Optical coherence tomography reveals retinal thinning in schizophrenia spectrum disorders.

BACKGROUND: Schizophrenia spectrum disorders (SSDs) are presumed to be associated with retinal thinning. However, evidence is lacking as to whether these retinal alterations reflect a disease-specific process or are rather a consequence of comorbid diseases or concomitant microvascular impairment. METHODS: The study included 126 eyes of 65 patients with SSDs and 143 eyes of 72 healthy controls. We examined macula and optic disc measures by optical coherence tomography (OCT) and OCT angiography (OCT-A). Additive mixed models were used to assess the impact of SSDs on retinal thickness and perfusion and to explore the association of retinal and clinical disease-related parameters by controlling for several ocular and systemic covariates (age, sex, spherical equivalent, intraocular pressure, body mass index, diabetes, hypertension, smoking status, and OCT signal strength). RESULTS: OCT revealed significantly lower parafoveal macular, macular ganglion cell-inner plexiform layer (GCIPL), and macular retinal nerve fiber layer (RNFL) thickness and thinner mean and superior peripapillary RNFL in SSDs. In contrast, the applied OCT-A investigations, which included macular and peripapillary perfusion density, macular vessel density, and size of the foveal avascular zone, did not reveal any significant between-group differences. Finally, a longer duration of illness and higher chlorpromazine equivalent doses were associated with lower parafoveal macular and macular RNFL thickness. CONCLUSIONS: This study strengthens the evidence for disease-related retinal thinning in SSDs.

Spironolactone alleviates schizophrenia-related reversal learning in Tcf4 transgenic mice subjected to social defeat.

Cognitive deficits are a hallmark of schizophrenia, for which no convincing pharmacological treatment option is currently available. Here, we tested spironolactone as a repurposed compound in Tcf4 transgenic mice subjected to psychosocial stress. In this '2-hit' gene by environment mouse (GxE) model, the animals showed schizophrenia-related cognitive deficits. We had previously shown that spironolactone ameliorates working memory deficits and hyperactivity in a mouse model of cortical excitatory/inhibitory (E/I) dysbalance caused by an overactive NRG1-ERBB4 signaling pathway. In an add-on clinical study design, we used spironolactone as adjuvant medication to the standard antipsychotic drug aripiprazole. We characterized the compound effects using our previously established Platform for Systematic Semi-Automated Behavioral and Cognitive Profiling (PsyCoP). PsyCoP is a widely applicable analysis pipeline based on the Research Domain Criteria (RDoC) framework aiming at facilitating translation into the clinic. In addition, we use dimensional reduction to analyze and visualize overall treatment effect profiles. We found that spironolactone and aripiprazole improve deficits of several cognitive domains in Tcf4tg x SD mice but partially interfere with each other's effect in the combination therapy. A similar interaction was detected for the modulation of novelty-induced activity. In addition to its strong activity-dampening effects, we found an increase in negative valence measures as a side effect of aripiprazole treatment in mice. We suggest that repurposed drug candidates should first be tested in an adequate preclinical setting before initiating clinical trials. In addition, a more specific and effective NRG1-ERBB4 pathway inhibitor or more potent E/I balancing drug might enhance the ameliorating effect on cognition even further.

Expression of Lineage Transcription Factors Identifies Differences in Transition States of Induced Human Oligodendrocyte Differentiation.

Oligodendrocytes (OLs) are critical for myelination and are implicated in several brain disorders. Directed differentiation of human-induced OLs (iOLs) from pluripotent stem cells can be achieved by forced expression of different combinations of the transcription factors SOX10 (S), OLIG2 (O), and NKX6.2 (N). Here, we applied quantitative image analysis and single-cell transcriptomics to compare different transcription factor (TF) combinations for their efficacy towards robust OL lineage conversion. Compared with S alone, the combination of SON increases the number of iOLs and generates iOLs with a more complex morphology and higher expression levels of myelin-marker genes. RNA velocity analysis of individual cells reveals that S generates a population of oligodendrocyte-precursor cells (OPCs) that appear to be more immature than those generated by SON and to display distinct molecular properties. Our work highlights that TFs for generating iOPCs or iOLs should be chosen depending on the intended application or research question, and that SON might be beneficial to study more mature iOLs while S might be better suited to investigate iOPC biology.

Circadian gene × environment perturbations influence alcohol drinking in Cryptochrome-deficient mice.

Alcohol use disorder (AUD) is a widespread addiction disorder with severe consequences for health. AUD patients often suffer from sleep disturbances and irregular daily patterns. Conversely, disruptions of circadian rhythms are considered a risk factor for AUD and alcohol relapses. In this study, we investigated the extent to which circadian genetic and environmental disruptions and their interaction alter alcohol drinking behaviour in mice. As a model of genetic circadian disruption, we used Cryptochrome1/2-deficient (Cry1/2-/- ) mice with strongly suppressed circadian rhythms and found that they exhibit significantly reduced preference for alcohol but increased incentive motivation to obtain it. Similarly, we found that low circadian SCN amplitude correlates with reduced alcohol preference in WT mice. Moreover, we show that the low alcohol preference of Cry1/2-/- mice concurs with high corticosterone and low levels of the orexin precursor prepro-orexin and that WT and Cry1/2-/- mice respond differently to alcohol withdrawal. As a model of environmentally induced disruption of circadian rhythms, we exposed mice to a "shift work" light/dark regimen, which also leads to a reduction in their alcohol preference. Interestingly, this effect is even more pronounced when genetic and environmental circadian perturbations interact in Cry1/2-/- mice under "shift work" conditions. In conclusion, our study demonstrates that in mice, disturbances in circadian rhythms have pronounced effects on alcohol consumption as well as on physiological factors and other behaviours associated with AUD and that the interaction between circadian genetic and environmental disturbances further alters alcohol consumption behaviour.

An in-depth neurobehavioral characterization shows anxiety-like traits, impaired habituation behavior, and restlessness in male Cryptochrome-deficient mice.

Many psychiatric disorders, for example, anxiety, are accompanied by disturbances of circadian rhythms, including disturbed sleep/wake cycles, changes in locomotor activity, and abnormal endocrine function. Conversely, alternations of circadian rhythms are a risk factor for the development of psychiatric disorders. This assumption is supported by animals with clock gene mutations which often display behaviors that resemble human psychiatric disorders. In this study, we performed an in-depth behavioral analysis with male mice lacking the central clock genes Cryptochrome 1 and 2 (Cry1/2-/- ), which are thus unable to express endogenous circadian rhythms. With wild-type and Cry1/2-/- mice, we performed an extensive behavioral analysis to study their cognitive abilities, social behavior, and their expression of depression-like and anxiety-like behavior. While Cry1/2-/- mice showed only mild abnormalities at cognitive and social behavioral levels, they were consistently more anxious than wildtype mice. Anxiety-like behavior was particularly evident in reduced mobility in new environments, altered ability to habituate, compensatory behavior, and consistent restless behavior across many behavioral tests. In line with their anxiety-like behavioral phenotype, Cry1/2-/- mice have higher c-Fos activity in the amygdala after exposure to an anxiogenic stressor than wild-type mice. In our study, we identified Cry1/2-/- mice as animals that qualify as a translational mouse model for anxiety disorder in humans because of its consistent behavior of restlessness, increased immobility, and dysfunctional habituation in new environments.

PsyCoP - A Platform for Systematic Semi-Automated Behavioral and Cognitive Profiling Reveals Gene and Environment Dependent Impairments of Tcf4 Transgenic Mice Subjected to Social Defeat.

Recently, hundreds of risk genes associated with psychiatric disorders have been identified. These are thought to interact with environmental stress factors in precipitating pathological behaviors. However, the individual phenotypes resulting from specific genotype by environment (G×E) interactions remain to be determined. Toward a more systematic approach, we developed a novel standardized and partially automatized platform for systematic behavioral and cognitive profiling (PsyCoP). Here, we assessed the behavioral and cognitive disturbances in Tcf4 transgenic mice (Tcf4tg) exposed to psychosocial stress by social defeat during adolescence using a "two-hit" G×E mouse model. Notably, TCF4 has been repeatedly identified as a candidate risk gene for different psychiatric diseases and Tcf4tg mice display behavioral endophenotypes such as fear memory impairment and hyperactivity. We use the Research Domain Criteria (RDoC) concept as framework to categorize phenotyping results in a translational approach. We propose two methods of dimension reduction, clustering, and visualization of behavioral phenotypes to retain statistical power and clarity of the overview. Taken together, our results reveal that sensorimotor gating is disturbed by Tcf4 overexpression whereas both negative and positive valence systems are primarily influenced by psychosocial stress. Moreover, we confirm previous reports showing that deficits in the cognitive domain are largely dependent on the interaction between Tcf4 and psychosocial stress. We recommend that the standardized analysis and visualization strategies described here should be applied to other two-hit mouse models of psychiatric diseases and anticipate that this will help directing future preclinical treatment trials.

Assessing behavior and cognition in rodents, nonhuman primates, and humans: where are the limits of translation?
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New psychopharmacological treatments are needed for affective and nonaffective psychoses, especially for the associated negative and cognitive symptoms. Earlier developments mostly failed, probably partly because of limitations in behavioral models used for validation. Now, deeper understanding of the genetics underlying disease pathogenesis and progress in genetic engineering will generate many rodent models with increased construct validity. To improve these models' translational value, we need complementary data from nonhuman primates. We also have to improve and streamline behavioral test systems to cope with increased demand. Here, we propose a comprehensive neurocognitive test battery that should overcome the disadvantages of single tests and yield cognitive/behavioral profiles for modeling subsets of patient symptoms. Further, we delineate a concept for classifying disease-relevant cognitive endophenotypes to balance between face and construct validity and clinical diagnostics. In summary, this review discusses new concepts and the limitations and future potential of translational research on cognition in psychiatry.
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Se requiere de nuevos tratamientos psicofarmacológicos para las psicosis afectivas y no afectivas, especialmente para los síntomas negativos y cognitivos asociados. La mayoría de los desarrollos anteriores fallaron; en parte debido, probablemente, a las limitaciones en los modelos conductuales empleados para la validación. Ahora, una comprensión más profunda de la genética subyacente a la patogénesis de la enfermedad y el progreso en la ingeniería genética generará muchos modelos de roedores con una mayor validez de constructo. Para mejorar el valor de estos modelos translacionales se requiere de datos complementarios de primates no humanos. También hay que mejorar y racionalizar los sistemas de pruebas conductuales para hacer frente a una mayor demanda. En este artículo se propone una batería completa de pruebas neurocognitivas que debería superar las desventajas de las pruebas individuales y generar perfiles cognitivo-conductuales para modelar subconjuntos de síntomas del paciente. Además, se plantea un concepto para clasificar los endofenotipos cognitivos relevantes para la enfermedad a fin de equilibrar la validez aparente y de constructo con el diagnóstico clínico. En resumen, esta revisión analiza nuevos conceptos, y las limitaciones y el potencial futuro de la investigación translacional sobre la cognición en psiquiatría.

De nouveaux traitements psychopharmacologiques sont nécessaires pour les psychoses dysthymiques ou non, surtout pour les symptômes associés négatifs et cognitifs. Par le passé, la plupart des développements ont échoué, probablement en partie en raison des limites des modèles comportementaux utilisés pour la validation. Aujourd'hui, une meilleure compréhension de la génétique de la pathogenèse de la maladie et les progrès du génie génétique vont produire de nombreux modèles de rongeurs mieux construits. Des données supplémentaires issues de primates non humains sont nécessaires pour améliorer la valeur traductive de ces modèles. Afin de satisfaire une demande croissante, nous devons aussi améliorer et rationaliser les systèmes de tests comportementaux. Nous proposons ici une batterie complète de tests neurocognitifs susceptible de palier les inconvénients des tests isolés et de fournir des profils cognitifs/comportementaux pour des sous-groupes de modélisation des symptômes des patients. En outre, nous définissons un concept pour classer les endophénotypes cognitifs pertinents pour la maladie afin de trouver un équilibre entre une validité de façade et de construit et les diagnostics cliniques. En résumé, cet article analyse de nouveaux concepts ainsi que les limites et les futures possibilités de la recherche translationnelle sur la cognition en psychiatrie.