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1.
Brain Dev ; 23(7): 533-8, 2001 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-11701250

RESUMO

West syndrome (WS) is associated with diverse etiological factors. This fact has suggested that there must be a 'final common pathway' for these etiologies, which operates on the immature brain to result in WS only at the maturational state present during infancy. Any theory for the pathogenesis of WS has to account for the unique features of this disorder. For example, how can a single entity have so many etiologies? Why does WS arise only in infancy, even when a known insult had occurred prenatally, and why does it disappear? Why is WS associated with lasting cognitive dysfunction? And, importantly, why do these seizures--unlike most others--respond to treatment by a hormone, ACTH? The established hormonal role of ACTH in human physiology is to function in the neuroendocrine cascade of the responses to all stressful stimuli, including insults to the brain. As part of this function, ACTH is known to suppress the production of corticotropin releasing hormone (CRH), a peptide that is produced in response to diverse insults and stressors.The many etiologies of WS all lead to activation of the stress response, including increased production and secretion of the stress-neurohormone CRH. CRH has been shown, in infant animal models, to cause severe seizures and death of neurons in areas involved with learning and memory. These effects of CRH are restricted to the infancy period because the receptors for CRH, which mediate its action on neurons, are most abundant during this developmental period. ACTH administration is known to inhibit production and release of CRH via a negative feedback mechanism. Therefore, the efficacy of ACTH for WS may depend on its ability to decrease the levels of the seizure-promoting stress-neurohormone CRH.This CRH-excess theory for the pathophysiology of WS is consistent not only with the profile of ACTH effects, but also with the many different 'causes' of WS, with the abnormal ACTH levels in the cerebrospinal fluid of affected infants and with the spontaneous disappearance of the seizures. Furthermore, if CRH is responsible for the seizures, and CRH-mediated neuronal injury contributes to the worsened cognitive outcome of individuals with WS, then drugs which block the actions of CRH on its receptors may provide a better therapy for this disorder.


Assuntos
Hormônio Liberador da Corticotropina/fisiologia , Espasmos Infantis/etiologia , Espasmos Infantis/fisiopatologia , Hormônio Adrenocorticotrópico/fisiologia , Encéfalo/fisiopatologia , Humanos , Lactente
2.
J Neuroendocrinol ; 13(9): 799-807, 2001 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-11578530

RESUMO

Chronic stress early in postnatal life influences hormonal and behavioural responses to stress persistently, but the mechanisms and molecular cascades that are involved in this process have not been clarified. To approach these issues, a chronic stress paradigm for the neonatal rat, using limited bedding material to alter the cage environment, was devised. In 9-day-old rats subjected to this chronic stress for 1 week, significant and striking changes in the expression and release patterns of key molecules that govern the neuroendocrine stress responses were observed. The presence of sustained stress was evident from enhanced activation of peripheral elements of the neuroendocrine stress response, i.e. increased basal plasma corticosterone concentrations, high adrenal weight and decreased body weight. Central regulatory elements of the neuroendocrine stress response were perturbed, including reduced expression of hypothalamic corticotropin-releasing hormone that, surprisingly, was accompanied by reduced glucocorticoid receptor expression. Thus, the effects of chronic sustained stress in the neonatal rat on the hypothalamic-pituitary-adrenal axis included substantial changes in the expression and activity of major regulators of this axis. Importantly, the changes induced by this chronic stress differed substantially from those related to acute or recurrent stress, providing a novel model for studying the long-term effects of chronic, early life stress on neuroendocrine functions throughout life.


Assuntos
Animais Recém-Nascidos/fisiologia , Regulação da Expressão Gênica , Sistema Hipotálamo-Hipofisário/fisiopatologia , Proteínas do Tecido Nervoso/metabolismo , Sistema Hipófise-Suprarrenal/fisiopatologia , Estresse Fisiológico/genética , Estresse Fisiológico/fisiopatologia , Glândulas Suprarrenais/patologia , Animais , Roupas de Cama, Mesa e Banho , Doença Crônica , Corticosterona/sangue , Hormônio Liberador da Corticotropina/genética , Feminino , Lobo Frontal/metabolismo , Hipocampo/metabolismo , Masculino , Tamanho do Órgão , Núcleo Hipotalâmico Paraventricular/metabolismo , RNA Mensageiro/metabolismo , Ratos , Receptores de Hormônio Liberador da Corticotropina/genética , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Receptores de Glucocorticoides/genética , Estresse Fisiológico/patologia
3.
Proc Natl Acad Sci U S A ; 98(15): 8856-61, 2001 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-11447269

RESUMO

Stress early in postnatal life may result in long-term memory deficits and selective loss of hippocampal neurons. The mechanisms involved are poorly understood, but they may involve molecules and processes in the immature limbic system that are activated by stressful challenges. We report that administration of corticotropin-releasing hormone (CRH), the key limbic stress modulator, to the brains of immature rats reproduced the consequences of early-life stress, reducing memory functions throughout life. These deficits were associated with progressive loss of hippocampal CA3 neurons and chronic up-regulation of hippocampal CRH expression. Importantly, they did not require the presence of stress levels of glucocorticoids. These findings indicate a critical role for CRH in the mechanisms underlying the long-term effects of early-life stress on hippocampal integrity and function.


Assuntos
Hormônio Liberador da Corticotropina/farmacologia , Hipocampo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Estresse Fisiológico/patologia , Animais , Contagem de Células , Hormônio Liberador da Corticotropina/administração & dosagem , Glucocorticoides/metabolismo , Hipocampo/citologia , Masculino , Neurônios/citologia , Ratos , Ratos Sprague-Dawley , Estresse Fisiológico/metabolismo , Fatores de Tempo
4.
Ann Neurol ; 49(3): 304-12, 2001 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11261504

RESUMO

The hormone corticotropin (ACTH) is employed as therapy for diverse neurological disorders, but the mechanisms for its efficacy remain unknown. ACTH promotes the release of adrenal steroids (glucocorticoids), and most ACTH effects on the central nervous system (CNS) have been attributed to activation of glucocorticoid receptors. However, in several human disorders, ACTH has therapeutic actions that differ qualitatively or quantitatively from those of steroids. This study tested the hypothesis that ACTH directly influences limbic neurons via the recently characterized melanocortin receptors and focused on the effects of ACTH on the expression of corticotropin-releasing hormone (CRH), a neuropeptide involved in neuroimmune functions and in certain developmental seizures. The results demonstrated that ACTH potently reduced CRH expression in amygdala neurons. This down-regulation was not abolished by experimental elimination of steroids or by blocking their receptors and was reproduced by a centrally administered ACTH fragment that does not promote steroid release. Importantly, selective blocking of melanocortin receptors prevented ACTH-induced down-regulation of CRH expression. Taken together, these data indicate that ACTH activates central melanocortin receptors to modulate CRH gene expression in amygdala, supporting the notion that direct, steroid-independent actions of ACTH may account for some of its established clinical effects on the CNS.


Assuntos
Hormônio Adrenocorticotrópico/metabolismo , Tonsila do Cerebelo/metabolismo , Tonsila do Cerebelo/fisiologia , Hormônio Liberador da Corticotropina/metabolismo , Regulação para Baixo/fisiologia , Regulação da Expressão Gênica , Neurônios/metabolismo , RNA Mensageiro/análise , Animais , Ratos , Ratos Sprague-Dawley
5.
Nat Med ; 7(3): 331-7, 2001 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11231632

RESUMO

Febrile seizures are the most common type of developmental seizures, affecting up to 5% of children. Experimental complex febrile seizures involving the immature rat hippocampus led to a persistent lowering of seizure threshold despite an upregulation of inhibition. Here we provide a mechanistic resolution to this paradox by showing that, in the hippocampus of rats that had febrile seizures, the long-lasting enhancement of the widely expressed intrinsic membrane conductance Ih converts the potentiated synaptic inhibition to hyperexcitability in a frequency-dependent manner. The altered gain of this molecular inhibition-excitation converter reveals a new mechanism for controlling the balance of excitation-inhibition in the limbic system. In addition, here we show for the first time that h-channels are modified in a human neurological disease paradigm.


Assuntos
Hipocampo/fisiopatologia , Potenciais da Membrana , Convulsões Febris/fisiopatologia , Animais , Simulação por Computador , Ratos , Ratos Sprague-Dawley
6.
Endocrinology ; 142(1): 89-97, 2001 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-11145570

RESUMO

Early-life experiences, including maternal interaction, profoundly influence hormonal stress responses during adulthood. In rats, daily handling during a critical neonatal period leads to a significant and permanent modulation of key molecules that govern hormonal secretion in response to stress. Thus, hippocampal glucocorticoid receptor (GR) expression is increased, whereas hypothalamic CRH-messenger RNA (mRNA) levels and stress-induced glucocorticoid release are reduced in adult rats handled early in life. Recent studies have highlighted the role of augmented maternal sensory input to handled rats as a key determinant of these changes. However, the molecular mechanisms, and particularly the critical, early events leading from enhanced sensory experience to long-lasting modulation of GR and CRH gene expression, remain largely unresolved. To elucidate the critical primary genes governing this molecular cascade, we determined the sequence of changes in GR-mRNA levels and in hypothalamic and amygdala CRH-mRNA expression at three developmental ages, and the temporal relationship between each of these changes and the emergence of reduced hormonal stress-responses. Down-regulation of hypothalamic CRH-mRNA levels in daily-handled rats was evident already by postnatal day 9, and was sustained through postnatal days 23 and 45, i.e. beyond puberty. In contrast, handling-related up-regulation of hippocampal GR-mRNA expression emerged subsequent to the 23rd postnatal day, i.e. much later than changes in hypothalamic CRH expression. The hormonal stress response of handled rats was reduced starting before postnatal day 23. These findings indicate that early, rapid, and persistent changes of hypothalamic CRH gene expression may play a critical role in the mechanism(s) by which early-life experience influences the hormonal stress-response long-term.


Assuntos
Envelhecimento/fisiologia , Hormônio Liberador da Corticotropina/genética , Regulação da Expressão Gênica no Desenvolvimento , Hipocampo/fisiologia , Hipotálamo/fisiologia , Estresse Psicológico/fisiopatologia , Transcrição Gênica , Tonsila do Cerebelo/crescimento & desenvolvimento , Tonsila do Cerebelo/fisiologia , Animais , Temperatura Baixa , Feminino , Manobra Psicológica , Hipocampo/crescimento & desenvolvimento , Hipotálamo/crescimento & desenvolvimento , Comportamento Materno , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Restrição Física , Estresse Psicológico/genética
7.
Ann Neurol ; 47(3): 336-44, 2000 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-10716253

RESUMO

Febrile seizures (FSs) constitute the most prevalent seizure type during childhood. Whether prolonged FSs alter limbic excitability, leading to spontaneous seizures (temporal lobe epilepsy) during adulthood, has been controversial. Recent data indicate that, in the immature rat model, prolonged FSs induce transient structural changes of some hippocampal pyramidal neurons and long-term functional changes of hippocampal circuitry. However, whether these neuroanatomical and electrophysiological changes promote hippocampal excitability and lead to epilepsy has remained unknown. By using in vivo and in vitro approaches, we determined that prolonged hyperthermia-induced seizures in immature rats caused long-term enhanced susceptibility to limbic convulsants that lasted to adulthood. Thus, extensive hippocampal electroencephalographic and behavioral monitoring failed to demonstrate spontaneous seizures in adult rats that had experienced hyperthermic seizures during infancy. However, 100% of animals developed hippocampal seizures after systemic administration of a low dose of kainate, and most progressed to status epilepticus. Conversely, a minority of normothermic and hyperthermic controls had (brief) seizures, none developing status epilepticus. In vitro, spontaneous epileptiform discharges were not observed in hippocampal-entorhinal cortex slices derived from either control or experimental groups. However, Schaeffer collateral stimulation induced prolonged, self-sustaining, status epilepticus-like discharges exclusively in slices from experimental rats. These data indicate that hyperthermic seizures in the immature rat model of FSs do not cause spontaneous limbic seizures during adulthood. However, they reduce thresholds to chemical convulsants in vivo and electrical stimulation in vitro, indicating persistent enhancement of limbic excitability that may facilitate the development of epilepsy.


Assuntos
Hipocampo/fisiopatologia , Convulsões Febris/fisiopatologia , Animais , Comportamento Animal/fisiologia , Temperatura Corporal/fisiologia , Modelos Animais de Doenças , Estimulação Elétrica , Eletroencefalografia , Febre/fisiopatologia , Masculino , Ratos , Ratos Sprague-Dawley , Fatores de Tempo
8.
Brain Res Dev Brain Res ; 114(2): 265-8, 1999 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-10320766

RESUMO

Maternal deprivation (MDep) of neonatal rats significantly influences the hypothalamic-pituitary-adrenal (HPA) axis. This study hypothesized that GR-mRNA modulation constituted an early, critical mechanism for the acute effects of MDep on neuroendocrine stress-responses. GR-mRNA hybridization signal in hippocampal CA1, hypothalamic paraventricular nucleus (PVN) and frontal cortex was significantly reduced immediately following 24 h MDep. In amygdala, cingulate cortex, PVN and CA1, apparent gender-dependent MDep effects on GR-mRNA expression were observed, without significant differences in absolute levels. Thus, rapid, region-specific MDep effects on GR-mRNA expression in HPA-regulating areas are shown, consistent with involvement of GR-expression in mechanisms of MDep influence on HPA tone.


Assuntos
Envelhecimento/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Hipotálamo/metabolismo , Sistema Límbico/metabolismo , Privação Materna , RNA Mensageiro/genética , Tonsila do Cerebelo/crescimento & desenvolvimento , Tonsila do Cerebelo/metabolismo , Animais , Córtex Cerebral/crescimento & desenvolvimento , Córtex Cerebral/metabolismo , Feminino , Hipocampo/crescimento & desenvolvimento , Hipocampo/metabolismo , Hipotálamo/crescimento & desenvolvimento , Sistema Límbico/crescimento & desenvolvimento , Masculino , Núcleo Hipotalâmico Paraventricular/crescimento & desenvolvimento , Núcleo Hipotalâmico Paraventricular/metabolismo , Ratos , Ratos Sprague-Dawley , Caracteres Sexuais , Transcrição Gênica
9.
J Neurosci ; 19(10): 3982-91, 1999 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-10234028

RESUMO

The physiological consequences of activating corticotropin-releasing factor receptor type 2 (CRF2) are not fully understood. The neuroanatomic distribution of this CRF receptor family member is consistent with roles in mediating the actions of CRF and similar ligands on food intake control and integrative aspects of stress-related behaviors. However, CRF2 expression in the adult rat is not influenced by stress, corticosterone (CORT), or food intake. In immature rat we have demonstrated striking downregulation of CRF2mRNA in hypothalamic ventromedial nucleus (VMH) after 24 hr of maternal deprivation, a paradigm consisting of both physiological/psychological stress and food deprivation. The current study aimed to distinguish which element or elements of maternal deprivation govern CRF2mRNA expression by isolating the effects of food intake and discrete maternal sensory cues on CRF2mRNA levels in VMH and in reciprocally communicating amygdala nuclei. In maternally deprived pups, CRF2mRNA levels in VMH and basomedial (BMA) and medial (MEA) amygdala nuclei were 62, 72, and 102% of control levels, respectively. Sensory inputs of grooming and handling as well as of the pups' own suckling activity-but not food intake-fully restored CRF2mRNA expression in VMH. In contrast, all manipulations tended to increase CRF2mRNA levels in BMA of maternally deprived rats, and surrogate grooming increased CRF2mRNA expression significantly above that of nondeprived controls. CRF2mRNA expression was not influenced significantly by plasma adrenocorticotropic hormone (ACTH) and CORT levels. Thus, in the immature rat, (1) CRF2 expression is regulated differentially in hypothalamic and amygdala regions, and (2) CRF2mRNA levels in VMH are governed primarily by maternal or suckling-derived sensory input rather than food intake or peripheral stress hormones. These findings indicate a region-specific regulation of CRF2mRNA, supporting the participation of the receptor in neurochemically defined circuits integrating sensory cues to influence specific behavioral and visceral functions.


Assuntos
Tonsila do Cerebelo/metabolismo , Comportamento Alimentar/fisiologia , Hipotálamo Médio/metabolismo , Receptores de Hormônio Liberador da Corticotropina/fisiologia , Hormônio Adrenocorticotrópico/sangue , Animais , Corticosterona/sangue , Regulação para Baixo , Ratos , Ratos Sprague-Dawley
10.
Brain Res Dev Brain Res ; 107(1): 81-90, 1998 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-9602071

RESUMO

Corticotropin releasing factor (CRF) activates two known receptor types, CRF1, and CRF2. In the adult rat brain, CRF2 has a distinct distribution pattern, suggesting that it may mediate functions exclusive of CRF1. The goal of this study was to determine the age-dependent distribution of CRF2-messenger RNA (CRF2-mRNA) in the rat brain. Brains from rats sacrificed under stress-free conditions on fetal days (F) 15, 16, 17 and 19, and postnatal days 1, 3, 5, 7, 9, 12, 15, 25, 49, and 90 (adult) were analyzed using semiquantitative in situ hybridization histochemistry. The onset and distribution of CRF2-mRNA in the developing rat brain revealed important differences from the adult expression pattern: earliest expression of CRF2-mRNA was observed in the ventromedial hypothalamus (VMH) on F16. High levels of CRF2-mRNA were present in the fronto-parietal cortex in the fetal and early postnatal brain but not later. Conversely, no CRF2-mRNA was detectable in the ventroposterior (lateral and medial) thalamic nuclei prior to postnatal day 7. Distinct developmental profiles of CRF2-mRNA were also observed in the lateral septum, medial, basal and cortical amygdala nuclei, and in several hippocampal fields. In conclusion, CRF2 is expressed in the hypothalamus on F16, prior to the detection of CRF itself in the paraventricular nucleus. The differential levels and distributions of CRF2-mRNA in hypothalamic and limbic brain regions indicate a precise regulation of this receptor's expression during development, as shown for CRF1. Regulation of the levels of CRF2 may modulate the effects of CRF (and related ligands) on target neurons, consistent with differential maturation of the functions mediated by this receptor.


Assuntos
Envelhecimento/metabolismo , Encéfalo/metabolismo , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Animais , Animais Recém-Nascidos/crescimento & desenvolvimento , Animais Recém-Nascidos/metabolismo , Encéfalo/embriologia , Encéfalo/crescimento & desenvolvimento , Embrião de Mamíferos/metabolismo , Embrião de Mamíferos/fisiologia , Desenvolvimento Embrionário e Fetal/fisiologia , Histocitoquímica , Hipotálamo/metabolismo , Hibridização In Situ , Sistema Límbico/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Hormônio Liberador da Corticotropina/genética , Distribuição Tecidual
11.
Endocrinology ; 138(11): 5048-51, 1997 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-9348237

RESUMO

The stress neurohormone corticotropin releasing factor (CRF) activates at least two receptor types. Expression of corticotropin releasing factor receptor type II (CRF2) has been demonstrated in the hypothalamic ventromedial nucleus (VMH) of the adult and developing rat, but the physiological functions of VMH-CRF2 have not been elucidated. The VMH has been documented as an important participant in the regulation of food intake and its interactions with the hypothalamic-pituitary-adrenal axis and circadian rhythms. Regulation of VMH-CRF2 may thus play a role in the interplay of physiological alterations in metabolic state with the neuroendocrine and anorexic effects of CRF. This study determined the regulation of CRF2-mRNA expression in infant rats by the physiological consequences of maternal deprivation, i.e., fasting and stress. Using in situ hybridization, maternally deprived pups had an average 62% reduction of VMH-CRF2-mRNA levels compared with stress-free controls. Maternal deprivation also resulted in elevated plasma corticosterone levels (3.8 +/- 0.3 vs. 1.3 +/- 0.1 microg/dl) and an average 5.7% body weight loss. This study demonstrates that maternal deprivation, via fasting and HPA activation, leads to a dramatic decrease of CRF2-mRNA levels in the VMH. These results are consistent with a role for CRF2 activation in mediating some of the complex interactions of CRF (or urocortin) with regulation of food intake in the developing rat.


Assuntos
Animais Recém-Nascidos/metabolismo , Privação Materna , RNA Mensageiro/metabolismo , Receptores de Hormônio Liberador da Corticotropina/genética , Núcleo Hipotalâmico Ventromedial/metabolismo , Animais , Cortisona/sangue , Hibridização In Situ , Ratos , Ratos Sprague-Dawley , Valores de Referência
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