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Notwithstanding the huge progress in molecular and cellular neuroscience, our ability to understand the brain and develop effective treatments promoting mental health is still limited. This can be partially ascribed to the reductionist, deterministic and mechanistic approaches in neuroscience that struggle with the complexity of the central nervous system. Here, I introduce the Context theory of constrained systems proposing a novel role of contextual factors and genetic, molecular and neural substrates in determining brain functioning and behavior. This theory entails key conceptual implications. First, context is the main driver of behavior and mental states. Second, substrates, from genes to brain areas, have no direct causal link to complex behavioral responses as they can be combined in multiple ways to produce the same response and different responses can impinge on the same substrates. Third, context and biological substrates play distinct roles in determining behavior: context drives behavior, substrates constrain the behavioral repertoire that can be implemented. Fourth, since behavior is the interface between the central nervous system and the environment, it is a privileged level of control and orchestration of brain functioning. Such implications are illustrated through the Kitchen metaphor of the brain. This theoretical framework calls for the revision of key concepts in neuroscience and psychiatry, including causality, specificity and individuality. Moreover, at the clinical level, it proposes treatments inducing behavioral changes through contextual interventions as having the highest impact to reorganize the complexity of the human mind and to achieve a long-lasting improvement in mental health.
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INTRODUCTION: The 18-kDa translocator protein (TSPO) is increasingly recognized as a molecular target for PET imaging of inflammatory responses in various central nervous system (CNS) disorders. However, the reported sensitivity and specificity of TSPO PET to identify brain inflammatory processes appears to vary greatly across disorders, disease stages, and applied quantification methods. To advance TSPO PET as a potential biomarker to evaluate brain inflammation and anti-inflammatory therapies, a better understanding of its applicability across disorders is needed. We conducted a transdiagnostic systematic review and meta-analysis of all in vivo human TSPO PET imaging case-control studies in the CNS. Specifically, we investigated the direction, strength, and heterogeneity associated with the TSPO PET signal across disorders in pre-specified brain regions, and explored the demographic and methodological sources of heterogeneity. METHODS: We searched for English peer-reviewed articles that reported in vivo human case-control TSPO PET differences. We extracted the demographic details, TSPO PET outcomes, and technical variables of the PET procedure. A random-effects meta-analysis was applied to estimate case-control standardized mean differences (SMD) of the TSPO PET signal in the lobar/whole-brain cortical grey matter (cGM), thalamus, and cortico-limbic circuitry between different illness categories. Heterogeneity was evaluated with the I2 statistic and explored using subgroup and meta-regression analyses for radioligand generation, PET quantification method, age, sex, and publication year. Significance was set at the False Discovery Rate (FDR)-corrected P < 0.05. RESULTS: 156 individual case-control studies were included in the systematic review, incorporating data for 2381 healthy controls and 2626 patients. 139 studies documented meta-analysable data and were grouped into 11 illness categories. Across all the illness categories, we observed a significantly higher TSPO PET signal in cases compared to controls for the cGM (n = 121 studies, SMD = 0.358, PFDR < 0.001, I2 = 68%), with a significant difference between the illness categories (P = 0.004). cGM increases were only significant for Alzheimer's disease (SMD = 0.693, PFDR < 0.001, I2 = 64%) and other neurodegenerative disorders (SMD = 0.929, PFDR < 0.001, I2 = 73%). Cortico-limbic increases (n = 97 studies, SMD = 0.541, P < 0.001, I2 = 67%) were most prominent for Alzheimer's disease, mild cognitive impairment, other neurodegenerative disorders, mood disorders and multiple sclerosis. Thalamic involvement (n = 79 studies, SMD = 0.393, P < 0.001, I2 = 71%) was observed for Alzheimer's disease, other neurodegenerative disorders, multiple sclerosis, and chronic pain and functional disorders (all PFDR < 0.05). Main outcomes for systemic immunological disorders, viral infections, substance use disorders, schizophrenia and traumatic brain injury were not significant. We identified multiple sources of between-study variance to the TSPO PET signal including a strong transdiagnostic effect of the quantification method (explaining 25% of between-study variance; VT-based SMD = 0.000 versus reference tissue-based studies SMD = 0.630; F = 20.49, df = 1;103, P < 0.001), patient age (9% of variance), and radioligand generation (5% of variance). CONCLUSION: This study is the first overarching transdiagnostic meta-analysis of case-control TSPO PET findings in humans across several brain regions. We observed robust increases in the TSPO signal for specific types of disorders, which were widespread or focal depending on illness category. We also found a large and transdiagnostic horizontal (positive) shift of the effect estimates of reference tissue-based compared to VT-based studies. Our results can support future studies to optimize experimental design and power calculations, by taking into account the type of disorder, brain region-of-interest, radioligand, and quantification method.
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Chronic psychological stress is one of the most important triggers and environmental risk factors for neuropsychiatric disorders. Chronic stress can influence all organs via the secretion of stress hormones, including glucocorticoids by the adrenal glands, which coordinate the stress response across the body. In the brain, glucocorticoid receptors (GR) are expressed by various cell types including microglia, which are its resident immune cells regulating stress-induced inflammatory processes. To study the roles of microglial GR under normal homeostatic conditions and following chronic stress, we generated a mouse model in which the GR gene is depleted in microglia specifically at adulthood to prevent developmental confounds. We first confirmed that microglia were depleted in GR in our model in males and females among the cingulate cortex and the hippocampus, both stress-sensitive brain regions. Then, cohorts of microglial-GR depleted and wild-type (WT) adult female mice were housed for 3 weeks in a standard or stressful condition, using a chronic unpredictable mild stress (CUMS) paradigm. CUMS induced stress-related behavior in both microglial-GR depleted and WT animals as demonstrated by a decrease of both saccharine preference and progressive ratio breakpoint. Nevertheless, the hippocampal microglial and neural mechanisms underlying the adaptation to stress occurred differently between the two genotypes. Upon CUMS exposure, microglial morphology was altered in the WT controls, without any apparent effect in microglial-GR depleted mice. Furthermore, in the standard environment condition, GR depleted-microglia showed increased expression of pro-inflammatory genes, and genes involved in microglial homeostatic functions (such as Trem2, Cx3cr1 and Mertk). On the contrary, in CUMS condition, GR depleted-microglia showed reduced expression levels of pro-inflammatory genes and increased neuroprotective as well as anti-inflammatory genes compared to WT-microglia. Moreover, in microglial-GR depleted mice, but not in WT mice, CUMS led to a significant reduction of CA1 long-term potentiation and paired-pulse ratio. Lastly, differences in adult hippocampal neurogenesis were observed between the genotypes during normal homeostatic conditions, with microglial-GR deficiency increasing the formation of newborn neurons in the dentate gyrus subgranular zone independently from stress exposure. Together, these findings indicate that, although the deletion of microglial GR did not prevent the animal's ability to respond to stress, it contributed to modulating hippocampal functions in both standard and stressful conditions, notably by shaping the microglial response to chronic stress.
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Microglia , Receptores de Glucocorticoides , Animais , Feminino , Hipocampo/metabolismo , Masculino , Glicoproteínas de Membrana , Camundongos , Microglia/metabolismo , Neurogênese , Neurônios/metabolismo , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Receptores Imunológicos , Estresse PsicológicoRESUMO
OBJECTIVE: Produced by adipocytes, adiponectin crosses the blood-brain barrier to bind with specific receptors in the hypothalamus, brainstem, hippocampus, and cortex. In patients with major depressive disorder (MDD), circulating levels of adiponectin inversely related with antidepressant response to ketamine, and predicted a better response to multi-target drug combinations than to escitalopram. We investigated the effect of adiponectin on response to antidepressants in a naturalistic setting. METHODS: We assessed baseline plasma levels of adiponectin in 121 MDD inpatients, treated with antidepressant drug monotherapy based on clinical need (selective serotonin reuptake inhibitors, venlafaxine, duloxetine) in a specialized hospital setting. Severity of depression was weekly assessed with Hamilton scale ratings. RESULTS: Adiponectin plasma levels were higher in patients with MDD compared with healthy controls, and negatively influenced the pattern of antidepressant response (higher baseline levels, worse response) independent of the drug class and of the baseline severity of depression, and of age, sex, and body mass index. CONCLUSIONS: The identification of adiponectin as a predictor of antidepressant response to drugs of different mechanism of action, such as ketamine, SSRIs, and SNRIs, and both in experimental and in clinical settings, warrants interest for further study of its pathways to search for novel biomarkers and therapeutic targets.
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Transtorno Depressivo Maior , Adiponectina/uso terapêutico , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Humanos , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Cloridrato de Venlafaxina/uso terapêuticoRESUMO
Selective serotonin reuptake inhibitors (SSRIs), the most prescribed antidepressant drugs, have incomplete efficacy and no clear mechanism of action. In addition, no reliable methods to identify patients who will benefit from treatment is available. In this study, we show that citalopram, a commonly used SSRI, produces a dose-dependent amplification of the influence of the environment on mood, making the severity of symptoms dependent on the level of socioeconomic status (SES). As a consequence, based on SES, we were able to predict which patients would show remission following 12 weeks of treatment in the high, but not the low dose group. Our findings support a novel mechanism of action for SSRIs, which calls for a permissive rather than an instructive role of these drugs, and indicate that treatment outcome can be predicted based on SES and dose. Finally, our findings suggest that the patient's social and economic conditions should be considered in setting up personalized strategies aimed at enhancing SSRI efficacy.
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Antidepressivos/uso terapêutico , Citalopram/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Adolescente , Adulto , Afeto/efeitos dos fármacos , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Classe Social , Resultado do Tratamento , Adulto JovemRESUMO
An increasing number of studies show that both inflammation and neural plasticity act as key players in the vulnerability and recovery from psychiatric disorders and neurodegenerative diseases. However, the interplay between these two players has been limitedly explored. In fact, while a few studies reported an immune activation, others conveyed an immune suppression, associated with an impairment in neural plasticity. Therefore, we hypothesized that deviations in inflammatory levels in both directions may impair neural plasticity. We tested this hypothesis experimentally, by acute treatment of C57BL/6 adult male mice with different doses of two inflammatory modulators: lipopolysaccharide (LPS), an endotoxin, and ibuprofen (IBU), a nonselective cyclooxygenase inhibitor, which are respectively a pro- and an anti-inflammatory agent. The results showed that LPS and IBU have different effects on behavior and inflammatory response. LPS treatment induced a reduction of body temperature, a decrease of body weight and a reduced food and liquid intake. In addition, it led to increased levels of inflammatory markers expression, both in the total hippocampus and in isolated microglia cells, including Interleukin (IL)-1ß, and enhanced the concentration of prostaglandin E2 (PGE2). On the other hand, IBU increased the level of anti-inflammatory markers, decreased tryptophan 2,3-dioxygenase (TDO2), the first step in the kynurenine pathway known to be activated during inflammatory conditions, and PGE2 levels. Though LPS and IBU administration differently affected mediators related with pro- or anti-inflammatory responses, they produced overlapping effects on neural plasticity. Indeed, higher doses of both LPS and IBU induced a statistically significant decrease in the amplitude of long-term potentiation (LTP), in Brain-Derived Neurotrophic Factor (BDNF) expression levels and in the phosphorylation of the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor subunit GluR1, compared to the control group. Such effect appears to be dose-dependent since only the higher, but not the lower, dose of both compounds led to a plasticity impairment. Overall, the present findings indicate that acute treatment with pro- and anti-inflammatory agents impair neural plasticity in a dose dependent manner.
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Fator Neurotrófico Derivado do Encéfalo/biossíntese , Inflamação/metabolismo , Potenciação de Longa Duração/fisiologia , Plasticidade Neuronal/fisiologia , Animais , Anti-Inflamatórios/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Inibidores de Ciclo-Oxigenase/farmacologia , Citocinas/imunologia , Citocinas/metabolismo , Dinoprostona/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Ibuprofeno/farmacologia , Inflamação/imunologia , Interleucina-1beta/metabolismo , Cinurenina/metabolismo , Lipopolissacarídeos/farmacologia , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Plasticidade Neuronal/imunologia , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
An increasing number of studies show that selective serotonin reuptake inhibitors (SSRIs) exert their therapeutic action, at least in part, by amplifying the influence of the living environment on mood. As a consequence, when administered in a favorable environment, SSRIs lead to a reduction of symptoms, but in stressful conditions, they show limited efficacy. Therefore, novel therapeutic approaches able to neutralize the influence of the stressful environment on treatment are needed. The aim of our study was to test whether, in a mouse model of depression, the combined administration of SSRI fluoxetine and metformin, a drug able to improve the metabolic profile, counteracts the limited efficacy of fluoxetine alone when administered in stressful conditions. Indeed, metabolic alterations are associated to both the onset of major depression and the antidepressant efficacy. To this goal, adult C57BL/6 male mice were exposed to stress for 6 weeks; the first two weeks was aimed at generating a mouse model of depression. During the remaining 4 weeks, mice received one of the following treatments: vehicle, fluoxetine, metformin, or a combination of fluoxetine and metformin. We measured liking- and wanting-type anhedonia as behavioral phenotypes of depression and assessed the expression levels of selected genes involved in major depressive disorder and antidepressant response in the dorsal and ventral hippocampus, which are differently involved in the depressive symptomatology. The combined treatment was more effective than fluoxetine alone in ameliorating the depressive phenotype after one week of treatment. This was associated to an increase in IGF2 mRNA expression and enhanced long-term potentiation, specifically in the dorsal hippocampus, at the end of treatment. Overall, the present results show that, when administered in stressful conditions, the combined fluoxetine and metformin treatment may represent a more effective approach than fluoxetine alone in a short term. Finally, our findings highlight the relevance of polypharmacological strategy as effective interventions to increase the efficacy of the antidepressant drugs currently available.
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Anedonia/efeitos dos fármacos , Antidepressivos/uso terapêutico , Transtorno Depressivo/tratamento farmacológico , Fluoxetina/uso terapêutico , Hipocampo/efeitos dos fármacos , Fator de Crescimento Insulin-Like II/metabolismo , Metformina/uso terapêutico , Animais , Antidepressivos/farmacologia , Transtorno Depressivo/metabolismo , Modelos Animais de Doenças , Quimioterapia Combinada , Fluoxetina/farmacologia , Hipocampo/metabolismo , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Masculino , Metformina/farmacologia , Camundongos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/uso terapêuticoRESUMO
The past decade has witnessed a revolution in our understanding of microglia. These immune cells were shown to actively remodel neuronal circuits, leading to propose new pathogenic mechanisms. To study microglial implication in the loss of synapses, the best pathological correlate of cognitive decline across chronic stress, aging, and diseases, we recently conducted ultrastructural analyses. Our work uncovered the existence of a new microglial phenotype that is rarely present under steady state conditions, in hippocampus, cerebral cortex, amygdala, and hypothalamus, but becomes abundant during chronic stress, aging, fractalkine signaling deficiency (CX3 CR1 knockout mice), and Alzheimer's disease pathology (APP-PS1 mice). Even though these cells display ultrastructural features of microglia, they are strikingly distinct from the other phenotypes described so far at the ultrastructural level. They exhibit several signs of oxidative stress, including a condensed, electron-dense cytoplasm and nucleoplasm making them as "dark" as mitochondria, accompanied by a pronounced remodeling of their nuclear chromatin. Dark microglia appear to be much more active than the normal microglia, reaching for synaptic clefts, while extensively encircling axon terminals and dendritic spines with their highly ramified and thin processes. They stain for the myeloid cell markers IBA1 and GFP (in CX3 CR1-GFP mice), and strongly express CD11b and microglia-specific 4D4 in their processes encircling synaptic elements, and TREM2 when they associate with amyloid plaques. Overall, these findings suggest that dark microglia, a new phenotype that we identified based on their unique properties, could play a significant role in the pathological remodeling of neuronal circuits, especially at synapses.
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Envelhecimento/patologia , Doença de Alzheimer/patologia , Córtex Cerebral/patologia , Microglia/patologia , Estresse Psicológico/patologia , Aldeído Desidrogenase/genética , Aldeído Desidrogenase/metabolismo , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Antígenos CD/metabolismo , Receptor 1 de Quimiocina CX3C , Modelos Animais de Doenças , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas do Tecido Nervoso/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo CH-NH , Fenótipo , Presenilina-1/genética , Presenilina-1/metabolismo , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/metabolismo , Estresse Psicológico/genéticaRESUMO
Chronic stress is one of the most relevant triggering factors for major depression. Microglial cells are highly sensitive to stress and, more generally, to environmental challenges. However, the role of these brain immune cells in mediating the effects of stress is still unclear. Fractalkine signaling - which comprises the chemokine CX3CL1, mainly expressed by neurons, and its receptor CX3CR1, almost exclusively present on microglia in the healthy brain - has been reported to critically regulate microglial activity. Here, we investigated whether interfering with microglial function by deleting the Cx3cr1 gene affects the brain's response to chronic stress. To this purpose, we housed Cx3cr1 knockout and wild-type adult mice in either control or stressful environments for 2weeks, and investigated the consequences on microglial phenotype and interactions with synapses, synaptic transmission, behavioral response and corticosterone levels. Our results show that hampering neuron-microglia communication via the CX3CR1-CX3CL1 pathway prevents the effects of chronic unpredictable stress on microglial function, short- and long-term neuronal plasticity and depressive-like behavior. Overall, the present findings suggest that microglia-regulated mechanisms may underlie the differential susceptibility to stress and consequently the vulnerability to diseases triggered by the experience of stressful events, such as major depression.
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Comportamento Animal/fisiologia , Receptor 1 de Quimiocina CX3C/deficiência , Transtorno Depressivo Maior/fisiopatologia , Microglia , Plasticidade Neuronal/fisiologia , Neurônios , Transdução de Sinais/fisiologia , Estresse Psicológico/fisiopatologia , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
It has been hypothesized that selective serotonin reuptake inhibitors (SSRIs), the most common treatment for major depression, affect mood through changes in immune function. However, the effects of SSRIs on inflammatory response are contradictory since these act either as anti- or pro-inflammatory drugs. Previous experimental and clinical studies showed that the quality of the living environment moderates the outcome of antidepressant treatment. Therefore, we hypothesized that the interplay between SSRIs and the environment may, at least partially, explain the apparent incongruence regarding the effects of SSRI treatment on the inflammatory response. In order to investigate such interplay, we exposed C57BL/6 mice to chronic stress to induce a depression-like phenotype and, subsequently, to fluoxetine treatment or vehicle (21days) while being exposed to either an enriched or a stressful condition. At the end of treatment, we measured the expression levels of several anti- and pro-inflammatory cytokines and inflammatory mediators in the whole hippocampus and in isolated microglia. We also determined microglial density, distribution, and morphology to investigate their surveillance state. Results show that the effects of fluoxetine treatment on inflammation and microglial function, as compared to vehicle, were dependent on the quality of the living environment. In particular, fluoxetine administered in the enriched condition increased the expression of pro-inflammatory markers compared to vehicle, while treatment in a stressful condition produced anti-inflammatory effects. These findings provide new insights regarding the effects of SSRIs on inflammation, which may be crucial to devise pharmacological strategies aimed at enhancing antidepressant efficacy by means of controlling environmental conditions.
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Encefalite/metabolismo , Meio Ambiente , Fluoxetina/administração & dosagem , Microglia/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Animais , Citocinas/metabolismo , Depressão , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Mediadores da Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Microglia/fisiologia , Estresse PsicológicoRESUMO
A supportive early environment can strengthen the developing individual and build the foundation for a lifelong health. By contrast, severe stress can alter brain architecture and lead to increased susceptibility for psychopathology. There is a growing emphasis on setting up models that recapitulate the complexity of the perinatal environment, particularly the social experiences, on developmental trajectories. Special attention is paid, on the one hand, to the role of the mother in programming the behavioral, neuroendocrine and metabolic development of the offspring and, on the other, to the relevance of the social interactions with mother and peers in building up the adult individual. Overall, these studies confirm the strong and complex influence of the early ecological niche on adult brain function and behavior and illustrate how a comparative approach provides an important contribution to unravel the mechanisms underlying increased risk for mental illness in a translational perspective.
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Animais Recém-Nascidos , Encéfalo , Modelos Animais , Meio Social , Estresse Psicológico/metabolismo , Animais , Animais Recém-Nascidos/crescimento & desenvolvimento , Animais Recém-Nascidos/metabolismo , Animais Recém-Nascidos/fisiologia , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Encéfalo/fisiologia , Camundongos , Estresse Psicológico/fisiopatologiaRESUMO
BACKGROUND: The effects of the selective serotonin reuptake inhibitors (SSRIs), the first-line antidepressant treatment, have been proposed to be affected, at least in part, by the living environment. Since the quality of the environment depends not only on its objective features, but also on the subjective experience, we hypothesized that the latter plays a key role in determining SSRI treatment outcome. METHODS: We chronically administered the SSRI fluoxetine to two groups of adult CD-1 male mice that reportedly show distinct subjective experiences of the environment measured as consistent and significantly different responses to the same emotional and social stimuli. These distinct socioemotional profiles were generated by rearing mice either in standard laboratory conditions (SN) or in a communal nest (CN) where three dams breed together their offspring, sharing caregiving behavior. RESULTS: At adulthood, CN mice displayed higher levels of agonistic and anxiety-like behaviors than SN mice, indicating that they experience the environment as more socially challenging and potentially dangerous. We then administered fluoxetine, which increased offensive and anxious response in SN, while producing opposite effects in CN mice. BDNF regulation was modified by the treatment accordingly. LIMITATIONS: Subjective experience in mice was assessed as behavioral response to the environment. CONCLUSIONS: These results show that the subjective experience of the environment determines fluoxetine outcome. In a translational perspective, our findings suggest considering not only the objective quality, but also the subjective appraisal, of the patient's living environment for developing effective personalized therapeutic approaches in psychiatry.
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Antidepressivos , Fluoxetina , Adulto , Camundongos , Masculino , Animais , Humanos , Fluoxetina/farmacologia , Fluoxetina/uso terapêutico , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Ansiedade , Resultado do TratamentoRESUMO
Anxiety disorders are very prevalent and often persistent mental disorders, with a considerable rate of treatment resistance which requires regulatory clinical trials of innovative therapeutic interventions. However, an explicit definition of treatment-resistant anxiety disorders (TR-AD) informing such trials is currently lacking. We used a Delphi method-based consensus approach to provide internationally agreed, consistent and clinically useful operational criteria for TR-AD in adults. Following a summary of the current state of knowledge based on international guidelines and an available systematic review, a survey of free-text responses to a 29-item questionnaire on relevant aspects of TR-AD, and an online consensus meeting, a panel of 36 multidisciplinary international experts and stakeholders voted anonymously on written statements in three survey rounds. Consensus was defined as ≥75% of the panel agreeing with a statement. The panel agreed on a set of 14 recommendations for the definition of TR-AD, providing detailed operational criteria for resistance to pharmacological and/or psychotherapeutic treatment, as well as a potential staging model. The panel also evaluated further aspects regarding epidemiological subgroups, comorbidities and biographical factors, the terminology of TR-AD vs. "difficult-to-treat" anxiety disorders, preferences and attitudes of persons with these disorders, and future research directions. This Delphi method-based consensus on operational criteria for TR-AD is expected to serve as a systematic, consistent and practical clinical guideline to aid in designing future mechanistic studies and facilitate clinical trials for regulatory purposes. This effort could ultimately lead to the development of more effective evidence-based stepped-care treatment algorithms for patients with anxiety disorders.
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Early experiences profoundly affect the adult coping response to stress and, consequently, adult vulnerability to psychopathologies triggered by stressing conditions, such as major depression. Though studies in animal models have demonstrated that individuals reared in different conditions are differently vulnerable to a stressor of a specific quality, no information is available as to whether such vulnerability differs when facing stressors of different qualities. To this purpose, we reared C57BL/6 male mice either in standard laboratory rearing condition (SN) or in Communal Nest (CN) condition, the latter consisting of a single nest where three mothers keep their pups together and share care-giving behavior until weaning. We scored the amount of interactions with the mother and with peers and found that CN is a form of social enrichment because both these components are significantly increased. At adulthood, we exposed SN and CN mice, for 4 weeks, to either a physical (forced swim) or a social stress (social instability). Immediately before, at week 1 and at week 4 of the stress procedure, corticosterone levels and the hedonic profile were measured. The results show that CN mice are more resilient to social stress than SN mice since they displayed no anhedonia and lower corticosterone levels. By contrast, both experimental groups were similarly vulnerable to physical stress. Overall, our results show that, in male mice, the adult vulnerability to stress changes according to the quality of the stressor, as a function of early experiences. In addition, the stressor to which CN mice are resilient is qualitatively similar to the stimuli they have experienced early on, both concerning the social domain.
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Corticosterona/sangue , Comportamento Materno/fisiologia , Comportamento de Nidação/fisiologia , Comportamento Social , Estresse Psicológico/psicologia , Anedonia/fisiologia , Animais , Animais Recém-Nascidos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Testes Neuropsicológicos , Meio Social , Estresse Psicológico/sangue , Estresse Psicológico/classificaçãoRESUMO
Plasticity is increasingly recognized as a critical concept in psychiatry and mental health because it allows the reorganization of neural circuits and behavior during the transition from psychopathology to wellbeing. Differences in individual plasticity may explain why therapies, such as psychotherapeutic and environmental interventions, are highly effective in some but not in all patients. Here I propose a mathematical formula to assess plasticity - i.e., the susceptibility to change - to identify, at baseline, which individuals or populations are more likely to modify their behavioral outcome according to therapies or contextual factors. The formula is grounded in the network theory of plasticity so that, when representing a system (e.g., a patient's psychopathology) as a weighed network where the nodes are the system features (e.g., symptoms) and the edges are the connections (i.e., correlations) among them, the network connectivity strength is an inverse measure of the plasticity of the system: the weaker the connectivity, the higher the plasticity and the greater the susceptibility to change. The formula is predicted to be generalizable, measuring plasticity at multiple scales, from the single cell to the whole brain, and can be applied to a wide range of research fields, including neuroscience, psychiatry, ecology, sociology, physics, market and finance.
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Neurociências , Psiquiatria , Humanos , Saúde Mental , Ciência de Dados , Encéfalo/patologia , Plasticidade NeuronalRESUMO
Major depressive disorder (MDD) is a chronic, recurring, and potentially life-threatening illness, which affects over 300 million people worldwide. MDD affects not only the emotional and social domains but also cognition. However, the currently available treatments targeting cognitive deficits in MDD are limited. Minocycline, an antibiotic with anti-inflammatory properties recently identified as a potential antidepressant, has been shown to attenuate learning and memory deficits in animal models of cognitive impairment. Here, we explored whether minocycline recovers the deficits in cognition in a mouse model of depression. C57BL6/J adult male mice were exposed to two weeks of chronic unpredictable mild stress to induce a depressive-like phenotype. Immediately afterward, mice received either vehicle or minocycline for three weeks in standard housing conditions. We measured anhedonia as a depressive-like response, and place learning to assess cognitive abilities. We also recorded long-term potentiation (LTP) as an index of hippocampal functional plasticity and ran immunohistochemical assays to assess microglial proportion and morphology. After one week of treatment, cognitive performance in the place learning test was significantly improved by minocycline, as treated mice displayed a higher number of correct responses when learning novel spatial configurations. Accordingly, minocycline-treated mice displayed higher LTP compared to controls. However, after three weeks of treatment, no difference between treated and control animals was found for behavior, neural plasticity, and microglial properties, suggesting that minocycline has a fast but short effect on cognition, without lasting effects on microglia. These findings together support the usefulness of minocycline as a potential treatment for cognitive impairment associated with MDD.
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Transtornos Cognitivos , Transtorno Depressivo Maior , Camundongos , Animais , Masculino , Minociclina/farmacologia , Transtorno Depressivo Maior/tratamento farmacológico , Antibacterianos/farmacologia , Cognição , HipocampoRESUMO
The IntelliMaze allows automated behavioral analysis of group housed laboratory mice while individually assigned protocols can be applied concomitantly for different operant conditioning components. Here we evaluate the effect of additional component availability (enrichment) on behavioral and cognitive performance of mice in the IntelliCage, by focusing on aspects that had previously been found to consistently differ between three strains, in four European laboratories. Enrichment decreased the activity level in the IntelliCages and enhanced spatial learning performance. However, it did not alter strain differences, except for activity during the initial experimental phase. Our results from non-enriched IntelliCages proved consistent between laboratories, but overall laboratory-consistency for data collected using different IntelliCage set-ups, did not hold for activity levels during the initial adaptation phase. Our results suggest that the multiple conditioning in spatially and cognitively enriched environments are feasible without affecting external validity for a specific task, provided animals have adapted to such an IntelliMaze.
Assuntos
Cognição/fisiologia , Meio Ambiente , Aprendizagem em Labirinto/fisiologia , Atividade Motora/fisiologia , Desempenho Psicomotor/fisiologia , Adaptação Psicológica/fisiologia , Animais , Peso Corporal/fisiologia , Extinção Psicológica/fisiologia , Feminino , Abrigo para Animais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Meio Social , Especificidade da EspécieRESUMO
INTRODUCTION: BDNF is present in human serum and its level changes have been used as a marker of antidepressant efficacy in some psychiatric disorders. In addition, the positive effects of light therapy on major depression suggest that circadian-regulated factors should be taken into account in the management of mood disorders. The aim of the present study was to test ultradian fluctuations in serum and salivary BDNF levels and their interaction with light therapy in a sample of healthy women. METHODS: The study included 16 young women. Psychopathological status and chronotype traits were assessed by SPAQ, BDI, STAI, TAS, and MEQ. Standard light treatment protocol was applied. Serum and saliva were collected at 8.00, 13.00 and 20.00 hrs on the same day and at the end of light therapy. RESULTS: BDNF levels declined over the course of the day both in serum and saliva, and a correlation between diurnal BDNF trend and personality traits and habits characterizing the morning and evening types in healthy women was found. CONCLUSIONS: The present study is one of the first to show measurable BDNF in human saliva and to demonstrate its daily fluctuations in both saliva and serum of healthy young women. The correlation between diurnal changes in BDNF and the personality traits associated with body rhythms corroborates the notion that salivary BDNF may be a useful biomarker for stress-related research and different clinical investigations.
Assuntos
Relógios Biológicos , Fator Neurotrófico Derivado do Encéfalo/sangue , Ritmo Circadiano , Fototerapia , Saliva/metabolismo , Adulto , Biomarcadores/sangue , Depressão/sangue , Feminino , Humanos , Personalidade , Inventário de Personalidade , Estudos de Amostragem , Estatísticas não Paramétricas , Estresse Psicológico/sangue , EstudantesRESUMO
Despite the huge and constant progress in the molecular and cellular neuroscience fields, our capability to understand brain alterations and treat mental illness is still limited. Therefore, a paradigm shift able to overcome such limitation is warranted. Behavior and the associated mental states are the interface between the central nervous system and the living environment. Since, in any system, the interface is a key regulator of system organization, behavior is proposed here as a unique and privileged level of control and orchestration of brain structure and activity. This view has relevant scientific and clinical implications. First, the study of behavior represents a singular starting point for the investigation of neural activity in an integrated and comprehensive fashion. Second, behavioral changes, accomplished through psychotherapy or environmental interventions, are expected to have the highest impact to specifically reorganize the complexity of the human mind and thus achieve a solid and long-lasting improvement in mental health.