RESUMO
Adult hippocampal neurogenesis (AHN) represents a remarkable form of neuroplasticity that has increasingly been linked to the stress response in recent years. However, the hippocampus does not itself support the expression of the different dimensions of the stress response. Moreover, the main hippocampal functions are essentially preserved under AHN depletion and adult-born immature neurons (abGNs) have no extrahippocampal projections, which questions the mechanisms by which abGNs influence functions supported by brain areas far from the hippocampus. Within this framework, we propose that through its computational influences AHN is pivotal in shaping adaption to environmental demands, underlying its role in stress response. The hippocampus with its high input convergence and output divergence represents a computational hub, ideally positioned in the brain (1) to detect cues and contexts linked to past, current and predicted stressful experiences, and (2) to supervise the expression of the stress response at the cognitive, affective, behavioral, and physiological levels. AHN appears to bias hippocampal computations toward enhanced conjunctive encoding and pattern separation, promoting contextual discrimination and cognitive flexibility, reducing proactive interference and generalization of stressful experiences to safe contexts. These effects result in gating downstream brain areas with more accurate and contextualized information, enabling the different dimensions of the stress response to be more appropriately set with specific contexts. Here, we first provide an integrative perspective of the functional involvement of AHN in the hippocampus and a phenomenological overview of the stress response. We then examine the mechanistic underpinning of the role of AHN in the stress response and describe its potential implications in the different dimensions accompanying this response.
Assuntos
Células-Tronco Neurais , Neurônios , Hipocampo/metabolismo , Neurogênese/fisiologia , Plasticidade Neuronal/fisiologia , Neurônios/metabolismoRESUMO
The study was designed to assess whether repeated administration of diazepam (Valium®, Roche)-a benzodiazepine exerting an agonist action on GABAA receptors-may alleviate both the short (1 week, 1W) and long-term (6 weeks, 6W) deleterious effects of alcohol withdrawal occurring after chronic alcohol consumption (6 months; 12% v/v) in C57/BL6 male mice. More pointedly, we first evidenced that 1W and 6W alcohol-withdrawn mice exhibited working memory deficits in a sequential alternation task, associated with sustained exaggerated corticosterone rise and decreased pCREB levels in the prefrontal cortex (PFC). In a subsequent experiment, diazepam was administered i.p. for 9 consecutive days (1 injection/day) during the alcohol withdrawal period at decreasing doses ranging from 1.0 mg/kg to 0.25 mg/kg. Diazepam was not detected in the blood of withdrawn mice at the time of memory testing, occurring 24 hours after the last diazepam injection. Repeated diazepam administration significantly improved alternation rates and normalized levels of glucocorticoids and pCREB activity in the PFC in 1W but not in 6W withdrawn mice. Thus, repeated diazepam administration during the alcohol-withdrawal period only transitorily canceled out the working memory impairments and glucocorticoid alterations in the PFC of alcohol-withdrawn animals.
Assuntos
Alcoolismo/tratamento farmacológico , Diazepam/farmacologia , Transtornos da Memória/tratamento farmacológico , Nootrópicos/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Alcoolismo/complicações , Alcoolismo/metabolismo , Alcoolismo/psicologia , Animais , Ansiedade/tratamento farmacológico , Ansiedade/etiologia , Ansiedade/metabolismo , Depressores do Sistema Nervoso Central/efeitos adversos , Depressores do Sistema Nervoso Central/sangue , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Diazepam/sangue , Modelos Animais de Doenças , Etanol/efeitos adversos , Etanol/sangue , Agonistas de Receptores de GABA-A/sangue , Agonistas de Receptores de GABA-A/farmacologia , Glucocorticoides/metabolismo , Masculino , Transtornos da Memória/etiologia , Transtornos da Memória/metabolismo , Memória de Curto Prazo/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Nootrópicos/sangue , Córtex Pré-Frontal/metabolismo , Síndrome de Abstinência a Substâncias/metabolismo , Síndrome de Abstinência a Substâncias/psicologia , Fatores de TempoRESUMO
Both human and animal studies indicate that alcohol withdrawal following chronic alcohol consumption (CAC) impairs many of the cognitive functions which rely on the prefrontal cortex (PFC). A candidate signaling cascade contributing to memory deficits during alcohol withdrawal is the protein kinase A (PKA)/cAMP-responsive element binding (CREB) cascade, although the role of PKA/CREB cascade in behavioral and molecular changes during sustained withdrawal period remains largely unknown. We demonstrated that 1 week (1W) or 6 weeks (6W) withdrawal after 6-month CAC impairs working memory (WM) in a T-maze spontaneous alternation task and reduces phosphorylated CREB (pCREB) in the PFC but not the dorsal CA1 region (dCA1) of the hippocampus compared with CAC and water conditions. In contrast, both CAC-unimpaired and withdrawn-impaired mice exhibited decreased pCREB in dCA1 as well as reduced histone H4 acetylation in PFC and dCA1, compared with water controls. Next, we showed that enhancing CREB activity through rolipram administration prior to testing improved WM performance in withdrawn mice but impaired WM function in water mice. In addition, WM improvement correlates positively with increased pCREB level selectively in the PFC of withdrawn mice. Results further indicate that direct infusion of the PKA activator (Sp-cAMPS) into the PFC significantly improves or impairs, respectively, WM performance in withdrawn and water animals. In contrast, Sp-cAMPS had no effect on WM when infused into the dCA1. Collectively, these results provide strong support that dysregulation of PKA/CREB-dependent processes in prefrontal neurons is a critical molecular signature underlying cognitive decline during alcohol withdrawal.
Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Transtornos da Memória/fisiopatologia , Memória de Curto Prazo/fisiologia , Córtex Pré-Frontal/fisiopatologia , Síndrome de Abstinência a Substâncias/fisiopatologia , Alcoolismo/metabolismo , Alcoolismo/fisiopatologia , Animais , Transtornos Cognitivos/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Hipocampo/metabolismo , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Córtex Pré-Frontal/metabolismo , Transdução de Sinais/fisiologia , Síndrome de Abstinência a Substâncias/metabolismoRESUMO
Interactions between genetic and environmental factors, like exposure to stress, have an important role in the pathogenesis of mood-related psychiatric disorders, such as major depressive disorder. The polyspecific organic cation transporters (OCTs) were shown previously to be sensitive to the stress hormone corticosterone in vitro, suggesting that these transporters might have a physiologic role in the response to stress. Here, we report that OCT2 is expressed in several stress-related circuits in the brain and along the hypothalamic-pituitary-adrenocortical (HPA) axis. Genetic deletion of OCT2 in mice enhanced hormonal response to acute stress and impaired HPA function without altering adrenal sensitivity to adrenocorticotropic hormone (ACTH). As a consequence, OCT2(-/-) mice were potently more sensitive to the action of unpredictable chronic mild stress (UCMS) on depression-related behaviors involving self-care, spatial memory, social interaction and stress-sensitive spontaneous behavior. The functional state of the glycogen synthase kinase-3ß (GSK3ß) signaling pathway, highly responsive to acute stress, was altered in the hippocampus of OCT2(-/-) mice. In vivo pharmacology and western blot experiments argue for increased serotonin tonus as a main mechanism for impaired GSK3ß signaling in OCT2(-/-) mice brain during acute response to stress. Our findings identify OCT2 as an important determinant of the response to stress in the brain, suggesting that in humans OCT2 mutations or blockade by certain therapeutic drugs could interfere with HPA axis function and enhance vulnerability to repeated adverse events leading to stress-related disorders.
Assuntos
Encéfalo/fisiopatologia , Quinase 3 da Glicogênio Sintase/metabolismo , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Estresse Psicológico/metabolismo , Potenciais de Ação/efeitos dos fármacos , Doença Aguda , Animais , Encéfalo/efeitos dos fármacos , Doença Crônica , Corticosterona/administração & dosagem , Corticosterona/metabolismo , Depressão/metabolismo , Glicogênio Sintase Quinase 3 beta , Hormônios/administração & dosagem , Hormônios/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Norepinefrina/metabolismo , Proteínas de Transporte de Cátions Orgânicos/genética , Transportador 2 de Cátion Orgânico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células Piramidais/efeitos dos fármacos , Células Piramidais/fisiologia , Resiliência Psicológica , Serotonina/metabolismo , IncertezaRESUMO
In recent years, both major depression and antidepressant therapy have been linked to adult hippocampal neurogenesis. The hippocampus is not a homogeneous brain area, and a converging body of evidence indicates a functional dissociation along its septo-temporal axis, the dorsal part being involved more in learning/memory and spatial navigation, while the ventral sub-region is linked more to emotional behavior and regulation of the neuroendocrine stress axis. Research has therefore been conducted in an attempt to relate effects of models of depression and of antidepressant therapies to adult neurogenesis along the septo-temporal axis of the hippocampus. The present paper reviews the current literature addressing this question and discusses the possible mechanisms involved and the functional significance of such regional effects. This review shows that animal models of depression elicit an effect restricted to the ventral hippocampus more frequently than a dorsal-specific effect. However, this is also stage specific, and concerns neurogenesis, rather than cell proliferation or survival. Surprisingly, the same does not apply regarding the effects of selective serotonin re-uptake inhibitors that act in a more uniform way on dorsal and ventral adult neurogenesis in most studies. Some recently introduced clinical compounds (e.g., agomelatine) or putative antidepressants have a specific action on the ventral sub-region, indicating that an action restricted to this part of the brain may be sufficient to achieve remission. Finally, non-pharmacological manipulations that are also endowed with antidepressant effects, such as environmental enrichment or physical exercise, also act on both subdivisions, although some studies pointed to specificity of dorsal neurogenesis. The different treatments, acting either on the dorsal or on the ventral sub-regions, could promote recovery by improving either ventral- or dorsal-related functions, both contributing in a different way to treatment efficacy.
Assuntos
Antidepressivos/farmacologia , Depressão/fisiopatologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Neurogênese/fisiologia , Animais , Depressão/tratamento farmacológico , HumanosRESUMO
RATIONALE: The selective CRF1 (corticotropin releasing factor type 1) receptor antagonist SSR125543 has been previously shown to attenuate the long-term cognitive deficit produced by traumatic stress exposure. Memory disturbances described in post-traumatic stress disorder (PTSD) patients are believed to be associated with changes in neuronal activity, in particular at the level of the hippocampus. OBJECTIVES: The present study aims at investigating whether the effects of SSR125543 (10 mg/kg/day for 2 weeks) on cognitive impairment induced by traumatic stress exposure are associated with changes in hippocampal excitability. Effects of SSR125543 were compared to those of the 5-HT reuptake inhibitor, paroxetine (10 mg/kg/day), and the partial N-methyl-D-aspartate (NMDA) receptor agonist, D-cycloserine (10 mg/kg/day), two compounds which have demonstrated clinical efficacy against PTSD. METHODS: Mice received two unavoidable electric foot-shocks. Then, 1 or 16 days after stress, they were tested for their memory performance using the object recognition test. Neuronal excitability was recorded during the third week post-stress in the CA1 area of the hippocampus. Drugs were administered from day 1 post-stress to the day preceding the electrophysiological study. RESULTS: Application of electric shocks produced cognitive impairment 16, but not 1 day after stress, an effect which was associated with a decrease in hippocampal neuronal excitability. Both stress-induced effects were prevented by repeated administration of SSR125543, paroxetine and D-cycloserine. CONCLUSIONS: These findings confirm that the CRF1 receptor antagonist SSR125543 is able to attenuate the behavioral effects of traumatic stress exposure and indicate that these effects are associated with a normalization of hippocampal neuronal excitability impaired by stress.
Assuntos
Transtornos Cognitivos/tratamento farmacológico , Hidrocarbonetos Halogenados/farmacologia , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Estresse Psicológico/tratamento farmacológico , Tiazinas/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Transtornos Cognitivos/etiologia , Ciclosserina/farmacologia , Eletrochoque , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Masculino , Camundongos , Paroxetina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Estresse Psicológico/complicações , Fatores de TempoRESUMO
The gabra5 gene is associated with pharmacological properties (myorelaxant, amnesic, anxiolytic) of benzodiazepines. It is tightly located (0.5 cM) close to the pink-eyed dilution (p) locus which encodes for fur color on mouse chromosome 7. We tested the putative role of the gabra5 gene in pharmacological properties of the full non specific agonist chlordiazepoxide (CDP), using behavioral and molecular approaches in mutated p/p mice and wild type F2 from crosses between two multiple markers inbred strain ABP/Le and C57BL/6By strain. From our results, using rotarod, light-dark box, elevated maze and radial arm maze tests, we demonstrate that p/p mice are more sensitive than WT to the sensory motor, anxiolytic and amnesic effect of CDP. This is associated with the presence of a haplotypic block on the murine chromosome 7 and with an up regulation of gabra5 mRNAs in hippocampi of p/p F2 mice.
Assuntos
Comportamento Animal/efeitos dos fármacos , Benzodiazepinas/agonistas , Clordiazepóxido , Regulação da Expressão Gênica/efeitos dos fármacos , Mutação/genética , Receptores de GABA-A/genética , Adaptação Psicológica/efeitos dos fármacos , Adaptação Psicológica/fisiologia , Animais , Benzodiazepinas/metabolismo , Proteínas de Transporte/genética , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/genética , Haplótipos/genética , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Atividade Motora/efeitos dos fármacos , Atividade Motora/genética , RNA Mensageiro/metabolismo , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/genética , Teste de Desempenho do Rota-Rod , Percepção Espacial/efeitos dos fármacos , Percepção Espacial/fisiologiaRESUMO
The selective antagonist at the CRF1 receptor, SSR125543, has been shown to produce anxiolytic-like effects in a number of animal models. The aim of the present study was to verify whether these effects are mediated by an action on the hypothalamic pituitary adrenal (HPA) axis. SSR125543 effects were evaluated in a mouse model of post-traumatic stress disorder. Animals received two unavoidable electric foot-shocks (1.5 mA/2 s). Two weeks later they were placed in the shock context and fecal and plasma corticosterone levels were measured by enzyme-immunoassay. Their cognitive performances were evaluated using the object recognition task following administration of SSR125543 at 3, 10 and 30 mg/kg or paroxetine at 20 mg/kg (i.p.), used as positive control. To assess the involvement of the HPA axis in the drug effects, a separate group of animals was subjected to the same procedure and drug regimen, but was treated with dexamethasone to blunt the HPA axis. Stressed mice had higher levels of corticosterone following re-exposure to the context and displayed impaired cognitive performance as compared to control animals. Corticosterone levels were normalized in stressed mice by SSR125543 and the cognitive deficit was significantly attenuated by SSR125543 and paroxetine, whether the HPA axis was blunted or not. These findings confirm that SSR125543 is able to attenuate the deleterious effects of stressful exposure. Importantly, the observation that these effects were still present in dexamethasone-treated mice indicates that this action does not necessarily involve pituitary-adrenal axis blockade, thereby suggesting that extra-pituitary CRF1 receptors may play a role in these effects.
Assuntos
Transtornos Cognitivos/psicologia , Hidrocarbonetos Halogenados/farmacologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Receptores de Hormônio Liberador da Corticotropina/agonistas , Estresse Psicológico/psicologia , Tiazinas/farmacologia , Animais , Transtornos Cognitivos/etiologia , Corticosterona/análise , Corticosterona/sangue , Corticosterona/metabolismo , Dexametasona/farmacologia , Eletrochoque , Fezes/química , Masculino , Camundongos , Paroxetina/farmacologia , Reconhecimento Psicológico/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Estresse Psicológico/complicaçõesRESUMO
Recent research suggests an involvement of hippocampal neurogenesis in behavioral effects of antidepressants. However, the precise mechanisms through which newborn granule neurons might influence the antidepressant response remain elusive. Here, we demonstrate that unpredictable chronic mild stress in mice not only reduces hippocampal neurogenesis, but also dampens the relationship between hippocampus and the main stress hormone system, the hypothalamo-pituitary-adrenal (HPA) axis. Moreover, this relationship is restored by treatment with the antidepressant fluoxetine, in a neurogenesis-dependent manner. Specifically, chronic stress severely impairs HPA axis activity, the ability of hippocampus to modulate downstream brain areas involved in the stress response, the sensitivity of the hippocampal granule cell network to novelty/glucocorticoid effects and the hippocampus-dependent negative feedback of the HPA axis. Remarkably, we revealed that, although ablation of hippocampal neurogenesis alone does not impair HPA axis activity, the ability of fluoxetine to restore hippocampal regulation of the HPA axis under chronic stress conditions, occurs only in the presence of an intact neurogenic niche. These findings provide a mechanistic framework for understanding how adult-generated new neurons influence the response to antidepressants. We suggest that newly generated neurons may facilitate stress integration and that, during chronic stress or depression, enhancing neurogenesis enables a dysfunctional hippocampus to restore the central control on stress response systems, then allowing recovery.
Assuntos
Fluoxetina/farmacologia , Fluoxetina/uso terapêutico , Hipocampo/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Estresse Psicológico/tratamento farmacológico , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Contagem de Células/métodos , Contagem de Células/estatística & dados numéricos , Corticosterona/sangue , Corticosterona/metabolismo , Depressão/tratamento farmacológico , Depressão/fisiopatologia , Dexametasona , Modelos Animais de Doenças , Hipocampo/diagnóstico por imagem , Hipocampo/fisiopatologia , Humanos , Hidrocarbonetos Halogenados/farmacologia , Hidrocarbonetos Halogenados/uso terapêutico , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neurogênese/fisiologia , Testes de Função Adreno-Hipofisária/métodos , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/fisiopatologia , Radiografia , Estresse Psicológico/fisiopatologia , Tiazinas/farmacologia , Tiazinas/uso terapêuticoRESUMO
The experience of traumatic stress often leads to long-lasting alteration in sleep quality and behavior. The objective of the present experiment was to investigate the short- and long-term effects of acute inescapable stress (i.e. two electric foot-shocks of 1.5 mA; 2s) on sleep/wakefulness parameters and behavior in Swiss mice using electroencephalographic (EEG) analysis. Baseline EEG recording was performed in the home cage for 6h prior to the application of the foot-shocks in the presence of an object (i.e. a plastic prism). One, 7, 14 or 21 days later, a second 6h EEG recording session was performed after mice had been exposed or not to the same object for 5 min in their home cage. Results showed that at day 1, 7, 14 and 21 post-stress, shocked mice displayed sleep fragmentation as shown by an increase in the number of sleep episodes, regardless the presence of the object or not. In animals exposed to the object, the total duration of wakefulness over 6h was significantly increased at days 7, 14 and 21 post-stress, and rapid eye movement (REM) sleep was significantly decreased at day 14 post-shock. Moreover, in the behavioral experiment, conditioned avoidance to a shock-paired object, which appeared as soon as 24h after shock application, turned into generalized avoidance towards an unknown object 21 days after stress. These findings demonstrate that an acute inescapable stress exposure may cause long-lasting alterations in sleep patterns and behavior. Such modifications may be reminiscent of the profound changes observed in patients suffering from post-traumatic stress disorder.
Assuntos
Aprendizagem da Esquiva/fisiologia , Modelos Animais de Doenças , Transtornos do Sono-Vigília/fisiopatologia , Sono REM/fisiologia , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Estresse Psicológico/fisiopatologia , Animais , Sinais (Psicologia) , Eletroencefalografia/métodos , Eletrochoque/efeitos adversos , Masculino , Camundongos , Vigília/fisiologiaRESUMO
OBJECTIVE: Aging is associated with cognitive changing. Central auditory processing dysfunction may explain some understanding difficulties in elderly. It may be evaluated with the dichotic listening (DL) test, a widely-used experimental paradigm for studying inter-hemispheric interactions and attentional processes. This study examines central auditory language processing with a dichotic listening task in right-handed old subjects according to their age. DESIGN: Cross sectional-study. SETTING: memory clinic and geriatric unit. PARTICIPANTS: Adult group (Ad) consisted in 26 subjects (21 women and 5 men) aged 50-69 years and an old adults group (Old-Ad) consisted in 20 subjects (19 women and 1 man) aged 70 to 89 years. MEASUREMENTS: DL consisted in a free-recall word task and a digit forced-attention task (forced-right: FR and forced-left: FL) in order to study central auditory language processing. In addition, we used neuropsychological tests to study executive functions and cognitive control, sustained by the prefrontal cortex. RESULTS: In the free recall condition, we confirmed the classic right ear advantage (REA) in both groups, particularly in older subjects. In the forced condition, we observed an ear advantage with a change in ear asymmetry as a consequence of instruction: REA in FR and a left-ear advantage (LEA) in FL. We compared contaminations by the contra-lateral inattentive ear: reports of the left ear (LE) in the FR condition and reports of the right ear (RE) in the FL condition. Contaminations by the RE in the FL condition were more pronounced in Old-Ad suggesting difficulties in competition between the natural tendency for the RE and the instruction. In the Old-Ad group, the correlation between the RE score in FL and TMT B-A/A suggests an impairment in mental flexibility. CONCLUSION: DL may be helpful to study central auditory dysfunction in aging. Our results suggest difficulties in attentional control and executive functions. Central auditory dysfunction should be evaluated in elderly because it potentially contributes to difficulty of hearing in noisy environment with consequences in the rehabilitation of presbyacousic subjects. More studies are needed to investigate the predictive value of DL as a marker of cognitive decline, particularly executive functions.
Assuntos
Atenção , Percepção Auditiva , Transtornos Cognitivos/diagnóstico , Função Executiva , Avaliação Geriátrica/métodos , Transtornos da Audição/diagnóstico , Memória , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/fisiologia , Estudos Transversais , Testes com Listas de Dissílabos/métodos , Orelha , Feminino , Lateralidade Funcional , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Córtex Pré-Frontal , ProibitinasRESUMO
Research on depression and antidepressant drugs is necessary, as many patients display poor response to therapy. Different symptomatic and pathophysiological features have been proposed as end points of the depressive phenotype and of the antidepressant action, including anhedonia, depressed mood, alterations in morphology and activity of some brain areas (amygdala, nucleus accumbens, hippocampus, prefrontal cortex and cingulate cortex), modifications in the connectivity between brain structures, changes in neurotransmitters (serotonin, noradrenaline, glutamate and neuropeptides), brain plasticity (neurogenesis, neurotrophins) and abnormal function of the hypothalamic-pituitary adrenal axis. However, few models have been proposed to describe how these end points could induce the depressive phenotype and are involved in the mechanism of action of antidepressants. Here we propose a connectionist-inspired network of depression and antidepressant action, in which the different aetiological factors participating in the release of a depressive episode are represented by input nodes, the different symptomatic as well as pathophysiological end points are represented by an intermediate layer, and the onset of depression or of comorbid disease is represented by the output node. The occurrence of depression and the mechanism of the antidepressant action thus depend upon the weight of the interactions between the different end points, none of them being per se crucial to the onset of a depressive phenotype or to the antidepressant action. This model is heuristic to draw future lines of research concerning new antidepressant therapies, designing new animal models of depression and for a better understanding of the depressive pathology and of its comorbid pathology such as anxiety disorders.
Assuntos
Antidepressivos/farmacologia , Encéfalo/efeitos dos fármacos , Transtorno Depressivo Maior/tratamento farmacológico , Modelos Biológicos , Animais , Antidepressivos/uso terapêutico , Encéfalo/metabolismo , Transtorno Depressivo Maior/metabolismo , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Determinação de Ponto Final , Humanos , Plasticidade Neuronal/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacosRESUMO
The aim of this study was to examine the effects of supplementation with n-3 polyunsaturated fatty acids (PUFAs) on stress responses in mice subjected to an unpredictable chronic mild stress (UCMS) procedure. Stress-induced modifications in coat and aggressiveness were evaluated, and phospholipid PUFA profiles and monoamine levels were analyzed in the frontal cortex, hippocampus, and striatum. The results showed that repeated exposure to mild stressors induced degradation in the physical state of the coat, lowered body weight gain, and increased aggressiveness, without any effect of n-3 PUFA supplementation. The UCMS induced a significant decrease in the levels of norepinephrine in the frontal cortex and striatum, and a nonsignificant decrease in the hippocampus. The tissue levels of serotonin (5-HT) were 40% to 65% decreased in the three brain regions studied. Interestingly, the n-3 PUFA supplementation reversed this stress-induced reduction in 5-HT levels. These findings showed that supplementation in n-3 long-chain PUFAs might reverse certain effects of UCMS in cerebral structures involved in stress-related behaviors.
Assuntos
Monoaminas Biogênicas/metabolismo , Encéfalo/metabolismo , Suplementos Nutricionais , Ácidos Graxos Ômega-3/administração & dosagem , Estresse Psicológico/metabolismo , Animais , Comportamento Animal/fisiologia , Ácidos Graxos Ômega-3/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fosfolipídeos , Valor Preditivo dos Testes , Tempo de Reação/fisiologia , Estresse Psicológico/dietoterapiaRESUMO
It is known that 5-HT(4) receptor agonists increase sAPPalpha levels in the cortex and hippocampus of mice as well as in a model of Alzheimer's disease (AD). As sAPPalpha is thought to have pro-mnesic properties, we assessed whether its increase induces cognitive improvement in a spatial memory task and whether it reverses a scopolamine-induced memory deficit. Mice treated or not treated with scopolamine were trained in the Morris water maze for 3 days. Before the probe test, they received an injection of either a 5-HT(4) receptor agonist (prucalopride or RS 67333), or an acetylcholinesterase inhibitor (donepezil), or both drugs. As expected, scopolamine decreased performance, an effect that was not reversed by the drugs tested when injected alone. However, prucalopride (5 mg kg(-1), s.c.) acted synergistically with donepezil (0.75 mg kg(-1), s.c.) to counteract completely scopolamine-induced amnesia. Western blot analysis of tissue homogenates in the cortex and hippocampus shows that sAPPalpha levels did not differ between saline- and scopolamine-treated mice. Furthermore, a region-dependent drug action was observed since the scopolamine-treated mice display a tendency to increase sAPPalpha levels in the hippocampus after donepezil or in the cortex after prucalopride. Our results suggest that a combined treatment with a 5-HT(4) receptor agonist with an acetylcholinesterase inhibitor has beneficial effects on memory in mice. Moreover, it seems to enhance sAPPalpha levels in two brain regions highly affected in AD. Thus, a drug polytherapy could be interesting not only to enhance cognitive performance and decrease drawbacks but also to get the best action in each brain region.
Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Benzofuranos/farmacologia , Indanos/farmacologia , Aprendizagem em Labirinto/efeitos dos fármacos , Nootrópicos/farmacologia , Piperidinas/farmacologia , Agonistas do Receptor 5-HT4 de Serotonina , Precursor de Proteína beta-Amiloide/efeitos dos fármacos , Análise de Variância , Compostos de Anilina/farmacologia , Animais , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Inibidores da Colinesterase/farmacologia , Donepezila , Sinergismo Farmacológico , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Transtornos da Memória/induzido quimicamente , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Escopolamina , Estatísticas não ParamétricasRESUMO
Numerous data from human and animal studies suggest that hippocampal plasticity might be a key element in depression. However, the connection remains loose at best and further data are needed. Human studies are of necessity limited, but animal models can help providing further insight. Unpredictable chronic mild stress (UCMS) is a commonly used model because it mimics depression-like phenotypes satisfactorily. Its rationale is based on the underlying stress-induced difficulties found in many depressed patients. We therefore studied learning and hippocampal neurogenesis in mice from three different inbred strains subjected to UCMS. Learning was assessed in different hippocampus-dependent and independent tasks. The rate of survival of newly generated brain cells was determined in behaviorally-naive animals. Results demonstrated a dramatic reduction of surviving new brain cells in both the hippocampus and the subventricular zone of UCMS-treated animals. This reduction was observed both for neurons and for other cells of the hippocampus. Behavioral data demonstrated an impairment of hippocampus-dependent learning, whereas hippocampus-independent learning was spared. However, the specific results were strongly dependent on strain and sex so that there does not appear to be a direct causative relationship between the deficits in neurogenesis and behavior.
Assuntos
Proliferação de Células , Hipocampo/fisiopatologia , Deficiências da Aprendizagem/fisiopatologia , Plasticidade Neuronal/fisiologia , Estresse Psicológico/fisiopatologia , Animais , Divisão Celular/fisiologia , Sobrevivência Celular/fisiologia , Doença Crônica/psicologia , Transtorno Depressivo/etiologia , Transtorno Depressivo/fisiopatologia , Regulação para Baixo/fisiologia , Feminino , Deficiências da Aprendizagem/etiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Neurônios/fisiologia , Caracteres Sexuais , Especificidade da Espécie , Células-Tronco/fisiologia , Estresse Psicológico/complicações , Estresse Psicológico/psicologiaRESUMO
Normal aging of the brain differs from pathological conditions and is associated with increased risk for psychiatric and neurological disorders. In addition to its role in the etiology and treatment of mood disorders, altered serotonin (5-HT) signaling is considered a contributing factor to aging; however, no causative role has been identified in aging. We hypothesized that a deregulation of the 5-HT system would reveal its contribution to age-related processes and investigated behavioral and molecular changes throughout adult life in mice lacking the regulatory presynaptic 5-HT(1B) receptor (5-HT(1B)R), a candidate gene for 5-HT-mediated age-related functions. We show that the lack of 5-HT(1B)R (Htr1b(KO) mice) induced an early age-related motor decline and resulted in decreased longevity. Analysis of life-long transcriptome changes revealed an early and global shift of the gene expression signature of aging in the brain of Htr1b(KO) mice. Moreover, molecular changes reached an apparent maximum effect at 18-months in Htr1b(KO) mice, corresponding to the onset of early death in that group. A comparative analysis with our previous characterization of aging in the human brain revealed a phylogenetic conservation of age-effect from mice to humans, and confirmed the early onset of molecular aging in Htr1b(KO) mice. Potential mechanisms appear independent of known central mechanisms (Bdnf, inflammation), but may include interactions with previously identified age-related systems (IGF-1, sirtuins). In summary, our findings suggest that the onset of age-related events can be influenced by altered 5-HT function, thus identifying 5-HT as a modulator of brain aging, and suggesting age-related consequences to chronic manipulation of 5-HT.
Assuntos
Envelhecimento/fisiologia , Regulação da Expressão Gênica/genética , Expressão Gênica/genética , Atividade Motora/genética , Receptor 5-HT1B de Serotonina/deficiência , Fatores Etários , Análise de Variância , Animais , Animais Recém-Nascidos , Comportamento Animal/fisiologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Ensaio de Imunoadsorção Enzimática/métodos , Força da Mão/fisiologia , Hibridização In Situ , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Knockout , Análise em Microsséries/métodos , Tempo de Reação/fisiologia , Receptor 5-HT1B de Serotonina/genética , Análise de SobrevidaRESUMO
This paper aimed at reviewing the involvement of neuropeptides in various psychiatric diseases, particularly in depression, and anxiety disorders. General features of neuropeptides are first described, including the history of their discovery, their definition, classification, biosynthesis, transport, release, inactivation, as well as their interaction with specific neuronal receptors. The differences with classical neurotransmitters are mentioned, as well as the different patterns of co-transmission. Finally, different mechanisms, both at the cellular and at the systemic level, are proposed that may explain the involvement of these molecules in various psychiatric diseases. Indeed, at the cellular level, a neuropeptide can be involved in a psychiatric disease, either because it is co-localized with a classical neurotransmitter involved in a disease, or because the neuropeptide-containing neuron projects on a target neuron involved in the disease. At the systemic level, a neuropeptide can play a direct role in the expression of a symptom of the disease. This is illustrated by different examples.
Assuntos
Transtornos de Ansiedade/metabolismo , Química Encefálica/fisiologia , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Transtorno Depressivo/metabolismo , Neuropeptídeos/metabolismo , Animais , Transtornos de Ansiedade/fisiopatologia , Transtorno Depressivo/fisiopatologia , Humanos , Neuropeptídeos/classificação , Neurotransmissores/metabolismo , Terminações Pré-Sinápticas/metabolismo , Receptores de Neurotransmissores/metabolismo , Transmissão Sináptica/fisiologiaRESUMO
This study aimed at investigating the relationship between anxiety-like and depressive-like behaviour in mice. Therefore, we assessed the behaviour of mice from eight different strains (FVB/NA, BALB/c, C57BL/6, DBA/2, 129/Sv, C3H/He, CBA and BA) confronted first to anxiety models (the elevated plus-maze and the free exploratory test) and then to tests of depressive-like behaviours (forced swim test and unpredictable subchronic mild stress). In the forced swim test, mice from the DBA/2, the BA and the C3H/He strains displayed higher immobility than mice from the 129/Sv, the BALB/c, the C57BL/6 and the CBA strains. In the subchronic mild stress, mice from the C57BL/6 and the CBA strains displayed low sensitivity when compared with mice from all the others strains. A stepwise multiple regression analysis suggests that behaviour in the elevated plus-maze is associated with the time of immobility in the forced swim test (20%) and with the susceptibility to the unpredictable subchronic stress procedure (31%). The behaviour in the free exploratory paradigm is slightly associated with behaviours in the two tests of depression. These results suggest that anxiety may be a factor contributing, among others, to the susceptibility to depressive-like behaviours.
Assuntos
Nível de Alerta , Medo , Aprendizagem em Labirinto , Estresse Psicológico/complicações , Animais , Ansiedade/psicologia , Depressão/psicologia , Ingestão de Líquidos , Comportamento Exploratório , Asseio Animal , Masculino , Camundongos , Camundongos Endogâmicos , Motivação , Atividade Motora , Piloereção , Análise de Regressão , Especificidade da Espécie , Estatística como Assunto , PaladarRESUMO
As in many complex behavioral responses, inter-individual variability can be observed in the responses to a chronic mild stress. While some subjects exhibit more resilient behaviours, others appear more susceptible to stress. This study hypothesizes that this variability relies on the individual appraisal of the stressful event. To study this assumption, mice were first subjected to a conditioned task occurring in a circular arena. In this task, a mild air-puff (i.e. stressor) in a given quadrant of the arena was coupled with the presence or the absence of a light in the same quadrant. Half of mice were then submitted to a 15-day subchronic stress consisting in various environmental and social mild stressors randomly applied two or three times a day. At the end of this procedure, the occurrence of depressive-like behaviours in stressed mice was assessed using measures of the stress regime (i.e. physical state, choice test, grooming test). The physical state assessed the physical appearance of mice. The grooming test consisted in measuring the time spent in grooming after mice were sprayed upon with a viscous solution. The choice test consisted in measuring the time spent in an uncomfortable place (i.e. whose floor was covered with damp sawdust) versus a more comfortable one (i.e. with dry sawdust) to evaluate the reactivity to a negative stimulus previously encountered during the subchronic stress. Multiple regression analyses revealed a relationship between attention toward salient stressful stimuli in the conditioned task and susceptibility to the subchronic stress procedure. These results are discussed regarding their relevance for the understanding of aetiologies of depressive illnesses.