances and depressive symptoms are correlated. • Genes associated with sleep problems and depressive symptoms are overlapped. • Variants that confer risk for insomnia and depression converge on similar synaptic pathways. [ABSTRACT FROM AUTHOR]

Multiple observational studies have reported substantial comorbidity between neuropsychiatric disorders and cardiovascular disease (CVD), but the underlying mechanisms remain largely unknown. Using GWAS summary datasets of 8 neuropsychiatric disorders and 6 cardiovascular diseases, an integrative analysis incorporating linkage-disequilibrium-score-regression (LDSC), Mendelian randomization (MR), functional mapping and annotation (FUMA), and functional enrichment analysis, was conducted to investigate shared genetic etiology of the brain-heart axis from the whole genome level, single-nucleotide polymorphism (SNP) level, gene level, and biological pathway level. In LDSC analysis, 18 pairwise traits between neuropsychiatric disorders and CVD were identified with significant genetic overlaps, revealing extensive genome-wide genetic correlations. In bidirectional MR analysis, 19 pairwise traits were identified with significant causal relationships. Genetic liabilities to neuropsychiatric disorders, particularly attention-deficit hyperactivity disorder and major depressive disorder, conferred extensive significant causal effects on the risk of CVD, while hypertension seemed to be a risk factor for multiple neuropsychiatric disorders, with no significant heterogeneity or pleiotropy. In FUMA analysis, 13 shared independent significant SNPs and 887 overlapping protein-coding genes were detected between neuropsychiatric disorders and CVD. With GO and KEEG functional enrichment analysis, biological pathways of the brain-heart axis were highly concentrated in neurotransmitter synaptic transmission, lipid metabolism, aldosterone synthesis and secretion, glutathione metabolism, and MAPK signaling pathway. Extensive genetic correlations and genetic overlaps between neuropsychiatric disorders and CVD were identified in this study, which might provide some new insights into the brain-heart axis and the therapeutic targets in clinical practice. • This is the first integrative multi-phenotype genetic analysis between neuropsychiatric disorders and CVDs. • Extensive genome-wide genetic correlations between neuropsychiatric disorders and CVDs were revealed in LDSC analysis. • Bidirectional MR analysis showed extensive significant causal relationships between neuropsychiatric disorders and CVDs. • 13 shared SNPs and 887 overlapping genes were detected between neuropsychiatric disorders and CVDs in FUMA analysis. • Several biological pathways of the brain-heart axis were identified in functional enrichment analysis. [ABSTRACT FROM AUTHOR]

Recent advances in open neuroimaging data are enhancing our comprehension of neuropsychiatric disorders. By pooling images from various cohorts, statistical power has increased, enabling the detection of subtle abnormalities and robust associations, and fostering new research methods. Global collaborations in imaging have furthered our knowledge of the neurobiological foundations of brain disorders and aided in imaging-based prediction for more targeted treatment. Large-scale magnetic resonance imaging initiatives are driving innovation in analytics and supporting generalizable psychiatric studies. We also emphasize the significant role of big data in understanding neural mechanisms and in the early identification and precise treatment of neuropsychiatric disorders. However, challenges such as data harmonization across different sites, privacy protection, and effective data sharing must be addressed. With proper governance and open science practices, we conclude with a projection of how large-scale imaging resources and collaborations could revolutionize diagnosis, treatment selection, and outcome prediction, contributing to optimal brain health. [ABSTRACT FROM AUTHOR]

Beyond canonical roles in mediating synapse development, synapse organizers directly contribute to activity-dependent changes in synaptic strength. Synapse organizers promote molecular reconfiguration of active synapses through regulation of neurotransmitter receptors, inter- and intracellular signaling, and macromolecular synthesis. This link between synapse organizers and activity-dependent refinement of synapses further establishes the role of these central regulators in neurodevelopmental and neuropsychiatric disorders. Synapse organizing proteins are multifaceted molecules that coordinate the complex processes of brain development and plasticity at the level of individual synapses. Their importance is demonstrated by the major brain disorders that emerge when their function is compromised. The mechanisms whereby the various families of organizers govern synapses are diverse, but converge on the structure, function, and plasticity of synapses. Therefore, synapse organizers regulate how synapses adapt to ongoing activity, a process central for determining the developmental trajectory of the brain and critical to all forms of cognition. Here, we explore how synapse organizers set the conditions for synaptic plasticity and the associated molecular events, which eventually link to behavioral features of neurodevelopmental and neuropsychiatric disorders. We also propose central questions on how synapse organizers influence network function through integrating nanoscale and circuit-level organization of the brain. [ABSTRACT FROM AUTHOR]

The re-ignition of memory reconsolidation research sparked by Karim Nader in the early 2000s led to great excitement that 'reconsolidation-based' interventions might be developed for mental health disorders such as post-traumatic stress disorder and substance use disorder. Two decades on, it is clear that reconsolidation-based interventions have been more challenging to translate to the clinic than initially thought. We argue that this challenge could be addressed with a better understanding of how prior expectations interact with information presented in a putative memory reactivation / cue reminder session, and through the identification of non-invasive biomarkers for memory destabilisation that would allow reminder sessions to be 'tuned' to enhance memory lability in an ad hoc manner. [ABSTRACT FROM AUTHOR]

The dopamine D2 receptor (DRD2) represents a pivotal target for therapeutic intervention in the treatment of neuropsychiatric disorders, including schizophrenia, bipolar disorder, and Parkinson's disease. The successful discovery of numerous effective DRD2 inhibitors has led to their clinical application and ongoing evaluation in various clinical trials. This review explores the synthetic approaches and clinical applications of prototypical small-molecule DRD2 inhibitors that have received approval or are currently undergoing clinical trials, highlighting their therapeutic potential and challenges. The synthesis of these inhibitors employs various chemical strategies, including modifications of phenothiazine and butyrophenone structures, which have yielded significant antipsychotic agents like chlorpromazine and haloperidol. Additionally, newer classes of inhibitors, such as aripiprazole, exhibit partial agonist activity at DRD2, offering a unique therapeutic profile. Clinically, DRD2 inhibitors demonstrate efficacy in managing positive symptoms of schizophrenia, manic episodes in bipolar disorder, and dopaminergic imbalance in Parkinson's disease. However, the emergence of adverse effects, including tardive dyskinesia, extrapyramidal symptoms and metabolic syndrome, presents substantial challenges. Advances in the development of second-generation antipsychotics aim to balance efficacy with a better side effect profile by targeting additional neurotransmitter receptors. This review aims to deliver an overview of the synthesis and clinical applications of representative small-molecule DRD2 inhibitors across various clinical phases, thereby offering strategic insights for the advancement of DRD2 inhibitor development. [Display omitted] • An overview of small-molecule DRD2 inhibitors that are approved or in clinical trials are organized. • Synthesis and Clinical Application of representative DRD2 inhibitors are highlighted. • This review provides valuable information for future design of DRD2 inhibitors. [ABSTRACT FROM AUTHOR]

• Hepatic RNA-seq profiling figured out HCV-related cirrhosis pathogenesis and diagnostic biomarkers. • LTB, ISLR, ZAP70, MOXD1, KLRB1, and Slitrk3, were identified as potential biomarkers. • Inflammation-enhancing pathways, cytokine-cytokine receptor interaction, NF-κB signaling, and Rheumatoid arthritis, were highlighted in HCV-related cirrhosis. • Neural DEGs, MOXD1 and SLITRK3, were involved in neuropsychiatric disorders of cirrhotic patients. • TNF signaling, bile secretion, FoxO signaling, and axon guidance were highlighted in relation to neurological disorders in cirrhosis patients. Chronic hepatitis C virus infection is a major cause of mortality due to liver cirrhosis globally. Despite the advances in recent therapeutic strategies, there is yet a high burden of HCV-related cirrhosis worldwide concerning low coverage of newly developed antiviral therapies, insufficient validity of the current diagnostic methods for cirrhosis, and incomplete understanding of the pathogenesis in this stage of liver disease. Hence we aimed to clarify the molecular events in HCV-related cirrhosis and identify a liver-specific gene signature to potentially improve diagnosis and prognosis of the disease. Through RNA-seq transcriptome profiling of liver samples of Iranian patients with HCV-related cirrhosis, the differentially expressed genes (DEGs) were identified and subjected to functional annotation including biological process (BP) and molecular function (MF) analysis and also KEGG pathway enrichment analysis. Furthermore, the validation of RNA-seq data was investigated for seven candidate genes using qRT-PCR. Moreover, the diagnostic and prognostic power of validated DEGs were analyzed in both forms of individual DEG and combined biomarkers through receiver operating characteristic (ROC) analysis. Finally, we explored the pair-wise correlation of these six validated DEGs in a new approach. We identified 838 significant DEGs (p adj ˂0.05) enriching 375 and 15 significant terms subjected to BP and MF, respectively (false discovery rate ˂ 0.01) and 46 significant pathways (p -value ˂ 0.05). Most of these biological processes and pathways were related to inflammation, immune responses, and cellular processes participating somewhat in the pathogenesis of liver disease. Interestingly, some neurological-associated genes and pathways were involved in HCV cirrhosis-related neuropsychiatric disorders. Out of seven candidate genes, six DEGs, including inflammation-related genes ISLR, LTB, ZAP70, KLRB1, and neuronal-related genes MOXD1 and Slitrk3 were significantly confirmed by qRT-PCR. There was a close agreement in the expression change results between RNA-seq and qRT-PCR for our candidate genes except for SAA2-SAA4 (P= 0.8). High validity and reproducibility of six novel DEGs as diagnostic and prognostic biomarkers were observed. We also found several pair-wise correlations between validated DEGs. Our findings indicate that the six genes LTB, ZAP70, KLRB1, ISLR, MOXD1, and Slitrk3 could stand as promising biomarkers for diagnosing of HCV-related cirrhosis. However, further studies are recommended to validate the diagnostic potential of these biomarkers and evaluate their capability as targets for the prevention and treatment of cirrhosis disease. [ABSTRACT FROM AUTHOR]

Obsessive-Compulsive Disorder (OCD) poses a multifaceted challenge in psychiatry, with various subtypes and severities greatly impacting well-being. Recent scientific attention has turned towards lipid metabolism, particularly the neurolipidome, in response to clinical demands for cost-effective diagnostics and therapies. This scoping review integrates recent animal, translational, and clinical studies to explore impaired neurolipid metabolism mechanisms in OCD's pathogenesis, aiming to enhance future diagnostics and therapeutics. Five key neurolipids - endocannabinoids, lipid peroxidation, phospholipids, cholesterol, and fatty acids - were identified as relevant. While the endocannabinoid system shows promise in animal models, its clinical application remains limited. Conversely, lipid peroxidation and disruptions in phospholipid metabolism exhibit significant impacts on OCD's pathophysiology based on robust clinical data. However, the role of cholesterol and fatty acids remains inconclusive. The review emphasises the importance of translational research in linking preclinical findings to real-world applications, highlighting the potential of the neurolipidome as a potential biomarker for OCD detection and monitoring. Further research is essential for advancing OCD understanding and treatment modalities. • OCD poses a complex challenge in psychiatry due to its various subtypes and severities, significantly impacting well-being. • Recent research focuses on neurolipid metabolism to develop cost-effective OCD diagnostics and therapies. • Endocannabinoids, phospholipids, cholesterol, and fatty acids are crucial in understanding OCD's pathophysiology. • The neurolipidome is a potential biomarker for OCD detection and monitoring. • Translational research is crucial to bridge preclinical findings to real-world applications, ultimately advancing OCD treatment. [ABSTRACT FROM AUTHOR]

Gynostemma pentaphyllum (Thunb.) Makino is a perennial creeping herb belonging to the Cucurbitaceae family that has a long history of usage in traditional oriental medicine. Gypenosides are the primary bioactive compounds in Gynostemma pentaphyllum. Because of the medicinal value of gypenosides, functional food and supplements containing gypenosides have been promoted and consumed with popularity, especially among Asian communities. This review presented the progress made in the research of pharmacological properties of gypenosides on diseases of the nervous system and their possible mechanism of action. To date, preclinical studies have demonstrated the therapeutic effects of gypenosides in alleviating neuropsychiatric disorders like depression, Parkinson's disease, Alzheimer's disease, secondary dementia, stroke, optic neuritis, etc. Pharmacological studies have discovered that gypenosides can modulate various major signaling pathways like NF-κB, Nrf2, AKT, ERK1/2, contributing to the neuroprotective properties. However, there is a dearth of clinical research on gypenosides, with current investigations on the compounds being mainly conducted in vitro and on animals. Future studies focusing on isolating and purifying novel gypenosides and investigations on exploring the potential molecular mechanism underlying their biological activities are warranted, which may serve as a foundation for further clinical trials for the betterment of human health. [Display omitted] [ABSTRACT FROM AUTHOR]

The basolateral amygdala (BLA) is the subregion of the amygdala located in the medial of the temporal lobe, which is connected with a wide range of brain regions to achieve diverse functions. Recently, an increasing number of studies have focused on the participation of the BLA in many neuropsychiatric disorders from the neural circuit perspective, aided by the rapid development of viral tracing methods and increasingly specific neural modulation technologies. However, how to translate this circuit-level preclinical intervention into clinical treatment using noninvasive or minor invasive manipulations to benefit patients struggling with neuropsychiatric disorders is still an inevitable question to be considered. In this review, we summarized the role of BLA-involved circuits in neuropsychiatric disorders including Alzheimer's disease, perioperative neurocognitive disorders, schizophrenia, anxiety disorders, depressive disorders, posttraumatic stress disorders, autism spectrum disorders, and pain-associative affective states and cognitive dysfunctions. Additionally, we provide insights into future directions and challenges for clinical translation. ● BLA displays extensive unidirectional or reciprocal projections with many brain regions. ● BLA-involved circuits regulate affective disorders in many neuropsychiatric diseases. ● BLA-involved circuits play critical roles in neurocognitive disorders. ● Clinical modulation of neural circuits may benefit patients with neuropsychiatric disorders. [ABSTRACT FROM AUTHOR]

It has been long-time known that oxytocin in plasma is bound to a carrier protein, a common feature of circulating peptide hormones, however, the nature of such protein was uncertain. A recent study revealed that about 60% of oxytocin present in plasma is bound to immunoglobulin G (IgG) and that oxytocin-binding IgG plays a role of a functional oxytocin carrier protein. Here, we review the historical background and methodology leading to this discovery. Moreover, we review the data showing the functional role of oxytocin-binding IgG in the modulation of oxytocin signaling relevant to the regulation of motivated behavior and several neuropsychiatric disorders. Furthermore, the possible role of gut microbiota in the origin of such IgG is discussed and the relevant new therapeutic strategies for the enhancement of oxytocin signaling are presented. • The key steps leading to identification of IgG as an oxytocin carrier protein are reviewed. • Functional effects of oxytocin-binding IgG in oxytocin receptor signaling are presented. • The putative origin of oxytocin-binding IgG in gut microbiota is discussed. [ABSTRACT FROM AUTHOR]

Understanding how social and affective behavioral states are controlled by neural circuits is a fundamental challenge in neurobiology. Despite increasing understanding of central circuits governing prosocial and agonistic interactions, how bodily autonomic processes regulate these behaviors is less resolved. Thermoregulation is vital for maintaining homeostasis, but also associated with cognitive, physical, affective, and behavioral states. Here, we posit that adjusting body temperature may be integral to the appropriate expression of social behavior and argue that understanding neural links between behavior and thermoregulation is timely. First, changes in behavioral states—including social interaction—often accompany changes in body temperature. Second, recent work has uncovered neural populations controlling both thermoregulatory and social behavioral pathways. We identify additional neural populations that, in separate studies, control social behavior and thermoregulation, and highlight their relevance to human and animal studies. Third, dysregulation of body temperature is linked to human neuropsychiatric disorders. Although body temperature is a "hidden state" in many neurobiological studies, it likely plays an underappreciated role in regulating social and affective states. [Display omitted] • Adjustments in core body temperature may be integral to the expression of social and affective behavioral states. • We highlight neural populations that, in separate studies, are demonstrated to control thermal and behavioral states. • Behaviors associated with thermoregulatory circuits include blushing, psychosocial stress, prosocial interaction, and aggression. • Some neuropsychiatric disorders are linked with thermoregulation dysfunction. [ABSTRACT FROM AUTHOR]

Transcranial direct current stimulation (tDCS) is a non-invasive sub-threshold stimulation, widely accepted for its amelioration of distinct neuropsychiatric disorders. The weak electric field of tDCS modulates the activity of cortical neurons, which in turn modifies brain functioning. However, the underlying mechanisms for that are not fully understood. Objective/Hypothesis: Previous studies demonstrated that the axons are the most sensitive subcellular compartment for tDCS-induced polarization. Moreover, it was posited that DCS-induced axonal polarization is amplified by modifying the conductance of ionic channels. We posit that voltage-gated potassium-channels that are highly expressed in axons play a crucial role in DCS-induced modulation of cortical neurons functioning. We examined the involvement of voltage-gated potassium-channels in the active modulation of spontaneous vesicle release by DCS. For that, we measured spontaneous excitatory postsynaptic currents (sEPSCs) from layer-V motor cortex during DCS application, while co-applying distinct voltage-gated potassium-channels blockers. Moreover, we examined the role of Kv1 potassium channels in DCS-induced modulation of action potential waveform at axon terminals by recording action potentials at terminal axon blebs during DCS application while locally inhibiting the Kv1 potassium-channels. We demonstrated that inhibiting voltage-gated potassium-channels occluded the DCS-induced modulation of subthreshold presynaptic vesicle release. Moreover, we showed that inhibiting Kv1 voltage-gated potassium-channels also occluded the DCS-induced modulation of action potential waveform at axon terminals. We suggest that DCS-induced depolarization inactivates the Kv1 potassium channels thus reducing potassium conductance, which amplifies axonal depolarization, subsequently enhancing the presynaptic component of synaptic transmission. Whereas DCS-induced hyperpolarization induces opposite effects. • tDCS is a neurostimulation technique that its underlying mechanism is unclear. • Potassium conductance plays a crucial role in DCS-induced neuromodulation. • Potassium Kv1 channels are involved in DCS modulation of sEPSCs and AP waveform. • We demonstrate that inhibition of Kv1 channels occludes the impact of DCS. [ABSTRACT FROM AUTHOR]

Background and Objective: Tuberous Sclerosis Complex (TSC) is a rare systemic disease with a high prevalence of sleep disorders (SD), although they are still largely under-recognized. The objective of this study was to assess the prevalence of SD in adult patients with TSC, and to evaluate the relationship between sleep, epilepsy, and TSC associated neuropsychiatric disorders (TAND).Materials and Methods: We administered Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI) and Epworth Sleepiness Scale (ESS) to 114 adult patients referring to different Italian centers. We also collected information on epilepsy and TAND.Results: PSQI, ISI, and ESS revealed a positive score, respectively, in 52 (46.0%), 30 (26.5%), and 16 (14.1%) patients. PSQI was positive in 26.7% of seizure free patients versus 61.9% with active epilepsy (p = 0.003), and the association remained significative applying a multivariate logistic model considering age, antiseizure medications, TAND and nocturnal epileptic seizures (p = 0.02). ISI was positive in 3.3% of seizure free patients versus 41.3% with active epilepsy (p = 0.0004). Applying a multivariate logistic model with the independent variables listed above, the association remained significant (p = 0.007). On the other hand, multivariate logistic model considering active epilepsy as an independent variable, revealed that TAND didn't appear a significant risk factor for positive PSQI (p = 0.43) nor ISI (p = 0.09).Conclusions: Our results confirmed that SD are highly prevalent in adults with TSC, with active epilepsy acting as a significant risk factor. A careful assessment of sleep, above all in epileptic patients, is of crucial importance. [ABSTRACT FROM AUTHOR]

Neuropsychiatric disorders including generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ) have been considered distinct categories of diseases despite their overlapping characteristics and symptomatology. We aimed to provide an in-depth review elucidating the role of glutamate/Glx and white matter (WM) abnormalities in these disorders from a transdiagnostic perspective. The PubMed online database was searched for studies published between 2010 and 2021. After careful screening, 401 studies were included. The findings point to decreased levels of glutamate in the Anterior Cingulate Cortex in both SZ and BD, whereas Glx is elevated in the Hippocampus in SZ and MDD. With regard to WM abnormalities, the Corpus Callosum and superior Longitudinal Fascicle were the most consistently identified brain regions showing decreased fractional anisotropy (FA) across all the reviewed disorders, except GAD. Additionally, the Uncinate Fasciculus displayed decreased FA in all disorders, except OCD. Decreased FA was also found in the inferior Longitudinal Fasciculus, inferior Fronto-Occipital Fasciculus, Thalamic Radiation, and Corona Radiata in SZ, BD, and MDD. Decreased FA in the Fornix and Corticospinal Tract were found in BD and SZ patients. The Cingulum and Anterior Limb of Internal Capsule exhibited decreased FA in MDD and SZ patients. The results suggest a gradual increase in severity from GAD to SZ defined by the number of brain regions with WM abnormality which may be partially caused by abnormal glutamate levels. WM damage could thus be considered a potential marker of some of the main neuropsychiatric disorders. [ABSTRACT FROM AUTHOR]

Over the last two decades deep brain stimulation (DBS) has become a widely used therapeutic alternative for a variety of neurological and psychiatric diseases. The extensive experience in the field of movement disorders has provided valuable knowledge and has led the path to its application to other hard-to-treat conditions. Despite the recognised symptomatic beneficial effects, its capacity to modify the course of a disease has been in constant debate. The ability to demonstrate neuroprotection relies on a thorough understanding of the functioning of both normal and pathological neural structures, as well as their stimulation induced alterations, all of which to this date remain incomplete. Consequently, there is no consensus over the definition of neuroprotection nor its means of quantification or evaluation. Additionally, neuroprotection has been indirectly addressed in most of the literature, challenging the efforts to narrow its interpretation. As such, a broad spectrum of evidence has been considered to demonstrate disease modifying interventions. This paper aims to provide a critical appraisal of the current evidence on potential neuroprotective effects of DBS in neurodegenerative brain disorders. • There are encouraging results from pre-clinical studies concerning the potential neuroprotective effect of deep brain stimulation • The evidence of DBS-induced neuroprotection in clinical studies is less clear • DBS is generally employed late in the course of neurodegenerative diseases • Reliable biomarkers of brain degenerative disease progression are lacking [ABSTRACT FROM AUTHOR]

Higher neuroticism and lower conscientiousness are risk factors for Alzheimer's disease and related dementias, but the underlying neuropathological correlates remain unclear. Our aim was to examine whether personality traits are associated with amyloid and tau neuropathology in a new sample and meta-analyses. Participants from the BLSA (Baltimore Longitudinal Study of Aging) completed the Revised NEO Personality Inventory and underwent amyloid (11C-labeled Pittsburgh compound B) and tau (18F-flortaucipir) positron emission tomography. Among cognitively normal BLSA participants, neuroticism was associated with higher cortical amyloid burden (odds ratio 1.68, 95% CI 1.20–2.34), and conscientiousness was associated with lower cortical amyloid burden (odds ratio 0.61, 95% CI 0.44–0.86). These associations remained significant after accounting for age, sex, education, depressive symptoms, hippocampal volume, and APOE ε4. Similar associations were found with tau in the entorhinal cortex. Random-effects meta-analyses of 12 studies found that higher neuroticism (N = 3015, r = 0.07, p =.008) and lower conscientiousness (N = 2990, r = −0.11, p <.001) were associated with more amyloid deposition. Meta-analyses of 8 studies found that higher neuroticism (N = 2231, r = 0.15, p <.001) and lower conscientiousness (N = 2206, r = −0.14, p <.001) were associated with more tau pathology. The associations were moderated by cognitive status, with stronger effects in cognitively normal compared with heterogeneous samples, suggesting that the associations between personality and proteopathies are not phenomena that emerge with neuropsychiatric clinical symptoms. By aggregating results across samples, this study advances knowledge on the association between personality and neuropathology. Neuroticism and conscientiousness may contribute to resistance against amyloid and tau neuropathology. [ABSTRACT FROM AUTHOR]

Recent genetic approaches have demonstrated that genetic factors contribute to the pathologic origins of neuropsychiatric disorders. Nevertheless, the exact pathophysiological mechanism for most cases remains unclear. Recent studies have demonstrated alterations in pathways of protein homeostasis (proteostasis) and identified several proteins that are misfolded and/or aggregated in the brains of patients with neuropsychiatric disorders, thus providing early evidence that disrupted proteostasis may be a contributing factor to their pathophysiology. Unlike neurodegenerative disorders in which massive neuronal and synaptic losses are observed, proteostasis impairments in neuropsychiatric disorders do not lead to robust neuronal death, but rather likely act via loss- and gain-of-function effects to disrupt neuronal and synaptic functions. Furthermore, abnormal activation of or overwhelmed endoplasmic reticulum and mitochondrial quality control pathways may exacerbate the pathophysiological changes initiated by impaired proteostasis, as these organelles are critical for proper neuronal functions and involved in the maintenance of proteostasis. This perspective article reviews recent findings implicating proteostasis impairments in the pathophysiology of neuropsychiatric disorders and explores how neuronal and synaptic functions may be impacted by disruptions in protein homeostasis. A greater understanding of the contributions by proteostasis impairment in neuropsychiatric disorders will help guide future studies to identify additional candidate proteins and new targets for therapeutic development. [ABSTRACT FROM AUTHOR]

• This article traces the development of ECT from its origin until today. • The advent of rTMS in the neuropsychiatric field is described. • ECT and rTMS play a complementary role in treatment of neuropsychiatric disorders. Electroconvulsive therapy (ECT) was applied for the first time in humans in 1938: after 80 years, it remains conceptually similar today except for modifications of the original protocol aimed to reduce adverse effects (as persistent memory deficits) without losing clinical efficacy. We illustrate the stages of development as well as ups and downs of ECT use in the last eighty years, and the impact that it still maintains for treatment of certain psychiatric conditions. Targeted, individualized and safe noninvasive neuromodulatory interventions are now possible for many neuropsychiatric disorders thanks to repetitive transcranial magnetic stimulation (rTMS) that injects currents in the brain through electromagnetic induction, powerful enough to depolarize cortical neurons and related networks. Although ECT and rTMS differ in basic concepts, mechanisms, tolerability, side effects and acceptability, and beyond their conceptual remoteness (ECT) or proximity (rTMS) to "precision medicine" approaches, the two brain stimulation techniques may be considered as complementary rather than competing in the current treatment of certain neuropsychiatric disorders. [ABSTRACT FROM AUTHOR]

Sleep disorders (SD) are very common in childhood, especially in certain genetic syndromes. Tuberous Sclerosis Complex (TSC) is a genetic syndromesassociated with a high rate of SD, although these are still under-recognized. The aim of this study was to assess the prevalence of SD in TSC, and to evaluate the relationship between sleep, epilepsy and TSC-associated neuropsychiatric disorders (TAND). We administered the Sleep Disturbance Scale for Children (SDSC) and the Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD) to parents of 177 children with TSC referring to different Italian centers. We also collected information on epilepsy and TAND. SDSC score was positive in 59.3% of patients, being positive in 30.4% of patients without and in 63.6% of those with epilepsy (p = 0.005). However, in a multivariate logistic model considering antiseizure medications and nocturnal seizures, epilepsy ceased to be a significant risk factor for positive SDSC (OR = 2.4; p = 0.17). As for TAND, SDSC was positive in 67.9% of patients with and in 32.5% of those without TAND (p < 0.001). After adding in a multivariate logistic model active epilepsy, age, and pharmacotherapies, TAND continued to be a significant risk factor for positive SDSC (p = 0.01, OR = 1.11). Our results revealed a high prevalence of SD in children with TSC. Epilepsy didn't increase the risk for SD, while a very strong association was found with TAND. An early detection of SD is of utmost importance in order to plan an individualized treatment, that in some cases might also ameliorate behavior and attention. • 59.3% of children and adolescents with TSC presented a pathologic SDSC total score. • Sleep disorders are more frequent in patients with neuropsychiatric disorders. • Significantly higher prevalence of sleep disorders in ASD and intellectual disability. • Sleep disorders exacerbate cognitive and behavioral difficulties. • High prevalence and burden, so SD are a significant focus for clinical intervention. [ABSTRACT FROM AUTHOR]

• Sex hormones and neurotransmitters interact during brain development. • Animals with same-sex preference have increased anxiety and depression symptoms. • Non-heterosexual individuals have higher prevalence of neuropsychiatric disorders. • Neurotransmitters changes during development may contribute to this relationship. • This has clinical implications for psychiatric medication during pregnancy. According to the neuro-hormonal theory, sexual orientation in humans develops in the womb under the influence of sex hormones. In this article, we review the evidence from basic research on the possible role of neurotransmitters on influencing sexual orientation. We show that pharmacological or genetically induced changes in neurotransmitter systems during development might, by hormone-mediated structural and functional brain changes, result in alterations in sexual preference in animal models. We propose that in humans this mechanism may contribute to the relationship between non-heterosexual orientation and increased prevalence of neuropsychiatric disorders. Data to support this idea are reviewed. We suggest that altered neurotransmitter levels during development will increase the chance for both non-heterosexual differentiation of the brain and neuropsychiatric disorders. This possibility may have clinical implications, because medication given to a pregnant woman may, in this way, alter brain development of the fetus in a permanent way. [ABSTRACT FROM AUTHOR]

• Inflammatory and trophic properties of microglia are independently linked to neuropsychiatric disease. • Microglia are a novel source of BDNF. • Microglial responses are influenced by sex and developmental stage. • Microglia can be induced to express therapeutically relevant trophic phenotype(s). • BDNF-TrkB signalling may underlie specific trophic phenotypes. Stressors ranging from psychogenic/social to neurogenic/injury to systemic/microbial can impact microglial inflammatory processes, but less is known regarding their effects on trophic properties of microglia. Recent studies do suggest that microglia can modulate neuronal plasticity, possibly through brain derived neurotrophic factor (BDNF). This is particularly important given the link between BDNF and neuropsychiatric and neurodegenerative pathology. We posit that certain activated states of microglia play a role in maintaining the delicate balance of BDNF release onto neuronal synapses. This focused review will address how different "activators" influence the expression and release of microglial BDNF and address the question of tropomyosin receptor kinase B (TrkB) expression on microglia. We will then assess sex-based differences in microglial function and BDNF expression, and how microglia are involved in the stress response and related disorders such as depression. Drawing on research from a variety of other disorders, we will highlight challenges and opportunities for modulators that can shift microglia to a "trophic" phenotype with a view to potential therapeutics relevant for stressor-related disorders. [ABSTRACT FROM AUTHOR]

Objective and Background: Sleep disorders (SD) are very common in childhood, especially in certain genetic syndromes. Tuberous Sclerosis Complex (TSC) is a genetic syndromesassociated with a high rate of SD, although these are still under-recognized. The aim of this study was to assess the prevalence of SD in TSC, and to evaluate the relationship between sleep, epilepsy and TSC-associated neuropsychiatric disorders (TAND).Methods: We administered the Sleep Disturbance Scale for Children (SDSC) and the Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD) to parents of 177 children with TSC referring to different Italian centers. We also collected information on epilepsy and TAND.Results: SDSC score was positive in 59.3% of patients, being positive in 30.4% of patients without and in 63.6% of those with epilepsy (p = 0.005). However, in a multivariate logistic model considering antiseizure medications and nocturnal seizures, epilepsy ceased to be a significant risk factor for positive SDSC (OR = 2.4; p = 0.17). As for TAND, SDSC was positive in 67.9% of patients with and in 32.5% of those without TAND (p < 0.001). After adding in a multivariate logistic model active epilepsy, age, and pharmacotherapies, TAND continued to be a significant risk factor for positive SDSC (p = 0.01, OR = 1.11).Conclusions: Our results revealed a high prevalence of SD in children with TSC. Epilepsy didn't increase the risk for SD, while a very strong association was found with TAND. An early detection of SD is of utmost importance in order to plan an individualized treatment, that in some cases might also ameliorate behavior and attention. [ABSTRACT FROM AUTHOR]

• Neuropsychiatric disorders display aberrant posttranslational modifications (PTM). • Lithium - a therapeutic agent for neurodegenerative and neuropsychiatric disorders. • Outline of the links between lithium's therapeutic mode of action and PTM homeostasis. • Posttranslational modifications as a hub for disease markers and lithium responsiveness. Several neurodegenerative diseases and neuropsychiatric disorders display aberrant posttranslational modifications (PTMs) of one, or many, proteins. Lithium treatment has been used for mood stabilization for many decades, and is highly effective for large subsets of patients with diverse neurological conditions. However, the differential effectiveness and mode of action are not fully understood. In recent years, studies have shown that lithium alters several protein PTMs, altering their function, and consequently neuronal physiology. The impetus for this review is to outline the links between lithium's therapeutic mode of action and PTM homeostasis. We first provide an overview of the principal PTMs affected by lithium. We then describe several neuropsychiatric disorders in which PTMs have been implicated as pathogenic. For each of these conditions, we discuss lithium's clinical use and explore the putative mechanism of how it restores PTM homeostasis, and thereby cellular physiology. Evidence suggests that determining specific PTM patterns could be a promising strategy to develop biomarkers for disease and lithium responsiveness. [ABSTRACT FROM AUTHOR]

• The neuropsychiatric effect of early repeated anaesthetic exposure was studied. • Repeated neonatal isoflurane exposure enhanced the susceptibility to chronic variable stress-induced anxiety-like behaviours in mice. • Repeated neonatal isoflurane exposure affected the neuronal activity in the basolateral amygdaloid nuclei (BLA) and hippocampal dentate gyrus (DG) regions in response to chronic variable stress. • Repeated neonatal isoflurane exposure facilitated chronic variable stress-induced neuroinflammation. Numerous studies have reported that prolonged or multiple exposures to anaesthetics in early life lead to detrimental effects on brain function, most having focused on neurocognitive function, and relatively few on long term neuropsychiatric performance. The present study investigated the impact of repeated neonatal isoflurane exposure on chronic variable stress (CVS)-induced psychiatric and behavioural outcomes together with CVS-related neuronal activity and neuro-inflammatory reactivity in relevant brain circuits. In the present study, C57BL/6J mice received either three exposures to isoflurane at postnatal days 7, 8, and 9 or a control exposure. From postnatal day 45, mice were exposed to a mild, 3-week, CVS paradigm or none and the CVS-related neuropsychiatric performance was evaluated using a series of behavioural tests. The neuronal activity in relevant brain regions was measured by ΔFosB immunopositivity and CVS-related neuroinflammation was assessed by analysing levels of pro-inflammatory cytokines IL-1α, IL-1β, IL-6, and TNF-α. In mice experiencing serial neonatal isoflurane exposure, we detected a significant enhancement in anxiety levels following CVS procedures, together with enhanced neuronal activity, and exacerbated neuroinflammation in the basolateral amygdaloid nuclei (BLA) and hippocampal dentate gyrus (DG) regions. No such change was found in control mice. These results indicate an association between early multiple isoflurane exposures in infant mice and susceptibility to a CVS-evoked anxious phenotype accompanied by enhanced neuronal activity in BLA and DG regions and high inflammatory reactivity in response to CVS. [ABSTRACT FROM AUTHOR]

The presentation of neurogenetic disorders such as 22q11.2 Deletion Syndrome (22q11.2DS) includes broad neuropsychiatric phenotypes that impact functioning and require assessment and treatment. Like in non-syndromal neuropsychiatric disorders, there is heterogeneity in symptom severity and illness course. The study of risk and resilience in the general population has benefited from measurement tools that parse heterogeneity and guide treatment. Suitability of such tools in neurogenetic disorders has not been examined and is essential to establish as prerequisite for examining whether similar processes modulate psychopathology in these populations. We applied the Risk & Resilience Battery assessing intrapersonal, interpersonal, and environmental domains, to 80 patients with 22q11.2DS, 30 from Philadelphia, USA and 50 from Tel-Aviv, Israel. We also evaluated global functioning and obtained self-reports of anxiety and depression. We examined the Risk & Resilience Battery reliability for each factor and used partial correlations to examine relations between the Risk & Resilience Battery factors and clinical measures. Across samples, items within each risk and resilience factor showed good to excellent internal consistency. Higher scores on peer victimization, emotion dysregulation, and hostile close relationships were related to reports of anxiety and depression. Higher levels of self-reliance related to lower anxiety while greater security in close relationships related to lower depression. The Risk & Resilience Battery can be applied to 22q11.2DS samples and advance Gene X Environment research and interventions. • Risk and Resilience factors in the general population are similarly prominent in a neurogenetic syndrome. • These Risk and Resilience factors modulate symptom severity and functioning in a neurogenetic syndrome. • The Risk and Resilience measures can be reliably applied across international sites. [ABSTRACT FROM AUTHOR]

Neurosteroids are steroids produced by endocrine glands and subsequently entering the brain, and also include steroids synthesis in the brain. It has been widely known that neurosteroids influence many neurological functions, including neuronal signaling, synaptic adaptations, and neuroprotective effects. In addition, abnormality in the synthesis and function of neurosteroids has been closely linked to neuropsychiatric disorders, such as Alzheimer's disease (AD), schizophrenia (SZ), and epilepsy. Given their important role in brain pathophysiology and disorders, neurosteroids offer potential therapeutic targets for a variety of neuropsychiatric diseases, and that therapeutic strategies targeting neurosteroids probably exert beneficial effects. We therefore summarized the role of neurosteroids in brain physiology and neuropsychiatric disorders, and introduced the recent findings of synthetic neurosteroid analogues for potential treatment of neuropsychiatric disorders, thereby providing insights for further research in the future. • Neurosteroids have capability to affect emotional states, cognitive processes, and behaviors. • Neurosteroids play a pivotal role in brain functions. • Neurosteroids provide a potential therapeutic target for multiple neurological disorders. [ABSTRACT FROM AUTHOR]

The imaging-based method of brainAGE aims to characterize an individual's vulnerability to age-related brain changes. The present study systematically reviewed brainAGE findings in neuropsychiatric conditions and discussed the potential of brainAGE as a marker for biological age. A systematic PubMed search (from inception to March 6th, 2023) identified 273 articles. The 30 included studies compared brainAGE between neuropsychiatric and healthy groups (n≥50). We presented results qualitatively and adapted a bias risk assessment questionnaire. The imaging modalities, design, and input features varied considerably between studies. While the studies found higher brainAGE in neuropsychiatric conditions (11 mild cognitive impairment/ dementia, 11 schizophrenia spectrum/ other psychotic and bipolar disorder, six depression/ anxiety, two multiple groups), the associations with clinical characteristics were mixed. While brainAGE is sensitive to group differences, limitations include the lack of diverse training samples, multi-modal studies, and external validation. Only a few studies obtained longitudinal data, and all have used algorithms built solely to predict chronological age. These limitations impede the validity of brainAGE as a biological age marker. • BrainAGE measures can be derived from neuroimaging data using machine learning. • BrainAGE is higher in neuropsychiatric populations than in healthy individuals. • Limitations include the lack of diverse samples, multi-modal studies, and validation. • The lack of longitudinal models restricts the validity of brainAGE as a marker of biological age. [ABSTRACT FROM AUTHOR]

The mechanisms by which genomic risks contribute to the onset of neuropsychiatric conditions remain a key challenge and a prerequisite for successful development of effective therapies. 15q11.2 copy number variation (CNV) containing the CYFIP1 gene is associated with autism and schizophrenia. Using stem cell models, we show that 15q11.2 deletion (15q11.2del) and CYFIP1 loss of function (CYFIP1-LoF) lead to premature neuronal differentiation, while CYFIP1 gain of function (CYFIP1-GoF) favors neural progenitor maintenance. CYFIP1 dosage changes led to dysregulated cholesterol metabolism and altered levels of 24S,25-epoxycholesterol, which can mimic the 15q11.2del and CYFIP1-LoF phenotypes by promoting cortical neuronal differentiation and can restore the impaired neuronal differentiation of CYFIP1-GoF neural progenitors. Moreover, the neurogenic activity of 24S,25-epoxycholesterol is lost following genetic deletion of liver X receptor (LXRβ), while compound deletion of LXRβ in CYFIP1 −/− background rescued their premature neurogenesis. This work delineates LXR-mediated oxysterol regulation of neurogenesis as a pathological mechanism in neural cells carrying 15q11.2 CNV and provides a potential target for therapeutic strategies for associated disorders. [Display omitted] • CYFIP1 safeguards cortical neurogenesis during development • Gain and loss of CYFIP1 function leads to disturbed cholesterol metabolism • 24S,25-epoxycholesterol restores delayed neurogenesis caused by elevated CYFIP1 • CYFIP1 regulation of neurogenesis is mediated through oxysterol signaling via LXR De La Fuente et al. reveal a regulatory role for CYFIP1 in cholesterol metabolism and oxysterol levels. CYFIP1 gain and loss of function and 15q11.2 deletion led to disturbed cortical neurogenesis, a pathological event mediated by altered levels of oxysterols and their interaction with the liver X receptor. [ABSTRACT FROM AUTHOR]

• Juvenile social isolation produces multiple behavioral abnormalities and alters the gut microbiota. • Gut microbiota mediated juvenile social isolation-induced neuropsychiatric behavioral abnormalities. • Juvenile social isolation causes reduction the expression of OXTR in the mPFC. • Juvenile social isolation increases PA that correlated with the expression of OXTR. • Antagonism of OXTR or administration of PA mimics effects of juvenile social isolation on multiple behavioral abnormalities. Social experiences during early life are thought to be critical for proper social and emotional development. Conversely, social insults during development causes long-lasting behavioral abnormalities later in life. However, how juvenile social deprivation influences social and emotional behaviors remains poorly understood. Here, we show that juvenile social isolation induces a shift in microbial ecology that negatively impacts social and emotional behaviors in adulthood. These behavioral changes, which occur during this critical period are transferable to antibiotic pre-treated mice by fecal microbiota transplant. In addition, juvenile social isolation decreases the expression of oxytocin receptor (OXTR) in the medial prefrontal cortex (mPFC), and increases the amounts of fecal propionic acid (PA), a short-chain fatty acid derived from gut micobiota. Accordingly, infusion with an OXTR antagonist (OXTR-A, l -368,899) specifically in the mPFC or supplementation of PA both can cause social deficits and anxiety-like behaviors in group housed mice. Collectively, our findings reveal that juvenile social experience regulates prefrontal cortical OXTR expression through gut microbiota-produced PA and that is essential for normal social and emotional behaviors, thus providing a cellular and molecular context to understand the consequences of juvenile social deprivation. [ABSTRACT FROM AUTHOR]

• Heterozygous CUL3 knockout (ko) iPSC and isogenic control lines were generated using CRISPR/Cas9 nickase. • Neuronal differentiation by small molecules showed delayed transition from radial glia to neurons in CUL3 ko cultures. • Direct neuronal conversion of CUL3 ko iPSC by lentiviral NGN2 overexpression obscured delayed neuronal differentiation. • Evoked neuronal activity is decreased in NGN2-induced neurons from CUL3 ko iPSC, while spontaneous activity is unchanged. • Fgf signaling is affected in CUL3 knockout neural precursor cells, while RhoA and Notch signaling is unaltered. Both rare, high risk, loss-of-function mutations and common, low risk, genetic variants in the CUL3 gene are strongly associated with neuropsychiatric disorders. Network analyses of neuropsychiatric risk genes have shown high CUL3 expression in the prenatal human brain and an enrichment in neural precursor cells (NPCs) and cortical neurons. The role of CUL3 in human neurodevelopment however, is poorly understood. In the present study, we used CRISPR/Cas9 nickase to knockout CUL3 in human induced pluripotent stem cells (iPSCs). iPSCs were subsequently differentiated into cortical glutamatergic neurons using two different protocols and tested for structural/functional alterations. Immunocytochemical analysis and transcriptomic profiling revealed that pluripotency of heterozygous CUL3 knockout (KO) iPSCs remained unchanged compared to isogenic control iPSCs. Following small molecule-mediated differentiation into cortical glutamatergic neurons however, we detected a significant delay in transition from proliferating radial glia cells/NPCs to postmitotic neurons in CUL3 KO cultures. Notably, direct neural conversion of CUL3 KO iPSCs by lentiviral expression of Neurogenin-2 massively attenuated the neurodevelopmental delay. However, both optogenetic and electrical stimulation of induced neurons revealed decreased excitability in Cullin-3 deficient cultures, while basal synaptic transmission remained unchanged. Analysis of target gene expression pointed to alterations in FGF signaling in CUL3 KO NPCs, which is required for NPC proliferation and self-renewal, while RhoA and Notch signaling appeared unaffected. Our data provide first evidence for a major role of Cullin-3 in neuronal differentiation, and for neurodevelopmental deficits underlying neuropsychiatric disorders associated with CUL3 mutations. [ABSTRACT FROM AUTHOR]

• Social withdrawal is an adaptive response, but will become maladaptive when chronic. • The brain's social decision-making network is a main driver of social approach and avoidance behaviour. • Studying social withdrawal requires innovative tools to assess social group dynamics. • Building relationships between 'social' genes and neural networks associated to social functioning can be initiated. Social withdrawal is found across neuropsychiatric disorders and in numerous animal species under various conditions. It has substantial impact on the quality of life in patients suffering from neuropsychiatric disorders. Often it occurs prodromal to the disease, suggesting that it is either an early biomarker or central to its etiology. Healthy social functioning is supported by the social brain of which the building blocks go back millions of years, showing overlap between humans, rodents and insects. Thus, to elucidate social withdrawal, we have to approach its environmental triggers and its neural and molecular genetic determinants in an evolutionary context. Pathological social withdrawal may originate from a faulty regulation of specific neural circuits. As there is considerable heritability in social disorders, the genetic building blocks of the social decision making network might be our most relevant target to obtain an understanding of the transition of normal social interaction into social withdrawal. [ABSTRACT FROM AUTHOR]

Background: Memory is significantly impaired in schizophrenia. However, memory measures are often complex and confounded by additional impairments such as motivation and task comprehension, which can affect behavioral performance and obscure neural function during memory tasks. Neural signatures of memory encoding that are robust to potential confounds may shed additional light on neural deficits contributing to memory impairment in schizophrenia.Methods: Here, we investigate a potential neural signature of memory-habituation-and its relationship with healthy and impaired memory function. To limit potential confounds, we used a passive depth of encoding memory task designed to elicit neural responses associated with memory encoding while limiting other cognitive demands. To determine whether habituation during encoding was predictive of intact memory processing, we first compared neural habituation over repeated encoding exposures with subsequent explicit memory in healthy individuals. We then tested whether a similar relationship existed in patients with schizophrenia.Results: Explicit memory performance was impaired in patients with schizophrenia relative to healthy control subjects. In healthy participants, more habituation over repeated exposures during encoding was associated with greater repetition-related increases in accuracy during testing. However, in patients with schizophrenia, better performance was associated with less habituation, or a more sustained neural response during encoding.Conclusions: These results suggest that sustained neural activity is required for normal repetition-related improvements in memory performance in schizophrenia, in line with a neural inefficiency model. Habituation may serve as a valuable index of neural processes that underlie behavioral memory performance. [ABSTRACT FROM AUTHOR]

Recent studies provided strong evidence that deficits in cholinergic signaling cause disorders of cognition and affect conscious processing. Technical advances that combine molecular approaches, in vivo recordings in awake behaving animals, human brain imaging, and genetics have strengthened our understanding of the roles of nicotinic acetylcholine receptors (nAChRs) in the modulation of cognitive behavior and network dynamics. Here, we review the emergent role of nAChRs in high-order cognitive processes and discuss recent work implicating cholinergic circuits in cognitive control, including conscious processing. nAChRs are oligomers composed of several categories of subunits, which determine their physiology and pharmacology in the brain. Cholinergic signaling through nAChRs modulate cognition and conscious awareness. The contribution of nAChRs oligomers to high-order cognitive processing has been investigated using genetically modified mice, which revealed, among other findings, that β2-subunit-containing nAChRs modulate sleep and anesthesia as well as several high-order cognitive functions. In humans, administration of nicotine ameliorates cognitive impairment such as deficits in attention, social interactions, and working memory and thus has a positive action on high-order cognitive processes. Conversely, repeated exposure to nicotine creates nicotine addiction and, consequently, loss of cognitive control and neural circuit impairments. Human genetic studies have identified variants in nAChRs that predispose individuals to neuropsychiatric diseases such as schizophrenia. Genetic, molecular, and mechanistic studies of the contribution of specific nicotinic subunits to mental disorders and neurodegenerative diseases is a promising strategy to unravel the involvement of nAChRs in the development of these pathologies and could provide targets for developing efficient pharmacological treatments. [ABSTRACT FROM AUTHOR]

Chandelier cells (ChCs) are a unique type of GABAergic interneuron that selectively innervate the axon initial segment (AIS) of excitatory pyramidal neurons; the subcellular domain where action potentials are initiated. The proper genesis and maturation of ChCs is critical for regulating neural ensemble firing in the neocortex throughout development and adulthood. Recently, genetic and molecular studies have shed new light on the complex innerworkings of ChCs in health and disease. This review presents an overview of recent studies on the developmental origins, migratory properties, and morphology of ChCs. In addition, attention is given to newly identified molecules regulating ChC morphogenesis and connectivity as well as recent work linking ChC dysfunction to neural disorders, including schizophrenia, epilepsy, and autism spectrum disorder (ASD). Interneurons, including GABAergic chandelier cells (ChCs), are critical for regulating circuit function in the central nervous system (CNS). Perturbations in excitatory/inhibitory balance or homeostasis via deficits in interneuron-mediated neurotransmission have been linked to debilitating neurological conditions. ChCs undergo a unique developmental program, which differs from that of other types of interneurons, to ensure their proper genesis, positioning, morphology, and connectivity in the neocortex. Recent studies using RNAi and animal models have begun to shed light on the molecules governing ChC axonal morphogenesis and synapse formation. Studying ChC biology via genetic, molecular, and cellular strategies is a promising approach to elucidate the pathophysiological mechanisms involved in the development of ChC-linked disorders, including schizophrenia, epilepsy, and autism spectrum disorder. [ABSTRACT FROM AUTHOR]

To be highly reliable, synaptic transmission needs postsynaptic receptors (Rs) in precise apposition to the presynaptic release sites. At inhibitory synapses, the postsynaptic protein gephyrin self-assembles to form a scaffold that anchors glycine and GABA A Rs to the cytoskeleton, thus ensuring the accurate accumulation of postsynaptic receptors at the right place. This protein undergoes several post-translational modifications which control protein–protein interaction and downstream signaling pathways. In addition, through the constant exchange of scaffolding elements and receptors in and out of synapses, gephyrin dynamically regulates synaptic strength and plasticity. The aim of the present review is to highlight recent findings on the functional role of gephyrin at GABAergic inhibitory synapses. We will discuss different approaches used to interfere with gephyrin in order to unveil its function. In addition, we will focus on the impact of gephyrin structure and distribution at the nanoscale level on the functional properties of inhibitory synapses as well as the implications of this scaffold protein in synaptic plasticity processes. Finally, we will emphasize how gephyrin genetic mutations or alterations in protein expression levels are implicated in several neuropathological disorders, including autism spectrum disorders, schizophrenia, temporal lobe epilepsy and Alzheimer's disease, all associated with severe deficits of GABAergic signaling. This article is part of a Special Issue entitled: Honoring Ricardo Miledi - outstanding neuroscientist of XX-XXI centuries. Unlabelled Image • Post-translational modifications of gephyrin clusters shape GABAergic transmission. • The subsynaptic nanoscale distribution of gephyrin affects GABAergic inhibitory synaptic plasticity. • Hampering gephyrin function with selective intrabodies reduces the probability of GABA release. • Dynamic changes of gephyrin govern lateral diffusion of GABA A receptors and synaptic plasticity processes. • Impaired gephyrin function is often associated with neurodevelopmental and neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Gamma oscillations (30–80 Hz) are well-known for their role in cortical signal transmission and cognitive brain functions. Aberrant gamma activity has been observed in various neuropsychiatric disorders, but the clinical potential of restoring gamma oscillations via noninvasive brain stimulation has been widely neglected. Only recently, therapeutic effects of gamma entrainment were documented in mouse models of Alzheimer's dementia (AD) using rhythmic sensory stimulation. In the present review, we first summarize the current status of the research on gamma entrainment in mouse models of AD and human AD patients. Then, we suggest transcranial alternating current stimulation (tACS) as an alternative brain stimulation technique and review the recent literature on the effects of gamma tACS in healthy volunteers and neuropsychiatric diseases to document the efficacy of gamma tACS in improving cognitive functions. We discuss several advantages of tACS compared to rhythmic sensory stimulation for the entrainment of gamma oscillations in the human brain and emphasize the need for more clinical studies applying tACS to drive gamma oscillations and, in turn, to improve cognitive functioning not only in AD but also in patients suffering from other neuropsychiatric disorders. • We review the current status on research about tACS in the gamma frequency band in healthy participants. • We address the importance of gamma-band oscillations in neuropsychiatric diseases. • We propose that using tACS may be used to modulate disturbed gamma-band oscillations in neuropsychiatric diseases. [ABSTRACT FROM AUTHOR]

Background: Many pregnant women are consuming diets of poor overall quality. Although many studies have linked poor prenatal diet quality to an increased risk of specific diseases in offspring, it is not known if exposure to poor prenatal diet affects core neurophysiological regulatory systems in offspring known to lie upstream of multiple diseases.Objective: We aimed to examine the association between prenatal diet quality and autonomic nervous system (ANS) function in infants at 6 mo of age.Methods: Data from 400 women (aged >18 y, with uncomplicated pregnancies) and their infants participating in the Maternal-Infant Research on Environmental Chemicals-Infant Development cohort were used to investigate links between prenatal diet quality and infant ANS function at 6 mo of age. Prenatal diet quality was assessed using the Healthy Eating Index (2010), calculated from a validated FFQ completed by women during the first trimester. Infant ANS function was measured using 2 assessments of heart rate variability (HRV) including root mean square of successive differences (RMSSD) and SD of N-N intervals (SDNN). Associations were analyzed before and after adjustment for socioeconomic status, maternal depression symptoms, maternal cardiometabolic dysfunction, breastfeeding, and prenatal smoking.Results: Poorer prenatal diet quality was associated with lower infant HRV assessed using RMSSD (B: 0.07; 95% CI: 0.01, 0.13; R2 = 0.013) and SDNN (B: 0.18; 95% CI: 0.02, 0.35; R2 = 0.011). These associations remained significant after adjustment for confounding variables [RMSSD: B: 0.09; 95% CI: 0.003, 0.18; squared semipartial correlation (sp2) = 0.14 and SDNN B: 0.24; 95% CI: 0.0, 0.49; sp2 = 0.13].Conclusions: In a large cohort study, poorer prenatal diet quality was associated with lower offspring HRV, a marker of decreased capacity of the ANS to respond adaptively to challenge. Therefore, poor prenatal diet may play a significant role in the programming of multiple organ systems and could increase general susceptibility to disease in offspring. [ABSTRACT FROM AUTHOR]

• Human and domesticate signals of selection occur on kainate and metabotropic receptor genes. • These genes are highly expressed in stress-response regions throughout development. • Kainate and metabotropic receptor genes are associated with multiple stress disorders. • These receptors attenuate stress responses by modulating excitation of the HPA axis. • This attenuation alters prenatal development in both domesticates and modern humans. There has been a recent resurgence of interest in the hypothesis that anatomically modern humans and domesticated species have followed convergent evolutionary paths. Here, we review results from domestication and modern-human evolutionary studies in order to evaluate evidence for shared changes to neurotransmission across these species. We compare genomic and, where available, brain-expression differences across 488 neurotransmitter receptor genes in 14 domesticated species and modern humans relative to their wild and archaic counterparts. This analysis highlights prevalent changes to glutamate — most notably kainate and metabotropic — receptor genes. We review evidence for these genes' expression and their respective receptor functions in the central nervous system, as well as phenotypes commonly associated with alterations to them. This evidence suggests an important role for kainate and metabotropic receptors in regulating hypothalamic–pituitary–adrenal axis excitation, and we provide a mechanistic account of their actions in attenuating the stress response. We assess the explanatory potential of such actions in contributing to the emergence of the (self-)domesticated phenotype, in particular to reduced reactive aggression. [ABSTRACT FROM AUTHOR]

A myriad of chemical modifications of DNA and histones involved in the epigenetic regulation of neural gene expression have been documented and studied in detail since many years. However, more recently, modifications in RNA and their implications for neural gene functions have been progressively investigated. Of these, the most widely studied is the N6-methyladenosine (m6A) modification. The discovery of the first m6A demethylase, known as the fat, mass and obesity (FTO) associated protein, has further fortified the field of epitranscriptomic regulatory mechanisms, owing to FTO's involvement in several biological processes including brain development and function. Concomitantly, multiple lines of evidence have associated FTO with neuropsychiatric disorders. In this review, we discuss how FTO can exert its effect by acting not only on m6A but also on O, N6-dimethyladenosine (m6A m) in different types of RNA and potentially influence the development of some major neuropsychiatric diseases. • RNA demethylase, FTO influences neural gene expression and brain development. • Studies implicate FTO in the development of neuropsychiatric diseases. • FTO exerts its effect by acting on m6A and O, N6-dimethyladenosine (m6A m) in different types of RNA substrates • The relevance of each substrate in any particular disease is yet to be studied. [ABSTRACT FROM AUTHOR]

Abstract The risk gene CACNA1C is strongly implicated in the etiology of all major psychiatric disorders, such as depressive disorder, bipolar disorder, autism spectrum disorder, and schizophrenia. These disorders feature high levels of comorbidity and share an overlap of symptoms; in particular, deficits in social functioning are common. Intriguingly, sex-dependent effects of CACNA1C single nucleotide polymorphisms on prevalence, health outcomes, and psychological traits have been reported, typically suggesting that women are more affected by CACNA1C mutations than men. In rodents, genetic modifications specifically targeting Cacna1c have repeatedly been linked to deficits in social behavior in male mice and rats but many studies neglect the sex-dependent effects observed in humans. Our study focused on the role of Cacna1c in regulating social behavior and communication in adult female rats. We compared social and non-social behavior together with concomitant emission of pro-social 50-kHz ultrasonic vocalizations (USV) associated with positive affect in constitutive heterozygous (Cacna1c+/−) rats to wildtype (Cacna1c+/+) littermate controls. Our results indicate that partial Cacna1c depletion leads to strongly reduced emission of 50-kHz USV and mild social deficits during female direct reciprocal social interaction. Detailed temporal analyses revealed most prominent reductions of 50-kHz USV during non-social behavior, suggesting that reduced positive affect occurs in a social context in Cacna1c+/− rats but is not specifically linked to social behavior. Finally, we observed increased self-grooming behavior in Cacna1c+/− rats, consistent with an autism-like phenotype. Our findings in rats thus support a role of Cacna1c in regulating behavioral phenotypes with relevance for several neuropsychiatric disorders. Highlights • The CACNA1C gene is involved in the etiology of neuropsychiatric disorders. • Women seem to be more affected by CACNA1C alterations than men. • In rodents, mutations of Cacna1c have been linked to reduced sociability. • In female rats, social deficits arise following partial Cacna1c depletion. • In particular, the emission of 50-kHz ultrasonic vocalizations is strongly reduced. [ABSTRACT FROM AUTHOR]

• Gene expression serves as a functional intermediate between genotype and phenotype. • The etiologically relevant tissue for studying neuropsychiatric disorders is brain. • Most current postmortem brain banks lack in ethnic diversity and sample sizes. In recent years, large scale meta-analysis of genome-wide association studies (GWAS) have reliably identified genetic polymorphisms associated with neuropsychiatric disorders such as schizophrenia (SCZ), bipolar disorder (BPD) and major depressive disorder (MDD). However, the majority of disease-associated single nucleotide polymorphisms (SNPs) appear within functionally ambiguous non-coding genomic regions. Recently, increased emphasis has been placed on identifying the functional relevance of disease-associated variants via correlating risk polymorphisms with gene expression levels in etiologically relevant tissues. For neuropsychiatric disorders, the etiologically relevant tissue is brain, which requires robust postmortem sample sizes from varying genetic backgrounds. While small sample sizes are of decreasing concern, postmortem brain databases are composed almost exclusively of Caucasian samples, which significantly limits study design and result interpretation. In this review, we highlight the importance of gene expression and expression quantitative loci (eQTL) studies in clinically relevant postmortem tissue while addressing the current limitations of existing postmortem brain databases. Finally, we introduce future collaborations to develop postmortem brain databases for neuropsychiatric disorders from Chinese and Asian subpopulations. [ABSTRACT FROM AUTHOR]

Serotonin (5-hydroxytriptamine; 5-HT) is a fascinating neurotransmitter that thanks to an extensive axonal network is released throughout the entire central nervous system (CNS) and exerts its action on the modulation of a countless number of physiological, behavioral and cognitive processes. In addition, cumulating evidences have linked alteration in 5-HT neurotransmission with the onset of psychiatric and neurodevelopmental disorders, such as depression, autisms and schizophrenia. Nevertheless only 5% of the total body content of serotonin exerts its action in the CNS, while the rest is synthetized and stored in peripheral tissues where it acts as an autacoid. In 2003 it became evident that two distinct isoforms of tryptophan hydroxylase (Tph), the rate-limiting enzyme for the synthesis of serotonin, are selectively expressed in peripheral tissues and in the CNS, with Tph2 as the brain specific isoform. In the present review we describe how the discovery of Tph2 has improved our understanding on the role of serotonergic neurotransmission. We mainly focus on the analysis of animal models generated by genetic manipulation of Tph2 , in which the synthesis of brain serotonin was either reduced or disrupted. The consequences of an altered serotonergic neurotransmission on brain development, as well as on physiological and behavioral processes will be assessed. Finally, we report on several association studies that have linked single nucleotide polymorphisms (SNPs) in the human TPH2 gene with behavioral disturbances and neuropsychiatric disorders. • Several genetic animal models with altered Tph2, the rate limiting enzyme for serotonin synthesis in the brain, have been generated in the past 15 years. • Lack of brain serotonin in Tph2 mouse models affects development and physiology. • Serotonin regulates the wiring of serotonergic circuitry in the brain. • Altered serotonin neurotransmission in Tph2 genetic mouse models affects animal behavior. • SNPs in the human Tph2 gene are associated with behavioral alterations and neuropsychiatric disorders. [ABSTRACT FROM AUTHOR]