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Steatotic liver disease (SLD) is a burgeoning health problem predominantly associated with excessive alcohol consumption, which causes alcohol-related liver disease (ALD), and high caloric intake, which results in metabolic dysfunction-associated SLD (MASLD). The pathogenesis of ALD and MASLD, which can progress from steatohepatitis to more severe conditions such as liver fibrosis, cirrhosis, and hepatocellular carcinoma, is complicated by several factors. Recently, extracellular ATP and adenosine (Ado), as damage-associated molecular patterns, were reported to promote inflammation and liver fibrosis, contributing to SLD pathogenesis. Here, we explored the in vivo dynamics of hepatic extracellular ATP and Ado during the progression of steatohepatitis using a genetically encoded GPCR-activation-based sensor (GRAB) in zebrafish models. We established hepatocyte-specific GRABATP and GRABAdo in zebrafish and investigated the changes in in vivo hepatic extracellular ATP and Ado levels under ALD or MASLD conditions. Disease-specific changes in hepatocyte extracellular ATP and Ado levels were observed, clearly indicating a correlation between hepatocyte extracellular ATP/Ado dynamics and disease progression. Furthermore, clodronate, a vesicular nucleotide transporter inhibitor, alleviated the MASLD phenotype by reducing the hepatic extracellular ATP and Ado content. These findings provide deep insights into extracellular ATP/Ado dynamics in disease progression, suggesting therapeutic potential for ALD and MASLD.
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Hígado Graso , Neoplasias Hepáticas , Enfermedades Metabólicas , Perciformes , Animales , Pez Cebra , Adenosina , Cirrosis Hepática , Progresión de la Enfermedad , Adenosina TrifosfatoRESUMEN
KPNA1 is a mediator of nucleocytoplasmic transport that is abundantly expressed in the mammalian brain and regulates neuronal differentiation and synaptic function. De novo mutations in Kpna1 have been identified using genome-wide association studies in humans with schizophrenia; however, it remains unclear how KPNA1 contributes to schizophrenia pathogenesis. Recent studies have suggested a complex combination of genetic and environmental factors that are closely related to psychiatric disorders. Here, we found that subchronic administration of phencyclidine, a psychotropic drug, induced vulnerability and behavioral abnormalities consistent with the symptoms of schizophrenia in Kpna1-deficient mice. Microarray assessment revealed that the expression levels of dopamine d1/d2 receptors, an RNA editing enzyme, and a cytoplasmic dynein component were significantly altered in the nucleus accumbens brain region in a gene-environment (G × E) interaction-dependent manner. Our findings demonstrate that Kpna1-deficient mice may be useful as a G × E interaction mouse model for psychiatric disorders and for further investigation into the pathogenesis of such diseases and disorders.
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Esquizofrenia , Humanos , Ratones , Animales , Esquizofrenia/inducido químicamente , Esquizofrenia/genética , Interacción Gen-Ambiente , Estudio de Asociación del Genoma Completo , Psicotrópicos/farmacología , Fenciclidina/farmacología , Núcleo Accumbens/metabolismo , Mamíferos/metabolismo , alfa Carioferinas/genética , alfa Carioferinas/metabolismoRESUMEN
RATIONALE: Clozapine N-oxide (CNO) has been developed as a ligand to selectively activate designer receptors exclusively activated by designer drugs (DREADDs). However, previous studies have revealed that peripherally injected CNO is reverse-metabolized into clozapine, which, in addition to activating DREADDs, acts as an antagonist at various neurotransmitter receptors, suggesting potential off-target effects of CNO on animal physiology and behaviors. Recently, second-generation DREADD agonists compound 21 (C21) and JHU37160 (J60) have been developed, but their off-target effects are not fully understood. OBJECTIVES: The present studies assessed the effect of novel DREADD ligands on reward-seeking behavior. METHODS: We first tested the possible effect of acute i.p. injection of low-to-moderate (0.1, 0.3, 1, 3 mg/kg) of CNO, C21, and J60 on motivated reward-seeking behavior in wild-type mice. We then examined whether a high dose (10 mg/kg) of these drugs might be able to alter responding. RESULTS: Low-to-moderate doses of all drugs and a high dose of CNO or C21 did not alter operant lick responding for a reward under a progressive ratio schedule of reinforcement, in which the number of operant lick responses to obtain a reward increases after each reward collection. However, high-dose J60 resulted in a total lack of responding that was later observed in an open field arena to be due to a sedative effect. CONCLUSIONS: This study provides definitive evidence that commonly used doses of CNO, C21, and J60 have negligible off-target effects on motivated reward-seeking but urges caution when using high doses of J60 due to sedative effects.
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Clozapina , Drogas de Diseño , Ratones , Animales , Clozapina/farmacología , Recompensa , Drogas de Diseño/farmacologíaRESUMEN
Schizophrenia is a psychiatric disorder that affects around 1% of the population in widespread populations, with severe cases leading to long-term hospitalization and necessitation of lifelong treatment. Recent studies on schizophrenia have highlighted the involvement of inflammatory and immunoregulatory mechanisms with the onset of symptoms, and the usage of anti-inflammatory treatments are being tested against periods of rapid psychosis. In the central nervous system, microglia are the innate immune population which are activated in response to a wide range of physical and psychological stress factors and produce proinflammatory mediators such as cytokines. Microglial activation and neuroinflammation has been associated to numerous psychiatric disorders including schizophrenia, especially during psychotic episodes. Thus, novel treatments which dampen microglial activation may be of great relevance in the treatment of psychiatric disorders. Fingolimod (FTY720) is a drug used as an immunosuppressive treatment to multiple sclerosis. Recent clinical trials have focused on FTY720 as a treatment for the behavioral symptoms in schizophrenia. However, the mechanisms of Fingolimod in treating the symptoms of schizophrenia are not clear. In this study we use a recently developed neuroinflammatory psychosis model in mice: cuprizone short-term exposure, to investigate the effects of FTY720 administration. FTY720 administration was able to completely alleviate methamphetamine hypersensitivity caused by cuprizone exposure. Moreover, administration of FTY720 improved multiple measures of neuroinflammation (microglial activation, cytokine production, and leucocyte infiltration). In conclusion, our results highlight the future use of FTY720 as a direct anti-inflammatory treatment against microglial activation and psychosis.
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Clorhidrato de Fingolimod , Trastornos Psicóticos , Animales , Ratones , Clorhidrato de Fingolimod/farmacología , Clorhidrato de Fingolimod/uso terapéutico , Cuprizona , Microglía , Enfermedades NeuroinflamatoriasRESUMEN
Vaccinia-related kinase 1 (VRK1) is a serine/threonine kinase, for which mutations have been reported cause to neurodegenerative diseases, including spinal muscular atrophy, characterized by microcephaly, motor dysfunction, and impaired cognitive function, in humans. Partial Vrk1 knockdown in mice has been associated with microcephaly and impaired motor function. However, the pathophysiological relationship between VRK1 and neurodegenerative disorders and the precise mechanism of VRK1-related microcephaly and motor function deficits have not been fully investigated. To address this, in this study, we established vrk1-deficient (vrk1-/-) zebrafish and found that they show mild microcephaly and impaired motor function with a low brain dopamine content. Furthermore, vrk1-/- zebrafish exhibited decreased cell proliferation, defects in nuclear envelope formation, and heterochromatin formation in the brain. To our knowledge, this is the first report demonstrating the important role of VRK1 in microcephaly and motor dysfunction in vivo using vrk1-/- zebrafish. These findings contribute to elucidating the pathophysiological mechanisms underlying VRK1-mediated neurodegenerative diseases associated with microcephaly.
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Microcefalia , Pez Cebra , Animales , Péptidos y Proteínas de Señalización Intracelular , Microcefalia/genética , Proteínas Serina-Treonina Quinasas/genética , Pez Cebra/genéticaRESUMEN
Cellular senescence, a state of irreversible cell-cycle arrest caused by a variety of cellular stresses, is critically involved in age-related tissue dysfunction in various organs. However, the features of cells in the central nervous system that undergo senescence and their role in neural impairment are not well understood as yet. Here, through comprehensive investigations utilising single-cell transcriptome analysis and various mouse models, we show that microglia, particularly in the white matter, undergo cellular senescence in the brain and spinal cord during ageing and in disease models involving demyelination. Microglial senescence is predominantly detected in disease-associated microglia, which appear in ageing and neurodegenerative diseases. We also find that commensal bacteria promote the accumulation of senescent microglia and disease-associated microglia during ageing. Furthermore, knockout of p16INK4a, a key senescence inducer, ameliorates the neuroinflammatory phenotype in damaged spinal cords in mice. These results advance our understanding of the role of cellular senescence in the central nervous system and open up possibilities for the treatment of age-related neural disorders.
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Microglía , Sustancia Blanca , Ratones , Animales , Envejecimiento/fisiología , Senescencia Celular/fisiología , FenotipoRESUMEN
The nucleus accumbens (NAc) is a critical component of a limbic basal ganglia circuit that is thought to play an important role in decision-making and the processing of rewarding stimuli. As part of this circuit, dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) of the NAc core are known to send a major projection to the substantia nigra pars reticulata (SNr). However, the functional role of this SNr-projecting NAc D1-MSN (NAcD1-MSN-SNr) pathway is still largely uncharacterized. Moreover, as the SNr is thought to belong to both limbic and motor information-processing basal ganglia loops, it is possible that the NAcD1-MSN-SNr pathway may be able to influence both limbic and motor functions. In this study, we investigated the effect of optogenetic manipulation of the NAcD1-MSN-SNr pathway on reward-learning and locomotor behavior in male mice. Stimulation of the axon terminals of NAc core D1-MSNs in the SNr induced a preference for a laser-paired location, self-stimulation via a laser-paired lever, and augmented instrumental responding for a liquid reward-paired lever. Additionally, stimulation was observed to increase locomotor behavior when delivered bilaterally and induced contralateral turning behavior when delivered unilaterally. However, interestingly, inhibition of this pathway did not alter either reward-related behaviors or locomotion. These findings indicate that the NAcD1-MSN-SNr pathway is able to control both reward learning and motor behaviors.
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Núcleo Accumbens , Porción Reticular de la Sustancia Negra , Ratones , Masculino , Animales , Núcleo Accumbens/metabolismo , Dopamina/metabolismo , Porción Reticular de la Sustancia Negra/metabolismo , Neuronas Dopaminérgicas/metabolismo , Aprendizaje , Receptores de Dopamina D1/metabolismo , Ratones Endogámicos C57BLRESUMEN
Learned associations between environmental cues and the outcomes they predict (cue-outcome associations) play a major role in behavioral control, guiding not only which responses we should perform, but also which we should inhibit, in order to achieve a specific goal. The encoding of such cue-outcome associations, as well as the performance of cue-guided choice behavior, is thought to involve dopamine D1 and D2 receptor-expressing medium spiny neurons (D1-/D2-MSNs) of the nucleus accumbens (NAc). Here, using a visual discrimination task in male mice, we assessed the role of NAc D1-/D2-MSNs in cue-guided inhibition of inappropriate responding. Cell-type specific neuronal silencing and in-vivo imaging revealed NAc D2-MSNs to contribute to inhibiting behavioral responses, with activation of NAc D2-MSNs following response errors playing an important role in optimizing future choice behavior. Our findings indicate that error-signaling by NAc D2-MSNs contributes to the ability to use environmental cues to inhibit inappropriate behavior.
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Núcleo Accumbens , Receptores de Dopamina D2 , Ratones , Masculino , Animales , Núcleo Accumbens/metabolismo , Ratones Transgénicos , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo , Neuronas/metabolismo , Receptores de Dopamina D1/genética , Receptores de Dopamina D1/metabolismo , Conducta de Elección , Ratones Endogámicos C57BLRESUMEN
The ability to use environmental cues to flexibly guide responses is crucial for adaptive behavior and is thought to be controlled within a series of cortico-basal ganglia-thalamo-cortical loops. Previous evidence has indicated that different prefrontal cortical regions control dissociable aspects of behavioral flexibility, with the medial prefrontal cortex (mPFC) necessary for the ability to shift attention to a novel strategy (set-shifting) and the orbitofrontal cortex (OFC) necessary for shifting attention between learned stimulus-outcome associations (reversal learning). The nucleus accumbens (NAc) is a major downstream target of both the mPFC and the OFC; however, its role in controlling reversal learning and set-shifting abilities is still unclear. Here we investigated the contribution of the two major NAc neuronal populations, medium spiny neurons expressing either dopamine D1 or D2 receptors (D1-/D2-MSNs), in guiding reversal learning and set-shifting in an attentional set-shifting task (ASST). Persistent inhibition of neurotransmitter release from NAc D2-MSNs, but not D1-MSNs, resulted in an impaired ability for reversal learning, but not set-shifting in male mice. These findings suggest that NAc D2-MSNs play a critical role in suppressing responding toward specific learned cues that are now associated with unfavorable outcomes (i.e., in reversal stages), but not in the suppression of more general learned strategies (i.e., in set-shifting). This study provides further evidence for the anatomical separation of reversal learning and set-shifting abilities within cortico-basal ganglia-thalamo-cortical loops.
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BACKGROUND: Social withdrawal (hikikomori) has become an internationally recognized phenomenon, but its pathology and related factors are not yet fully known. We previously conducted a statistical case-control study on adolescent patients with hikikomori in Japan, which revealed the non-specificity of pathology in patients with hikikomori. Further, environmental factors, such as the lack of communication between parents and Internet overuse, were found to be significant predictors of hikikomori severity. Here, we aimed to conduct a similar preliminary case-control study in France and to compare the results with those from the study conducted in Japan. METHODS: Parents of middle school students who underwent psychiatric outpatient treatment for hikikomori (n = 10) and control group parents (n = 115) completed the Child Behavior Checklist to evaluate their child's psychopathological characteristics and the Parental Assessment of Environment and Hikikomori Severity Scales, as in our previous study in Japan. We compared the descriptive statistics and intergroup differences in France with those from the previous study conducted in Japan. In the multiple regression analysis to find predictors of hikikomori severity in French and also Japanese subjects, the same dependent and independent variables were chosen for the present study (both differed from the previous study). These were used in order to make accurate intercountry comparisons. RESULTS: The comparisons revealed no differences in the pathology of hikikomori between Japan and France. Specifically, both studies found similarly increased scores for all symptom scales, with no specific bias. However, the statistical predictors of hikikomori severity in France (lack of communication between parents and child and lack of communication with the community) differed from those in Japan (lack of communication between parents). CONCLUSION: Hikikomori in Japan and France could be considered essentially the same phenomenon; moreover, our findings demonstrated the universal non-specificity and unbiasedness of the hikikomori pathology. This suggests that hikikomori is not a single clinical category with a specific psychopathology; instead, it is a common phenotype with various underlying pathologies. However, different strategies may be required in each country to prevent the onset and progression of hikikomori.
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Trastornos Mentales , Aislamiento Social , Estudios de Casos y Controles , Francia , Humanos , Japón , Trastornos Mentales/psicología , Fobia Social , Vergüenza , Aislamiento Social/psicologíaRESUMEN
Importin α3 (Gene: Kpna3, the ortholog of human Importin α4) is a member of the importin α family and participates in nucleocytoplasmic transport by forming trimeric complexes between cargo proteins and importin ß1. Evidence from human studies has indicated that single nucleotide polymorphisms (SNP) in the KPNA3 gene are associated with the occurrence of several psychiatric disorders accompanied by abnormal reward-related behavior, including schizophrenia, major depression, and substance addiction. However, the precise roles of importin α3 in controlling reward processing and motivation are still unclear. In this study, we evaluated the behavioral effects of Kpna3 knockout (KO) in mice on performance in touchscreen operant chamber-based tasks evaluating simple (fixed-ratio) and effortful (progressive-ratio) reward-seeking behaviors. While Kpna3 KO mice showed no significant differences in operant reward learning on a fixed-ratio schedule, they demonstrated significantly increased motivation (increased break point) to instrumentally respond for sucrose on a progressive-ratio schedule. We additionally measured the number of c-Fos-positive cells, a marker of neural activity, in 20 regions of the brain and identified a network of brain regions based on their interregional correlation coefficients. Network and graph-theoretic analyses suggested that Kpna3 deficiency enhanced overall interregional functional connectivity. These findings suggest the importance of Kpna3 in motivational control and indicate that Kpna3 KO mice may be an attractive line for modeling motivational abnormalities associated with several psychiatric disorders.
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Homeostatic control with oral nutrient intake is a vital complex system involving the orderly interactions between the external and internal senses, behavioral control, reward learning, and decision-making. Sodium appetite is a representative system and has been intensively investigated in animal models of homeostatic systems and oral nutrient intake. However, the system-level mechanisms for regulating sodium intake behavior and homeostatic control remain unclear. In the current study, we attempted to provide a mechanistic understanding of sodium appetite behavior by using a computational model, the homeostatic reinforcement learning model, in which homeostatic behaviors are interpreted as reinforcement learning processes. Through simulation experiments, we confirmed that our homeostatic reinforcement learning model successfully reproduced homeostatic behaviors by regulating sodium appetite. These behaviors include the approach and avoidance behaviors to sodium according to the internal states of individuals. In addition, based on the assumption that the sense of taste is a predictor of changes in the internal state, the homeostatic reinforcement learning model successfully reproduced the previous paradoxical observations of the intragastric infusion test, which cannot be explained by the classical drive reduction theory. Moreover, we extended the homeostatic reinforcement learning model to multimodal data, and successfully reproduced the behavioral tests in which water and sodium appetite were mediated by each other. Finally, through an experimental simulation of chemical manipulation in a specific neural population in the brain stem, we proposed a testable hypothesis for the function of neural circuits involving sodium appetite behavior. The study results support the idea that osmoregulation via sodium appetitive behavior can be understood as a reinforcement learning process, and provide a mechanistic explanation for the underlying neural mechanisms of decision-making related to sodium appetite and homeostatic behavior.
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Sensorimotor information processing underlies normal cognitive and behavioral traits and has classically been evaluated through prepulse inhibition (PPI) of a startle reflex. PPI is a behavioral dimension deregulated in several neurological and psychiatric disorders, yet the mechanisms underlying the cross-diagnostic nature of PPI deficits across these conditions remain to be understood. To identify circuitry mechanisms for PPI, we performed circuitry recording over the prefrontal cortex and striatum, two brain regions previously implicated in PPI, using wild-type (WT) mice compared to Disc1-locus-impairment (LI) mice, a model representing neuropsychiatric conditions. We demonstrated that the corticostriatal projection regulates neurophysiological responses during the PPI testing in WT, whereas these circuitry responses were disrupted in Disc1-LI mice. Because our biochemical analyses revealed attenuated brain-derived neurotrophic factor (Bdnf) transport along the corticostriatal circuit in Disc1-LI mice, we investigated the potential role of Bdnf in this circuitry for regulation of PPI. Virus-mediated delivery of Bdnf into the striatum rescued PPI deficits in Disc1-LI mice. Pharmacologically augmenting Bdnf transport by chronic lithium administration, partly via phosphorylation of Huntingtin (Htt) serine-421 and its integration into the motor machinery, restored striatal Bdnf levels and rescued PPI deficits in Disc1-LI mice. Furthermore, reducing the cortical Bdnf expression negated this rescuing effect of lithium, confirming the key role of Bdnf in lithium-mediated PPI rescuing. Collectively, the data suggest that striatal Bdnf supply, collaboratively regulated by Htt and Disc1 along the corticostriatal circuit, is involved in sensorimotor gating, highlighting the utility of dimensional approach in investigating pathophysiological mechanisms across neuropsychiatric disorders.
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Factor Neurotrófico Derivado del Encéfalo , Cuerpo Estriado , Proteínas del Tejido Nervioso , Corteza Prefrontal , Inhibición Prepulso , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Cuerpo Estriado/metabolismo , Humanos , Ratones , Proteínas del Tejido Nervioso/metabolismo , Corteza Prefrontal/metabolismo , Inhibición Prepulso/fisiología , Reflejo de Sobresalto/fisiología , Filtrado Sensorial/fisiologíaRESUMEN
Vaccinia-related kinase 2 (VRK2) is a serine/threonine kinase initially identified in highly proliferative cells such as thymocytes and fetal liver cells, and it is involved in cell proliferation and survival. VRK2 is also expressed in the brain; however, its molecular function in the central nervous system is mostly unknown. Many genome-wide association studies (GWASs) have reported that VRK2 is a potential candidate molecule for neuropsychiatric diseases such as schizophrenia in humans. However, the pathophysiological relationship between VRK2 and neuropsychiatric disorders has not been fully investigated. In this study, we evaluated vrk2-deficient (vrk2-/- ) zebrafish and found that vrk2-/- female zebrafish showed aggressive behavior and different social preference compared with control (vrk2+/+ ) zebrafish, with low gamma-aminobutyric acid (GABA) content in the brain and high density of neuronal dendrites when compared to vrk2+/+ zebrafish. These findings suggest that female vrk2-/- zebrafish were indeed a model of malbehavior characterized by aggression and social interaction, which can be attributed to the low levels of GABA content in their brain.
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Estudio de Asociación del Genoma Completo , Proteínas Serina-Treonina Quinasas , Pez Cebra , Agresión , Animales , Femenino , Proteínas Serina-Treonina Quinasas/genética , Pez Cebra/genética , Ácido gamma-AminobutíricoRESUMEN
The underlying pathologies of psychiatric disorders, which cause substantial personal and social losses, remain unknown, and their elucidation is an urgent issue. To clarify the core pathological mechanisms underlying psychiatric disorders, in addition to laboratory-based research that incorporates the latest findings, it is necessary to conduct large-sample-size research and verify reproducibility. For this purpose, it is critical to conduct multicenter collaborative research across various fields, such as psychiatry, neuroscience, molecular biology, genomics, neuroimaging, cognitive science, neurophysiology, psychology, and pharmacology. Moreover, collaborative research plays an important role in the development of young researchers. In this respect, the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortium and Cognitive Genetics Collaborative Research Organization (COCORO) have played important roles. In this review, we first overview the importance of multicenter collaborative research and our target psychiatric disorders. Then, we introduce research findings on the pathophysiology of psychiatric disorders from neurocognitive, neurophysiological, neuroimaging, genetic, and basic neuroscience perspectives, focusing mainly on the findings obtained by COCORO. It is our hope that multicenter collaborative research will contribute to the elucidation of the pathological basis of psychiatric disorders.
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Macrodatos , Análisis de Datos , Trastornos Mentales , Estudios Multicéntricos como Asunto , Psiquiatría , Investigación Biomédica Traslacional , Animales , Humanos , Trastornos Mentales/genética , Metaanálisis como Asunto , Neuroimagen , Reproducibilidad de los ResultadosRESUMEN
Importin α1/KPNA1 is a member of the Importin α family widely present in the mammalian brain and has been characterized as a regulator of neuronal differentiation, synaptic functionality, and anxiety-like behavior. In humans, a de novo mutation of the KPNA1 (human Importin α5) gene has been linked with schizophrenia; however, the precise roles of KPNA1 in disorder-related behaviors are still unknown. Moreover, as recent studies have highlighted the importance of gene-environment interactions in the development of psychiatric disorders, we investigated the effects of Kpna1 deletion and social isolation stress, a paradigm that models social stress factors found in human patients, on psychiatric disorder-related behaviors in mice. Through assessment in a behavioral battery, we found that Kpna1 knockout resulted in the following behavioral phenotype: (1) decreased anxiety-like behavior in an elevated plus maze test, (2) short term memory deficits in novel object recognition test (3) impaired sensorimotor gating in a prepulse inhibition test. Importantly, exposure to social isolation stress resulted in additional behavioral abnormalities where isolated Kpna1 knockout mice exhibited: (1) impaired aversive learning and/or memory in the inhibitory avoidance test, as well as (2) increased depression-like behavior in the forced swim test. Furthermore, we investigated whether mice showed alterations in plasma levels of stress-associated signal molecules (corticosterone, cytokines, hormones, receptors), and found that Kpna1 knockout significantly altered levels of corticosterone and LIX (CXCL5). Moreover, significant decreases in the level of prolactin were found in all groups except for group-housed wild type mice. Our findings demonstrate that Kpna1 deletion can trigger widespread behavioral abnormalities associated with psychiatric disorders, some of which were further exacerbated by exposure to adolescent social isolation. The use of Kpna1 knockout mice as a model for psychiatric disorders may show promise for further investigation of gene-environment interactions involved in the pathogenesis of psychiatric disorders.
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Ansiedad/genética , Conducta Animal , Depresión/genética , Esquizofrenia/genética , Aislamiento Social/psicología , alfa Carioferinas/genética , Animales , Ansiedad/sangre , Quimiocina CXCL5/sangre , Corticosterona/sangre , Depresión/sangre , Modelos Animales de Enfermedad , Femenino , Aprendizaje , Masculino , Memoria a Corto Plazo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Prolactina/sangre , Esquizofrenia/sangre , Transducción de Señal/genéticaRESUMEN
Metabolic dysfunction is thought to contribute to the severity of psychiatric disorders; however, it has been unclear whether current highsimple sugar diets contribute to pathogenesis of these diseases. Here, we demonstrate that a high-sucrose diet during adolescence induces psychosis-related behavioral endophenotypes, including hyperactivity, poor working memory, impaired sensory gating, and disrupted interneuron function in mice deficient for glyoxalase-1 (GLO1), an enzyme involved in detoxification of sucrose metabolites. Furthermore, the high-sucrose diet induced microcapillary impairments and reduced brain glucose uptake in brains of Glo1-deficient mice. Aspirin protected against this angiopathy, enhancing brain glucose uptake and preventing abnormal behavioral phenotypes. Similar vascular damage to our model mice was found in the brains of randomly collected schizophrenia and bipolar disorder patients, suggesting that psychiatric disorders are associated with angiopathy in the brain caused by various environmental stresses, including metabolic stress.
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Our brain can be recognized as a network of largely hierarchically organized neural circuits that operate to control specific functions, but when acting in parallel, enable the performance of complex and simultaneous behaviors. Indeed, many of our daily actions require concurrent information processing in sensorimotor, associative, and limbic circuits that are dynamically and hierarchically modulated by sensory information and previous learning. This organization of information processing in biological organisms has served as a major inspiration for artificial intelligence and has helped to create in silico systems capable of matching or even outperforming humans in several specific tasks, including visual recognition and strategy-based games. However, the development of human-like robots that are able to move as quickly as humans and respond flexibly in various situations remains a major challenge and indicates an area where further use of parallel and hierarchical architectures may hold promise. In this article we review several important neural and behavioral mechanisms organizing hierarchical and predictive processing for the acquisition and realization of flexible behavioral control. Then, inspired by the organizational features of brain circuits, we introduce a multi-timescale parallel and hierarchical learning framework for the realization of versatile and agile movement in humanoid robots.
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Inteligencia Artificial , Robótica , Control de la Conducta , Simulación por Computador , Humanos , AprendizajeRESUMEN
Neuroscience and artificial intelligence (AI) share a long history of collaboration. Advances in neuroscience, alongside huge leaps in computer processing power over the last few decades, have given rise to a new generation of in silico neural networks inspired by the architecture of the brain. These AI systems are now capable of many of the advanced perceptual and cognitive abilities of biological systems, including object recognition and decision making. Moreover, AI is now increasingly being employed as a tool for neuroscience research and is transforming our understanding of brain functions. In particular, deep learning has been used to model how convolutional layers and recurrent connections in the brain's cerebral cortex control important functions, including visual processing, memory, and motor control. Excitingly, the use of neuroscience-inspired AI also holds great promise for understanding how changes in brain networks result in psychopathologies, and could even be utilized in treatment regimes. Here we discuss recent advancements in four areas in which the relationship between neuroscience and AI has led to major advancements in the field; (1) AI models of working memory, (2) AI visual processing, (3) AI analysis of big neuroscience datasets, and (4) computational psychiatry.