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Protocadherins, a family of adhesion molecules with crucial role in cell-cell interactions, have emerged as key players in neurodevelopmental and psychiatric disorders. In particular, growing evidence links genetic alterations in Protocadherin 9 ( PCDH9 ) gene with Autism Spectrum Disorder (ASD) and Major Depressive Disorder (MDD). Furthermore, Pcdh9 deletion induces neuronal defects in the mouse somatosensory cortex, accompanied by sensorimotor and memory impairment. However, the synaptic and molecular mechanisms of PCDH9 in the brain remain largely unknown, particularly concerning its impact on brain pathology. To address this question, we conducted a comprehensive investigation of PCDH9 role in the male mouse hippocampus at the ultrastructural, biochemical, transcriptomic, electrophysiological and network level. We show that PCDH9 mainly localizes at glutamatergic synapses and its expression peaks in the first week after birth, a crucial time window for synaptogenesis. Strikingly, Pcdh9 KO neurons exhibit oversized presynaptic terminal and postsynaptic density (PSD) in the CA1. Synapse overgrowth is sustained by the widespread up-regulation of synaptic genes, as revealed by single-nucleus RNA-seq (snRNA-seq), and the dysregulation of key drivers of synapse morphogenesis, including the SHANK2/CORTACTIN pathway. At the functional level, these structural and transcriptional abnormalities result into increased excitatory postsynaptic currents (mEPSC) and reduced network activity in the CA1 of Pcdh9 KO mice. In conclusion, our work uncovers Pcdh9 pivotal role in shaping the morphology and function of CA1 excitatory synapses, thereby modulating glutamatergic transmission within hippocampal circuits. Significance statement Converging evidence indicates that genetic alterations in Protocadherin 9 ( PCDH9 ) gene are associated with Autism Spectrum Disorder (ASD) and Major Depressive Disorder (MDD). However, our understanding of PCDH9 physiological role and molecular mechanisms in the brain, as well as its connection to synaptic dysfunction and brain pathology, remains limited. Here we demonstrate that Pcdh9 regulates the transcriptional profile, morphology and function of glutamatergic synapses in the CA1, thereby tuning hippocampal network activity. Our results elucidate the molecular and synaptic mechanisms of a gene implicated in neurodevelopmental and psychiatric disorders, and suggest potential hippocampal alterations contributing to the cognitive deficits associated with these conditions., (Copyright © 2024 the authors.)

The failure rate of drugs being developed for neuropsychiatric indications remains high. Optimizing drug discovery and development requires not only a better neurobiological understanding of disease aetiology and development, but also the means by which we can measure relevant biological and clinical processes related to disease progression, drug target engagement, and sensitivity to treatment. Here we address the role and key considerations for the selection of biomarkers in clinical drug development for neuropsychiatric disorders. We do not provide an exhaustive list of biomarkers; rather we lay out a pragmatic, well-defined biomarker selection strategy that addresses the main goals for each of the phases in the drug development cycle. We discuss the key questions and issues that concern biomarker selection and implementation in each phase of development. For the better development of biomarkers, we emphasize the need to focus on discrete biological dysfunction and/or symptom domains rather than diagnoses. We also advocate the use of biomarker-based patient stratification in phase 2 and 3 to increase sensitivity and power and reduce costs. Our aim is to enhance precision and chances of success for these complex and heterogeneous brain disorders with a high unmet medical need., Competing Interests: Conflicts of interests DU is owner of xperimed LLC that provides consultation on all aspects of clinical drug development for neuropsychiatric indications, works on a contracting basis for Autifony Therapeutics and Gilgamesh pharmaceuticals and holds stocks of Roche, Novartis and Gilgamesh Pharmaceuticals. He has been consulting to Abbvie, Biogen, ERG, Forbion, Healthrhyhms, Kynexis, Psychogenic, Roche and Siesta. MJHK declares no conflicts of interest. GRD is owner of P1vital LTD that provides consultation on suitable biomarkers for inclusion in clinical clinicals and supplies biomarkers such as the Facial expression recognition task (FERT, described in the text to industry and academia., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Current nosology claims to separate mental disorders into distinct categories that do not overlap with each other. This nosological separation is not based on underlying pathophysiology but on convention-based clustering of qualitative symptoms of disorders which are typically measured subjectively. Yet, clinical heterogeneity and diagnostic overlap in disease symptoms and dimensions within and across different diagnostic categories of mental disorders is huge. While diagnostic categories provide the basis for general clinical management, they do not describe the underlying neurobiology that gives rise to individual symptomatic presentations. The ability to incorporate neurobiology into the diagnostic framework and to stratify patients accordingly will be a critical step forward for the development of new treatments for mental disorders. Furthermore, it will also allow physicians to provide patients with a better understanding of their illness's complexities and management. To realize this ambition, a paradigm shift is needed to build an understanding of how neuropsychiatric conditions can be defined more precisely using quantitative (multimodal) biological processes and markers and thus to significantly improve treatment success. The ECNP New Frontiers Meeting 2024 set out to develop a consensus roadmap for building a new diagnostic framework for mental disorders by discussing its rationale, outlook, and consequences with all stakeholders involved. This framework would instantiate a set of principles and procedures by which research could continuously improve precision diagnostics while moving away from traditional nosology. In this meeting report, the speakers' summaries from their presentations are combined to address three key elements for generating such a roadmap, namely, the application of innovative technologies, understanding the biology of mental illness, and translating biological understanding into new approaches. In general, the meeting indicated a crucial need for a biology-informed framework to establish more precise diagnosis and treatment for mental disorders to facilitate bringing the right treatment to the right patient at the right time., Competing Interests: Declaration of competing interest MJHK, DHM, MH, and BC declare no conflict of interest. SH is member of the scientific advisory boards for Johnson and Johnson (formerly Janssen) and F-Prime Capital, and he is member of the Boards of Directors for Voyager Therapeutics, Cyclerion Therapeutics, and Vesalius Therapeutics. LMW discloses the following patents in which she contributed, namely, US Patent App. 16/921,388, 16/368,774, 10,702,232 B2, 15/997,631, 10,285,658, 15/830,338, 10,034,645. LJdP declared consultancy and paid presentations for Boeringer-Ingelheim, paid presentation for Viatris – all outside the current work. LJdP is also the Co-chair of the ECNP Immuno-NeuroPsychiatry Network. CML is SAB for Myriad Neuroscience. Speaker & Consultancy fees from UCB and SYNLAB. AE receives salary and equity from Alto Neuroscience, and equity from Akili Interactive. PAL has received honoraria for talks presented at educational meetings organised by Boehringer-Ingelheim outside of the presented work. QJMH has obtained fees and options for consultancies for Aya Technologies and Alto Neuroscience. HM is a full-time employee of Boehringer Ingelheim Pharma GmbH., (Copyright © 2024. Published by Elsevier B.V.)

Our intricate social brain is implicated in a range of brain disorders, where social dysfunction emerges as a common neuropsychiatric feature cutting across diagnostic boundaries. Understanding the neurocircuitry underlying social dysfunction and exploring avenues for its restoration could present a transformative and transdiagnostic approach to overcoming therapeutic challenges in these disorders. The brain's default mode network (DMN) plays a crucial role in social functioning and is implicated in various neuropsychiatric conditions. By thoroughly examining the current understanding of DMN functionality, we propose that the DMN integrates diverse social processes, and disruptions in brain communication at regional and network levels due to disease hinder the seamless integration of these social functionalities. Consequently, this leads to an altered balance between self-referential and attentional processes, alongside a compromised ability to adapt to social contexts and anticipate future social interactions. Looking ahead, we explore how adopting an integrated neurocircuitry perspective on social dysfunction could pave the way for innovative therapeutic approaches to address brain disorders., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Many individuals with autism spectrum disorder (ASD) experience various degrees of impairment in social interaction and communication, restricted, repetitive behaviours, interests/activities. These impairments make a significant contribution to poorer everyday adaptive functioning. Yet, there are no pharmacological therapies to effectively treat the core symptoms of ASD. Since symptoms of ASD likely emerge from a complex interplay of vulnerabilities, environmental factors and compensatory mechanisms during the early developmental period, pharmacological interventions arguably would have the greatest impact to improve long-term outcomes when implemented at a young age. It is essential therefore, that clinical development programmes of investigational drugs in ASD include the paediatric population early on in clinical trials. Such trials need to offer the prospect of direct benefit (PDB) for participants. In most cases in drug development this prospect is supported by evidence of efficacy in adults. However, the effectiveness of treatment approaches may be age-dependent, so that clinical trials in adults may not provide sufficient evidence for a PDB in children. In this white paper, we consolidate recommendations from regulatory guidelines, as well as advice from the Food and Drug Administration, USA (FDA) and the Committee for Human Medicinal Products (CHMP) consultations on various development programmes on: 1) elements to support a PDB to participants in early paediatric clinical trials in ASD, including single-gene neurodevelopment disorders, 2) aspects of study design to allow for a PDB. This white paper is intended to be complementary to existing regulatory guidelines in guiding industry and academic sponsors in their conduct of early paediatric clinical trials in ASD., Competing Interests: Declaration of competing interest L.M.H., J.M.S., J.T., D.V., L.M., C.C., E.C.O., S.C., P.S. are full-time employees of F. Hoffmann - La Roche Ltd, Basel, Switzerland. H.S. is a full-time employee of Roche Products Ltd, Welwyn Garden City, UK. G.P. is a full-time employee of Janssen Research & Development, LLC, Raritan, NJ, USA . P.W. is an employee of Clinical Research Associates, LLC, CT, USA. M.K. has received (non-related) research funding from Novartis during the researching and writing of the manuscript. C.A. has been a consultant to or has received honoraria or grants from Acadia, Abbot, Ambrosetti, AMGEN, AstraZeneca, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Forum, Gedeon Richter, Janssen-Cilag, Lundbeck, Merck, Otsuka, Pfizer, Roche, Servier, Shire, Schering-Plough, Sunovion, and Takeda. D.M. has received funding for a PhD studentship from Compass, and for consulting from Jaguar Therapeutics and Hoffman La Roche., (Copyright © 2024. Published by Elsevier B.V.)

The EQIPD Quality System (QS) was conceptualized and established by an international consortium consisting of academic and industrial partners to ensure that non-regulated biomedical research will be conducted according to Good Research Practice expectations. The QS supports researchers to reflect on and improve internal practices by providing a systematic framework and guidance for implementing the EQIPD QS in a time and cost effective manner. This report describes the content of the EQIPD QS with its key features and 18 Core Requirements (CR) in more detail. It gives a short background on each CR and hands on examples on how they were addressed by two different research labs in their respective laboratory environments. Thereby, this article provides examples and direction for other research labs who aim to implement the QS as well. The final paragraphs discuss the potential benefits of the QS in respect to different user groups and stakeholders within the scientific community and summarize the overall governance structure of the EQIPD framework., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The current neuropsychiatric nosological categories underlie pragmatic treatment choice, regulation and clinical research but does not encompass biological rationale. However, subgroups of patients suffering from schizophrenia or Alzheimer's disease have more in common than the neuropsychiatric nature of their condition, such as the expression of social dysfunction. The PRISM project presents here initial quantitative biological insights allowing the first steps toward a novel trans-diagnostic classification of psychiatric and neurological symptomatology intended to reinvigorate drug discovery in this area. In this study, we applied spectral clustering on digital behavioural endpoints derived from passive smartphone monitoring data in a subgroup of Schizophrenia and Alzheimer's disease patients, as well as age matched healthy controls, as part of the PRISM clinical study. This analysis provided an objective social functioning characterization with three differential clusters that transcended initial diagnostic classification and was shown to be linked to quantitative neurobiological parameters assessed. This emerging quantitative framework will both offer new ways to classify individuals in biologically homogenous clusters irrespective of their initial diagnosis, and also offer insights into the pathophysiological mechanisms underlying these clusters., Competing Interests: Conflict of interest MK has received (non-related) research funding from Novartis during the conduct of the study. MM is employee and CFB is director and shareholder of SBGneuro Ltd. CA has been a consultant to or has received honoraria or grants from Acadia, Angelini, Gedeon Richter, Janssen Cilag, Lundbeck, Minerva, Otsuka, Roche, Sage, Servier, Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovion and Takeda. BP has received (non-related) research funding from Jansen Research and Boehringer Ingelheim during the conduct of the study. ACB and GRD were fully employed by P1Vital during the conduct of the study. BS was fully employed by Boehringer Ingelheim during the conduct of the study. HM was fully employed by Eli Lilly and Company during the conduct of the study. All other authors declare no conflict of interests., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

In humans, social factors (e.g., loneliness) have been linked to the risk of developing Alzheimer's Disease (AD). To date, AD pathology is primarily characterized by amyloid-β plaques and tau tangles. We aimed to assess the effect of single- and group-housing on AD-related pathology in a mouse model for amyloid pathology (J20, and WT controls) and a mouse model for tau pathology (P301L) with and without seeding of synthetic human tau fragments (K18). Female mice were either single housed (SH) or group housed (GH) from the age of 6-7 weeks onwards. In 12-week-old P301L mice, tau pathology was induced through seeding by injecting K18 into the dorsal hippocampus (P301L K18 ), while control mice received a PBS injection (P301L PBS ). P301L mice were sacrificed at 4 months of age and J20 mice at 10 months of age. In all mice brain pathology was histologically assessed by examining microglia, the CA1 pyramidal cell layer and specific AD pathology: analysis of plaques in J20 mice and tau hyperphosphorylation in P301L mice. Contrary to our expectation, SH-J20 mice interestingly displayed fewer plaques in the hippocampus compared to GH-J20 mice. However, housing did not affect tau hyperphosphorylation at Ser202/Thr205 of P301L mice, nor neuronal cell death in the CA1 region in any of the mice. The number of microglia was increased by the J20 genotype, and their activation (based on cell body to cell size ratio) in the CA1 was affected by genotype and housing condition (interaction effect). Single housing of P301L mice was linked to the development of stereotypic behavior (i.e. somersaulting and circling behavior). In P301L K18 mice, an increased number of microglia were observed, among which were rod microglia. Taken together, our findings point to a significant effect of social housing conditions on amyloid plaques and microglia in J20 mice and on the development of stereotypic behavior in P301L mice, indicating that the social environment can modulate AD-related pathology., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

It is well established that sleep deprivation after learning impairs hippocampal memory processes and can cause amnesia. It is unknown, however, whether sleep deprivation leads to the loss of information or merely the suboptimal storage of information that is difficult to retrieve. Here, we show that hippocampal object-location memories formed under sleep deprivation conditions can be successfully retrieved multiple days following training, using optogenetic dentate gyrus (DG) memory engram activation or treatment with the clinically approved phosphodiesterase 4 (PDE4) inhibitor roflumilast. Moreover, the combination of optogenetic DG memory engram activation and roflumilast treatment, 2 days following training and sleep deprivation, made the memory more persistently accessible for retrieval even several days later (i.e., without further optogenetic or pharmacological manipulation). Altogether, our studies in mice demonstrate that sleep deprivation does not necessarily cause memory loss but instead leads to the suboptimal storage of information that cannot be retrieved without drug treatment or optogenetic stimulation. Furthermore, our findings suggest that object-location memories, consolidated under sleep deprivation conditions and thought to be lost, can be made accessible again several days after the learning and sleep deprivation episode, using the clinically approved PDE4 inhibitor roflumilast., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Altered social behavior is one of the symptoms of Alzheimer's disease (AD) that results in social withdrawal and loneliness and provides a major burden on patients and their relatives. Furthermore, loneliness is associated with an increased risk to develop AD and related dementias., Objective: We aimed to investigate if altered social behavior is an early indicator of amyloid-β (Aβ) pathology in J20 mice, and if co-housing with wild type (WT) mice can positively influence this social phenotype., Methods: The social phenotype of group-housed mice was assessed using an automated behavioral scoring system for longitudinal recordings. Female mice were housed in a same-genotype (4 J20 or WT mice per colony) or mixed-genotype (2 J20 mice + 2 WT mice) colony. At 10 weeks of age, their behavior was assessed for five consecutive days., Results: J20 mice showed increased locomotor activity and social sniffing, and reduced social contact compared to WT mice housed in same-genotype colonies. Mixed-genotype housing reduced the social sniffing duration of J20 mice, increased social contact frequency of J20 mice, and increased nest hide by WT mice., Conclusion: Thus, altered social behavior can be used as an early indicator of Aβ-pathology in female J20 mice. Additionally, when co-housed with WT mice, their social sniffing phenotype is not expressed and their social contact phenotype is reduced. Our findings highlight the presence of a social phenotype in the early stages of AD and indicate a role for social environment variation in the expression of social behavior of WT and J20 mice.

Predictive models are essential for advancing knowledge of brain disorders. High variation in study outcomes hampers progress. To address the validity of predictive models, we performed a systematic review and meta-analysis on behavioural phenotypes of the knock-out rodent model for Fragile X syndrome according to the PRISMA reporting guidelines. In addition, factors accountable for the heterogeneity between findings were analyzed. The knock-out model showed good translational validity and replicability for hyperactivity, cognitive and seizure phenotypes. Despite low replicability, translational validity was also found for social behaviour and sensory sensitivity, but not for attention, aggression and cognitive flexibility. Anxiety, acoustic startle and prepulse inhibition phenotypes, despite low replicability, were opposite to patient symptomatology. Subgroup analyses for experimental factors moderately explain the low replicability, these analyses were hindered by under-reporting of methodologies and environmental conditions. Together, the model has translational validity for most clinical phenotypes, but caution must be taken due to low effect sizes and high inter-study variability. These findings should be considered in view of other rodent models in preclinical research., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Autism spectrum disorders (ASDs) are a group of neurodevelopmental conditions defined by behavioral deficits in social communication and interactions, mental inflexibility and repetitive behaviors. Converging evidence from observational and preclinical studies suggest that excessive repetitive behaviors in people with ASD may be due to elevated histaminergic H3 receptor signaling in the striatum. We hypothesized that systemic administration of pharmacological histamine H3 receptor antagonists would attenuate the expression of repetitive behaviors in the BTBR T+Itpr3tf/J (BTBR) mouse inbred strain, an established mouse model presenting autism-like repetitive behaviors and novelty-induced hyperactivity. We further aimed to investigate whether agonism of the histamine H3 receptor would be sufficient to induce repetitive behaviors in the C57BL/6J control mouse strain., Methods: Different doses of H3 receptor agonists (i.e., (R)-α-methylhistamine and immethridine) and H3 receptor antagonists/inverse agonists (i.e., ciproxifan and pitolisant) were administered via intraperitoneal (i.p.) injection in male mice to characterize the acute effects of these compounds on ASD-related behavioral readouts., Results: The highly selective H3 receptor agonist immethridine significantly increased the time spent in stereotypic patterns in C57BL/6J mice, but this effect appeared to be driven by general sedative properties of the compound. High doses of pitolisant significantly decreased locomotor hyperactivity in novel environments in BTBR mice, without significant effects on repetitive behaviors., Conclusions: Based on our findings, we conclude that acute H3 receptor manipulation mainly affected general motor activity levels in novel environments. Small changes in stereotyped behaviors were observed but appeared to be driven by altered general activity levels., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Genetics and biology may influence the age of onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to age of onset of AN and to investigate the genetic associations between age of onset of AN and age at menarche., Methods: A secondary analysis of the Psychiatric Genomics Consortium genome-wide association study (GWAS) of AN was performed, which included 9335 cases and 31,981 screened controls, all from European ancestries. We conducted GWASs of age of onset, early-onset AN (<13 years), and typical-onset AN, and genetic correlation, genetic risk score, and Mendelian randomization analyses., Results: Two loci were genome-wide significant in the typical-onset AN GWAS. Heritability estimates (single nucleotide polymorphism- h 2 ) were 0.01-0.04 for age of onset, 0.16-0.25 for early-onset AN, and 0.17-0.25 for typical-onset AN. Early- and typical-onset AN showed distinct genetic correlation patterns with putative risk factors for AN. Specifically, early-onset AN was significantly genetically correlated with younger age at menarche, and typical-onset AN was significantly negatively genetically correlated with anthropometric traits. Genetic risk scores for age of onset and early-onset AN estimated from independent GWASs significantly predicted age of onset. Mendelian randomization analysis suggested a causal link between younger age at menarche and early-onset AN., Conclusions: Our results provide evidence consistent with a common variant genetic basis for age of onset and implicate biological pathways regulating menarche and reproduction., (© 2021 The Authors.)

Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [r g ], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (r g = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (r g = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (r g = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (r gs = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors., (© 2020 Society for the Study of Addiction.)

Social withdrawal is associated with a variety of neuropsychiatric disorders, including neurodevelopmental disorders. Rodent studies provide the opportunity to study neurobiological mechanisms underlying social withdrawal, however, homologous paradigms to increase translatability of social behaviour between human and animal observation are needed. Standard behavioural rodent assays have limited ethological validity in terms of number of interaction partners, type of behaviour, duration of observation and environmental conditions. In addition, reproducibility of behavioural findings in rodents is further limited by manual and subjective behavioural scoring. Using a newly developed automated tracking tool for longitudinal monitoring of freely moving mice, we assessed social behaviours (approach, sniff, follow and leave) over seven consecutive days in colonies of BTBR and of C57BL/6J mice in two independent laboratories. Results from both laboratories confirmed previous findings of reduced social interaction in BTBR mice revealing a high level of reproducibility for this mouse phenotype using longitudinal colony assessments. In addition, we showed that detector settings contribute to laboratory specific findings as part of the behavioural data analysis procedure. Our cross-site study demonstrates reproducibility and robustness of reduced social interaction in BTBR mice using automated analysis in an ethologically relevant context., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Deficits in social behaviour, e.g. social withdrawal, appear as an early sign of many neuropsychiatric disorders. Investigation of the biological basis of social withdrawal and development of new targets for treatment requires reliable quantification methods of social behaviour., New Method: In order to study behavioural deficits in preclinical rodent models, we developed a tracking and analysis tool for behavioural observations in groups of mice. RFID-Assisted SocialScan is based on video tracking supported by radio-frequency identification (RFID). For this purpose, mice were labelled with RFID tags providing unique animal identity and location in the arena. An integrated software package enables automatic detection of predefined behavioural events, which are extracted from video recordings. We designed a social arena that can be flexibly adapted for various behavioural experiments., Results: We demonstrate the utility of our newly developed tracking tool by monitoring colonies of C57BL/6 J mice. We assessed social (approach, contact, follow, leave) and locomotor activities over multiple days., Comparison With Other Existing Methods: RFID-Assisted SocialScan is an automated tracking and analysis tool for long-term behavioural observations of multiple freely moving mice housed in ethologically relevant environment., Conclusions: Here, we demonstrate the performance of a newly developed behavioural tracking system that can be used for long-term translational studies of social behaviour in groups of freely moving mice., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Contactin-associated protein-like 2 (Caspr2) is found at the nodes of Ranvier and has been associated with physiological properties of white matter conductivity. Genetic variation in CNTNAP2, the gene encoding Caspr2, has been linked to several neurodevelopmental conditions, yet pathophysiological effects of CNTNAP2 mutations on axonal physiology and brain myelination are unknown. Here, we have investigated mouse mutants for Cntnap2 and found profound deficiencies in the clustering of Kv1-family potassium channels in the juxtaparanodes of brain myelinated axons. These deficits are associated with a change in the waveform of axonal action potentials and increases in postsynaptic excitatory responses. We also observed that the normal process of myelination is delayed in Cntnap2 mutant mice. This later phenotype is a likely modulator of the developmental expressivity of the stereotyped motor behaviors that characterize Cntnap2 mutant mice. Altogether, our results reveal a mechanism linked to white matter conductivity through which mutation of CNTNAP2 may affect neurodevelopmental outcomes.

Sensory processing is affected in multiple neuropsychiatric disorders like schizophrenia and autism spectrum disorders. Genetic and environmental factors guide the formation and fine-tuning of brain circuitry necessary to receive, organize, and respond to sensory input in order to behave in a meaningful and consistent manner. During certain developmental stages the brain is sensitive to intrinsic and external factors. For example, disturbed expression levels of certain risk genes during critical neurodevelopmental periods may lead to exaggerated brain plasticity processes within the sensory circuits, and sensory stimulation immediately after birth contributes to fine-tuning of these circuits. Here, the neurodevelopmental trajectory of sensory circuit development will be described and related to some example risk gene mutations that are found in neuropsychiatric disorders. Subsequently, the flow of sensory information through these circuits and the relationship to synaptic plasticity will be described. Research focusing on the combined analyses of neural circuit development and functioning are necessary to expand our understanding of sensory processing and behavioral deficits that are relevant across the neuropsychiatric spectrum., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Polyunsaturated fatty acids (PUFAs) are one of the main cellular building blocks, and dietary changes in PUFA composition are proposed as a potential route to influence brain development. For example, initial studies indicated that there is a relation between blood omega-6(n-6)/omega-3(n-3) PUFA ratios and neurodevelopmental disease diagnosis. To study the consequences of dietary n-6/n-3 PUFA ratio changes, we investigated the impact of a n-3 supplemented and n-3 deficient diet in developing BTBR T + Itpr3tf/J (BTBR) - a mouse inbred strain displaying Autism Spectrum Disorder (ASD)-like symptomatology - and control C57BL/6J mice. This study showed that pre- and postnatal changed dietary n-6/n-3 ratio intake has a major impact on blood and brain PUFA composition, and led to delayed physical development and puberty onset in both strains. The PUFA induced developmental delay did not impact adult cognitive performance, but resulted in reduced social interest, a main ASD behavioral feature. Thus, both chronic dietary n-3 PUFA supplementation and depletion may not be beneficial., (Copyright © 2018. Published by Elsevier B.V.)

Numerous novel neuroscience-based drug targets have been identified in recent years. However, it remains unclear how these targets relate to the expression of symptoms in central nervous system (CNS) disorders in general and psychiatric disorders in particular. To discuss this issue, a New Frontiers Meetings of European College of Neuropsychopharmacology (ECNP) was organized to address the challenges in translational neuroscience research that are impeding the effective development of new treatments. The main aim of this meeting was to discuss scientific insights, concepts and methodologies in order to improve drug development for psychiatric disorders. The meeting was designed to bring together stakeholders from academia, pharmaceutical industry, and regulatory agencies. Here we provide a synopsis of the proceedings from the meeting entitled 'New approaches to psychiatric drug development'. New views on psychiatric drug development were presented to address the challenges and pitfalls as identified by the different stakeholders. The general conclusion of the meeting was that drug discovery could be stimulated by designing new classification and sensitive assessment tools for psychiatric disorders, which bear closer relationships to neuropharmacological and neuroscientific developments. This is in line with the vision of precision psychiatry in which patients are clustered, not merely on symptoms, but primarily on biological phenotypes that represent pathophysiological relevant and 'drugable' processes. To achieve these goals, a closer collaboration between all stakeholders in early stages of development is essential to define the research criteria together and to reach consensus on new quantitative biological methodologies and etiology-directed treatments., (Copyright © 2018. Published by Elsevier B.V.)

Disrupted sociability and consequent social withdrawal are (early) symptoms of a wide variety of neuropsychiatric diseases, such as schizophrenia, autism spectrum disorders, depressive disorders and Alzheimer's disease. The paucity of objective measures to translationally assess social withdrawal characteristics has been an important limitation to study this behavioral phenotype, both in human and rodents. The aim of the present study was to investigate sociability and social withdrawal in rodents using an ethologically valid behavioral paradigm, the Visible Burrow System (VBS). The VBS mimics a natural environment, with male and female rodents housed together in an enclosure where a large open arena is connected to a continuously dark burrow system that includes 4 nest boxes. In this study, mixed-sex colonies of C57BL/6J and of BTBR mice have been investigated (n = 8 mice per colony). Results showed marked differences between the two strains, in terms of sociability as well as social withdrawal behaviors. In particular, BTBR mice performed less social behaviors and have a preference for non-social behaviors compared to C57BL/6J mice. Neurobiologically, the decreased sociability of BTBR was accompanied by reduced GABA and increased glutamate concentrations in brain prefrontal cortex (PFC) and amygdala regions. In conclusion, our study validated the use of the VBS as an ethologically relevant behavioral paradigm in group-housed mice to investigate individual sociability and social withdrawal features and their underlying neurobiology. This paradigm may provide new insights to develop new therapeutic treatments for behavioral dysfunctions that may be relevant across neuropsychiatric diseases., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Autism spectrum disorder (ASD) is multifactorial, with both genetic as well as environmental factors working in concert to develop the autistic phenotype. Immunological disturbances in autistic individuals have been reported and a role for food allergy has been suggested in ASD. Single gene mutations in mammalian target of rapamycin (mTOR) signaling pathway are associated with the development of ASD and enhanced mTOR signaling plays a central role in directing immune responses towards allergy as well. Therefore, the mTOR pathway may be a pivotal link between the immune disturbances and behavioral deficits observed in ASD. In this study it was investigated whether the mTOR pathway plays a role in food allergy-induced behavioral and immunological deficits. Mice were orally sensitized and challenged with whey protein. Meanwhile, cow's milk allergic (CMA) mice received daily treatment of rapamycin. The validity of the CMA model was confirmed by showing increased allergic immune responses. CMA mice showed reduced social interaction and increased repetitive self-grooming behavior. Enhanced mTORC1 activity was found in the brain and ileum of CMA mice. Inhibition of mTORC1 activity by rapamycin improved the behavioral and immunological deficits of CMA mice. This effect was associated with increase of Treg associated transcription factors in the ileum of CMA mice. These findings indicate that mTOR activation may be central to both the intestinal, immunological, and psychiatric ASD-like symptoms seen in CMA mice. It remains to be investigated whether mTOR can be seen as a therapeutic target in cow's milk allergic children suffering from ASD-like symptoms., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Food allergy has been suggested to contribute to the expression of psychological and psychiatric traits, including disturbed social behaviour and repetitive behaviour inherent in autism spectrum disorders (ASD). Most research in this field receives little attention, since fundamental evidence showing direct effects of food allergic immune responses on social behaviour is very limited. In the present study, we show that a food allergic reaction to cow's milk protein, induced shortly after weaning, reduced social behaviour and increased repetitive behaviour in mice. This food allergic reaction increased levels of serotonin (5-hydroxytryptamine; 5-HT) and the number of 5-HT positive cells, and decreased levels of 5-hydroxyindoleacetic acid (5-HIAA) in the intestine. Behavioural changes in food allergic mice were accompanied by reduced dopaminergic activity in the prefrontal cortex. Furthermore, neuronal activation (c-Fos expression) was increased in the prefrontal cortex and reduced in the paraventricular nucleus of the hypothalamus after exposure to a social target. We hypothesize that an intestinal allergic response regulates complex, but critical, neuroimmune interactions, thereby affecting brain circuits involved in social interaction, repetitive behaviour and cognition. Together with a genetic predisposition and multiple environmental factors, these effects of allergic immune activation may exacerbate behavioural abnormalities in patients with ASD., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Autism is a disease of brain plasticity. Inspiring work of Willem Hendrik Gispen on neuronal plasticity has stimulated us to investigate gene defects in autism and the consequences for brain development. The central process in the pathogenesis of autism is local dendritic mRNA translation which is dependent on axodendritic communication. Hence, most autism-related gene products (i) are part of the protein synthesis machinery itself, (ii) are components of the mTOR signal transduction pathway, or (iii) shape synaptic activity and plasticity. Accordingly, prototype drugs have been recognized that interfere with these pathways. The contactin (CNTN) family of Ig cell adhesion molecules (IgCAMs) harbours at least three members that have genetically been implicated in autism: CNTN4, CNTN5, and CNTN6. In this chapter we review the genetic and neurobiological data underpinning their role in normal and abnormal development of brain systems, and the consequences for behavior. Although data on each of these CNTNs are far from complete, we tentatively conclude that these three contactins play roles in brain development in a critical phase of establishing brain systems and their plasticity. They modulate neuronal activities, such as neurite outgrowth, synaptogenesis, survival, guidance of projections and terminal branching of axons in forming neural circuits. Current research on these CNTNs concentrate on the neurobiological mechanism of their developmental functions. A future task will be to establish if proposed pharmacological strategies to counteract ASD-related symptomes can also be applied to reversal of phenotypes caused by genetic defects in these CNTN genes., (© 2013 Elsevier B.V. All rights reserved.)

Obsessive-compulsive disorder (OCD) is a chronic and complex psychiatric disorder with a lifetime prevalence of 2-3%. Recent work has shown that OCD rituals were not only characterized by a high rate of repetition but also by an increased behavioral repertoire due to additional non-functional unique acts. These two behavioral characteristics may provide an ethological basis for studying compulsive behavior in an animal model of OCD. Here, quinpirole induced behavior (so far only investigated in rats) has been studied in A/J and C57BL/6J mice by using behavioral pattern analysis. The aim of this study is to investigate whether genetic background is mediating this behavior. Results showed that open field motor activity levels of saline treated C57BL/6J mice was significantly higher compared to A/J treated saline mice. Long-term quinpirole treatment increased open field motor activity levels in A/J, but not in C57BL/6J. Quinpirole treatment induced a strain dependent difference in behavioral repertoire. There was a dose dependent increase in the number of different behavioral patterns in A/J, whereas, in C57BL/6J there was a dose dependent decrease. This data suggest that genetic background is important in expressing quinpirole induced compulsive like behavior. Following quinpirole treatment, A/J mice express a greater behavioral repertoire with a high rate of repetition. This phenotype resembles that of OCD rituals in patients and indicates that this strain is very interesting to further validate for studying neurobiological mechanisms of compulsive behavior., (Copyright © 2012. Published by Elsevier B.V.)

Although deep brain stimulation (DBS) has been proven to be an effective treatment for several neuropsychiatric disorders, such as Parkinson's disease, the underlying working mechanisms are still largely unknown. Behavioral animal models are essential in examining the working mechanisms of DBS and especially mouse models are necessary to investigate the genetic component underlying specific behaviors related to psychiatric diseases. Unfortunately, currently available stimulation devices are unsuitable to test behavior in freely-moving mice. As such, no DBS studies in behaving mice have been reported thus far. In order to overcome this limitation we have developed a new light-weight wireless implantable micro stimulator device for mice that delivers biphasic pulse patterns to two individual electrode pairs, mimicking partly the clinical situation. This paper describes in detail the bench-top validation and in vivo implementation of this device. The results in this study indicate that the wireless implantable stimulator in mice reliably delivers continuous bilateral stimulation, importantly, does not restrict the animals mobility and hygiene (grooming behavior). In vivo testing furthermore showed that stimulation of the mice ventral striatum yields similar results as previously shown by others in rats where conventional deep brain stimulation techniques were used. This newly designed device can now be used in the highly needed DBS behavioral studies in mice, to further investigate the underlying mechanisms of DBS in behavioral animal models for psychiatric disorders., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Objective: A comparison of the efficacy of a novel treatment method for anorexia nervosa (AN), the Mandometer treatment (MT), with treatment as usual (TAU)., Method: During treatment data were collected to determine weight recovery and outcome as assessed by the Morgan Russell Outcome Assessment Schedule (MROAS)., Results: After treatment 63% of the MT group and 85% of the TAU group had reached a normal weight level and both MT and TAU showed a good outcome on the MROAS (75 and 71%, respectively). After two years more MT than TAU patients were still in treatment and more MT patients had relapsed., Discussion: The outcome for both treatments in our study were similar and comparable with, if not better than outcome data of other AN studies. MT is not superior to TAU in outcome results and in relapse rate during the first two years following admission for AN treatment., (Copyright © 2011 Wiley Periodicals, Inc.)

Obsessive-compulsive disorder (OCD) is a chronic and disabling psychiatric disease with a lifetime prevalence of 2-3%. People with OCD suffer from intrusive, unwanted and recurrent thoughts (obsessions) and/or repetitive ritualistic behaviors (compulsions). The aim of this study is to quantify the dimensions of ritualistic 'compulsive-like' behavior in quinpirole-induced behavior in rats by using T-pattern behavioral analysis. In addition, we investigated whether the behavioral effects elicited by quinpirole sensitization remained after 2 weeks of cessation of treatment. Finally, to study the neurobiological underpinnings of this 'compulsive-like' behavior, we investigated the effect of quinpirole treatment on the extracellular dopamine levels in the nucleus accumbens. Once established, 'compulsive-like' behavior is dependent upon quinpirole administration, as this behavior rapidly normalized after cessation of treatment. After a single dose of quinpirole the dopamine level decreased more in saline pre-treated animals as compared with animals given quinpirole treatment continuously. Furthermore, T-pattern analysis revealed that quinpirole-induced behavior consists, unlike OCD rituals, of a smaller behavioral repertoire. As seen in patients with OCD, quinpirole-treated animals performed these behaviors with a high rate of repetition. These findings suggest that quinpirole-induced behavior mimics only part of the compulsive behavior as shown in OCD patients.

Identifying the genetic and neurobiological mechanisms underlying certain behavioural traits is an important strategy to understand the aetiology of various psychiatric disorders and to find potential new treatment possibilities. It has proven a great challenge to develop paradigms that allow translational research for behavioural phenotypes that are relevant for disorders across the psychiatric spectrum. Recently, there has been increasing attention for studies that implement rodent behavioural paradigms in the home cage to assess the association between genetic backgrounds and behavioural traits. The application of interspecies genetics to unravel these traits has revealed novel insights in the genetic mechanisms that are encoding phenotypes relevant to biological processes underlying psychiatric disorders. By means of two examples, namely the stress-induced hyperthermia paradigm and the home cage environment, this review aims to show that by using individual genetic variations with phenotypes obtained from mice and across categories of neuropsychiatric disorders, novel insights in the neurobiological trajectory of psychiatric disorders can be obtained., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Current approaches to dissect the molecular neurobiology of complex neuropsychiatric disorders such as schizophrenia and major depression have been rightly criticized for failing to provide benefits to patients. Improving the translational potential of our efforts will require the development and refinement of better disease models that consider a wide variety of contributing factors, such as genetic variation, gene-by-environment interactions, endophenotype or intermediate phenotype assessment, cross species analysis, sex differences, and developmental stages. During a targeted expert meeting of the European College of Neuropsychopharmacology (ECNP) in Istanbul, we addressed the opportunities and pitfalls of current translational animal models of psychiatric disorders and agreed on a series of core guidelines and recommendations that we believe will help guiding further research in this area., (Copyright © 2010 Elsevier B.V. and ECNP. All rights reserved.)

We examined juvenile social recognition and discrimination in mice with early post-natal onset, transgenic CRF over-expression (CRF-OE) and in their wild-type littermates (WT). CRF-OE mice showed enhanced social investigation during the first encounter, normal short-term and facilitated long-term social recognition memory, compared to WT. These results suggest that chronically elevated brain CRF tone may contribute in better remembering ethologically relevant and emotionally salient stimuli, such as social interaction., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Repetitive and stereotyped behavior is a prominent element of both animal and human behavior. Similar behavior is seen across species, in diverse neuropsychiatric disorders and in key phases of typical development. This raises the question whether these similar classes of behavior are caused by similar neurobiological mechanisms or whether they are neurobiologically unique? In this paper we discuss fundamental animal research and translational models. Imbalances in corticostriatal function often result in repetitive behavior, where different classes of behavior appear to be supported by similar neural mechanisms. Although the exact nature of these imbalances are not yet fully understood, synthesizing the literature in this area provides a framework for studying the neurobiological systems involved in repetitive behavior., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

In young, typically developing children, repetitive behavior similar to that in certain neuropsychiatric syndromes is common. Whereas this behavior is adaptive in typical development, in many disorders it forms a core component of symptoms and causes prominent impairment in the daily life of affected individuals. Understanding the neurobiological mechanisms involved repetitive behavior will improve our understanding of the pathogenesis of developmental neuropsychiatric disorders, stimulating novel approaches to these conditions. However, studies on the neurobiology of human repetitive behavior have often been limited to distinct conditions and generalization has been hindered by inconsistent terminology. In this paper, we synthesize the 'disorder-driven' literature, building on findings from fundamental animal research and translational models. These findings suggest a model for classifying repetitive behavior by its neuroanatomical correlates., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Background: Several genetic mechanisms have been proposed for the variability of the Klinefelter syndrome (KS) phenotype such as the parent-of-origin of the extra X chromosome. Parent-of-origin effects on behavior in KS can possibly provide insights into X-linked imprinting effects on psychopathology that may be extrapolated to other populations. Here, we investigated whether the parent-of-origin of the supernumerary X chromosome influences autistic and schizotypal symptom profiles in KS., Methods: Parent-of-origin of the X chromosome was determined through analysis of the polymorphic CAG tandem repeat of the androgen receptor gene. Autistic traits (Autism Diagnostic Interview-Revised) were measured in a younger KS sample (n = 33) with KS and schizotypal traits (Schizotypal Personality Questionnaire) were assessed in an older KS sample (n = 43). Scale scores on these questionnaires were entered in statistical analyses to test parent-of-origin effects., Results: The results show that parent-of-origin of the X chromosome is reflected in autistic and schizotypal symptomatology. Differences were shown in the degree of both schizotypal and autistic symptoms between the parent-of-origin groups. Furthermore, the parent-of-origin could be correctly discriminated in more than 90% of subjects through Autism Diagnostic Interview-Revised scales and in around 80% of subjects through Schizotypal Personality Questionnaire scales., Conclusions: These findings point to parent-of-origin effects on psychopathology in KS and indicate that imprinted X chromosomal genes may have differential effects on autistic and schizotypal traits. Further exploration of imprinting effects on psychopathology in KS is needed to confirm and expand on our findings., (Copyright © 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: We performed gene expression profiling of the amygdala and hippocampus taken from inbred mouse strains C57BL/6J and A/J. The selected brain areas are implicated in neurobehavioral traits while these mouse strains are known to differ widely in behavior. Consequently, we hypothesized that comparing gene expression profiles for specific brain regions in these strains might provide insight into the molecular mechanisms of human neuropsychiatric traits. We performed a whole-genome gene expression experiment and applied a systems biology approach using weighted gene co-expression network analysis., Results: We were able to identify modules of co-expressed genes that distinguish a strain or brain region. Analysis of the networks that are most informative for hippocampus and amygdala revealed enrichment in neurologically, genetically and psychologically related pathways. Close examination of the strain-specific gene expression profiles, however, revealed no functional relevance but a significant enrichment of single nucleotide polymorphisms in the probe sequences used for array hybridization. This artifact was not observed for the modules of co-expressed genes that distinguish amygdala and hippocampus., Conclusions: The brain-region specific modules were found to be independent of genetic background and are therefore likely to represent biologically relevant molecular networks that can be studied to complement our knowledge about pathways in neuropsychiatric disease.

Obsessive-compulsive disorder (OCD) is a severe anxiety disorder characterized by obsessions and compulsions. The core symptom of OCD is compulsivity, the inability to stop thinking or acting when you want to, despite being aware of the uselessness of the content or the adverse consequences. To initiate a systematic search for genetic mechanisms underlying the pathophysiology of compulsivity, a panel of chromosome substitution (CS) strains, derived from mice that suppress (C57BL/6J strain) or maintain (A/J strain) high levels of repetitive wheel running during 2 hr of daily limited food access, was screened for this compulsive behavior. Following the genetic screen, we found linkage between compulsive wheel running and mouse chromosomes 2, 6, and 7 that show overlap with recently identified human linkage regions for OCD on chromosomes 7p and 15q. In the overlapping (human/mouse) genomic region, the CRH receptor 2 (CRHR2) gene was tested in a human case-control study. An initial exploration in OCD cases versus controls failed to detect an association between four-candidate CRH2R SNP's within this homologous linkage region and OCD. Genetic fine mapping of compulsivity in mice provides new opportunities to reveal mechanisms underlying this significant psychiatric trait., ((c) 2009 Wiley-Liss, Inc.)

Objective: Loci on mouse chromosome 2 have previously been associated with ethanol consumption. Here, we used a limited access choice paradigm in which mice consume large quantities of ethanol (2-3 g/kg/2 h) with a high preference (>80%). In addition, mouse chromosome substitution strains were used to further evaluate the contribution of chromosome 2 to ethanol consumption., Methods and Results: First, we compared the two parental inbred mouse strains, C57BL/6J and A/J, in the limited access choice paradigm for ethanol intake and ethanol preference, as well as for ethanol metabolism and taste sensitivity. Then, the effect of chromosome 2 substitution on these measures was determined. Compared with C57BL/6J mice, A/J and C57BL/6J-Chr 2/NaJ (CSS-2) mice showed profoundly reduced ethanol intake and preference. The strains were not different with regard to ethanol metabolism or taste sensitivity. Limited access ethanol consumption in F2 progeny derived from reciprocal C57BL/6J xCSS-2 and CSS-2 xC57BL/6J intercrosses and subsequent quantitative trait loci mapping identified two loci: one locus on chromosome 2 for ethanol intake and a separate locus on distal chromosome 2 for ethanol preference. This latter locus was dependent on the grandparental origin., Conclusion: Using a limited access choice paradigm, we found that mouse chromosome 2 carries an allelic variant of a locus for ethanol intake and a distinct locus selective for ethanol preference. The heritability of alcoholism has been suggested to be parent-specific, perhaps resulting from genetic imprinting. Our findings suggest that grandparent-influenced vulnerability for ethanol consumption is conferred by genes on chromosome 2, providing important new leads to enhance our understanding of the heritability of alcoholism.

Animal studies are important for the identification and functional characterization of the biological substrates underlying complex psychiatric disorders. However, novel insights into the relationship between the genome and behavior are needed for the development of fully valid translational models. Based on the notion that in different species, the same genes may independently give rise to alleles with similar functional and phenotypic effects, either under similar selection or through similar genomic mechanisms, we propose the use of genetic validity as a tool for identifying analogous pathology between animals and human neuropsychiatric disorders. Furthermore, the identification of copy number variants which disrupt entire genes, reinforces the notion that transgenic animals, such as knockouts or knock-ins, may provide unexpectedly valid disease models for psychiatric traits. To illustrate interspecies comparison of genetic variations in relation to neurobehavioral traits, examples are provided for the BDNF, COMT, and DISC1 genes in mouse and man. We propose that alignment of individual genetic variations with endophenotypes obtained from mice and across categories of neuropsychiatric disorders will provide an important step in translational research., ((c) 2008 Wiley-Liss, Inc.)

Family and twin studies have indicated that genetic factors play a role in the development of eating disorders, such as anorexia and bulimia nervosa, but novel views and tools may enhance the identification of neurobiological mechanisms underlying these conditions. Here we propose an integrative genetic approach to reveal novel biological substrates of eating disorder traits analogous in mouse and human. For example, comparable to behavioral hyperactivity that is observed in 40-80% of anorexia nervosa patients, inbred strains of mice with different genetic backgrounds are differentially susceptible to develop behavioral hyperactivity when food restricted. In addition, a list of characteristics that are relevant to eating disorders and approaches to their measurement in humans together with potential analogous rodent models has been generated. Interspecies genetics of neurobehavioral characteristics of eating disorders has the potential to open new roads to identify and functionally test genetic pathways that influence neurocircuits relevant for these heterogeneous psychiatric disorders., ((c) 2008 Wiley-Liss, Inc.)

The existence of sexual dysfunctions in men, including premature and retarded ejaculation poses challenges to develop translational models in rats that may help in improving treatment and delineate the neural mechanisms of action. Most of our current understanding of the neurobiology, neuroanatomy and psychopharmacology of sexual behavior and ejaculatory function has been derived from preclinical studies in the rat. When large populations of male rats are tested on sexual activity during four successive tests, over time individual rats display a very stable sexual behavior that is either slow, normal or fast as characterized by the number of ejaculations performed. These sexual endophenotypes are postulated as rat counterparts of premature (fast rats) or retarded ejaculation (slow rats). Psychopharmacology in these endophenotypes may help to delineate the underlying mechanisms and pathology. This is illustrated by the effects of serotonergic antidepressants and serotonergic compounds on sexual and ejaculatory behavior of rats. Further unravelling of sexual endophenotypes may benefit from the use of chromosomal substitution strains in mice that enable the localization of relevant chromosomal areas and genes involved in ejaculation processes. These preclinical studies and models contribute to a better understanding of the neurobiology of ejaculation and boost the development of novel drug targets to treat ejaculatory disorders such as premature and retarded ejaculation.

The pharmacological treatment of mood and anxiety disorders has for long relied on the serendipitous findings of monoaminergic and benzodiazepine drugs more than 50 years ago. These treatments, however, are therapeutically insufficient and even though more recently developed drugs are particularly improving side effects, the efficacy or response rate of the drugs has fundamentally not improved. Therefore it is necessary to develop new methods to identify novel mechanisms not based on merely the symptomatology, but on biologically relevant (endo) phenotypes. This review examines the option of integrating mouse and human behavioural genetics to aid the identification of the putative underlying pathophysiological mechanisms and pharmacological targets for psychiatric disorders.

Deficiency of the meso-diencephalic dopamine (mdDA) neuron specific transcription factor Pitx3 in aphakia (ak) mice results in the loss of the substantia nigra compacta (SNc). Concomitantly, reduced spontaneous locomotor behavior, symptoms reminiscent to those in Parkinson's disease, has been reported. However, the ak mouse line originates from the 1960s and has been compared to C57BL/6J inbred controls. Therefore, to define Pitx3 gene function in baseline and novelty-induced locomotor behavior and mdDA neuronal activity, we analyzed Pitx3-deficiency in a controlled genetic and epigenetic background. The analysis implicated that, in contrast to the controversial and previously reported hypo-activity in ak mice, Pitx3-/- mice showed normal dark phase motor activity levels. Our data also revealed that ak and Pitx3-/- mice both display a similar neuro-anatomical and physiological phenotype, and, interestingly, showed increased spontaneous home cage activity levels during their habitual sleep phase. Further behavioral analysis revealed that both ak and Pitx3-/- mice have reduced transitions but increased consolidation of specific locomotor behaviors, such as rearing and horizontal movement. Thus, Pitx3 is not involved in the expression of nighttime motor activity levels, but is critical for selective mdDA neuronal activity and associated with increased consolidation of movement.

Objective: To investigate whether serum levels of follicle-stimulating hormone (FSH), inhibin B, and anti-Müllerian hormone (AMH) can be used as predictors of recovery of ovarian function in anorexia nervosa after weight gain., Design: Follow-up cohort study., Setting: Two specialized treatment centers for eating disorders, one for adolescents (aged between 12 and 17 years) and one for adults (older than the age of 17 years)., Patient(s): Sixty-one young women (mean age, 18.2 years) with anorexia nervosa., Intervention(s): None (standard treatment program)., Main Outcome Measure(s): Time to recovery of menses., Result(s): Forty-two (69%) patients recovered in weight within the 1st year, of which only 24 (39%) reached resumption of regular menstrual cycles. Next to weight gain itself, initial ovarian endocrine markers such as FSH, inhibin B, and AMH hormone were capable of predicting chances for resumption of menses in a multivariate analysis with time to recovery as the main outcome measure., Conclusion(s): Initial ovarian endocrine markers FSH, inhibin B, and AMH can predict successful recovery of ovarian function in anorexia nervosa patients undergoing treatment to gain weight.

Recent studies suggest running wheel activity to be naturally rewarding and reinforcing; considering the shared neuro-behavioural characteristics with drug-induced reward situations, wheel running behaviour gains interest as a tool to study mechanisms underlying reward-sensitivity. Previously, we showed that wheel running has the potential to disrupt the daily organization of home cage behaviour in female C57BL/6 [de Visser L, van den Bos R, Spruijt BM. Automated home cage observations as a tool to measure the effects of wheel running on cage floor locomotion. Behav Brain Res 2005;160:382-8]. In the present study, we investigated the effects of novelty-induced stress on wheel running and its impact on home cage behaviour in male C57BL/6 and DBA/2 mice. Our aim was to determine whether wheel running may be used as a tool to study both genetic and environmentally induced differences in sensitivity to rewarding behaviour in mice. One group of male mice was placed in an automated home cage observation system for 2 weeks with a wheel integrated in the cage. A second group of mice was allowed to habituate to this cage for 1 week before a running wheel was introduced. Results showed a pronounced sensitising effect of novelty on the level of wheel running in C57Bl/6 mice but not in DBA mice. Overall levels of wheel running were higher in DBA/2 mice. Furthermore, wheel running affected circadian rhythmicity in DBA/2 mice but not in C57BL/6 mice. From these findings we tentatively suggest that wheel running behaviour could serve as a tool to study the interaction between genetic and environmental factors in sensitivity to rewarding behaviour in mice. As it is displayed spontaneously and easy to monitor, wheel running may be well suitable to be included in high-throughput phenotyping assays.

Food restricted rodents develop activity-based anorexia in the presence of a running wheel, characterised by increased physical activity, weight loss and decreased leptin levels. Here, we determined trait differences in the development of activity-based anorexia between C57BL/6J and DBA/2J inbred mouse lines previously reported as having low and high anxiety, respectively. C57BL/6J mice housed with running wheels and exposed to scheduled feeding reduced their wheel activity, in contrast to DBA/2J mice which exhibited increased behavioural activity under these conditions. Food restriction induced hypoleptinemia in both strains, but the decline in plasma leptin was stronger in DBA/2J mice and correlated with increased activity only in that strain. These data suggest that plasma leptin level dynamics rather than hypoleptinemia alone influences the development of activity-based anorexia and that recombinant inbred panels based on these progenitor lines offer opportunities for the identification of molecular determinants for anorexia nervosa related behavioural traits.

Food restriction paradigms are widely used in animal studies to investigate systems involved in energy regulation. We have observed behavioral, physiological, and molecular differences in response to food restriction in three inbred mouse strains, C57BL/6J, A/J, and DBA/2J. These are the progenitors of chromosome substitution and recombinant inbred mouse strains used for mapping complex traits. DBA/2J and A/J mice increased their locomotor activity during food restriction, and both displayed a decrease in body temperature, but the decrease was significantly larger in DBA/2J compared with A/J mice. C57BL/6J mice did not increase their locomotor activity and displayed a large decrease in their body temperature. The large decline in body temperature during food restriction in DBA/2J and C57BL/6J strains was associated with a robust reduction in plasma leptin levels. DBA/2J mice showed a marked decrease in white and brown adipose tissue masses and an upregulation of the antithermogenic hypothalamic neuropeptide Y Y(1) receptor. In contrast, A/J mice showed a reduction in body temperature to a lesser extent that may be explained by downregulation of the thermogenic melanocortin 3 receptor and by behavioral thermoregulation as a consequence of their increased locomotor activity. These data indicate that genetic background is an important parameter in controlling an animal's adaptation strategy in response to food restriction. Therefore, mouse genetic mapping populations based on these progenitor lines are highly valuable for investigating mechanisms underlying strain-dependent differences in behavioral physiology that are seen during reduced food availability.

The central melanocortin (MC) system is one of the best-characterized neuropeptidergic systems involved in the regulation of energy balance. This short review describes the role of the central MC system in feeding behavior. Pharmacological, anatomical and genetic studies show that activation of the MC system reduces meal size, whereas de-activation of the MC system increases meal size. Several brain regions, including distinct hypothalamic nuclei and the hindbrain, are involved in this process. Further dissection of MC pathways in feeding behavior is the subject of recent and probably future studies. As the MC system is involved in animal models of obesity and (possibly) anorexia, it appears that this is a target system for development of drugs for the treatment of disturbed human eating behavior.

Activity-based anorexia (ABA) mimics starvation and hyperactivity of anorexia nervosa patients in rats. Activation of the melanocortin (MC) system leads to hypophagia and increased energy expenditure in ad libitum fed rats. Therefore, activation of the MC system might underlie the development and propagation of ABA. Pro-opiomelanocortin (POMC) gene expression is normally decreased during negative energy balance. Strikingly, we found a transient up-regulation of POMC mRNA levels in the arcuate nucleus during the development of ABA, indicating a hyperactive MC system. However, wheel running and food intake were not influenced by treating ABA rats with the competitive antagonist SHU9119. This suggests that agonism of MC receptors by endogenous alpha-melanocyte-stimulating hormone (alpha-MSH) levels does not underlie ABA. Instead, treatment with the inverse agonist AgRP(83-132) did ameliorate signs of ABA. This implies that modulation of constitutive MC receptor activity rather than antagonizing putative alpha-MSH release contributes to the development and propagation of ABA.

Background: Anorexia nervosa (AN) patients often show extreme hypophagia and excessive physical activity. Activity-based anorexia (ABA) is considered an animal model of AN and mimics food restriction and hyperactivity in rats. This study investigated whether treatment with olanzapine (Zyprexa) reduces the development of ABA in rats. The effect of olanzapine treatment in AN patients was also evaluated in a small open-label study., Methods: Rats were chronically (1 week) infused with olanzapine (7.5 mg/kg) and exposed to the ABA model or ad libitum feeding. Hyperactive AN patients were followed for up to 3 months of olanzapine treatment (5 mg/kg)., Results: Olanzapine treatment reduced development of ABA in rats by reducing running wheel activity, starvation-induced hypothermia and activation of the hypothalamus-pituitary-adrenal axis. Olanzapine treatment reduced activity levels of AN patients compared with untreated AN patients, without affecting body weight and plasma leptin levels., Conclusions: Olanzapine treatment reduced wheel running and thereby diminished development of ABA in rats. Olanzapine treatment also reduced physical activity in hyperactive AN patients in a small open-label study. These data support the need for controlled studies investigating the putative beneficial effects of olanzapine treatment in AN patients.