RESUMO
Prenatal stress (PS) is a major risk factor for the development of emotional disorders in adulthood that may be mediated by an altered hypothalamic-pituitary-adrenal axis response to stress. Although the early onset of stress-related disorders is recognized as a major public health problem, to date, there are relatively few studies that have examined the incidence of early-life stressors in younger individuals. In this study, we assessed PS impact on the stress-coping response of juvenile offspring in behavioral tests and in the induced molecular changes in the hippocampus. Furthermore, we assessed if pregnancy stress could be driving changes in patterns of maternal behavior during early lactation. We found that PS modified stress-coping abilities of both sex offspring. In the hippocampus, PS increased the expression of bdnf-IV and crfr1 and induced sex difference changes on glucocorticoids and BDNF mRNA receptor levels. PS changed the hippocampal epigenetic landscape mainly in male offspring. Stress during pregnancy enhanced pup-directed behavior of stressed dams. Our study indicates that exposure to PS, in addition to enhanced maternal behavior, induces dynamic neurobehavioral variations at juvenile ages of the offspring that should be considered adaptive or maladaptive, depending on the characteristics of the confronting environment. Our present results highlight the importance to further explore risk factors that appear early in life that will be important to allow timely prevention strategies to later vulnerability to stress-related disorders.
Assuntos
Adaptação Psicológica , Complicações na Gravidez , Efeitos Tardios da Exposição Pré-Natal , Restrição Física , Estresse Fisiológico , Estresse Psicológico , Animais , Feminino , Masculino , Gravidez , Ratos , Ansiedade/etiologia , Ansiedade/genética , Ansiedade/fisiopatologia , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Fator Neurotrófico Derivado do Encéfalo/genética , Corticosterona/sangue , Hormônio Liberador da Corticotropina/biossíntese , Hormônio Liberador da Corticotropina/genética , Teste de Labirinto em Cruz Elevado , Regulação da Expressão Gênica , Glucocorticoides/biossíntese , Glucocorticoides/genética , Hipocampo/embriologia , Hipocampo/fisiologia , Sistema Hipotálamo-Hipofisário/embriologia , Sistema Hipotálamo-Hipofisário/fisiopatologia , Lactação/fisiologia , Lactação/psicologia , Comportamento Materno , Sistema Hipófise-Suprarrenal/embriologia , Sistema Hipófise-Suprarrenal/fisiopatologia , Complicações na Gravidez/fisiopatologia , Complicações na Gravidez/psicologia , Ratos Wistar , Receptor trkB/biossíntese , Receptor trkB/genética , Receptores de Hormônio Liberador da Corticotropina/biossíntese , Receptores de Hormônio Liberador da Corticotropina/genética , Receptores de Glucocorticoides/biossíntese , Receptores de Glucocorticoides/genética , Restrição Física/efeitos adversos , Caracteres Sexuais , Estresse Fisiológico/fisiologia , Estresse Psicológico/fisiopatologia , NataçãoRESUMO
RATIONALE: Stress is a common antecedent reported by people suffering major depression. In these patients, extrahypothalamic brain areas, like the hippocampus and basolateral amygdala (BLA), have been found to be affected. The BLA synthesizes CRF, a mediator of the stress response, and projects to hippocampus. The main hippocampal target for this peptide is the CRF subtype 1 receptor (CRF1). Evidence points to a relationship between dysregulation of CRF/CRF1 extrahypothalamic signaling and depression. OBJECTIVE: Because selective serotonin reuptake inhibitors (SSRIs) are the first-line pharmacological treatment for depression, we investigated the effect of chronic treatment with the SSRI fluoxetine on long-term changes in CRF/CRF1 signaling in animals showing a depressive-like behavior. METHODS: Male Wistar rats were exposed to the learned helplessness paradigm (LH). After evaluation of behavioral impairment, the animals were treated with fluoxetine (10 mg/kg i.p.) or saline for 21 days. We measured BLA CRF expression with RT-PCR and CRF1 expression in CA3 and the dentate gyrus of the hippocampus with in situ hybridization. We also studied the activation of one of CRF1's major intracellular signaling targets, the extracellular signal-related kinases 1 and 2 (ERK1/2) in CA3. RESULTS: In saline-treated LH animals, CRF expression in the BLA increased, while hippocampal CRF1 expression and ERK1/2 activation decreased. Treatment with fluoxetine reversed the changes in CRF and CRF1 expressions, but not in ERK1/2 activation. CONCLUSION: In animals exposed to the learned helplessness paradigm, there are long-term changes in CRF and CRF1 expression that are restored with a behaviorally effective antidepressant treatment.
Assuntos
Hormônio Liberador da Corticotropina/biossíntese , Fluoxetina/farmacologia , Desamparo Aprendido , Receptores de Hormônio Liberador da Corticotropina/biossíntese , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Depressão/tratamento farmacológico , Depressão/metabolismo , Depressão/psicologia , Imunofluorescência , Fluoxetina/uso terapêutico , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hibridização In Situ , Masculino , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real , Inibidores Seletivos de Recaptação de Serotonina/uso terapêuticoRESUMO
A mucoepidermoid carcinoma of the lung (ICD classification 8430/3) resected from a patient with no clinical signs of pituitary-adrenal alterations was transplanted into 2-month-old athymic nu/nu nude mice, with the purpose of studying the effects exerted by the human tumour on the host hypothalamo-pituitary-adrenal axis. The tumour produces peptides derived from different regions of pro-opiomelanocortin (POMC: ACTH, 7.6 +/- 0.7; N-terminal POMC, 6.6 +/- 0.6; beta-LPH/endorphin, 7.3 +/- 0.7; and alpha-MSH;3.8 +/- 0.5 pmol/g wet tissue) and the neuropeptides corticotrophin-releasing hormone and arginine vasopressin (CRH: 3.6 +/- 0.4 and AVP: 1.1 +/- 0.2 pmol/g wet tissue). Immunohistochemical staining of consecutive sections of the tumour indicated that staining of tumour cells for the different peptides was not uniform and although some cells co-stained with CRH and AVP, POMC-positive cells appeared to be distinct from CRH and AVP cells. Tumour extracts were chromatographed on Sephadex G-75 and fractions monitored for POMC-derived peptides. A single peak with characteristics of alpha-MSH was detected. The ACTH, N-POMC and beta-LPH/endorphin radioimmunoassays (RIA) detected a peak at large molecular weight, eluting at the position expected for POMC. These RIA systems also revealed an ACTH(1-39) peak and another peak which probably correspond to 13 kDa ACTH, a peak eluting at the position of hN-POMC(1-48), a beta-LPH-like peak, and a smaller sized peak which may represent alpha- or gamma-endorphin. The ACTH, N-POMC and beta-LPH/endorphin contents of anterior lobe (AL) extracts, but not neutrointermediate lobe (NIL) extracts, showed a striking decrease in tumour-bearing (TB) nude mice. However, while no difference was seen in the alpha-MSH content of AL extract between TB and control (C) nude mice, it decreased in NIL extracts of TB animals. The contents of CRH and AVP in stalk-median eminence extracts of TB nude mice was significantly lower than that of C nude mice. Basal plasma corticosteroids were raised in TB nude mice at levels comparable to those in stressed C nude mice, and although adrenal weights did not vary between TB and C nude mice, morphological changes indicating hypertrophy were found in the adrenal glands of the host animals. It was concluded that the tumour dramatically alters the hypothalamo-pituitary-adrenal axis of the host, and that it may be a useful model for studying tumour-host interactions in ectopic hormone-producing tumours.
Assuntos
Arginina Vasopressina/biossíntese , Hormônio Liberador da Corticotropina/biossíntese , Neoplasias Pulmonares/metabolismo , Pró-Opiomelanocortina/biossíntese , Hormônio Adrenocorticotrópico/análise , Animais , Carcinoma/metabolismo , Feminino , Humanos , Sistema Hipotálamo-Hipofisário/fisiopatologia , Neoplasias Pulmonares/fisiopatologia , Hormônios Estimuladores de Melanócitos/análise , Camundongos , Camundongos Nus , Transplante de Neoplasias , Adeno-Hipófise/análise , Sistema Hipófise-Suprarrenal/fisiopatologiaRESUMO
In order to investigate the production and secretion of hypothalamic factors by the prolactin and proopiomelanocortin (POMC)-derived, peptide-producing, transplantable rat pituitary tumor 7315a, we determined the concentrations of corticotropin-releasing factor (CRF)- and vasopressin (AVP)-like immunoreactivities (IR) in the tumor extracts [14.0 +/- 1.6 (SE) and 4.2 +/- 0.9 pmol/g, respectively] and incubation media (0.26 +/- 0.01 and 0.07 +/- 0.01 pmol/10(7) cells/h, respectively). Total peptide content correlated well with tumor weight. Moreover, there is a very good correlation between the CRF and AVP IR, but not as good between CRF or AVP IR and POMC peptide IR tumor contents. Tumor extracts were chromatographed on Sephadex G-75 and compared with chromatograms of stalk median eminence (SME) extracts from normal Buffalo rats. CRF IR in tumor chromatograms gave an unusual pattern of peaks. About 31% of the total CRF IR was eluted in the high molecular weight region. The major portion of CRF IR was located in a wide region of lower molecular weight. The AVP radioimmunoassay revealed a similar pattern of peaks in tumor and SME chromatograms. A propressophysin-like peak and a smaller peak coeluting with synthetic AVP were detected. Immunohistochemical staining of consecutive sections of the tumor indicated that AVP and CRF are often found in the same cell, but the CRF and AVP-producing cells are clearly distinct from the POMC peptide-producing cells.