RESUMO
Stress is assumed to cause a shift from flexible 'cognitive' memory to more rigid 'habit' memory. In the spatial memory domain, stress impairs place learning depending on the hippocampus whereas stimulus-response learning based on the striatum appears to be improved. While the neural basis of this shift is still unclear, previous evidence in rodents points towards cortisol interacting with the mineralocorticoid receptor (MR) to affect amygdala functioning. The amygdala is in turn assumed to orchestrate the stress-induced shift in memory processing. However, an integrative study testing these mechanisms in humans is lacking. Therefore, we combined functional neuroimaging of a spatial memory task, stress-induction, and administration of an MR-antagonist in a full-factorial, randomized, placebo-controlled between-subjects design in 101 healthy males. We demonstrate that stress-induced increases in cortisol lead to enhanced stimulus-response learning, accompanied by increased amygdala activity and connectivity to the striatum. Importantly, this shift was prevented by an acute administration of the MR-antagonist spironolactone. Our findings support a model in which the MR and the amygdala play an important role in the stress-induced shift towards habit memory systems, revealing a fundamental mechanism of adaptively allocating neural resources that may have implications for stress-related mental disorders.
Assuntos
Tonsila do Cerebelo/fisiopatologia , Conectoma , Hidrocortisona/metabolismo , Transtornos da Memória/fisiopatologia , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Neostriado/fisiopatologia , Receptores de Mineralocorticoides/metabolismo , Aprendizagem Espacial/fisiologia , Estresse Psicológico/complicações , Adulto , Tonsila do Cerebelo/diagnóstico por imagem , Tonsila do Cerebelo/efeitos dos fármacos , Humanos , Imageamento por Ressonância Magnética , Masculino , Transtornos da Memória/etiologia , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Neostriado/diagnóstico por imagem , Neostriado/efeitos dos fármacos , Aprendizagem Espacial/efeitos dos fármacos , Estresse Psicológico/metabolismo , Adulto JovemRESUMO
Early life adversity can have long-lasting impact on learning and memory processes and increase the risk to develop stress-related psychopathologies later in life. In this study we investigated (i) how chronic early life stress (ELS) - elicited by limited nesting and bedding material from postnatal day 2 to 9 - affects conditioned fear in adult mice and (ii) whether these effects can be prevented by blocking glucocorticoid receptors (GRs) at adolescent age. In adult male and female mice, ELS did not affect freezing behavior to the first tone 24h after training in an auditory fear-conditioning paradigm. Exposure to repeated tones 24h after training also resulted in comparable freezing behavior in ELS and control mice, both in males and females. However, male (but not female) ELS compared to control mice showed significantly more freezing behavior between the tone-exposures, i.e. during the cue-off periods. Intraperitoneal administration of the GR antagonist RU38486 during adolescence (on postnatal days 28-30) fully prevented enhanced freezing behavior during the cue-off period in adult ELS males. Western blot analysis revealed no effects of ELS on hippocampal expression of glucocorticoid receptors, neither at postnatal day 28 nor at adult age, when mice were behaviorally tested. We conclude that ELS enhances freezing behavior in adult mice in a potentially safe context after cue-exposure, which can be normalized by brief blockade of glucocorticoid receptors during the critical developmental window of adolescence.
Assuntos
Medo/fisiologia , Reação de Congelamento Cataléptica/fisiologia , Antagonistas de Hormônios/farmacologia , Receptores de Glucocorticoides/fisiologia , Estresse Psicológico/fisiopatologia , Fatores Etários , Animais , Sinais (Psicologia) , Feminino , Antagonistas de Hormônios/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mifepristona/administração & dosagem , Mifepristona/farmacologia , Receptores de Glucocorticoides/antagonistas & inibidores , Fatores SexuaisRESUMO
Mineralocorticoid receptors (MRs) have been implicated in behavioral adaptation and learning and memory. Since-at least in humans-MR function seems to be sex-dependent, we examined the behavioral relevance of MR in female mice exhibiting transgenic MR overexpression in the forebrain. Transgenic MR overexpression did not affect contextual fear memory or cued fear learning and memory. Moreover, MR overexpressing and control mice discriminated equally well between fear responses in a combined cue and context fear conditioning paradigm. Also context-memory in an object recognition task was unaffected in MR overexpressing mice. We conclude that MR overexpression in female animals does not affect fear conditioned responses and object recognition memory.
RESUMO
BACKGROUND: Fear learning in stressful situations is highly adaptive for survival by steering behavior in subsequent situations, but fear learning can become disproportionate in vulnerable individuals. Despite the potential clinical significance, the mechanism by which stress modulates fear learning is poorly understood. Memory theories state that stress can cause a shift away from more controlled processing depending on the hippocampus toward more reflexive processing supported by the amygdala and striatum. This shift may be mediated by activation of the mineralocorticoid receptor (MR) for cortisol. We investigated how stress shifts processes underlying cognitively demanding learning versus less demanding fear learning using a combined trace and delay fear conditioning paradigm. METHODS: In a pharmacological functional magnetic resonance imaging study, we tested 101 healthy men probing the effects of stress (socially evaluated cold pressor vs. control procedure) and MR-availability (400 mg spironolactone vs. placebo) in a randomized, placebo-controlled, full-factorial, between-subjects design. RESULTS: Effective stress induction and successful conditioning were confirmed by subjective, physiologic, and somatic data. In line with a stress-induced shift, stress enhanced later recall of delay compared with trace conditioning in the MR-available groups as indexed by skin conductance responses. During learning, this was accompanied by a stress-induced reduction of learning-related hippocampal activity for trace conditioning. The stress-induced shift in fear and neural processing was absent in the MR-blocked groups. CONCLUSIONS: Our results are in line with a stress-induced shift in fear learning, mediated by the MR, resulting in a dominance of cognitively less demanding amygdala-based learning, which might be particularly prominent in individuals with high MR sensitivity.
Assuntos
Tonsila do Cerebelo/fisiopatologia , Condicionamento Clássico/fisiologia , Medo/fisiologia , Hipocampo/fisiopatologia , Receptores de Mineralocorticoides/fisiologia , Estresse Psicológico/fisiopatologia , Adulto , Tonsila do Cerebelo/efeitos dos fármacos , Mapeamento Encefálico , Temperatura Baixa , Condicionamento Clássico/efeitos dos fármacos , Método Duplo-Cego , Medo/efeitos dos fármacos , Resposta Galvânica da Pele , Hipocampo/efeitos dos fármacos , Humanos , Hidrocortisona/metabolismo , Imageamento por Ressonância Magnética , Masculino , Rememoração Mental/efeitos dos fármacos , Rememoração Mental/fisiologia , Receptores de Mineralocorticoides/agonistas , Espironolactona/farmacologia , Adulto JovemRESUMO
Two research lines argue for rapid stress-induced reallocations of neural network activity involving the amygdala. One focuses on the role of norepinephrine (NE) in mediating a shift towards the salience network and improving vigilance processing, whereas the other focuses on the role of cortisol in enhancing automatic, habitual responses. It has been suggested that the mineralocorticoid receptor (MR) is critical in shifting towards habitual responses, which are supported by the dorsal striatum. However, until now it remained unclear whether these two reallocations of neural recourses might be part of the same phenomenon and develop immediately after stress onset. We combined methods used in both approaches and hypothesized specifically that stress would lead to rapidly enhanced involvement of the striatum as assessed by amygala-striatal connectivity. Furthermore, we tested the hypothesis that this shift depends on cortisol interacting with the MR, by using a randomized, placebo-controlled, full-factorial, between-subjects design with the factors stress and MR-blockade (spironolactone). We investigated 101 young, healthy men using functional magnetic resonance imaging after stress induction, which led to increased negative mood, heart rate, and cortisol levels. We confirmed our hypothesis by revealing a stress-by-MR-blockade interaction on the functional connectivity between the centromedial amygdala (CMA) and the dorsal striatum. Stress rapidly enhanced CMA-striatal connectivity and this effect was correlated with the stress-induced cortisol response, but required MR availability. This finding might suggest that the stress-induced shift described by distinct research lines might capture different aspects of the same phenomenon, ie, a reallocation of neural resources coordinated by both NE and cortisol.
Assuntos
Corpo Estriado/fisiopatologia , Complexo Nuclear Corticomedial/fisiopatologia , Vias Neurais/fisiologia , Receptores de Mineralocorticoides/metabolismo , Estresse Psicológico/prevenção & controle , Adulto , Pressão Sanguínea/efeitos dos fármacos , Temperatura Baixa/efeitos adversos , Corpo Estriado/irrigação sanguínea , Corpo Estriado/efeitos dos fármacos , Complexo Nuclear Corticomedial/irrigação sanguínea , Complexo Nuclear Corticomedial/efeitos dos fármacos , Face , Voluntários Saudáveis , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hidrocortisona/metabolismo , Masculino , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Vias Neurais/efeitos dos fármacos , Oxigênio/sangue , Reconhecimento Visual de Modelos/efeitos dos fármacos , Estimulação Luminosa , Tempo de Reação/efeitos dos fármacos , Espironolactona/administração & dosagem , Estresse Psicológico/etiologia , Adulto JovemRESUMO
The postnatal development of the mouse is characterized by a period of hypo-responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis to mild stressors. Maternal deprivation (MD) during this period can disrupt the quiescence of the HPA-axis. The present study examined the influence of strain (outbred CD1 vs. inbred C57BL/6J mice) on some central and peripheral components of the HPA-axis in neonatal mice (5-day-old) in the presence of their mother or after 24 h MD (on postnatal day 4) under basal or mild stressful conditions. In the presence of the dam, adrenal corticosterone (CORT) secretion was low in both mouse strains. Compared to CD1 mice, C57BL/6J had lower CORT levels associated with higher ACTH levels and ACTH/CORT ratio (i.e., lower adrenal sensitivity to ACTH), and higher glucocorticoid receptor (GR) mRNA expression in the paraventricular nucleus. Although MD disinhibited the HPA-axis in both strains as reflected by increased basal CORT and ACTH, we found a strain-dependent pattern. MD increased CORT more in C57BL/6J compared to CD1 mice together with a lower ACTH/CORT ratio (i.e., higher adrenal sensitivity to ACTH), while GR mRNA was no longer different in the two strains. However, this increased adrenal sensitivity in maternally deprived C57BL/6J mice was not reflected in their CORT response to a subsequent novelty stressor, possibly due to an MD-induced ceiling effect in their steroidogenic capacity. In conclusion, the immediate outcome of MD depends on the genetic background of the mother-infant dyad, suggesting that maybe also the outcome in later-life cannot be generalized.
RESUMO
Stress glucocorticoids and insulin are important endocrine regulators of energy homeostasis, but little is known about their central interaction on the reward-related processing of food cues. According to a balanced group design, healthy food deprived men received either 40IU intranasal insulin (n=13), 30mg oral cortisol (n=12), both (n=15), or placebo (n=14). Acoustic startle responsiveness was assessed during presentation of food and non-food pictures. Cortisol enhanced startle responsiveness during visual presentation of "high glycemic" food pictures, but not during presentation of neutral and pleasant non-food pictures. Insulin had no effect. Based on the "frustrative nonreward" model these results suggest that the reward value of high glycemic food items is specifically increased by cortisol.
Assuntos
Encéfalo/efeitos dos fármacos , Hidrocortisona/farmacologia , Insulina/farmacologia , Reflexo de Sobressalto/efeitos dos fármacos , Administração Intranasal , Adulto , Sinais (Psicologia) , Emoções , Privação de Alimentos , Humanos , Hidrocortisona/análise , Masculino , Recompensa , Saliva/química , Adulto JovemRESUMO
Social interaction with unknown individuals requires fast processing of information to decide whether it is friend or foe. This process of discrimination and decision-making is stressful and triggers secretion of corticosterone activating mineralocorticoid receptor (MR) and glucocorticoid receptor (GR). The MR is involved in appraisal of novel experiences and risk assessment. Recently, we have demonstrated in a dual-solution memory task that MR plays a role in the early stage of information processing and decision-making. Here we examined social approach and social discrimination in male and female mice lacking MR from hippocampal-amygdala-prefrontal circuitry and controls. The social approach task allows the assessment of time spent with an unfamiliar mouse and the ability to discriminate between familiar and unfamiliar conspecifics. The male and female test mice were both more interested in the social than the non-social experience and deletion of their limbic MR increased the time spent with an unfamiliar mouse. Unlike controls, the male MR(CaMKCre) mice were not able to discriminate between an unfamiliar and the familiar mouse. However, the female MR mutant had retained the discriminative ability between unfamiliar and familiar mice. Administration of the MR antagonist RU28318 to male mice supported the role of the MR in the discrimination between an unfamiliar mouse and a non-social stimulus. No effect was found with a GR antagonist. Our findings suggest that MR is involved in sociability and social discrimination in a sex-specific manner through inhibitory control exerted putatively via limbic-hippocampal efferents. The ability to discriminate between familiar and unfamiliar conspecifics is of uttermost importance for territorial defense and depends on a role of MR in decision-making.
RESUMO
Adrenal corticosteroid hormones act via mineralocorticoid (MR) and glucocorticoid receptors (GR) in the brain, influencing learning and memory. MRs have been implicated in the initial behavioral response in novel situations, which includes behavioral strategies in learning tasks. Different strategies can be used to solve navigational tasks, for example hippocampus-dependent spatial or striatum-dependent stimulus-response strategies. Previous studies suggested that MRs are involved in spatial learning and induce a shift between learning strategies when animals are allowed a choice between both strategies. In the present study, we further explored the role of MRs in spatial and stimulus-response learning in two separate circular holeboard tasks using female mice with forebrain-specific MR deficiency and MR overexpression and their wildtype control littermates. In addition, we studied sex-specific effects using male and female MR-deficient mice. First, we found that MR-deficient compared to control littermates and MR-overexpressing mice display altered exploratory and searching behavior indicative of impaired acquisition of novel information. Second, female (but not male) MR-deficient mice were impaired in the spatial task, while MR-overexpressing female mice showed improved performance in the spatial task. Third, MR-deficient mice were also impaired in the stimulus-response task compared to controls and (in the case of females) MR-overexpressing mice. We conclude that MRs are important for coordinating the processing of information relevant for spatial as well as stimulus-response learning.
Assuntos
Encéfalo/fisiologia , Aprendizagem em Labirinto/fisiologia , Memória/fisiologia , Receptores de Mineralocorticoides/metabolismo , Animais , Encéfalo/metabolismo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Insulin and cortisol play a key role in the regulation of energy homeostasis, appetite, and satiety. Little is known about the action and interaction of both hormones in brain structures controlling food intake and the processing of neurovisceral signals from the gastrointestinal tract. In this study, we assessed the impact of single and combined application of insulin and cortisol on resting regional cerebral blood flow (rCBF) in the insular cortex. After standardized periods of food restriction, 48 male volunteers were randomly assigned to receive either 40 IU intranasal insulin, 30 mg oral cortisol, both, or neither (placebo). Continuous arterial spin labeling (CASL) sequences were acquired before and after pharmacological treatment. We observed a bilateral, locally distinct rCBF increase after insulin administration in the insular cortex and the putamen. Insulin effects on rCBF were present regardless of whether participants had received cortisol or not. Our results indicate that insulin, but not cortisol, affects blood flow in human brain structures involved in the regulation of eating behavior.
Assuntos
Córtex Cerebral/efeitos dos fármacos , Circulação Cerebrovascular/efeitos dos fármacos , Hidrocortisona/administração & dosagem , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Administração Oral , Adulto , Análise de Variância , Relação Dose-Resposta a Droga , Método Duplo-Cego , Jejum , Humanos , Hidrocortisona/metabolismo , Imageamento por Ressonância Magnética , Masculino , Saliva/metabolismo , Marcadores de Spin , Fatores de Tempo , Escala Visual Analógica , Adulto JovemRESUMO
Previous research has shown that food deprivation enhances the acoustic startle reflex when it is elicited during presentation of visual food cues. Frustrative nonreward may explain this effect, since visual food cues are also rated to be more appetitive and arousing during food deprivation. However, the impact of menstrual cycle and sex on this effect remains unclear, and it is also not known whether this effect is influenced by hunger and motivation to eat. According to a within-study design, 20 healthy women in different menstrual cycle phases and 14 healthy men participated twice, in normal and food-deprived conditions. After 18 h of food deprivation, acoustic startle was attenuated by appetitive nonfood foreground pictures, but enhanced by presentation of food pictures. No differences between menstrual cycle phases and sexes appeared. The effect correlated with hunger changes, suggesting that motivational factors play a role.
Assuntos
Privação de Alimentos/fisiologia , Alimentos , Ciclo Menstrual/fisiologia , Reflexo de Sobressalto/fisiologia , Recompensa , Estimulação Acústica , Adulto , Sinais (Psicologia) , Feminino , Humanos , Masculino , Caracteres Sexuais , Adulto JovemRESUMO
There is general agreement that the substantial modification in memory and motivational states exerted by corticosteroids after a traumatic experience is mediated in complementary manner by the mineralocorticoid (MR) and glucocorticoid (GR) receptors. Here we tested the hypothesis that pharmacological manipulation of MR activity would affect behavioral strategy and information storage in an olfactory fear conditioning (OFC) task. Male Wistar rats were submitted to the OFC with different training intensities. We observed that following high intensity OFC acquisition, a set of defensive coping strategies, which includes avoidance and risk assessment behaviors, was elicited when subjects were exposed to the conditioned stimulus (CS) 48 h later. In addition, following either OFC acquisition or retrieval (CS-I test) a profound corticosterone secretion was also detected. Systemic administration of the MR antagonist spironolactone altered the behavioral coping style irrespective the antagonist was administered 60 min prior to the acquisition or before the retrieval session. Surprisingly, the MR agonist fludrocortisone given 60 min prior to acquisition or retrieval of OFC had similar effects as the antagonist. In addition, post-training administration of fludrocortisone, following a weak training procedure, facilitated the consolidation of OFC. Fludrocortisone rather than spironolactone reduced serum corticosterone levels, suggesting that, at least in part, the effects of the MR agonist may derive from additional GR-mediated HPA-axis suppression. In conclusion, the present study suggests the involvement of the MR in the fine-tuning of behavioral adaptation necessary for optimal information storage and expression, as revealed by the marked alterations in the risk assessment behavior.
Assuntos
Condicionamento Psicológico/efeitos dos fármacos , Medo/efeitos dos fármacos , Memória/efeitos dos fármacos , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Percepção Olfatória/efeitos dos fármacos , Receptores de Mineralocorticoides/agonistas , Animais , Condicionamento Psicológico/fisiologia , Corticosterona/sangue , Medo/fisiologia , Fludrocortisona/farmacologia , Masculino , Memória/fisiologia , Atividade Motora/efeitos dos fármacos , Percepção Olfatória/fisiologia , Ratos , Ratos Wistar , Receptores de Mineralocorticoides/metabolismo , Espironolactona/farmacologiaRESUMO
Prolonged maternal separation (MS) activates the neonate's hypothalamus-pituitary-adrenal axis causing elevated basal and stress-induced corticosterone levels that may initiate amygdala-dependent fear learning. Here we test the hypothesis that the adult fearful phenotype is programmed by the pup's stressful experience during prolonged MS rather than by prolonged maternal absence per se. For this purpose, Wistar rat pups were exposed, on postnatal-day (pnd) 3, to: (i) repeated-MS in home-environment (HOME-SEP), 8h-MS daily for three days with the pups remaining together in the home-cage; (ii) repeated-MS in a novel-environment (NOVEL-SEP), with the same separation procedure, but now the pups were individually housed in a novel-environment during the 8h dam's absence; (iii) repeated handling, which consisted of daily brief (15 min instead of 8h) MS in the home-altogether or in a novel-environment individually (HOME-HAN and NOVEL-HAN, respectively); (iv) no-separation/no-handling (NON-SEP/NON-HAN) control condition, in which pups were left undisturbed in their home-cage. Compared to HOME-SEP rats, the NOVEL-SEP rats showed one day after the last MS enhanced stress-induced amygdala c-Fos expression and ACTH-release, despite of reduced adrenal corticosterone secretion. The higher amygdala c-Fos expression, ACTH-release and reduced corticosterone output observed postnatally, persisted into adulthood of the NOVEL-SEP animals. Behaviorally, NOVEL-SEP juvenile rats displayed deficits in social play, had intact spatial memory in the peri-pubertal period and showed more contextual fear memory compared to HOME-SEP in adulthood. Finally, NOVEL-HAN, compared to HOME-HAN, displayed increased stress-induced corticosterone output, no deficits in social play and reduced contextual fear. In conclusion, programming of an adult fearful phenotype linked to amygdala priming develops if pups are repeatedly isolated from peers in a novel-environment, while away from the dam for a prolonged period of time.
Assuntos
Tonsila do Cerebelo/fisiopatologia , Meio Ambiente , Medo/fisiologia , Abrigo para Animais , Privação Materna , Tonsila do Cerebelo/metabolismo , Animais , Animais Recém-Nascidos/fisiologia , Comportamento Exploratório/fisiologia , Jogos e Brinquedos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Wistar , Comportamento Social , Estresse Psicológico/metabolismo , Estresse Psicológico/fisiopatologiaRESUMO
Corticosterone facilitates behavioral adaptation to a novel experience in a coordinate manner via mineralocorticoid (MR) and glucocorticoid receptors (GR). Initially, MR mediates corticosterone action on appraisal processes, risk assessment and behavioral flexibility and then, GR activation promotes consolidation of the new information into memory. Here, we studied on the circular holeboard (CHB) the spatial performance of female mice with genetic deletion of MR from the forebrain (MR(CaMKCre)) and their wild type littermates (MR(flox/flox) mice) over the estrous cycle and in response to an acute stressor. The estrous cycle had no effect on the spatial performance of MR(flox/flox) mice and neither did the acute stressor. However, the MR(CaMKCre) mutants needed significantly more time to find the exit and made more hole visit errors than the MR(flox/flox) mice, especially when in proestrus and estrus. In addition, stressed MR(CaMKCre) mice in estrus had a shorter exit latency than the control estrus MR(CaMKCre) mice. About 70% of the female MR(CaMKCre) and MR(flox/flox) mice used a hippocampal (spatial, extra maze cues) rather than the caudate nucleus (stimulate-response, S-R, intra-maze cue) strategy and this preference did neither change over the estrous cycle nor after stress. However, stressed MR(CaMKCre) mice using the S-R strategy needed significantly more time to find the exit hole as compared to the spatial strategy using mice suggesting that the MR could be needed for the stress-induced strategy switch toward a spatial strategy. In conclusion, the results suggest that loss of MR interferes with performance of a spatial task especially when estrogen levels are high suggesting a strong interaction between stress and sex hormones.
RESUMO
Early experiences affect brain development and thus adult brain function and behavior. We employed a novel early experience model involving denial (DER) or receipt of expected reward (RER) through maternal contact in a T-maze. Exposure to the DER experience for the first time, on postnatal day 10 (PND10), was stressful for the pups, as assessed by increased corticosterone levels, and was accompanied by enhanced activation of the amygdala, as assessed by c-Fos immunohistochemistry. Re-exposure to the same experience on days 11-13 led to adaptation. Corticosterone levels of the RER pups did not differ on the first and last days of training (PND10 and 13 respectively), while on PND11 and 12 they were lower than those of the CTR. The RER experience did not lead to activation of the amygdala. Males and females exposed as neonates to the DER or RER experience, and controls were tested as adults in the open field task (OF), the elevated plus maze (EPM), and cued and contextual fear conditioning (FC). No group differences were found in the EPM, while in the OF, both male and female DER animals, showed increased rearings, compared to the controls. In the FC, the RER males had increased memory for both context and cued conditioned fear, than either the DER or CTR. On the other hand, the DER males, but not females showed an increased activation, as assessed by c-Fos expression, of the amygdala following fear conditioning. Our results show that the DER early experience programmed the function of the adult amygdala as to render it more sensitive to fearful stimuli. This programming by the DER early experience could be mediated through epigenetic modifications of histones leading to chromatin opening, as indicated by our results showing increased levels of phospho-acetyl-histone-3 in the amygdala of the DER males.
Assuntos
Tonsila do Cerebelo/crescimento & desenvolvimento , Comportamento Materno/fisiologia , Privação Materna , Recompensa , Caracteres Sexuais , Acetilação , Adaptação Psicológica , Tonsila do Cerebelo/fisiologia , Animais , Animais Recém-Nascidos , Condicionamento Clássico , Corticosterona/análise , Sinais (Psicologia) , Eletrochoque , Epigênese Genética , Comportamento Exploratório/fisiologia , Medo/fisiologia , Feminino , Reação de Congelamento Cataléptica/fisiologia , Histonas/metabolismo , Masculino , Aprendizagem em Labirinto/fisiologia , Fosforilação , Processamento de Proteína Pós-Traducional , Proteínas Proto-Oncogênicas c-fos/análise , Ratos , Ratos WistarRESUMO
Emotional behavioral traits associated with stress response are well documented to be affected by early life events. In the present work, we used a novel paradigm of neonatal experience, in which pups were trained in a T-maze and either received (RER rats) or were denied (DER) the reward of maternal contact, during postnatal days 10-13. We then evaluated stress coping and key factors controlling the function of the hypothalamic-pituitary-adrenal axis in adulthood. Adult male DER rats exposed to a single session of forced swim stress (FSS) showed increased immobility, while RER rats exhibited increased escape attempts. The corticosterone response following this stressor was higher although not prolonged in the DER rats. Their CRH mRNA levels in the PVN were increased up to 2h after the forced swim. However, basal levels of these hormones did not differ among groups. In addition, the DER neonatal experience induced an increase in hippocampal GR but a decrease in CRH-R1 immunopositive cells in the CA1 area of the hippocampus and the central amygdala. Overall, these data show a distinct stress response profile in the DER male rats, characterized by passive coping during the forced swim, increased hormonal response following stress, increased inhibitory control through GR and an indirect contribution of CRH-R1, the latter two factors resulting in a modified regulation of the response termination. It thus appears that DER rats have an enhanced potential for appropriate reactivity upon an incoming challenge, while maintaining in parallel an adequate control of the duration of their stress responses.
Assuntos
Sistema Hipotálamo-Hipofisário/metabolismo , Privação Materna , Sistema Hipófise-Suprarrenal/metabolismo , Recompensa , Estresse Psicológico/metabolismo , Adaptação Psicológica , Hormônio Adrenocorticotrópico/sangue , Tonsila do Cerebelo/metabolismo , Animais , Animais Recém-Nascidos , Corticosterona/sangue , Hormônio Liberador da Corticotropina/biossíntese , Feminino , Hipocampo/metabolismo , Masculino , Núcleo Hipotalâmico Paraventricular/metabolismo , Ratos , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Receptores de Glucocorticoides/metabolismo , Estresse Psicológico/sangue , Estresse Psicológico/psicologiaRESUMO
Pathological fear and anxiety can be studied, in rodents, with fear conditioning and exposure to reminder cues. These paradigms are thought to critically involve the ventral hippocampus, which also serves as key site of glucocorticoid action in the brain. Here, we demonstrate a long-lasting reduction of kainate-induced gamma oscillations in slice preparations of the ventral hippocampal area CA3, 30 days after a single fear conditioning training. Reduction of gamma power was sensitive to corticosterone application and associated with a decrease in glucocorticoid and mineralocorticoid receptor mRNA expression across strata of the ventral hippocampal CA3. A fear reactivation session 24 h after the initial conditioning normalized receptor expression levels and attenuated the corticosterone-mediated recovery of gamma oscillations. It moreover increased both baseline and stimulus-induced corticosterone plasma levels and evoked a generalization of fear memory to the background context. Reduced ventral hippocampal gamma oscillation in both fear reactivated and non-reactivated mice were associated with a decrease of anxiety-like behavior in an elevated plus maze. Taking advantage of the circadian fluctuation in corticosterone, we demonstrated the association of high endogenous basal corticosterone plasma concentrations during morning hours with reduced anxiety-like behavior in fear reactivated mice. The anxiolytic effect of the hormone was verified with local applications to the ventral hippocampus. Our data suggest that corticosterone acting on ventral hippocampal network activity has anxiolytic-like effects following fear exposure, highlighting its potential therapeutic value for anxiety disorders.
Assuntos
Ansiolíticos/farmacologia , Corticosterona/sangue , Medo/fisiologia , Hipocampo/fisiologia , Memória/fisiologia , Rede Nervosa/fisiologia , Animais , Ondas Encefálicas/efeitos dos fármacos , Ondas Encefálicas/fisiologia , Medo/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Rede Nervosa/efeitos dos fármacos , Técnicas de Cultura de Órgãos , Fatores de Tempo , Resultado do TratamentoRESUMO
Both emotion and attention are known to influence the startle response. Stress influences emotion and attention, but the impact of stress on the human startle response remains unclear. We used an established physiological stressor, the Cold Pressor Test (CPT), to induce stress in a non-clinical human sample (24 student participants) in a within-subjects design. Autonomic (heart rate and skin conductance) and somatic (eye blink) responses to acoustic startle probes were measured during a pre-stress baseline, during a three minutes stress intervention, and during the subsequent recovery period. Startle skin conductance and heart rate responses were facilitated during stress. Compared to baseline, startle eye blink responses were not affected during the intervention but were diminished afterwards. These data describe a new and unique startle response pattern during stress: facilitation of autonomic stress responses but no such facilitation of somatic startle eye blink responses. The absence of an effect of stress on startle eye blink responsiveness may illustrate the importance of guaranteeing uninterrupted visual input during periods of stress.
Assuntos
Temperatura Baixa , Reflexo de Sobressalto/fisiologia , Estresse Fisiológico/fisiologia , Piscadela/fisiologia , Eletromiografia , Resposta Galvânica da Pele/fisiologia , Alemanha , Frequência Cardíaca/fisiologia , Humanos , Adulto JovemRESUMO
Synthetic glucocorticoids such as dexamethasone (DEX) are used to prevent or treat respiratory disorders in prematurely born infants. Besides the short-term benefit on lung development, numerous human and animal studies have reported adverse neurodevelopmental side effects. In contrast, maternal care is known to exert a positive influence on neurodevelopmental outcome in rodents. The aim of the current study was therefore to investigate whether neonatal handling (days 1-21), known to induce maternal care, might serve as an intervention strategy modulating the adverse effects of DEX treatment (days 1-3). For this purpose we have measured the outcome of these early-life manipulations on development as well as adult endocrine and behavioral phenotype of male rats. Maternal care was observed during the first week of life and indeed enhanced in response to handling. Eye opening was accelerated and body weight reduced in DEX-treated animals. In adulthood, we report that handling ameliorated impaired spatial learning observed in DEX treated non-handled animals in the T-maze. Additionally, handling reduced susceptibility to the impact of DEX treatment in the water maze. Although DEX treatment and handling both resulted in enhanced negative feedback of the stress-induced corticosterone response and both reduced startle reactivity, the acquisition of fear was only reduced by handling, without effect of DEX. Interestingly, handling had a beneficial effect on pre-pulse inhibition, which was diminished after DEX treatment. In conclusion, these findings indicate that handling of the neonate enhances maternal care and attenuates specific DEX-induced alterations in the adult behavioral phenotype.
Assuntos
Comportamento Animal/efeitos dos fármacos , Dexametasona/efeitos adversos , Crescimento e Desenvolvimento/efeitos dos fármacos , Manobra Psicológica , Comportamento Materno/psicologia , Estimulação Acústica , Animais , Animais Recém-Nascidos , Comportamento Animal/fisiologia , Dexametasona/farmacologia , Medo/efeitos dos fármacos , Medo/fisiologia , Feminino , Crescimento e Desenvolvimento/fisiologia , Inibição Psicológica , Masculino , Comportamento Materno/fisiologia , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Condicionamento Físico Animal/fisiologia , Condicionamento Físico Animal/psicologia , Gravidez , Distribuição Aleatória , Ratos , Ratos Long-Evans , Reflexo de Sobressalto/efeitos dos fármacos , Reflexo de Sobressalto/fisiologia , Fatores de TempoRESUMO
Reduced responsiveness to positive stimuli is a core symptom of depression, known as anhedonia. In the present study, we assessed the expression of anhedonia in our chronic stress mouse model using a subset of read-out parameters. In line with this, we investigated in how far chronic stress would affect the facilitating effect of post-training self-administration of sugar, as we previously observed in naïve mice. Male C57BL/6J mice were repeatedly and at unpredictable times exposed to rats (no physical contact) over the course of two weeks. Following novelty exploration, (non-) spatial learning and memory processes with and without post-training sugar acting as reinforcer, emotionality, reward sensitivity and corticosterone levels were determined. We found that (1) the effects of chronic stress persisted beyond the period of the actual rat exposure. (2) Post-training self-administration of sugar as reinforcer improved spatial performance in naïve mice, whereas (3) in stressed mice sugar partially "normalized" the impaired performance to the level of controls without sugar. Chronic stress (4) increased behavioral inhibition in response to novelty; (5) induced dynamic changes in the pattern of circadian corticosterone secretion during the first week after rat stress and (6) increased the intake of sucrose and water. (7) Chronic stress and sugar consumed during spatial training facilitated the memory for the location of the sucrose bottle weeks later. Concluding, our chronic stress paradigm induces the expression of anhedonia in mice, at different levels of behavior. The behavioral inhibition appears to be long lasting in stressed mice. Interestingly, sugar consumed in close context with spatial learning partially rescued the stress-induced emotional and cognitive impairments. This suggests that reward can ameliorate part of the negative consequences of chronic stress on memory.