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Early-life stress (ES) leads to cognitive dysfunction in female adolescents, but the underlying neural mechanisms remain elusive. Recent evidence suggests that the cell adhesion molecules NECTIN1 and NECTIN3 play a role in cognition and ES-related cognitive deficits in male rodents. In this study, we aimed to investigate whether and how nectins contribute to ES-induced cognitive dysfunction in female adolescents. Applying the well-established limited bedding and nesting material paradigm, we found that ES impairs recognition memory, suppresses prefrontal NECTIN1 and hippocampal NECTIN3 expression, and upregulates corticotropin-releasing hormone (Crh) and its receptor 1 (Crhr1) mRNA levels in the hippocampus of adolescent female mice. Genetic experiments revealed that the reduction of dorsal CA1 (dCA1) NECTIN3 mediates ES-induced object recognition memory deficits, as knocking down dCA1 NECTIN3 impaired animals' performance in the novel object recognition task, while overexpression of dCA1 NECTIN3 successfully reversed the ES-induced deficits. Notably, prefrontal NECTIN1 knockdown did not result in significant cognitive impairments. Furthermore, acute systemic administration of antalarmin, a CRHR1 antagonist, upregulated hippocampal NECTIN3 levels and rescued object and spatial memory deficits in stressed mice. Our findings underscore the critical role of dCA1 NECTIN3 in mediating ES-induced object recognition memory deficits in adolescent female mice, highlighting it as a potential therapeutic target for stress-related psychiatric disorders in women.
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Vortioxetine is a novel multimodal antidepressant, but its precise efficacy and dose-response relationship for treating different symptoms in major depressive disorder (MDD) is still unclear. This umbrella review aims to assess the effectiveness, tolerability, and dose-response relationship of vortioxetine across a comprehensive range of clinical features in adults with MDD, including cognition, depression, anxiety, quality of life, and side effects. We meticulously searched eight electronic databases and included systematic reviews (SRs) and meta-analyses (MAs) of vortioxetine. The methodological quality of each included SR was independently assessed using the AMSTAR2 tool. To evaluate the credibility of the evidence, we utilized the GRADE framework and the Ioannidis criteria. In total, 35 SRs with 278 MAs met the inclusion criteria and based on these studies we performed 56 MAs of interest. While vortioxetine has been consistently shown to have positive effects on various domains, the evidence regarding cognitive performance and depression symptoms is notably robust compared to placebo, despite of relatively overall low quality of evidence. Finally, a dose-response relationship was observed across all categories within the treatment range of 5-20 mg/d and a dosage of vortioxetine 20 mg/d is recommended for adult MDD patients to achieve full functional recovery.
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Antidepresivos , Trastorno Depresivo Mayor , Relación Dosis-Respuesta a Droga , Vortioxetina , Vortioxetina/farmacología , Vortioxetina/administración & dosificación , Humanos , Trastorno Depresivo Mayor/tratamiento farmacológico , Antidepresivos/farmacología , Antidepresivos/administración & dosificación , Calidad de VidaRESUMEN
BACKGROUND: As a central hub in cognitive and emotional brain circuits, the striatum is considered likely to be integrally involved in the psychopathology of bipolar disorder (BD). However, it remains unclear how alterations in striatal function contribute to distinct symptomatology of BD during different mood states. METHODS: Behavioral assessment (i.e., emotional symptoms and cognitive performance) and neuroimaging data were collected from 125 participants comprising 31 (hypo)manic, 31 depressive, and 31 euthymic patients with BD, and 32 healthy control participants. We compared the functional connectivity (FC) of striatal subregions across BD mood states with healthy control participants and then used a multivariate data-driven approach to explore dimensional associations between striatal connectivity and behavioral performance. Finally, we compared the FC and behavioral composite scores, which reflect the individual weighted representation of the associations, among different mood states. RESULTS: Patients in all mood states exhibited increased FC between the bilateral ventral rostral putamen and ventrolateral thalamus. Bipolar (hypo)mania uniquely exhibited increased ventral rostral putamen connectivity and superior ventral striatum connectivity. One latent component was identified, whereby increased FCs of striatal subregions were associated with distinct psychopathological symptomatology (more manic symptoms, elevated positive mood, less depressive symptoms, and worse cognitive performance). Patients with bipolar (hypo)mania had the highest FC and behavioral composite scores while bipolar patients with depression had the lowest scores. CONCLUSIONS: Our data demonstrated both trait features of BD and state features specific to bipolar (hypo)mania. The findings underscored the fundamental role of the striatum in the pathophysiological processes underlying specific symptomatology across all mood states.
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Afecto , Trastorno Bipolar , Cuerpo Estriado , Imagen por Resonancia Magnética , Humanos , Trastorno Bipolar/fisiopatología , Trastorno Bipolar/diagnóstico por imagen , Masculino , Femenino , Adulto , Afecto/fisiología , Cuerpo Estriado/fisiopatología , Cuerpo Estriado/diagnóstico por imagen , Persona de Mediana Edad , Manía/fisiopatología , Estriado Ventral/fisiopatología , Estriado Ventral/diagnóstico por imagen , Vías Nerviosas/fisiopatología , Adulto JovenRESUMEN
Trace amine-associated receptor 1 (TAAR1) is an intracellular expressed G-protein-coupled receptor that is widely expressed in major dopaminergic areas and plays a crucial role in modulation of central dopaminergic neurotransmission and function. Pharmacological studies have clarified the roles of dopamine D1 receptor (D1R) in the medial prefrontal cortex (mPFC) in cognitive function and social behaviors, and chronic stress can inhibit D1R expression due to its susceptibility. Recently, we identified TAAR1 in the mPFC as a potential target for treating chronic stress-induced cognitive and social dysfunction, but whether D1R is involved in mediating the effects of TAAR1 agonist remains unclear. Combined genomics and transcriptomic studies revealed downregulation of D1R in the mPFC of TAAR1-/- mice. Molecular dynamics simulation showed that hydrogen bond, salt bridge, and Pi-Pi stacking interactions were formed between TAAR1 and D1R indicating a stable TAAR1-D1R complex structure. Using pharmacological interventions, we found that D1R antagonist disrupted therapeutic effect of TAAR1 partial agonist RO5263397 on stress-related cognitive and social dysfunction. Knockout TAAR1 in D1-type dopamine receptor-expressing neurons reproduced adverse effects of chronic stress, and TAAR1 conditional knockout in the mPFC led to similar deficits, along with downregulation of D1R expression, all of these effects were ameliorated by viral overexpression of D1R in the mPFC, suggesting the functional interaction between TAAR1 and D1R. Collectively, our data elucidate the possible molecular mechanism that D1R in the mPFC mediates the effects of TAAR1 activation on chronic stress-induced cognitive and social deficits.
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Ratones Endogámicos C57BL , Ratones Noqueados , Corteza Prefrontal , Receptores de Dopamina D1 , Receptores Acoplados a Proteínas G , Estrés Psicológico , Animales , Corteza Prefrontal/metabolismo , Corteza Prefrontal/efectos de los fármacos , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/agonistas , Estrés Psicológico/metabolismo , Masculino , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/genética , Ratones , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/etiología , Conducta SocialRESUMEN
Witnessing violent or traumatic events is common during childhood and adolescence and could cause detrimental effects such as increased risks of psychiatric disorders. This stressor could be modeled in adolescent laboratory animals using the chronic witnessing social defeat (CWSD) paradigm, but the behavioral consequences of CWSD in adolescent animals remain to be validated for cognitive, anxiety-like, and depression-like behaviors and, more importantly, the underlying neural mechanisms remain to be uncovered. In this study, we first established the CWSD model in adolescent male mice and found that CWSD impaired cognitive function and increased anxiety levels and that these behavioral deficits persisted into adulthood. Based on the dorsal-ventral functional division in hippocampus, we employed immediate early gene c-fos immunostaining after behavioral tasks and found that CWSD-induced cognition deficits were associated with dorsal CA3 overactivation and anxiety-like behaviors were associated with ventral CA3 activity reduction. Indeed, chemogenetic activation and inhibition of dorsal CA3 neurons mimicked and reversed CWSD-induced recognition memory deficits (not anxiety-like behaviors), respectively, whereas both inhibition and activation of ventral CA3 neurons increased anxiety-like behaviors in adolescent mice. Finally, chronic administration of vortioxetine (a novel multimodal antidepressant) successfully restored the overactivation of dorsal CA3 neurons and the cognitive deficits in CWSD mice. Together, our findings suggest that dorsal CA3 overactivation mediates CWSD-induced recognition memory deficits in adolescent male mice, shedding light on the pathophysiology of adolescent CWSD-induced adverse effects and providing preclinical evidence for early treatment of stress-induced cognitive deficits.
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Región CA3 Hipocampal , Trastornos de la Memoria , Reconocimiento en Psicología , Estrés Psicológico , Animales , Masculino , Ratones , Trastornos de la Memoria/etiología , Reconocimiento en Psicología/fisiología , Reconocimiento en Psicología/efectos de los fármacos , Región CA3 Hipocampal/metabolismo , Región CA3 Hipocampal/efectos de los fármacos , Derrota Social , Ansiedad/etiología , Ratones Endogámicos C57BL , Modelos Animales de EnfermedadRESUMEN
Major depressive disorder (MDD) is associated with functional disturbances in subcortical regions. In this naturalistic prospective study (NCT03294525), we aimed to investigate relationships among subcortical functional connectivity (FC), mood symptom profiles and treatment outcome in MDD using multivariate methods. Medication-free participants with MDD (n = 135) underwent a functional magnetic resonance imaging scan at baseline and completed posttreatment clinical assessment after 8 weeks of antidepressant monotherapy. We used partial least squares (PLS) correlation analysis to explore the association between subcortical FC and mood symptom profiles. FC score, reflecting the weighted representation of each individual in this association, was computed. Replication analysis was undertaken in an independent sample (n = 74). We also investigated the relationship between FC score and treatment outcome in the main sample. A distinctive subcortical connectivity pattern was found to be associated with negative affect. In general, higher FC between the caudate, putamen and thalamus was associated with greater negative affect. This association was partly replicated in the independent sample (similarity between the two samples: r = 0.66 for subcortical connectivity, r = 0.75 for mood symptom profile). Lower FC score predicted both remission and response to treatment after 8 weeks of antidepressant monotherapy. The emphasis here on the role of dorsal striatum and thalamus consolidates prior work of subcortical connectivity in MDD. The findings provide insight into the pathogenesis of MDD, linking subcortical FC with negative affect. However, while the FC score significantly predicted treatment outcome, the low odds ratio suggests that finding predictive biomarkers for depression remains an aspiration.
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Trastorno Depresivo Mayor , Humanos , Afecto , Antidepresivos/uso terapéutico , Trastorno Depresivo Mayor/diagnóstico por imagen , Trastorno Depresivo Mayor/tratamiento farmacológico , Estudios Prospectivos , Resultado del TratamientoRESUMEN
Trace amine-associated receptor 1 (TAAR1) is a classical type of G-protein-coupled receptor, which is widely distributed in the brain of mammals, especially in the limbic system and the region rich in monoaminergic neurons, and it is a highly conserved TAAR subtype in all species. TAAR1 can specifically respond to endogenous trace amines in the central nervous system and peripheral tissues, and plays an important role in the pathophysiological mechanisms involving the dysregulation of monoamine system and glutamate system leading to mental disorders. In addition, TAAR1 modulator can act on inwardly rectifying potassium channels and regulate synaptic transmission and neuronal activity. According to the latest research findings, TAAR1 exerts a series of functions by regulating signal pathways and substrate phosphorylation, which is related to emotion, cognition, fear and addiction. Therefore, we conducted a detailed review of relevant studies on the TAAR1 signaling pathways, aiming at revealing the great potential of TAAR1 as a new target for drug treatment of neuropsychiatric disorders.
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Receptores Acoplados a Proteínas G , Transmisión Sináptica , Animales , Humanos , Encéfalo , Aminas , MamíferosRESUMEN
Multiple lines of evidence suggest that the trace amine-associated receptor 1 (TAAR1) holds promise as a potential target for stress-related disorders, such as treating major depressive disorder (MDD). The role of TAAR1 in the regulation of adult neurogenesis is recently supported by transcriptomic data. However, it remains unknown whether TAAR1 in dentate gyrus (DG) mediate chronic stress-induced negative effects on hippocampal plasticity and related behavior in mice. The present study consisted of a series of experiments using RNAscope, genetic approaches, behavioral tests, immunohistochemical staining, Golgi-Cox technique to unravel the effects of TAAR1 on alterations of dentate neuronal plasticity and cognitive function in the chronic social defeat stress model. The mice subjected to chronic defeat stress exhibited a noteworthy decrease in the mRNA level of TAAR1 in DG. Additionally, they exhibited compromised social memory and spatial object recognition memory, as well as impaired proliferation and maturation of adult-born dentate granule cells. Moreover, the selective knockout TAAR1 in DG mostly mimicked the cognitive function deficits and neurogenesis impairment induced by chronic stress. Importantly, the administration of the selective TAAR1 partial agonist RO5263397 during stress exposure attenuated the adverse effects of chronic stress on cognitive function, adult neurogenesis, dendritic arborization, and the synapse number of dentate neurons in DG. In summary, our findings suggest that TAAR1 plays a crucial role in mediating the detrimental effects of chronic stress on hippocampal plasticity and cognition. TAAR1 agonists exhibit therapeutic potential for individuals suffering from cognitive impairments associated with MDD.
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Giro Dentado , Trastorno Depresivo Mayor , Receptores Acoplados a Proteínas G , Animales , Ratones , Giro Dentado/fisiología , Hipocampo/fisiología , Cognición/fisiología , Plasticidad Neuronal/fisiología , NeurogénesisRESUMEN
The sex difference that females are more vulnerable to depression than males has been recently replicated in an animal model of early-life stress (ES) called the limited bedding and nesting material (LBN) paradigm. Adopting this animal model, we have previously examined the effects of ES on monoamine transporter (MATs) expression in stress-related regions in adult female mice, and the reversal effects of a novel multimodal antidepressant, vortioxetine. In this study, replacing vortioxetine with a classical antidepressant, fluoxetine, we aimed to replicate the ES effects in adult female mice and to elucidate the commonality and differences between fluoxetine and vortioxetine. We found that systemic 30-day treatment with fluoxetine successfully reversed ES-induced depression-like behaviors (especially sucrose preference) in adult female mice. At the molecular level, we largely replicated the ES effects, such as reduced serotonin transporter (SERT) expression in the amygdala and increased norepinephrine transporter (NET) expression in the medial prefrontal cortex (mPFC) and hippocampus. Similar reversal effects of fluoxetine and vortioxetine were observed, including SERT in the amygdala and NET in the mPFC, whereas different reversal effects were observed for NET in the hippocampus and vesicular monoamine transporters expression in the nucleus accumbens. Overall, these results demonstrate the validity of the LBN paradigm to induce depression-like behaviors in female mice, highlight the involvement of region-specific MATs in ES-induced depression-like behaviors, and provide insights for further investigation of neurobiological mechanisms, treatment, and prevention associated with depression in women.
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Experiencias Adversas de la Infancia , Fluoxetina , Humanos , Femenino , Ratones , Masculino , Animales , Fluoxetina/farmacología , Vortioxetina , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Depresión/tratamiento farmacológicoRESUMEN
The gut microbial communities interact with the host immunity and physiological functions. In this study, we investigated the bacterial composition in Litopenaeus vannamei shrimp's gut and rearing water under different host (developmental stage: juvenile and adult; health status: healthy and diseased) and environmental factors (temperature 25 °C and 28 °C; and light intensity: low and high). The PCoA analysis showed that all water samples were clustered together in a quarter, whereas the gut samples spread among three quarters. In terms of functional bacteria, gut samples of adult shrimp, healthy adult shrimp, adult shrimp raised at 28 °C, and juvenile shrimp under high light intensity exhibited a higher abundance of Vibrionaceae compared to each other opposite group. Gut samples of juvenile shrimp, infected adult shrimp, juvenile shrimp with low light intensity, and adult shrimp with a water temperature of 25 °C showed a higher abundance of Pseudoaltromonadaceae bacteria compared to each other opposite group. Gut samples of juvenile shrimp, healthy adult shrimp, adult shrimp raised at a water temperature of 28 °C, and juvenile shrimp with high light intensity showed the higher abundance of Firmicutes/Bacteroidota ratio compared to each other opposite group. Our results showed that L. vannamei juveniles are more sensitive to bacterial infections; besides, water temperature of 28 °C and high light intensity groups were both important conditions improving the shrimp gut bacterial composition under industrial indoor farming systems. KEY POINTS: ⢠Bacteria diversity was higher among shrimp intestinal microbiota compared to the rearing water. ⢠Shrimp juveniles are more sensitive to bacterial infection compared to adults. ⢠Water temperature of 28 °C and high light intensity are recommended conditions for white shrimp aquaculture.
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Microbioma Gastrointestinal , Microbiota , Penaeidae , Animales , Agricultura , Granjas , AguaRESUMEN
BACKGROUND: Exploring the neural basis related to different mood states is a critical issue for understanding the pathophysiology underlying mood switching in bipolar disorder (BD), but research has been scarce and inconsistent. METHODS: Resting-state functional magnetic resonance imaging data were acquired from 162 patients with BD: 33 (hypo)manic, 64 euthymic, and 65 depressive, and 80 healthy controls (HCs). The differences of large-scale brain network functional connectivity (FC) between the four groups were compared and correlated with clinical characteristics. To validate the generalizability of our findings, we recruited a small longitudinal independent sample of BD patients (n = 11). In addition, we examined topological nodal properties across four groups as exploratory analysis. RESULTS: A specific strengthened pattern of network FC, predominantly involving the default mode network (DMN), was observed in (hypo)manic patients when compared with HCs and bipolar patients in other mood states. Longitudinal observation revealed an increase in several network FCs in patients during (hypo)manic episode. Both samples evidenced an increase in the FC between the DMN and ventral attention network, and between the DMN and limbic network (LN) related to (hypo)mania. The altered network connections were correlated with mania severity and positive affect. Bipolar depressive patients exhibited decreased FC within the LN compared with HCs. The exploratory analysis also revealed an increase in degree in (hypo)manic patients. CONCLUSIONS: Our findings identify a distributed pattern of large-scale network disturbances in the unique context of (hypo)mania and thus provide new evidence for our understanding of the neural mechanism of BD.
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Trastorno Bipolar , Humanos , Manía , Mapeo Encefálico/métodos , Vías Nerviosas/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , EncéfaloRESUMEN
BACKGROUND: The social signal transduction theory of depression proposes that life stress can be transformed into inflammatory signals, and ultimately lead to the development of major depressive disorder (MDD). The hypotheses of this study were: (1) The pro-inflammatory effect of life stress was only seen in patients with MDD, but not in healthy controls (HCs); (2) Inflammation can mediate the relationship between life stress and depressive symptoms. METHODS: This study included 170 MDD patients and 196 HCs, and 13 immune-inflammatory biomarkers closely related to MDD were measured, principal component analysis (PCA) was adopted to extract the inflammatory index. Life stress was assessed by Life Event Scale (LES), a total score of >32 points on the LES was considered as adulthood adversity (AA). Path analyses were used to explore the relationship among adulthood stress, inflammatory index, and severity of depression. RESULTS: Among MDD patients, α2M, CXCL-1, IL-1ß, and TLR-1 levels were higher in patients with AA than non-AA group (all FDR-adjusted P values <0.05), meanwhile, the levels of CCL-2 and IL-18 were lower. Path analyses suggested that pro- and anti-inflammatory index could mediate the association between AA and severity of depression in MDD patients. CONCLUSION: This study found that inflammatory signals can mediate the relationship between adulthood adversity and depression, however, the causal relationship need to be further confirmed. These findings shed light on further understanding the theory of social signal transduction in MDD and provide clues for stress management and controlling inflammation strategies in depression. CLINICAL TRIALS: NCT02023567.
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Trastorno Depresivo Mayor , Humanos , Adulto , Depresión , Fenotipo , Inflamación , Transducción de SeñalRESUMEN
BACKGROUND: The neural correlate of cognitive deficits in bipolar disorder (BD) is an issue that warrants further investigation. However, relatively few studies have examined the intrinsic functional connectivity (FC) underlying cognitive deficits involving sustained attention and executive function at both the region and network levels, as well as the different relationships between connectivity patterns and cognitive performance, in BD patients and healthy controls (HCs). METHODS: Patients with BD (n = 59) and HCs (n = 52) underwent structural and resting-state functional magnetic resonance imaging and completed the Wisconsin Card Sorting Test (WCST), the continuous performance test and a clinical assessment. A seed-based approach was used to evaluate the intrinsic FC alterations in three core neurocognitive networks (the default mode network [DMN], the central executive network [CEN] and the salience network [SN]). Finally, we examined the relationship between FC and cognitive performance by using linear regression analyses. RESULTS: Decreased FC was observed within the DMN, in the DMN-SN and DMN-CEN and increased FC was observed in the SN-CEN in BD. The alteration direction of regional FC was consistent with that of FC at the brain network level. Decreased FC between the left posterior cingulate cortex and right anterior cingulate cortex was associated with longer WCST completion time in BD patients (but not in HCs). CONCLUSIONS: These findings emphasize the dominant role of the DMN in the psychopathology of BD and provide evidence that cognitive deficits in BD may be associated with aberrant FC between the anterior and posterior DMN.
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Trastorno Bipolar , Humanos , Trastorno Bipolar/complicaciones , Trastorno Bipolar/diagnóstico por imagen , Función Ejecutiva , Vías Nerviosas/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Encéfalo/diagnóstico por imagen , Mapeo Encefálico/métodos , CogniciónRESUMEN
Cognitive dysfunction is a significant, untreated clinical need in patients with psychiatric disorders, for which preclinical studies are needed to understand the underlying mechanisms and to identify potential therapeutic targets. Early-life stress (ELS) leads to long-lasting deficits of hippocampus-dependent learning and memory in adult mice, which may be associated with the hypofunction of the brain-derived neurotrophic factor (BDNF) and its high-affinity receptor, tropomyosin receptor kinase B (TrkB). In this study, we carried out eight experiments using male mice to examine the causal involvement of the BDNF-TrkB pathway in dentate gyrus (DG) and the therapeutic effects of the TrkB agonist (7,8-DHF) in ELS-induced cognitive deficits. Adopting the limited nesting and bedding material paradigm, we first demonstrated that ELS impaired spatial memory, suppressed BDNF expression and neurogenesis in the DG in adult mice. Downregulating BDNF expression (conditional BDNF knockdown) or inhibition of the TrkB receptor (using its antagonist ANA-12) in the DG mimicked the cognitive deficits of ELS. Acute upregulation of BDNF (exogenous human recombinant BDNF microinjection) levels or activation of TrkB receptor (using its agonist, 7,8-DHF) in the DG restored ELS-induced spatial memory loss. Finally, acute and subchronic systemic administration of 7,8-DHF successfully restored spatial memory loss in stressed mice. Subchronic 7,8-DHF treatment also reversed ELS-induced neurogenesis reduction. Our findings highlight BDNF-TrkB system as the molecular target of ELS-induced spatial memory deficits and provide translational evidence for the intervention at this system in the treatment of cognitive deficits in stress-related psychiatric disorders, such as major depressive disorder.
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Disfunción Cognitiva , Trastorno Depresivo Mayor , Estrés Psicológico , Animales , Humanos , Masculino , Ratones , Factor Neurotrófico Derivado del Encéfalo , Cognición , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/etiología , Giro Dentado , Trastornos de la Memoria , Receptor trkB , TropomiosinaRESUMEN
Trace amines are endogenous molecules distributed in the central nervous system and peripheral tissues that resemble common biogenic amines in terms of subcellular localization, chemical structure, and metabolism. Trace amine-associated receptor (TAAR) is a kind of evolutionarily conserved G-protein-coupled receptors in vertebrates, in which TAAR1 is a functional regulator of monoamine transmitters such as dopamine and serotonin. TAAR1 is widely considered as a potential therapeutic target for schizophrenia, depression and drug addiction. Moreover, TAAR1 is also expressed in peripheral tissues. The homeostasis imbalance of trace aminergic system can induce over-activation of peripheral immune system and central immune inflammatory response. TAAR1 modulators are becoming potential emerging drugs for the treatment of immune-related illnesses, because they may play a major role in the activation or modulation of immune response.
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Receptores Acoplados a Proteínas G , Trastornos Relacionados con Sustancias , Animales , Humanos , Receptores Acoplados a Proteínas G/metabolismo , Aminas Biogénicas , DopaminaRESUMEN
BACKGROUND: A recent study revealed disrupted topological organization of whole-brain networks in patients with major depressive disorder (MDD); however, these results were mostly driven by recurrent MDD patients, rather than first-episode drug-naïve (FEDN) patients. Furthermore, few longitudinal studies have explored the effects of antidepressant therapy on the topological organization of whole-brain networks. METHODS: We collected clinical and neuroimaging data from 159 FEDN MDD patients and 152 normal controls (NCs). A total of 115 MDD patients completed an eight-week antidepressant treatment procedure. Topological features of brain networks were calculated using graph theory-based methods and compared between FEDN MDD patients and NCs, as well as before and after treatment. RESULTS: Decreased global efficiency, local efficiency, small-worldness, and modularity were found in pretreatment FEDN MDD patients compared with NCs. Nodal degrees, betweenness, and efficiency decreased in several networks compared with NCs. After antidepressant treatment, the global efficiency increased, while the local efficiency, the clustering coefficient of the network, the path length, and the normalized characteristic path length decreased. Moreover, the reduction rate of the normalized characteristic path length was positively correlated with the reduction rate of retardation factor scores. LIMITATIONS: The interaction effects of groups and time on the topological features were not explored because of absence of the eighth-week data of NC group. CONCLUSIONS: The topological architecture of functional brain networks is disrupted in FEDN MDD patients. After antidepressant therapy, the global efficiency shifted toward recovery, but the local efficiency deteriorated, suggesting a correlation between recovery of retardation symptoms and global efficiency.
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Trastorno Depresivo Mayor , Humanos , Trastorno Depresivo Mayor/diagnóstico por imagen , Trastorno Depresivo Mayor/tratamiento farmacológico , Imagen por Resonancia Magnética/métodos , Encéfalo/diagnóstico por imagen , Mapeo Encefálico , Antidepresivos/uso terapéuticoRESUMEN
OBJECTIVE: Bulimia nervosa (BN) is an eating disorder associated with the dysfunction of intrinsic brain networks. However, whether the network disruptions in BN patients manifest as dysconnectivity or imbalances of network modular segregation remains unclear. METHOD: We collected data from 41 women with BN and 41 matched healthy control (HC) women. We performed graph theory analysis based on resting-state functional magnetic resonance imaging (RS-fMRI) data; then, we computed the participation coefficient (PC) among brain modules to characterize the modular segregation for the BN and HC groups. The number of intra- and inter-modular connections was calculated to explain the PC changes. Additionally, we examined the potential associations of the measures mentioned above with clinical variables within the BN group. RESULTS: Compared with the HC group, the BN group showed significantly decreased PC in the fronto-parietal network (FPN), cingulo-opercular network (CON), and cerebellum (Cere). Additionally, the number of intra-modular connections of the default mode network (DMN) and the number of the inter-modular connections between the DMN and CON, FPN and Cere, and CON and Cere in the BN group were lower than those in the HC group. The nodal level analysis showed that the BN group had a decreased PC of the anterior prefrontal cortex (aPFC), dorsal frontal cortex (dFC), inferior parietal lobule (IPL), thalamus, and angular gyrus. Further, these metrics were significantly correlated with clinical variables in the BN group. DISCUSSION: These findings may provide novel insights to capture atypical topologies associated with pathophysiology mechanisms and clinical symptoms underlying BN.
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Bulimia Nerviosa , Trastornos de Alimentación y de la Ingestión de Alimentos , Humanos , Femenino , Bulimia Nerviosa/diagnóstico por imagen , Imagen por Resonancia Magnética , Encéfalo/diagnóstico por imagen , Corteza Prefrontal , Mapeo EncefálicoRESUMEN
Adverse experiences in early life have long-lasting negative impacts on behavior and the brain in adulthood, one of which is sleep disturbance. As the corticotropin-releasing hormone (CRH)-corticotropin-releasing hormone receptor 1 (CRHR1) system and nucleus accumbens (NAc) play important roles in both stress responses and sleep-wake regulation, in this study we investigated whether the NAc CRH-CRHR1 system mediates early-life stress-induced abnormalities in sleep-wake behavior in adult mice. Using the limited nesting and bedding material paradigm from postnatal days 2 to 9, we found that early-life stress disrupted sleep-wake behaviors during adulthood, including increased wakefulness and decreased non-rapid eye movement (NREM) sleep time during the dark period and increased rapid eye movement (REM) sleep time during the light period. The stress-induced sleep disturbances were accompanied by dendritic atrophy in the NAc and both were largely reversed by daily systemic administration of the CRHR1 antagonist antalarmin during stress exposure. Importantly, Crh overexpression in the NAc reproduced the effects of early-life stress on sleep-wake behavior and NAc morphology, whereas NAc Crhr1 knockdown reversed these effects (including increased wakefulness and reduced NREM sleep in the dark period and NAc dendritic atrophy). Together, our findings demonstrate the negative influence of early-life stress on sleep architecture and the structural plasticity of the NAc, and highlight the critical role of the NAc CRH-CRHR1 system in modulating these negative outcomes evoked by early-life stress.
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Trastornos del Sueño-Vigilia , Estrés Psicológico , Animales , Ratones , Hormona Liberadora de Corticotropina/metabolismo , Núcleo Accumbens/metabolismo , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Sueño , Estrés Psicológico/complicacionesRESUMEN
OBJECTIVE: To investigate the prevalence of psychotic depression and the differences in sociodemographic and clinical characteristics and prescription patterns of psychotropic medications between patients with psychotic depression (PD) and patients with nonpsychotic depression (NPD) in China. METHODS: We conducted a cross-sectional study in 13 major psychiatric hospitals or the psychiatric units of general hospitals in China from September 1, 2010, to February 28, 2011. PD was defined according to the psychotic disorder section of the Mini International Neuropsychiatric Interview (MINI). The sociodemographic and clinical characteristics and the prescription patterns of psychotropic medications were compared between the PD and NPD groups. Multivariate logistic regression analysis was used to investigate factors associated with an increased likelihood of PD. RESULTS: Among 1172 MDD patients, the prevalence of psychotic features was 9.2% in the present study. The logistic regression analysis indicated that unmarried (OR = 2.08, p < 0.001), frequent depressive episodes (OR = 2.10, p = 0.020), depressive episodes with suicidal ideation and attempts (OR = 1.91, p = 0.004), and patients who were prescribed any antipsychotics (OR = 2.94, p < 0.001) were associated with psychotic features in patients with MDD. LIMITATIONS: Cross-sectional design, retrospective recall of some data CONCLUSION: The prevalence of PD is high in China, and there were some differences in demographic and clinical characteristics between patients with PD and patients with NPD. Clinicians should regularly assess psychotic symptoms and consider intensive treatment and close monitoring when treating subjects with PD.
Asunto(s)
Depresión , Trastornos Psicóticos , Estudios Transversales , Humanos , Prescripciones , Prevalencia , Trastornos Psicóticos/tratamiento farmacológico , Trastornos Psicóticos/epidemiología , Estudios RetrospectivosRESUMEN
OBJECTIVES: Genome-wide analyses of antidepressant response have suggested that genes initially associated with risk for schizophrenia may also serve as promising candidates for selective serotonin reuptake inhibitor (SSRI) efficacy. Protein tyrosine phosphatase, receptor-type, zeta-1 (PTPRZ1) has previously been shown to be associated with schizophrenia, but it has not been investigated as a predictor of antidepressant efficacy. The main objective of the study was to assess whether SSRI-mediated depressive and anxiety symptom remission in Chinese patients with major depressive disorder (MDD) are associated with specific PTPRZ1 variants. METHODS: Two independent cohorts were investigated, the first sample (N = 344) received an SSRI (i.e. fluoxetine, sertraline, citalopram, escitalopram, fluvoxamine, or paroxetine) for 8 weeks. The second sample (N = 160) only received escitalopram for 8 weeks. Hamilton Depression and Hamilton Anxiety Rating Scale scores at 8-weeks post-baseline in both cohorts were used to determine remission status. Five PTPRZ1 variants (rs12154537, rs6466810, rs6466808, rs6955395, and rs1918031) were genotyped in both cohorts. RESULTS: Anxiety symptom remission was robustly associated with PTPRZ1 rs12154537 (P = 0.004) and the G-G-G-G haplotype (rs12154537-rs6466810-rs6466808-rs6955395; P = 0.005) in cohort 2 but not cohort 1 (mixed SSRI use). Associations with depressive symptom remission did not survive correction for multiple testing. CONCLUSIONS: These findings suggest that PTPRZ1 variants may serve as a marker of escitalopram-mediated anxiety symptom remission in MDD.