RESUMEN
The hypothalamic-pituitary-adrenal (HPA) axis displays a characteristic circadian pattern of corticosterone release, with higher levels at the onset of the active phase and lower levels at the onset of the inactive phase. As corticosterone levels modify the response to stress and influence the susceptibility to and/or severity of stress-related sequelae, we examined the effects of an acute psychological trauma applied at different zeitgeber times (ZTs) on behavioral stress responses. Rats were exposed to stress either at the onset of the inactive-(light) phase (ZT=0) or at the onset of the active-(dark) phase (ZT=12). Their behavior in the elevated plus-maze and acoustic startle response paradigms were assessed 7 days post exposure for retrospective classification into behavioral response groups. Serum corticosterone levels and the dexamethasone suppression test were used to assess the stress response and feedback inhibition of the HPA axis. Immunoreactivity for neuropeptide Y (NPY) and NPY-Y1 receptor (Y1R) in the paraventricular (PVN) and arcuate (ARC) hypothalamic nuclei, hippocampus, and basolateral amygdala were measured. The behavioral effects of NPY/Y1R antagonist microinfused into the PVN 30 min before stress exposure during the inactive or active phase, respectively, were evaluated. PVN immunoreactivity for NPY and Y1R was measured 1 day after the behavioral tests. The time of day of the traumatic exposure markedly affected the pattern of the behavioral stress response and the prevalence of rats showing an extreme behavioral response. Rats exposed to the stressor at the onset of their inactive phase displayed a more traumatic behavioral response, faster post-exposure corticosterone decay, and a more pronounced stress-induced decline in NPY and Y1R expression in the PVN and arcuate hypothalamic nuclei. Blocking PVN Y1R before stress applied in the active phase, or administering NPY to the PVN before stress applied in the inactive phase, had a resounding behavioral effect. The time at which stress occurred significantly affected the behavioral stress response. Diurnal variations in HPA and NPY/Y1R significantly affect the behavioral response, conferring more resilience at the onset of the active phase and more vulnerability at the onset of the inactive phase, implying that NPY has a significant role in conferring resilience to stress-related psychopathology.
Asunto(s)
Ritmo Circadiano/fisiología , Sistema Hipotálamo-Hipofisario/fisiología , Neuropéptido Y/metabolismo , Sistema Hipófiso-Suprarrenal/fisiología , Trauma Psicológico/fisiopatología , Receptores de Neuropéptido Y/fisiología , Estrés Psicológico/fisiopatología , Administración Intranasal , Amígdala del Cerebelo/metabolismo , Animales , Núcleo Arqueado del Hipotálamo/metabolismo , Arginina/administración & dosificación , Arginina/análogos & derivados , Arginina/farmacología , Corticosterona/sangre , Hipocampo/metabolismo , Masculino , Aprendizaje por Laberinto/fisiología , Microinyecciones , Neuropéptido Y/administración & dosificación , Neuropéptido Y/farmacología , Núcleo Hipotalámico Paraventricular/metabolismo , Pruebas de Función Adreno-Hipofisaria , Trauma Psicológico/sangre , Trauma Psicológico/metabolismo , Trauma Psicológico/psicología , Ratas , Receptores de Neuropéptido Y/antagonistas & inhibidores , Receptores de Neuropéptido Y/metabolismo , Reflejo de Sobresalto/fisiología , Estrés Psicológico/sangre , Estrés Psicológico/metabolismo , Estrés Psicológico/psicología , Factores de TiempoRESUMEN
Alterations in cytoarchitecture and molecular signaling have been observed in adaptive and maladaptive responses to stress and presumably underlie the physiological and behavioral changes observed. The relationship between behavioral responses to stress exposure and changes in cytoarchitecture of subregions of the hippocampus and amygdala was investigated in an animal model of PTSD. Behaviors in elevated plus-maze and acoustic startle response tests were assessed in rats 7 days after exposure to predator scent stress. Brains were harvested 24h later. Neurons from CA1, CA3, and dentate gyrus subregions and basolateral amygdala were reconstructed and subjected to Sholl analysis and spine density estimation. Glucocorticoid receptor, brain-derived neurotrophic factor, phospho-NR1-Ser-889, phospho-GluR1-Ser-845, phospho-calcium/calmodulin dependent protein kinase II-Thy-286, post-synaptic density protein 95 and phospho-CREB-Ser-133 were evaluated in the hippocampus. Data were analyzed by retrospective classification of individual rats into three behavioral response groups. The extent and distribution of changes in the morphology of hippocampal and amygdalar dendrites was significantly associated with stress-induced behavioral response classification. Extreme (PTSD-like) behavioral disruption was associated with extensive neuronal retraction in the hippocampus and proliferation in the amygdala. Neither structure displayed such changes in minimal behavioral responders. Partial behavioral response was associated with identical changes in the hippocampus only. Patterns of change in requisite molecular signaling genes and endophenotypic markers corresponded to the structural and behavioral responses. The extent and distribution of changes in the cytoarchitecture of hippocampal and amygdalar subregions is directly related to the pattern of behavioral response of the individual to stress exposure.
Asunto(s)
Amígdala del Cerebelo/patología , Modelos Animales de Enfermedad , Hipocampo/patología , Trastornos por Estrés Postraumático/patología , Amígdala del Cerebelo/metabolismo , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Proteína de Unión a CREB/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Dendritas/patología , Dendritas/ultraestructura , Homólogo 4 de la Proteína Discs Large , Hipocampo/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Masculino , Aprendizaje por Laberinto , Proteínas de la Membrana/metabolismo , Neuronas/patología , Ratas , Receptores AMPA/metabolismo , Receptores de Glucocorticoides/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Reflejo de Sobresalto , Trastornos por Estrés Postraumático/metabolismoRESUMEN
Poststroke depression (PSD) is the most frequent psychological sequela following stroke. While previous studies describe the impact of age on brain infarct volume, brain edema, and blood-brain barrier (BBB) breakdown following ischemia, the role of age on PSD has yet to be described. Here, we examine the influence of age on PSD progression in a rat model of PSD by middle cerebral artery occlusion (MCAO). One hundred forty-three rats were divided into three groups. 48 rats 20 weeks of age underwent a sham procedure, 51 rats 20 weeks of age had MCAO, and 44 rats 22-26 months of age had MCAO. Groups were further divided into two subgroups. The first subgroup was used to measure infarct lesion volume, brain edema, and BBB breakdown at 24 h. In the second subgroup at 3 weeks after MCAO, rats were subjected to a sucrose preference test, two-way shuttle avoidance task, forced swimming test, and a brain-derived neurotrophic factor (BDNF) protein level measurement. Total and striatal infarct volume, brain edema, and BBB breakdown in the striatum were increased in older rats, as compared with younger rats. While both old and young rats exhibited depressive-like behaviors on each of the behavioral tests and lower BDNF levels post-MCAO, as compared with control rats, there were no differences between old and young rats. Although older rats suffered from larger infarct volumes, increased brain edema and more BBB disruption following MCAO, the lack of behavioral differences between young and old rats suggests that there was no effect of rat age on the incidence of PSD.
Asunto(s)
Envejecimiento , Depresión/etiología , Infarto de la Arteria Cerebral Media/complicaciones , Factores de Edad , Animales , Reacción de Prevención/fisiología , Encéfalo/metabolismo , Edema Encefálico/etiología , Infarto Encefálico/etiología , Infarto Encefálico/patología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Modelos Animales de Enfermedad , Preferencias Alimentarias , Infarto de la Arteria Cerebral Media/patología , Masculino , Examen Neurológico , Ratas , Ratas Sprague-Dawley , Sacarosa/administración & dosificación , Edulcorantes/administración & dosificación , Natación/psicologíaRESUMEN
Reliable evidence supports the role of sleep in learning and memory processes. In rodents, sleep deprivation (SD) negatively affects consolidation of hippocampus-dependent memories. As memory is integral to post-traumatic stress symptoms, the effects of post-exposure SD on various aspect of the response to stress in a controlled, prospective animal model of post-traumatic stress disorder (PTSD) were evaluated. Rats were deprived of sleep for 6 h throughout the first resting phase after predator scent stress exposure. Behaviors in the elevated plus-maze and acoustic startle response tests were assessed 7 days later, and served for classification into behavioral response groups. Freezing response to a trauma reminder was assessed on day 8. Urine samples were collected daily for corticosterone levels, and heart rate (HR) was also measured. Finally, the impact of manipulating the hypothalamus-pituitary-adrenal axis and adrenergic activity before SD was assessed. Mifepristone (MIFE) and epinephrine (EPI) were administered systemically 10-min post-stress exposure and behavioral responses and response to trauma reminder were measured on days 7-8. Hippocampal expression of glucocorticoid receptors (GRs) and morphological assessment of arborization and dendritic spines were subsequently evaluated. Post-exposure SD effectively ameliorated long-term, stress-induced, PTSD-like behavioral disruptions, reduced trauma reminder freezing responses, and decreased hippocampal expression of GR compared with exposed-untreated controls. Although urine corticosterone levels were significantly elevated 1 h after SD and the HR was attenuated, antagonizing GRs with MIFE or stimulation of adrenergic activity with EPI effectively abolished the effect of SD. MIFE- and EPI-treated animals clearly demonstrated significantly lower total dendritic length, fewer branches and lower spine density along dentate gyrus dendrites with increased levels of GR expression 8 days after exposure, as compared with exposed-SD animals. Intentional prevention of sleep in the early aftermath of stress exposure may well be beneficial in attenuating traumatic stress-related sequelae. Post-exposure SD may disrupt the consolidation of aversive or fearful memories by facilitating correctly timed interactions between glucocorticoid and adrenergic systems.
Asunto(s)
Agonistas Adrenérgicos/uso terapéutico , Epinefrina/uso terapéutico , Antagonistas de Hormonas/uso terapéutico , Mifepristona/uso terapéutico , Privación de Sueño/fisiopatología , Trastornos por Estrés Postraumático/prevención & control , Estimulación Acústica/efectos adversos , Agonistas Adrenérgicos/farmacología , Análisis de Varianza , Animales , Corticosterona/orina , Dendritas/efectos de los fármacos , Dendritas/metabolismo , Dendritas/ultraestructura , Modelos Animales de Enfermedad , Electrocardiografía , Reacción Cataléptica de Congelación/efectos de los fármacos , Reacción Cataléptica de Congelación/fisiología , Regulación de la Expresión Génica/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/ultraestructura , Antagonistas de Hormonas/farmacología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Mifepristona/farmacología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/ultraestructura , Ratas , Ratas Sprague-Dawley , Receptores de Glucocorticoides/metabolismo , Reflejo de Sobresalto/efectos de los fármacos , Reflejo de Sobresalto/fisiología , Tinción con Nitrato de Plata , Trastornos por Estrés Postraumático/fisiopatología , Telemetría , Factores de TiempoRESUMEN
In humans, the diagnosis of PTSD is made only if an individual exhibits a certain number of symptoms from each of three quite well defined symptom clusters over a certain period of time. Animal behavioral studies, however, have generally tended to overlook this aspect and have commonly regarded the entire group of animals subjected to certain study conditions as homogeneous. Thus, in an attempt to develop animal models of long-term chronic behavioral responses to stress (i.e. PTSD) in a comparable manner to human diagnosis, we applied cut-off inclusion/exclusion criteria to behavioral data for a cohort of animals exposed to a stress paradigm. This grouped them as behaviorally affected or unaffected by the stress. This model takes into account the variability in degree of the individual's response to the stress paradigm, thereby modeling the fact that not all humans exposed to traumatic stress respond with affective disorder. This article will present and discuss findings from a series of studies employing a model of individual behavioral response classification. This article will discuss the concept of the model and its background and present a selection of studies employing and examining the model, alongside the underlying translational rationale of each. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.
Asunto(s)
Conducta Animal/fisiología , Trastornos por Estrés Postraumático/psicología , Animales , Modelos Animales de Enfermedad , Humanos , Investigación Biomédica TraslacionalRESUMEN
Converging evidence implicates the regulatory neuropeptide Y (NPY) in anxiety- and depression-related behaviors. The present study sought to assess whether there is an association between the magnitude of behavioral responses to stress and patterns of NPY in selected brain areas, and subsequently, whether pharmacological manipulations of NPY levels affect behavior in an animal model of PTSD. Animals were exposed to predator-scent stress for 15 min. Behaviors were assessed with the elevated plus maze and acoustic startle response tests 7 days later. Preset cutoff criteria classified exposed animals according to their individual behavioral responses. NPY protein levels were assessed in specific brain regions 8 days after the exposure. The behavioral effects of NPY agonist, NPY-Y1-receptor antagonist, or placebo administered centrally 1 h post-exposure were evaluated in the same manner. Immunohistochemical technique was used to detect the expression of the NPY, NPY-Y1 receptor, brain-derived neurotrophic factor, and GR 1 day after the behavioral tests. Animals whose behavior was extremely disrupted (EBR) selectively displayed significant downregulation of NPY in the hippocampus, periaqueductal gray, and amygdala, compared with animals whose behavior was minimally (MBR) or partially (PBR) disrupted, and with unexposed controls. One-hour post-exposure treatment with NPY significantly reduced prevalence rates of EBR and reduced trauma-cue freezing responses, compared with vehicle controls. The distinctive pattern of NPY downregulation that correlated with EBR as well as the resounding behavioral effects of pharmacological manipulation of NPY indicates an intimate association between NPY and behavioral responses to stress, and potentially between molecular and psychopathological processes, which underlie the observed changes in behavior. The protective qualities attributed to NPY are supported by the extreme reduction of its expression in animals severely affected by the stressor and imply a role in promoting resilience and/or recovery.
Asunto(s)
Neuropéptido Y/fisiología , Neuropéptido Y/uso terapéutico , Resiliencia Psicológica , Trastornos por Estrés Postraumático/tratamiento farmacológico , Trastornos por Estrés Postraumático/fisiopatología , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/fisiopatología , Animales , Arginina/análogos & derivados , Arginina/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatología , Factor Neurotrófico Derivado del Encéfalo/biosíntesis , Modelos Animales de Enfermedad , Regulación hacia Abajo/fisiología , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/fisiología , Humanos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Neuropéptido Y/biosíntesis , Neuropéptido Y/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Neuropéptido Y/agonistas , Receptores de Neuropéptido Y/antagonistas & inhibidores , Receptores de Neuropéptido Y/biosíntesis , Reflejo de Sobresalto/efectos de los fármacos , Reflejo de Sobresalto/fisiología , Trastornos por Estrés Postraumático/metabolismo , Estrés Psicológico/metabolismoRESUMEN
In mammals, the circadian and stress systems are involved in adaptation to predictable and unpredictable stimuli, respectively. A series of experiments examined the relationship between stress-induced posttraumatic stress (PTSD)-like behavioral response patterns in rats and brain levels of genes related to circadian rhythms. The effects of agomelatine, administered immediately after exposure, on stress-related behavior and on local expression of Per1 and Per2 were assessed. Animals were exposed to predator scent stress. The outcome measures included behavior in an elevated plus-maze (EPM) and acoustic startle response (ASR) 7days after the exposure. Pre-set cut-off behavioral criteria classified exposed animals according to behavioral responses in EPM and ASR paradigms as those with 'extreme behavioral response' (EBR), 'minimal behavioral response (MBR),' or 'partial behavioral response' (PBR). Per1 and Per2 expression in hippocampal subregions, frontal cortex and suprachiasmatic nucleus (SCN) 8days after exposure were evaluated using immunohistochemical and RT-PCR techniques at zeitgeber-times 19 and 13. The effects of agomelatine, on behavioral tests were evaluated on Day 8. Local brain expression of Per1 and Per2 mRNA was subsequently assessed. Data were analyzed in relation to individual behavior patterns. Animals with extreme behavioral response (EBR) displayed a distinct pattern of Per1 and Per2 expression in the SCN, which was the opposite of that observed in the control and MBR animals. In the DG, no variation in Per2 expression was observed in the EBR and PBR animals. Immediate post-exposure treatment with agomelatine significantly reduced percentage of extreme-responders and normalized the expression of Per1 and Per2 as compared to controls. Stress-induced alterations in Per genes in the EBR animals may represent an imbalance between normally precisely orchestrated physiological and behavioral processes and psychopathological processes. These findings indicate that these circadian-related genes play a role in the neurobiological response to predator scent stress and provide supportive evidence that the use of agomelatine immediately after traumatic experience may be protective against the subsequent development of PTSD.
Asunto(s)
Acetamidas/farmacología , Encéfalo/efectos de los fármacos , Ritmo Circadiano/genética , Expresión Génica/efectos de los fármacos , Proteínas Circadianas Period/genética , Estrés Psicológico/genética , Animales , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Encéfalo/metabolismo , Proteínas Circadianas Period/metabolismo , Ratas , Ratas Sprague-Dawley , Reflejo de Sobresalto/efectos de los fármacos , Reflejo de Sobresalto/fisiología , Estrés Psicológico/metabolismoRESUMEN
Nuclear factor-κB (NF-κB) is a ubiquitously expressed transcription factor for genes involved in cell survival, differentiation, inflammation, and growth. This study examined the role of NF-κB pathway in stress-induced PTSD-like behavioral response patterns in rats. Immunohistochemical technique was used to detect the expression of the NF-κB p50 and p65 subunits, I-κBα, p38, and phospho-p38 in the hippocampal subregions at 7 days after exposure to predator scent stress. Expression of p65 nuclear translocation was quantified by western blot as the level of NF-κB activation. The effects of intraperitoneally administered corticosterone or a selective NF-κB inhibitor (pyrrolidine dithiocarbamate (PDTC)) at 1 h post exposure on behavioral tests (elevated plus-maze and acoustic startle response) were evaluated 7 days later. Hippocampal expressions of those genes were subsequently evaluated. All data were analyzed in relation to individual behavior patterns. Extreme behavioral responder animals displayed significant upregulation of p50 and p65 with concomitant downregulation of I-κBα, p38, and phospho-p38 levels in hippocampal structures compared with minimal behavioral responders and controls. Immediate post-exposure treatment with high-dose corticosterone and PDTC significantly reduced prevalence rates of extreme responders and normalized the expression of those genes. Stress-induced upregulation of NF-κB complex in the hippocampus may contribute to the imbalance between what are normally precisely orchestrated and highly coordinated physiological and behavioral processes, thus associating it with stress-related disorders.
Asunto(s)
Corticosterona/administración & dosificación , FN-kappa B/biosíntesis , Pirrolidinas/administración & dosificación , Trastornos por Estrés Postraumático/tratamiento farmacológico , Estrés Psicológico/tratamiento farmacológico , Tiocarbamatos/administración & dosificación , Regulación hacia Arriba/efectos de los fármacos , Animales , Gatos , Esquema de Medicación , Masculino , FN-kappa B/antagonistas & inhibidores , Ratas , Ratas Sprague-Dawley , Trastornos por Estrés Postraumático/metabolismo , Estrés Psicológico/metabolismo , Factores de Tiempo , Regulación hacia Arriba/fisiologíaRESUMEN
High-dose corticosteroids have been reported to reduce symptoms of acute stress and post-traumatic stress in polytrauma patients and in animal studies. The underlying mechanism of action remains largely unclear. These issues were addressed in parallel in the clinical and preclinical studies below. In this preliminary study, 25 patients with acute stress symptoms were administered a single intravenous bolus of high-dose hydrocortisone (100-140 mg) or placebo within 6 h of a traumatic event in a prospective, randomized, double-blind, placebo-controlled pilot study. Early single high-dose hydrocortisone intervention attenuated the core symptoms of both the acute stress and of subsequent PTSD in patients. High-dose hydrocortisone treatment given in the first few hours after a traumatic experience was associated with significant favorable changes in the trajectory of exposure to trauma, as expressed by the reduced risk of the development of PTSD post-trauma. In parallel, a comparative study of morphological arborization in dentate gyrus and its modulating molecules was performed in stress-exposed animals treated with high-dose hydrocortisone. Steroid-treated stressed animals displayed significantly increased dendritic growth and spine density, with increased levels of brain-derived neurotrophic factor (BDNF) and obtunded postsynaptic density-95 (PSD-95) levels. The animal study provided insights into the potential mechanism of this intervention, as it identified relevant morphological and biochemical associations to the clinical observations. Thus, evidence from clinical and animal studies suggests that there is a "window of opportunity" in the early aftermath of trauma to help those who are vulnerable to the development of chronic PTSD.
Asunto(s)
Antiinflamatorios/uso terapéutico , Hidrocortisona/uso terapéutico , Trastornos por Estrés Postraumático/prevención & control , Heridas y Lesiones/tratamiento farmacológico , Estimulación Acústica , Adulto , Análisis de Varianza , Animales , Ansiedad/tratamiento farmacológico , Ansiedad/etiología , Encéfalo/patología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Espinas Dendríticas/patología , Espinas Dendríticas/ultraestructura , Modelos Animales de Enfermedad , Homólogo 4 de la Proteína Discs Large , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Estudios de Seguimiento , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Persona de Mediana Edad , Neuronas/patología , Neuronas/ultraestructura , Dimensión del Dolor , Ratas , Ratas Sprague-Dawley , Reflejo de Sobresalto/efectos de los fármacos , Tinción con Nitrato de Plata , Trastornos por Estrés Postraumático/etiología , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/patología , Factores de Tiempo , Índices de Gravedad del Trauma , Resultado del Tratamiento , Heridas y Lesiones/complicaciones , Heridas y Lesiones/patología , Adulto JovenRESUMEN
BACKGROUND: Protein kinase M zeta (PKMzeta), a constitutively active isoform of protein kinase C, has been implicated in protein synthesis-dependent maintenance of long-term potentiation and memory storage in the brain. Recent studies reported that local application of ZIP, a membrane-permeant PKMzeta inhibitor, into the insular cortex (IC) of behaving rats abolished long-term memory of taste associations. METHOD: This study assessed the long-term effects of local applications of ZIP microinjected immediately (1 h) or 10 days after predator scent stress exposure, in a controlled prospectively designed animal model for PTSD. Four brain structures known to be involved in memory processes and in anxiety were investigated: lateral ventricle (LV), dorsal hippocampus (DH), basolateral amygdala and IC. The outcome measures included behavior in an elevated plus maze and acoustic startle response 7 days after microinjection, and freezing behavior upon exposure to trauma-related cue 8 days after microinjection. Previously acquired/encoded memories associated with the IC were also assessed. RESULTS: Inactivation of PKMzeta in the LV or DH within 1h of exposure effectively reduced PTSD-like behavioral disruption and trauma cue response 8 days later. Inactivation of PKMzeta 10 days after exposure had equivalent effects only when administered in the IC. The effect was demonstrated to be specific for trauma memories, whereas previously acquired data were unaffected by the procedure. CONCLUSION: Predator scent related memories are located in different brain areas at different times beginning with an initial hippocampus-dependent consolidation process, and are eventually stored in the IC. These bring the IC to the forefront as a potential region of significance in processes related to traumatic stress-induced disorders.
Asunto(s)
Mapeo Encefálico , Encéfalo/efectos de los fármacos , Lipopéptidos/farmacología , Memoria/efectos de los fármacos , Vías Nerviosas/efectos de los fármacos , Proteína Quinasa C/antagonistas & inhibidores , Trastornos por Estrés Postraumático/tratamiento farmacológico , Estrés Psicológico/tratamiento farmacológico , Animales , Señales (Psicología) , Modelos Animales de Enfermedad , Reacción Cataléptica de Congelación , Lipopéptidos/administración & dosificación , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Microinyecciones , Ratas , Ratas Sprague-Dawley , Reflejo de Sobresalto/efectos de los fármacosRESUMEN
BACKGROUND: Activation of glucocorticoid receptors (GR) increases expression of the mitogen-activated protein kinase (MAPK) pathway leading to increased expression of Zif/268, an effector immediate early gene involved in cellular growth, intracellular signaling, and synaptic modification. Glucocorticoids induce expression of Zif/268 through two distinct mechanisms: a rapid-onset, MAPK-independent pathway and a slower-onset, MAPK-dependent mechanism. METHOD: This study investigated both rapid and long-term expression of GR protein in the cytosolic extract, its translocation to the nucleus, and expression of mRNA for the Zif/268 gene in selected brain areas, associated with circulating levels of corticosterone, in an animal model of PTSD. Trauma cue-triggered Zif/268 expression was assessed eight days after stress exposure. RESULTS: The results demonstrated a pattern of response that was common to all exposed individuals at 30 min after exposure, characterized by a significant elevation in GR translocation to the nucleus and elevated levels of Zif/268 mRNA in the hippocampus. A distinct pattern associated with extreme behavioral response (EBR) was revealed upon further bioassay of behavioral response groups, classified according to their individual patterns of behavioral response at seven days. These EBR individuals displayed significantly higher circulating corticosterone and nuclear GR levels, compared to minimal behavioral responders and controls. No difference in Zif/268 mRNA levels was observed between the exposed and naïve animals. CONCLUSION: Following the uniform acute response, the patterns of GR protein levels and Zif/268 mRNA levels are associated with degree of behavioral disruption. Since the slower-onset mechanism for glucocorticoid-induced Zif/268 expression depends on activation of the MAPK pathway, the pattern observed only in EBR rats may be related to disruptions of this pathway.
Asunto(s)
Proteína 1 de la Respuesta de Crecimiento Precoz/metabolismo , Líquido Extracelular/metabolismo , Regulación de la Expresión Génica/fisiología , Reflejo de Sobresalto/fisiología , Estrés Psicológico/metabolismo , Estrés Psicológico/fisiopatología , Análisis de Varianza , Animales , Encéfalo/metabolismo , Gatos , Corticosterona/sangre , Modelos Animales de Enfermedad , Proteína 1 de la Respuesta de Crecimiento Precoz/genética , Masculino , Aprendizaje por Laberinto , Transporte de Proteínas/fisiología , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Glucocorticoides/metabolismo , Trastornos por Estrés Postraumático/fisiopatología , Estrés Psicológico/patología , Factores de TiempoRESUMEN
Early-life stress produces a cascade of neurobiological events that cause enduring changes in neural plasticity and synaptic efficacy that appear to play pivotal roles in the pathophysiology of post-traumatic stress disorder (PTSD). Brain-derived neurotrophic factor (BDNF) has been implicated in the neurobiological mechanisms of these changes, in interaction with components of the stress response, such as corticosterone. This study examined the consequences of juvenile stress for behavior during adulthood in association with circulating corticosterone levels and BDNF expression. The experiments examined single exposure to predator scent stress (soiled cat litter for 10 min) as compared to repeated exposure, early in life and later on. Behavioral responses were assessed in the elevated plus maze and the acoustic startle response paradigms at 28, 60 and 90 days of age. Plasma corticosterone was measured and brain areas analyzed for BDNF levels. The results show that juvenile stress exposure increased anxiety-like behavior and startle amplitude and decreased plasma corticosterone. This response was seen immediately after exposure and also long term. Adult stress exposure increased anxiety-like behavior, startle amplitude and plasma corticosterone. Exposure to both early and later life trauma elicited reduced levels of corticosterone following the initial exposure, which were not raised by re-exposure, and elicited significant downregulation of BDNF mRNA and protein levels in the hippocampus CA1 subregion. The consequences of adult stress exposure were more severe in rats were exposed to the same stressor as juveniles, indicated increased vulnerability. The results suggest that juvenile stress has resounding effects in adulthood reflected in behavioral responses. The concomitant changes in BDNF and corticosterone levels may mediate the changes in neural plasticity and synaptic functioning underlying clinical manifestations of PTSD.
Asunto(s)
Conducta Animal/fisiología , Factor Neurotrófico Derivado del Encéfalo/sangre , Corticosterona/sangre , Maduración Sexual/fisiología , Estrés Psicológico/sangre , Factores de Edad , Algoritmos , Animales , Encéfalo/metabolismo , Encéfalo/fisiología , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Corticosterona/metabolismo , Conducta Exploratoria/fisiología , Cadena Alimentaria , Masculino , Aprendizaje por Laberinto , Plasticidad Neuronal/genética , Plasticidad Neuronal/fisiología , Ratas , Ratas Sprague-Dawley , Reflejo de Sobresalto/fisiología , Trastornos por Estrés Postraumático/etiología , Trastornos por Estrés Postraumático/genética , Trastornos por Estrés Postraumático/fisiopatología , Estrés Psicológico/fisiopatologíaRESUMEN
BACKGROUND: Most epidemiological studies report higher prevalence rates of stress-related disorders such as acute stress disorder, post-traumatic stress disorder (PTSD) and major depressive disorder in women than in men. Few animal models of PTSD have taken gender differences into account and have typically used male subjects. In order to explore gender-related PTSD-like stress-responses more thoroughly, we applied an animal model that focuses selectively on individual patterns of behavioural responses. METHODS: Prevalence rates of individual behavioural response to a single exposure to predator scent stress (PSS) were assessed by both elevated plus-maze and startle response paradigms. Prevalence rates of extreme behavioural disruption (EBR) on both tests were assessed, correlated to corticosterone levels, and compared to global population response data. In addition, we assessed learning and memory in the Morris water-maze (MWM). RESULTS: There were no significant differences between the behavioural responses related to oestrous cycle phase in terms of global data for the groups or in terms of prevalence rates of EBR. The overall patterns of response of males and females were affected, yet females demonstrated greater levels of baseline anxiety-like behaviour and lower peak levels of post-exposure anxiety-like behaviour than males. However, the prevalence rates of individual subjects who responded with PTSD-like behaviour were equal for female and male subjects. PSS-exposed female subjects demonstrated significantly compromised performance in the MWM compared to males. CONCLUSIONS: In this animal model, the results clarified that the assumption that females are more vulnerable is true for the magnitude of the response, but not for the prevalence of pathological response patterns in rat populations.
Asunto(s)
Trastornos de Ansiedad/epidemiología , Trastornos de Ansiedad/etiología , Trastorno Depresivo Mayor/epidemiología , Trastorno Depresivo Mayor/etiología , Conducta Social , Trastornos por Estrés Postraumático/psicología , Animales , Conducta Animal , Corticosterona/sangre , Modelos Animales de Enfermedad , Ciclo Estral , Femenino , Incidencia , Masculino , Aprendizaje por Laberinto , Prevalencia , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Reflejo de Sobresalto , Factores SexualesRESUMEN
BACKGROUND: Converging evidence implicates the regulatory neuropeptide galanin in anxiety- and depression-related behaviors, through modulation of neuroendocrine, serotonergic, and noradrenergic systems. This study examined the relationship between stress-induced posttraumatic stress disorder (PTSD)-like behavioral response patterns in rats and galanin mRNA levels in key brain areas and the effects of acute phase pharmacologic manipulation using an agonist (galnon) on behavioral, physiologic, and response patterns of brain-derived neurotrophic factor (BDNF) and 5-hydroxytryptamine-1A (5HT-1A). METHOD: Galanin mRNA expression was assessed in the frontal cortex and hippocampus in the short- and long-term (30 min and 7 days) after exposure to predator scent stress. The effects of intraperitoneal galnon .5 mg/kg versus saline 1 hour postexposure on behavioral tests (elevated plus maze and acoustic startle response) were evaluated 7 days later. Trauma-cue response, circulating corticosterone, and localized brain expression of 5HT-1A receptors and BDNF were subsequently assessed. All data were analyzed in relation to individual behavior patterns. RESULTS: Whereas animals with minimal behavioral disruption displayed a lasting upregulation of galanin mRNA in the hippocampal CA1 area, those with extreme behavioral responses displayed downregulation in both CA1 and frontal cortex. Immediate postexposure treatment with galnon significantly reduced prevalence rates of extreme responders, reduced trauma-cue freezing responses, corrected the corticosterone response, and increased CA1 expression of 5HT-1A and BDNF mRNA compared with saline controls. CONCLUSIONS: Galanin is actively involved in the neurobiological response to predator scent stress with resilience/recovery after stress exposure and thus warrants further study as a potential therapeutic avenue for the treatment of anxiety-related disorders.
Asunto(s)
Galanina/fisiología , Trastornos por Estrés Postraumático/fisiopatología , Estrés Psicológico , Animales , Conducta Animal , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Corticosterona/antagonistas & inhibidores , Corticosterona/sangre , Cumarinas/farmacología , Modelos Animales de Enfermedad , Regulación hacia Abajo , Lóbulo Frontal/metabolismo , Galanina/antagonistas & inhibidores , Galanina/genética , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT1A/metabolismo , Trastornos por Estrés Postraumático/metabolismo , Trastornos por Estrés Postraumático/psicología , Regulación hacia ArribaRESUMEN
Mechanisms involved in adaptative and maladaptive changes in neural plasticity and synaptic efficacy in various brain areas are pivotal to understanding the physiology of the response to stress and the pathophysiology of posttraumatic stress disorder (PTSD). Activity-regulated cytoskeletal-associated protein (Arc) is an effector immediate early gene (IEG) which has direct effects on intracellular homeostatic functions. Increased expression of Arc has been associated with increased neuronal activity and with consolidation of long-term memory. It may thus play an important role in mediating experience-induced reorganization and/or development of synaptic connections. This study sought to characterize the pattern of expression of mRNA for the Arc gene in selected brain areas of test subjects classified according to their individual pattern of behavioral response to a stressor, correlated with circulating levels of corticosterone (as a physiological marker of stress response). The hippocampal CA1 and CA3 subregions of individuals whose behavior was minimally or partially disrupted in response to predator scent stress demonstrated significantly increased levels of mRNA for Arc, compared to unexposed controls. The group whose behavior was severely disrupted demonstrated no such upregulation. Consistent with the hypothesis that the Arc gene has a promoting effect on neuronal function and/or structural changes, the lack of Arc expression in the behaviorally and physiologically more severely affected individuals raises the possibility that Arc may be associated with resilience and/or recovery after stress exposure.
Asunto(s)
Adaptación Fisiológica/fisiología , Proteínas del Citoesqueleto/metabolismo , Regulación de la Expresión Génica/fisiología , Proteínas del Tejido Nervioso/metabolismo , Trastornos por Estrés Postraumático/fisiopatología , Estrés Psicológico/fisiopatología , Análisis de Varianza , Animales , Conducta Animal/fisiología , Gatos , Corticosterona/sangre , Proteínas del Citoesqueleto/genética , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Masculino , Aprendizaje por Laberinto , Proteínas del Tejido Nervioso/genética , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Estadística como Asunto , Trastornos por Estrés Postraumático/sangre , Trastornos por Estrés Postraumático/genética , Trastornos por Estrés Postraumático/patología , Estrés Psicológico/sangre , Estrés Psicológico/genética , Factores de TiempoRESUMEN
This study aimed to assess the effects of anisomycin, a protein synthesis inhibitor, on behavioral responses, brain-derived neurotrophic factor (BDNF) and TrkB mRNA levels, and circulating corticosterone in rats-when administered before or after initial exposure to a predator scent stress stimulus. Magnitude of changes in prevalence of anxiety-like behaviors on the elevated plus-maze and exaggerated startle reaction as well as corticosterone levels and mRNA BDNF and TrkB were compared in rats exposed to predator stress, microinjected with anisomycin before or after stress exposure. Administration of anisomycin before or after stress exposure reduced anxiety-like behavior in the elevated plus-maze and reduced the mean startle amplitude 7 days postexposure. Although the behavioral responses were similar when anisomycin was microinjected before or after stress exposure, the levels of mRNAs for BDNF and TrkB, which play a role in modulation of synaptic plasticity and the consolidation process, showed varying responses.
Asunto(s)
Anisomicina/farmacología , Factor Neurotrófico Derivado del Encéfalo/genética , Corticosterona/sangre , Miedo/fisiología , Lóbulo Frontal/efectos de los fármacos , Hipocampo/efectos de los fármacos , Inhibidores de la Síntesis de la Proteína/farmacología , ARN Mensajero/genética , Receptor trkB/genética , Estrés Psicológico/complicaciones , Animales , Conducta Animal/efectos de los fármacos , Lóbulo Frontal/patología , Hipocampo/patología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Microinyecciones , Plasticidad Neuronal/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Reflejo de Sobresalto/efectos de los fármacosRESUMEN
Brain-derived neurotrophic factor (BDNF) and its intracellular kinase-activating receptor TrkB, have been implicated in the neurobiological mechanisms underlying the clinical manifestations of PTSD, especially those related to synaptic efficacy and neural plasticity. BDNF interacts with components of the stress response such as corticosterone, and plays an important role in growth, maintenance and functioning of several neuronal systems. This study employed an animal model of PTSD to investigate the relationship between prevalence rates of distinct patterns of behavioural responses to predator stress, circulating levels of corticosterone and local levels of mRNA for BDNF, TrkB and two other neurotrophic factors in selected brain areas. Animals whose behaviour was extremely disrupted by exposure selectively displayed significant down-regulation of mRNA for BDNF and up-regulation of TrkB mRNA in the CA1 subregion of the hippocampus, compared to animals whose behaviour was minimally or partially affected and to unexposed controls. The response was consistent throughout the entire study only in CA1. The consistent long-term the BDNF down-regulation and TrkB up-regulation associated with extreme behavioural compromise may be associated with chronic stress-induced psychopathological processes, especially in the hippocampus. The corresponding changes in neural plasticity and synaptic functioning may mediate clinical manifestations of PTSD.
Asunto(s)
Conducta Animal/efectos de los fármacos , Factor Neurotrófico Derivado del Encéfalo/fisiología , Hipocampo/metabolismo , Trastornos por Estrés Postraumático/psicología , Estimulación Acústica , Animales , Ansiedad/psicología , Western Blotting , Química Encefálica/efectos de los fármacos , Factor Neurotrófico Derivado del Encéfalo/biosíntesis , Factor Neurotrófico Derivado del Encéfalo/genética , Corticosterona/sangre , Cartilla de ADN , Regulación hacia Abajo/efectos de los fármacos , Hipocampo/efectos de los fármacos , Masculino , Factor de Crecimiento Nervioso/metabolismo , Plasticidad Neuronal/efectos de los fármacos , Neurotrofina 3/metabolismo , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Ratas , Ratas Sprague-Dawley , Receptor trkB/metabolismo , Reflejo de Sobresalto/efectos de los fármacosRESUMEN
This study examined the effects of stress exposure on plasma levels of corticosterone, dehydroepiandrosterone (DHEA) and its sulphate derivative DHEA-S in relation to behavioural responses. The magnitude of anxiety-like behaviours on the elevated plus-maze and of non-habituated exaggerated startle reactions were assessed in rats exposed to stress compared to controls. Individuals displaying extreme behavioural changes were termed extreme behavioural response (EBR), as opposed to minimal behavioural response (MBR) in both paradigms performed consecutively. Significantly increased circulating corticosterone levels and decreased DHEA levels were found 7 d post-exposure only in EBR individuals, not in their MBR counterparts. DHEA-S levels were reduced in both EBR and MBR stress-exposed rats compared to controls. This suggests that concomitantly decreased circulatory levels of DHEA and elevated corticosterone levels may be associated with an extreme (pathological) response to stress, whilst maintenance of normal levels of both steroids may be associated with minimal response, denoting resilience.
Asunto(s)
Conducta Animal/fisiología , Neurotransmisores/sangre , Esteroides/sangre , Trastornos por Estrés Postraumático/sangre , Trastornos por Estrés Postraumático/psicología , Estimulación Acústica , Animales , Ansiedad/sangre , Ansiedad/psicología , Ritmo Circadiano/fisiología , Corticosterona/sangre , Deshidroepiandrosterona/sangre , Sulfato de Deshidroepiandrosterona/sangre , Masculino , Odorantes , Conducta Predatoria , Ratas , Ratas Sprague-Dawley , Reflejo de Sobresalto/fisiología , Estrés Psicológico/sangre , Estrés Psicológico/psicologíaRESUMEN
BACKGROUND: Paradoxical changes in memory represent a troublesome characteristic of posttraumatic stress disorder (PTSD). Exceptionally vivid intrusive memories of some aspects of the trauma are mingled with patchy amnesia regarding other important aspects. Molecular studies of the memory process suggest that the conversion from labile short-term memory into long-term fixed traces involves protein synthesis. This study assessed the effects of administration of anisomycin, a protein synthesis inhibitor, after initial exposure, after exposure to a cue associated with triggering experience, and after reexposure to the triggering trauma in an animal model of PTSD. METHOD: Magnitude of changes in prevalence of anxiety-like behaviors on the elevated plus-maze and nonhabituated exaggerated startle reaction were compared in rats that were exposed to predator stress, with and without microinjection of anisomycin. RESULTS: Microinjection of anisomycin before and after stress exposure reduced anxiety-like and avoidant behavior, reduced the mean startle amplitude, and reversed the stress-induced habituation deficit 7 days later. The persistent anxiety-like behaviors that were seen after stress exposure do not appear to be sensitive to anisomycin after reexposure to a cue associated with the event or after reexposure to the index experience. CONCLUSIONS: Disruption of the process of traumatic memory consolidation may be useful for mitigating PTSD symptoms.
Asunto(s)
Anisomicina/administración & dosificación , Reacción de Prevención/efectos de los fármacos , Memoria/efectos de los fármacos , Inhibidores de la Síntesis de la Proteína/administración & dosificación , Trastornos por Estrés Postraumático/metabolismo , Estrés Psicológico/metabolismo , Análisis de Varianza , Animales , Ansiedad/etiología , Ansiedad/metabolismo , Ansiedad/prevención & control , Aprendizaje por Asociación/efectos de los fármacos , Modelos Animales de Enfermedad , Inyecciones Intraventriculares , Masculino , Microinyecciones , Ratas , Ratas Sprague-Dawley , Reflejo de Sobresalto/efectos de los fármacos , Trastornos por Estrés Postraumático/etiología , Trastornos por Estrés Postraumático/prevención & control , Estrés Psicológico/complicacionesRESUMEN
BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with low levels of circulating cortisol, and recent studies suggest that cortisol administration may reduce PTSD symptoms. This study investigated the role of cortisol in the manifestation of anxiety- and fear-like symptoms in an animal model of PTSD. METHOD: Magnitude of changes in prevalence of anxiety-like behaviors on the elevated plus-maze and nonhabituated exaggerated startle reaction were compared in three strains of rats exposed to predator stress, with and without prior corticosterone treatment. Extreme behavioral changes in both paradigms implied an extreme behavioral response (EBR), representing PTSD-like symptoms. RESULTS: Lewis rats exhibited greater baseline anxiety-like behaviors and greater stress-induced increases in anxiety-like behaviors than Fischer F344 or Sprague-Dawley rats, with only minor corticosterone increases following stress. Prevalence of EBR was 50% among Lewis rats compared with 10% of Fischer F344 and 25% of Sprague-Dawley rats. Administering corticosterone 1 hour before stress exposure reduced the prevalence of EBR from 50% to 8% in the Lewis rats. CONCLUSIONS: These results suggest that a blunted HPA response to stress may play a causal role in this model of PTSD and that this susceptibility may be prevented by administration of cortisol before stress exposure.