RESUMO
Stress resilience is the phenomenon that some people maintain their mental health despite exposure to adversity or show only temporary impairments followed by quick recovery. Resilience research attempts to unravel the factors and mechanisms that make resilience possible and to harness its insights for the development of preventative interventions in individuals at risk for acquiring stress-related dysfunctions. Biological resilience research has been lagging behind the psychological and social sciences but has seen a massive surge in recent years. At the same time, progress in this field has been hampered by methodological challenges related to finding suitable operationalizations and study designs, replicating findings, and modeling resilience in animals. We embed a review of behavioral, neuroimaging, neurobiological, and systems biological findings in adults in a critical methods discussion. We find preliminary evidence that hippocampus-based pattern separation and prefrontal-based cognitive control functions protect against the development of pathological fears in the aftermath of singular, event-type stressors [as found in fear-related disorders, including simpler forms of posttraumatic stress disorder (PTSD)] by facilitating the perception of safety. Reward system-based pursuit and savoring of positive reinforcers appear to protect against the development of more generalized dysfunctions of the anxious-depressive spectrum resulting from more severe or longer-lasting stressors (as in depression, generalized or comorbid anxiety, or severe PTSD). Links between preserved functioning of these neural systems under stress and neuroplasticity, immunoregulation, gut microbiome composition, and integrity of the gut barrier and the blood-brain barrier are beginning to emerge. On this basis, avenues for biological interventions are pointed out.
Assuntos
Neurobiologia , Resiliência Psicológica , Estresse Psicológico , Biologia de Sistemas , Humanos , Animais , Estresse Psicológico/fisiopatologia , EncéfaloRESUMO
Consistent evidence from human data points to successful threat-safety discrimination and responsiveness to extinction of fear memories as key characteristics of resilient individuals. To promote valid cross-species approaches for the identification of resilience mechanisms, we establish a translationally informed mouse model enabling the stratification of mice into three phenotypic subgroups following chronic social defeat stress, based on their individual ability for threat-safety discrimination and conditioned learning: the Discriminating-avoiders, characterized by successful social threat-safety discrimination and extinction of social aversive memories; the Indiscriminate-avoiders, showing aversive response generalization and resistance to extinction, in line with findings on susceptible individuals; and the Non-avoiders displaying impaired aversive conditioned learning. To explore the neurobiological mechanisms underlying the stratification, we perform transcriptome analysis within three key target regions of the fear circuitry. We identify subgroup-specific differentially expressed genes and gene networks underlying the behavioral phenotypes, i.e., the individual ability to show threat-safety discrimination and respond to extinction training. Our approach provides a translationally informed template with which to characterize the behavioral, molecular, and circuit bases of resilience in mice.
Assuntos
Condicionamento Clássico , Medo , Humanos , Camundongos , Animais , Medo/fisiologia , Condicionamento Clássico/fisiologia , Aprendizagem da Esquiva , Estresse Psicológico/genética , Afeto , Extinção Psicológica/fisiologiaRESUMO
SUMMARY: The IntelliCage systems offer the possibility to conduct long-term behavioral experiments on mice in social groups without human intervention. Although this setup provides new findings, only about 150 studies with the IntelliCage system have been published in the last two decades, which is also caused by the challenging problems of processing and handling the large and heterogeneous amounts of captured data. This application note introduces the Python-GUI IntelliPy, especially designed for users not very experienced in using programming languages. IntelliPy allows users to quickly analyze the IntelliCage output in a user-friendly way, thus making the systems more accessible to a broader audience. AVAILABILITY AND IMPLEMENTATION: https://github.com/NiRuff/IntelliPy. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Assuntos
Linguagens de Programação , Software , Animais , Camundongos , HumanosRESUMO
PURPOSE: The roles of vascular dysfunction and chronic stress have been extensively discussed in the pathophysiology of glaucoma. Our aim was to test whether chronic stress causes retinal vascular dysfunction and therewith induces retinal ganglion cells (RGCs) loss. METHODS: Twelve mice underwent chronic social defeat (CSD) stress, while 12 mice received control treatment only. Intraocular pressure (IOP) was measured with a rebound tonometer. Blood plasma corticosterone concentration and adrenal gland weight were used to assess stress levels. Brn-3a staining in retinas and PPD staining in optic nerve cross sections were conducted to assess the survival of RGCs and axons respectively. The ET-1 and α-SMA levels were determined in retina. Retinal vascular autoregulation, functional response to various vasoactive agents and vascular mechanics were measured using video microscopy. RESULTS: No significant difference in IOP levels was observed during and after CSD between CSD mice and controls. CSD stress caused hypercortisolemia 2 days post-CSD. However, increased corticosterone levels went back to normal 8 months after CSD. CSD-exposed mice developed adrenal hyperplasia 3 days post-CSD, which was normalized by 8 months. RGC and axon survival were similar between CSD mice and controls. However, CSD stress caused irreversible, impaired autoregulation and vascular dysfunction of retinal arterioles in CSD mice. In addition, impaired maximal dilator capacity of retinal arterioles was observed 8 months post-CSD rather than 3 days post-CSD. Remarkably, ET-1 levels were increased 3 days post-CSD while α-SMA levels were decreased 8 months post-CSD. CONCLUSIONS: We found that CSD stress does not cause IOP elevation, nor loss of RGCs and their axons. However, it strikingly causes irreversible impaired autoregulation and endothelial function in murine retinal arterioles. In addition, CSD changed vascular mechanics on a long-term basis. Increased ET-1 levels and loss of pericytes in retina vessels may involve in this process.
Assuntos
Artéria Retiniana/fisiopatologia , Doenças Retinianas/fisiopatologia , Células Ganglionares da Retina/patologia , Derrota Social , Estresse Psicológico/fisiopatologia , Actinas/metabolismo , Hiperplasia Suprarrenal Congênita/fisiopatologia , Animais , Sobrevivência Celular , Doença Crônica , Corticosterona/sangue , Modelos Animais de Doenças , Transtorno 46,XY do Desenvolvimento Sexual/fisiopatologia , Endotelina-1/metabolismo , Pressão Intraocular/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hipertensão Ocular/fisiopatologia , Nervo Óptico/fisiopatologia , Artéria Retiniana/metabolismo , Doenças Retinianas/metabolismo , Células Ganglionares da Retina/metabolismo , Estresse Psicológico/metabolismo , Tonometria Ocular , Fator de Transcrição Brn-3A/metabolismo , Gravação em VídeoRESUMO
BACKGROUND: Within a single depressive episode, most patients receive different antidepressants because of an inadequate response to the first-line antidepressant. A commonly used strategy is to switch from a selective serotonin reuptake inhibitor to a selective serotonin-norepinephrine reuptake inhibitor. However, little is known about the tolerability of this switch with consideration of dose and drug concentration in blood. METHODS: After 4 weeks of inadequate response to escitalopram (10-20 mg/d), medication was switched to another 4 weeks of venlafaxine (VF, 150-375 mg/d) in 234 depressed patients. Serum concentrations, depression severity, and adverse drug reactions (ADRs) were assessed weekly. RESULTS: The switch of medication led to an increase of ADRs such as reduced salivation (+11%), orthostatic dizziness (+11%), and sweating (+9.8%). The most frequent ADRs during treatment with VF were reduced salivation (28.6%), sweating (24.6%), and orthostatic dizziness (15.8%). In patients receiving high-dose VF, a significant improvement of depressive symptomatology was observed, and most ADRs decreased during the course of treatment, even in patients above the therapeutic reference range. LIMITATIONS: Patients and physicians were aware of medication, and there was no direct comparison with the herein presented switch of medication. IMPLICATIONS: This study provides important information about the tolerability of a commonly used antidepressant treatment strategy. More detailed information about putative ADRs may help clinicians increase compliance through effective patient education. Because ADRs of VF were associated with the plasma concentration, therapeutic drug monitoring is recommended to guide the therapy and manage problems of tolerability.
Assuntos
Antidepressivos/uso terapêutico , Citalopram/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Cloridrato de Venlafaxina/uso terapêutico , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: The suggested link between major depression disorder (MDD) and blood-brain barrier (BBB) alterations supports an impact on the neurovascular unit in this disease condition. Here we investigate how pericytes, a major component in the neurovascular unit, respond to stress, stress hormones, proinflammatory cytokine and depression. METHOD: Hippocampal sections of chronic unpredictable stressed (CMS) rats, MDD patients and respective controls were immuno-stained against NG2, where the number of NG2+ pericytes in the molecular layer was counted. Proliferation of cultured pericytes after treatment with cortisol and IL-1ß was analyzed using radioactive-labeled thymidine. FINDINGS: The number of NG2+ pericytes was significantly higher in CMS animals than controls. Higher number of NG2+ pericytes was also detected in MDD patients, but the increase did not reach significance. IL-1ß, but not cortisol, induced a significant increase in proliferation of cultured pericytes. CONCLUSION: Our results indicate that exposure to stressful conditions affects the hippocampal pericyte population. These findings add to our knowledge about the impact of stress on the neurovascular unit, which might be relevant for understanding the alterations in BBB found in MDD patients.
Assuntos
Pericitos , Estresse Psicológico , Animais , Barreira Hematoencefálica , Citocinas , Hipocampo , Humanos , RatosRESUMO
Stringent glucose demands render the brain susceptible to disturbances in the supply of this main source of energy, and chronic stress may constitute such a disruption. However, whether stress-associated cognitive impairments may arise from disturbed glucose regulation remains unclear. Here we show that chronic social defeat (CSD) stress in adult male mice induces hyperglycemia and directly affects spatial memory performance. Stressed mice developed hyperglycemia and impaired glucose metabolism peripherally as well as in the brain (demonstrated by PET and induced metabolic bioluminescence imaging), which was accompanied by hippocampus-related spatial memory impairments. Importantly, the cognitive and metabolic phenotype pertained to a subset of stressed mice and could be linked to early hyperglycemia 2 days post-CSD. Based on this criterion, â¼40% of the stressed mice had a high-glucose (glucose >150 mg/dL), stress-susceptible phenotype. The relevance of this biomarker emerges from the effects of the glucose-lowering sodium glucose cotransporter 2 inhibitor empagliflozin, because upon dietary treatment, mice identified as having high glucose demonstrated restored spatial memory and normalized glucose metabolism. Conversely, reducing glucose levels by empagliflozin in mice that did not display stress-induced hyperglycemia (resilient mice) impaired their default-intact spatial memory performance. We conclude that hyperglycemia developing early after chronic stress threatens long-term glucose homeostasis and causes spatial memory dysfunction. Our findings may explain the comorbidity between stress-related and metabolic disorders, such as depression and diabetes, and suggest that cognitive impairments in both types of disorders could originate from excessive cerebral glucose accumulation.
Assuntos
Comportamento Animal/fisiologia , Doença Crônica/psicologia , Hiperglicemia/fisiopatologia , Transtornos da Memória/fisiopatologia , Memória Espacial/fisiologia , Estresse Psicológico/fisiopatologia , Animais , Comportamento Animal/efeitos dos fármacos , Compostos Benzidrílicos/farmacologia , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Doença Crônica/tratamento farmacológico , Glucose/metabolismo , Glucosídeos/farmacologia , Hiperglicemia/tratamento farmacológico , Hiperglicemia/metabolismo , Hiperglicemia/psicologia , Masculino , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Transtornos da Memória/psicologia , Camundongos , Camundongos Endogâmicos C57BL , Desejabilidade Social , Memória Espacial/efeitos dos fármacos , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo , Estresse Psicológico/psicologiaRESUMO
Response to antidepressant treatment in major depressive disorder (MDD) cannot be predicted currently, leading to uncertainty in medication selection, increasing costs, and prolonged suffering for many patients. Despite tremendous efforts in identifying response-associated genes in large genome-wide association studies, the results have been fairly modest, underlining the need to establish conceptually novel strategies. For the identification of transcriptome signatures that can distinguish between treatment responders and nonresponders, we herein submit a novel animal experimental approach focusing on extreme phenotypes. We utilized the large variance in response to antidepressant treatment occurring in DBA/2J mice, enabling sample stratification into subpopulations of good and poor treatment responders to delineate response-associated signature transcript profiles in peripheral blood samples. As a proof of concept, we translated our murine data to the transcriptome data of a clinically relevant human cohort. A cluster of 259 differentially regulated genes was identified when peripheral transcriptome profiles of good and poor treatment responders were compared in the murine model. Differences in expression profiles from baseline to week 12 of the human orthologues selected on the basis of the murine transcript signature allowed prediction of response status with an accuracy of 76% in the patient population. Finally, we show that glucocorticoid receptor (GR)-regulated genes are significantly enriched in this cluster of antidepressant-response genes. Our findings point to the involvement of GR sensitivity as a potential key mechanism shaping response to antidepressant treatment and support the hypothesis that antidepressants could stimulate resilience-promoting molecular mechanisms. Our data highlight the suitability of an appropriate animal experimental approach for the discovery of treatment response-associated pathways across species.
Assuntos
Antidepressivos/farmacologia , Transtorno Depressivo Maior/tratamento farmacológico , Paroxetina/farmacologia , Receptores de Glucocorticoides/fisiologia , Animais , Antidepressivos/uso terapêutico , Biomarcadores Farmacológicos , Encéfalo/metabolismo , Corticosterona/sangue , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Camundongos , Camundongos Endogâmicos DBA , Família Multigênica , Paroxetina/metabolismo , Paroxetina/uso terapêutico , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismoRESUMO
One important symptom of patients with major depressive disorder (MDD) is memory dysfunction. However, little is known about the relationship between memory performance and depression severity, about the course of memory performance during antidepressant treatment as well as about the relationship between memory performance and brain-derived neurotrophic factor (BDNF). Memory function [learning and delayed recall) was assessed in 173 MDD patients (mean age 39.7 ± 11.3 years] treated by a pre-defined treatment algorithm within the early medication change (EMC) study at baseline, days 28 and 56. Depression severity was assessed in weekly intervals, BDNF plasma levels were measured at baseline, days 14 and 56, BDNF exon IV and p11 methylation status at baseline. Linear mixed regression models revealed that the course of depression severity was not associated with the course of learning or delayed recall in the total group. 63 (36%) of the investigated patients showed memory deficits (percent range ≤ 16) at baseline. Of those, 26(41%) patients experienced a normalization of their memory deficits during treatment. Patients with a normalization of their delayed recall performance had significantly higher plasma BDNF levels (p = 0.040) from baseline to day 56 than patients with persistent deficits. Baseline BDNF exon IV promoter and p11 gene methylation status were not associated with memory performance. Our results corroborate a concomitant amelioration of learning and delayed recall dysfunctions with successful antidepressant therapy in a subgroup of patients and support a role of BDNF in the neural mechanisms underlying the normalization of memory dysfunctions in MDD. ClinicalTrials.gov number: NCT00974155; EudraCT: 2008-008280-96.
Assuntos
Antidepressivos/farmacologia , Fator Neurotrófico Derivado do Encéfalo/sangue , Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/tratamento farmacológico , Transtornos da Memória/sangue , Transtornos da Memória/tratamento farmacológico , Rememoração Mental/efeitos dos fármacos , Avaliação de Resultados em Cuidados de Saúde , Adulto , Transtorno Depressivo Maior/complicações , Feminino , Humanos , Masculino , Transtornos da Memória/etiologia , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Rapid-acting antidepressants ketamine and (2R,6R)-hydroxynorketamine ((2R,6R)-HNK) have overcome some of the major limitations of classical antidepressants. However, little is known about sex-specific differences in the behavioral and molecular effects of ketamine and (2R,6R)-HNK in rodents. METHODS: We treated mice with an intraperitoneal injection of either saline, ketamine (30 mg kg-1) or (2R,6R)-HNK (10 mg kg-1). We performed a comprehensive behavioral test battery to characterize the Arc-CreERT2 × CAG-Sun1/sfGFP mouse line which enables targeted recombination in active populations. We performed a molecular study in Arc-CreERT2 × CAG-Sun1/sfGFP female mice using both immunohistochemistry and in situ hybridization. RESULTS: Arc-CreERT2 × CAG-Sun1/sfGFP mice showed sex differences in sociability and anxiety tests. Moreover, ketamine and (2R,6R)-HNK had opposite effects in the forced swim test (FST) depending on gender. In addition, in male mice, ketamine-treated animals were less immobile compared to (2R,6R)-HNK, thus showing a different profile of the two drugs in the FST. At the molecular level we identified Bdnf mRNA level to be increased after ketamine treatment in female mice. CONCLUSION: Arc-CreERT2 × CAG-Sun1/sfGFP mice showed sex differences in social and anxiety behavior and a different pattern between ketamine and (2R,6R)-HNK in the FST in male and female mice. At the molecular level, female mice treated with ketamine showed an increase of Bdnf mRNA level, as previously observed in male mice.
Assuntos
Comportamento Animal , Ketamina/análogos & derivados , Ketamina/administração & dosagem , Neurônios/metabolismo , Recombinação Genética , Caracteres Sexuais , Animais , Ansiedade/patologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Núcleo Celular/metabolismo , Modelos Animais de Doenças , Feminino , Proteínas de Fluorescência Verde/metabolismo , Hipocampo/metabolismo , Masculino , Memória Episódica , Camundongos Transgênicos , Comportamento SocialRESUMO
Gender differences play a pivotal role in the pathophysiology and treatment of major depressive disorder. This is strongly supported by a mean 2:1 female-male ratio of depression consistently observed throughout studies in developed nations. Considering the urgent need to tailor individualized treatment strategies to fight depression more efficiently, a more precise understanding of gender-specific aspects in the pathophysiology and treatment of depressive disorders is fundamental. However, current treatment guidelines almost entirely neglect gender as a potentially relevant factor. Similarly, the vast majority of animal experiments analysing antidepressant treatment in rodent models exclusively uses male animals and does not consider gender-specific effects. Based on the growing interest in innovative and rapid-acting treatment approaches in depression, such as the administration of ketamine, its metabolites or electroconvulsive therapy, this review article summarizes the evidence supporting the importance of gender in modulating response to rapid acting antidepressant treatment. We provide an overview on the current state of knowledge and propose a framework for rodent experiments to ultimately decode gender-dependent differences in molecular and behavioural mechanisms involved in shaping treatment response.
Assuntos
Antidepressivos/farmacologia , Animais , Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Eletroconvulsoterapia , Feminino , Humanos , Ketamina/metabolismo , Masculino , Resultado do TratamentoRESUMO
Cytoskeletal dynamics are pivotal to memory, learning, and stress physiology, and thus psychiatric diseases. Downregulated in renal cell carcinoma 1 (DRR1) protein was characterized as the link between stress, actin dynamics, neuronal function, and cognition. To elucidate the underlying molecular mechanisms, we undertook a domain analysis of DRR1 and probed the effects on actin binding, polymerization, and bundling, as well as on actin-dependent cellular processes. METHODS: DRR1 domains were cloned and expressed as recombinant proteins to perform in vitro analysis of actin dynamics (binding, bundling, polymerization, and nucleation). Cellular actin-dependent processes were analyzed in transfected HeLa cells with fluorescence recovery after photobleaching (FRAP) and confocal microscopy. RESULTS: DRR1 features an actin binding site at each terminus, separated by a coiled coil domain. DRR1 enhances actin bundling, the cellular F-actin content, and serum response factor (SRF)-dependent transcription, while it diminishes actin filament elongation, cell spreading, and actin treadmilling. We also provide evidence for a nucleation effect of DRR1. Blocking of pointed end elongation by addition of profilin indicates DRR1 as a novel barbed end capping factor. CONCLUSIONS: DRR1 impacts actin dynamics in several ways with implications for cytoskeletal dynamics in stress physiology and pathophysiology.
Assuntos
Actinas/metabolismo , Citoesqueleto/metabolismo , Proteínas Nucleares/metabolismo , Recuperação de Fluorescência Após Fotodegradação , Genes Supressores de Tumor , Células HeLa , Humanos , Microscopia Confocal , Proteínas Nucleares/genéticaRESUMO
We are delighted by the broad, intense, and fruitful discussion in reaction to our target article. A major point we take from the many comments is a prevailing feeling in the research community that we need significantly and urgently to advance resilience research, both by sharpening concepts and theories and by conducting empirical studies at a much larger scale and with a much more extended and sophisticated methodological arsenal than is the case currently. This advancement can be achieved only in a concerted international collaborative effort. In our response, we try to argue that an explicitly atheoretical, purely observational definition of resilience and a transdiagnostic, quantitative study framework can provide a suitable basis for empirically testing different competing resilience theories (sects. R1, R2, R6, R7). We are confident that it should be possible to unite resilience researchers from different schools, including from sociology and social psychology, behind such a pragmatic and theoretically neutral research strategy. In sections R3 to R5, we further specify and explain the positive appraisal style theory of resilience (PASTOR). We defend PASTOR as a comparatively parsimonious and translational theory that makes sufficiently concrete predictions to be evaluated empirically.
Assuntos
Pesquisa Empírica , Pesquisa , Psicologia Social , Características de Residência , Instituições AcadêmicasRESUMO
The well-replicated observation that many people maintain mental health despite exposure to severe psychological or physical adversity has ignited interest in the mechanisms that protect against stress-related mental illness. Focusing on resilience rather than pathophysiology in many ways represents a paradigm shift in clinical-psychological and psychiatric research that has great potential for the development of new prevention and treatment strategies. More recently, research into resilience also arrived in the neurobiological community, posing nontrivial questions about ecological validity and translatability. Drawing on concepts and findings from transdiagnostic psychiatry, emotion research, and behavioral and cognitive neuroscience, we propose a unified theoretical framework for the neuroscientific study of general resilience mechanisms. The framework is applicable to both animal and human research and supports the design and interpretation of translational studies. The theory emphasizes the causal role of stimulus appraisal (evaluation) processes in the generation of emotional responses, including responses to potential stressors. On this basis, it posits that a positive (non-negative) appraisal style is the key mechanism that protects against the detrimental effects of stress and mediates the effects of other known resilience factors. Appraisal style is shaped by three classes of cognitive processes--positive situation classification, reappraisal, and interference inhibition--that can be investigated at the neural level. Prospects for the future development of resilience research are discussed.
Assuntos
Transtornos Mentais/classificação , Resiliência Psicológica , HumanosRESUMO
In recent years, the glutamatergic system has been implicated in the development and treatment of psychiatric disorders. Glutamate signaling is processed by different receptors, including metabotropic glutamate receptors (mGluRs), which in turn interact with the scaffolding protein Homer1 to modulate downstream Ca(2+) signaling. Stress is a major risk factor for the incidence of psychiatric diseases, yet acute stress episodes may have diverging effects on individuals. Cognitive impairments have often been shown to occur after episodes of stress, however the specific role of mGluR5/Homer1 signaling in the interaction of stress and cognition has not yet been elucidated. In this study we show that a single episode of social defeat stress is sufficient to specifically induce cognitive impairments in mice 8 h after the stressor without affecting the animals' locomotion or anxiety levels. We also demonstrate that Homer1b/c levels as well as mGluR5/Homer1b/c interactions in the dorsal hippocampus are reduced up to 8 h after stress. Blockade of mGluR5 during the occurrence of social stress was able to rescue the cognitive impairments. In addition, a specific overexpression of Homer1b/c in the dorsal hippocampus also reversed the behavioral phenotype, indicating that both mGluR5 and Homer1b/c play a crucial role in the mediation of the stress effects. In summary, we could demonstrate that stress induces a cognitive deficit that is likely mediated by mGluR5/Homer1 signaling in the hippocampus. These findings help to reveal the underlying effects of cognitive impairments in patients suffering from stress-related psychiatric disorders.
Assuntos
Proteínas de Transporte/metabolismo , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/patologia , Hipocampo/metabolismo , Estresse Psicológico/complicações , Análise de Variância , Animais , Proteínas de Transporte/biossíntese , Proteínas de Transporte/genética , Transtornos Cognitivos/terapia , Dexametasona/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Terapia Genética , Vetores Genéticos/genética , Glucocorticoides/farmacologia , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Hipocampo/efeitos dos fármacos , Proteínas de Arcabouço Homer , Imunoprecipitação , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Piridinas/farmacologia , RNA Mensageiro/metabolismo , Receptor de Glutamato Metabotrópico 5 , Receptores de Glutamato Metabotrópico/genética , Receptores de Glutamato Metabotrópico/metabolismo , Reconhecimento Psicológico , Recompensa , Transdução de Sinais/fisiologia , Percepção Espacial/efeitos dos fármacos , Tiazóis/farmacologiaRESUMO
Stress has been identified as a major causal factor for many mental disorders. However, our knowledge about the chain of molecular and cellular events translating stress experience into altered behavior is still rather scant. Here, we have characterized a murine ortholog of the putative tumor suppressor gene DRR1 as a unique stress-induced protein in brain. It binds to actin, promotes bundling and stabilization of actin filaments, and impacts on actin-dependent neurite outgrowth. Endogenous DRR1 localizes to some, but not all, synapses, with preference for the presynaptic region. Hippocampal virus-mediated enhancement of DRR1 expression reduced spine density, diminished the probability of synaptic glutamate release, and altered cognitive performance. DRR1 emerges as a protein to link stress with actin dynamics, which in addition is able to act on synaptic function and cognition.
Assuntos
Cognição/fisiologia , Sinapses/fisiologia , Proteínas Supressoras de Tumor/fisiologia , Actinas/metabolismo , Animais , Comportamento Animal/fisiologia , Encéfalo/citologia , Encéfalo/fisiologia , Genes Supressores de Tumor , Células HEK293 , Humanos , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neuritos/metabolismo , Neuritos/ultraestrutura , Ligação Proteica , Estresse Fisiológico , Proteínas Supressoras de Tumor/genéticaRESUMO
BACKGROUND: Given the great interest in identifying reliable predictors of the response to antidepressant drugs, the present study investigated whether polygenic scores (PGS) for Major Depressive Disorder (MDD) and antidepressant treatment response (ADR) were related to the complex trait of antidepressant response in the Early Medication Change (EMC) cohort. METHODS: In this secondary analysis of the EMC trial (N = 889), 481 MDD patients were included and compared to controls from a population-based cohort. Patients were treated over eight weeks within a pre-defined treatment-algorithm. We investigated patients' genetic variation associated with MDD and ADR, using PGS and examined the association of PGS with treatment outcomes (early improvement, response, remission). Additionally, the influence of two cytochrome P450 drug-metabolizing enzymes (CYP2C19, CYP2D6) was determined. RESULTS: PGS for MDD was significantly associated with disorder status (NkR2 = 2.48 %, p < 1*10-12), with higher genetic burden in EMC patients compared to controls. The PGS for ADR did not explain remission status. The PGS for MDD and ADR were also not associated with treatment outcomes. In addition, there were no effects of common CYP450 gene variants on ADR. LIMITATIONS: The study was limited by variability in the outcome parameters due to differences in treatment and insufficient sample size in the used ADR genome-wide association study (GWAS). CONCLUSIONS: The present study confirms a polygenic contribution to MDD burden in the EMC patients. Larger GWAS with homogeneity in antidepressant treatments are needed to explore the genetic variation associated with ADR and realize the potential of PGS to contribute to specific response subtypes.
RESUMO
Laboratory mouse models offer opportunities to bridge the gap between basic neuroscience and applied stress research. Here we consider the ecological validity of social defeat stressors in mouse models of emotional vulnerability and resilience. Reports identified in PubMed from 1980 to 2020 are reviewed for the ecological validity of social defeat stressors, sex of subjects, and whether results are discussed in terms of vulnerability alone, resilience alone, or both vulnerability and resilience. Most of the 318 reviewed reports (95%) focus on males, and many reports (71%) discuss vulnerability and resilience. Limited ecological validity is associated with increased vulnerability and decreased resilience. Elements of limited ecological validity include frequent and repeated exposure to defeat stressors without opportunities to avoid or escape from unfamiliar conspecifics that are pre-screened and selected for aggressive behavior. These elements ensure defeat and may be required to induce vulnerability, but they are not representative of naturalistic conditions. Research aimed at establishing causality is needed to determine whether ecologically valid stressors build resilience in both sexes of mice.
Assuntos
Derrota Social , Estresse Psicológico , Masculino , Camundongos , Animais , Estresse Psicológico/psicologia , Agressão , Comportamento SocialRESUMO
Childhood traumatic events hamper the development of the hippocampus and impair declarative memory in susceptible individuals. Persistent elevations of hippocampal corticotropin-releasing factor (CRF), acting through CRF receptor 1 (CRF1), in experimental models of early-life stress have suggested a role for this endogenous stress hormone in the resulting structural modifications and cognitive dysfunction. However, direct testing of this possibility has been difficult. In the current study, we subjected conditional forebrain CRF1 knock-out (CRF1-CKO) mice to an impoverished postnatal environment and examined the role of forebrain CRF1 in the long-lasting effects of early-life stress on learning and memory. Early-life stress impaired spatial learning and memory in wild-type mice, and postnatal forebrain CRF overexpression reproduced these deleterious effects. Cognitive deficits in stressed wild-type mice were associated with disrupted long-term potentiation (LTP) and a reduced number of dendritic spines in area CA3 but not in CA1. Forebrain CRF1 deficiency restored cognitive function, LTP and spine density in area CA3, and augmented CA1 LTP and spine density in stressed mice. In addition, early-life stress differentially regulated the amount of hippocampal excitatory and inhibitory synapses in wild-type and CRF1-CKO mice, accompanied by alterations in the neurexin-neuroligin complex. These data suggest that the functional, structural and molecular changes evoked by early-life stress are at least partly dependent on persistent forebrain CRF1 signaling, providing a molecular target for the prevention of cognitive deficits in adults with a history of early-life adversity.
Assuntos
Transtornos Cognitivos/fisiopatologia , Hormônio Liberador da Corticotropina/fisiologia , Prosencéfalo/metabolismo , Receptores de Hormônio Liberador da Corticotropina/fisiologia , Estresse Psicológico/fisiopatologia , Animais , Proteínas de Ligação ao Cálcio , Moléculas de Adesão Celular Neuronais/metabolismo , Transtornos Cognitivos/complicações , Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/patologia , Transtornos Cognitivos/psicologia , Hormônio Liberador da Corticotropina/genética , Hormônio Liberador da Corticotropina/metabolismo , Espinhas Dendríticas/patologia , Modelos Animais de Doenças , Potenciais Pós-Sinápticos Excitadores/fisiologia , Feminino , Hipocampo/citologia , Potenciação de Longa Duração/genética , Potenciação de Longa Duração/fisiologia , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Proteínas do Tecido Nervoso/metabolismo , Moléculas de Adesão de Célula Nervosa/metabolismo , Receptores de Hormônio Liberador da Corticotropina/genética , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Comportamento Espacial/fisiologia , Estresse Psicológico/complicações , Estresse Psicológico/metabolismo , Estresse Psicológico/patologia , Estresse Psicológico/psicologiaRESUMO
Early-life stress may lead to persistent changes in central corticotropin-releasing hormone (CRH) and the CRH receptor 1 (CRHR1) system that modulates anxiety-related behavior. However, it remains unknown whether CRH-CRHR1 signaling is involved in early-life stress-induced anxiety-related behavior in adult animals. In the present study, we used conditional forebrain CRHR1 knockout (CRHR1-CKO) mice and examined the potential role of forebrain CRHR1 in the anxiogenic effects of early-life stress. As adults, wild-type mice that received unstable maternal care during the first postnatal week showed reduced body weight gain and increased anxiety levels in the open field test, which were prevented in stressed CRHR1-CKO mice. In the light-dark box test, control CRHR1-CKO mice were less anxious, but early-life stress increased anxiety levels in both wild-type and CRHR1-CKO mice. In the elevated plus maze test, early-life stress had only subtle effects on anxiety-related behavior. Moreover, early-life stress did not alter the basal home cage activity and gene expression levels of key hypothalamic-pituitary-adrenal axis regulators in adult wild-type and CRHR1-CKO mice, but enhanced neuroendocrine reactivity to acute immobilization stress in CRHR1-CKO mice. Our findings highlight the importance of forebrain CRHR1 in modulating some of the anxiogenic effects of early-life stress, and suggest that other neural circuits are also involved in the programming effects of early-life stress on anxiety-related behavior.