Most human seizures occur early in life, consistent with established excitability-promoting features of the developing brain. Surprisingly, the majority of developmental seizures are not spontaneous but are provoked by injurious or stressful stimuli. What mechanisms mediate 'triggering' of seizures and limit such reactive seizures to early postnatal life? Recent evidence implicates the excitatory neuropeptide, corticotropin-releasing hormone (CRH). Stress activates expression of the CRH gene in several limbic regions, and CRH-expressing neurons are strategically localized in the immature rat hippocampus, in which this neuropeptide increases the excitability of pyramidal cells in vitro. Indeed, in vivo, activation of CRH receptors -maximally expressed in hippocampus and amygdala during the developmental period which is characterized by peak susceptibility to 'provoked' convulsions -induces severe, age-dependent seizures. Thus, converging data indicate that activation of expression of CRH constitutes an important mechanism for generating developmentally regulated, triggered seizures, with considerable clinical relevance.The majority of seizures occurring in the developing human are not spontaneous, that is, they are not related to inherent abnormalities in the balance of neuronal excitation and inhibition 1 . Rather, most seizures during infancy and childhood are provoked or triggered by alterations in the normal milieu of excitable neurons 2 . Thus, rapid triggering by fever, hypoxia or trauma provokes the majority of seizures in the infant and young child. These seizures -a manifestation of rapid and transient enhancement of neuronal excitability in response to adverse and potentially injurious agents -demonstrate an exquisite age specificity (Table 1): febrile seizures are exclusive to infancy and early childhood 1,2 , immediate traumatic seizures (as opposed to posttraumatic epilepsy) are far more common in the young human compared with the adult, and anoxia-related seizures occur primarily in the full-term neonate 5,7 . Other seizures that are not genetic in origin, such as infantile spasms, which have been linked to a large number of injuries of the CNS and stressors that include infections and malformations, are highly age specific and primarily restricted to the first year of life 6 .In the present review, we focus on novel and evolving concepts regarding potential mechanisms for the rapid transduction of stressful alterations of neuronal milieu into enhanced excitability and resulting seizures. We discuss the cascade of molecular events triggered by 'stress', with an emphasis on the excitatory neuropeptide, corticotropinreleasing hormone (CRH). Established and novel in vivo and in vitro evidence for the role of CRH in enhancing excitation in key limbic circuits, particularly in the tri-synaptic hippocampal pathway, are discussed. Finally, we describe recent data regarding the receptors that mediate CRH-induced excitation, and provide the probable mechanisms underlying the remarkable age specificit...

Age-appropriate acute stress, such as cold exposure, provokes the secretion of corticotropin releasing factor (CRF) from the hypothalamus, leading to a robust increase of plasma corticosterone in the immature rat. This activation of the hypothalamic-pituitary-adrenal system is accompanied by a stress-induced increase of steady-state CRF-mRNA expression in the hypothalamic paraventricular nucleus (PVN). In the current study, we analysed changes in CRFmRNA expression in the PVN and the central nucleus of the amygdala (ACe) in the immature rat in response to a single episode of cold stress and three repeated exposures to this same stressor. CRF-mRNA expression in the PVN increased after a single, but not repeated exposures to cold stress, while repeated acute stress increased the content of the CRF peptide in the anterior hypothalamus. In the ACe, repeated episodes of cold stress resulted in increased expression of CRF-mRNA. These findings indicate a differential regulation of CRF gene expression in the PVN and ACe of the immature rat by single and repeated acute stress. Keywordscorticotropin releasing factor; neonatal rat; hypothalamus; stress; amygdala The developing rat responds to environmental stressors by activation of the hypothalamicpituitary-adrenal (HPA) axis (1, 2). However, the mechanisms of this hormonal stress response may differ in the neonatal rat compared with the adult. The developmental period between the third and fifteenth postnatal days has been characterized by attenuated hormonal responses and altered gene regulation in response to stress (2-5).The neurohormone corticotropin releasing factor (CRF) activates both hormonal and behavioural responses to a variety of stressors. In both the mature and the developing rat, stress leads to CRF release from the hypothalamic paraventricular nucleus (PVN), resulting in increased plasma adrenocorticotropin (ACTH) and corticosterone concentrations. The stress-induced elevation of plasma corticosterone in the immature rat is dependent on CRF secretion as demonstrated using antisera to CRF (2). Subsequent to the stress-induced CRF secretion, a compensatory increase in CRF-mRNA expression in the PVN has been observed in the adult rat (6) as well as in the developing rat starting in the second week of life (2). CRF-containing cells constitute a significant neuronal population in the central nucleus of the amygdala (ACe). The ACe has been shown to be a key regulator of the stress response mediated by CRF release from the PVN [reviewed in (7)]. For example, ablation or stimulation of the ACe attenuate or mimic, respectively, the effects of stress on CRF release from the PVN (8, 9). However, the modulation of CRF gene expression in the ACe by stress has not been examined in the developing rat.The spectrum of differential alterations in the neuroendocrine axis of the adult rat by repeated stress compared with a single acute stress has been a topic of intense study. However, there is relatively limited information regarding the modulation of the neuroendoc...

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.

Over the last few decades, concepts regarding the presence of hormonal and molecular responses to stress during the first postnatal weeks in the rat and the role of the neuropeptide corticotropin releasing hormone (CRH) in these processes, have been evolving. CRH has been shown to contribute critically to molecular and neuroendocrine responses to stress during development. In turn the expression of this neuropeptide in both hypothalamus and amygdala is differentially modulated by single and recurrent stress, and is determined also by the type of stress (eg, psychological or physiological). A likely transcriptional regulatory factor for modulating CRH gene expression, the cAMP responsive element binding protein CREB, is phosphorylated (activated) in the developing hypothalamus within seconds of stress onset, preceding the transcription of the CRH gene and initiating the activation of stress-induced cellular and neuroendocrine cascades. Finally, early life stress may permanently modify the hypothalamic pituitary adrenal axis and the response to further stressful stimuli, and recent data suggest that CRH may play an integral role in the mechanisms of these long-term changes. Molecular Psychiatry (2001) 6, 647-656.

Corticotropin-releasing hormone, a major neuromodulator of the neuroendocrine stress response, is expressed in the immature hippocampus, where it enhances glutamate receptor-mediated excitation of principal cells. Since the peptide influences hippocampal synaptic efficacy, its secretion from peptidergic interneuronal terminals may augment hippocampal-mediated functions such as learning and memory. However, whereas information regarding the regulation of corticotropin-releasing hormone's abundance in CNS regions involved with the neuroendocrine responses to stress has been forthcoming, the mechanisms regulating the peptide's levels in the hippocampus have not yet been determined. Here we tested the hypothesis that, in the immature rat hippocampus, neuronal stimulation, rather than neuroendocrine challenge, influences the peptide's expression. Messenger RNA levels of corticotropin-releasing hormone in hippocampal CA1, CA3 and the dentate gyrus, as well as in the hypothalamic paraventricular nucleus, were determined after cold, a physiological challenge that activates the hypothalamic pituitary adrenal system in immature rats, and after activation of hippocampal neurons by hyperthermia. These studies demonstrated that, while cold challenge enhanced corticotropin-releasing hormone messenger RNA levels in the hypothalamus, hippocampal expression of this neuropeptide was unchanged. Secondly, hyperthermia stimulated expression of hippocampal immediate-early genes, as well as of corticotropin-releasing hormone. Finally, the mechanism of hippocampal corticotropin-releasing hormone induction required neuronal stimulation and was abolished by barbiturate administration.Taken together, these results indicate that neuronal stimulation may regulate hippocampal corticotropin-releasing hormone expression in the immature rat, whereas the peptide's expression in the hypothalamus is influenced by neuroendocrine challenges. Keywordshippocampus; corticotropin-releasing factor; c-fos; rat; hypothalamus; stress Corticotropin-releasing hormone (CRH) is a peptide with both neuroendocrine and neurotransmitter properties. 57 The neuroendocrine effects of CRH, the key mediator of the stress response, originate from clusters of peptidergic cells in the hypothalamic paraventricular nucleus (PVN). 24,34 CRH also functions as a neuromodulator in a number of NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2011 July 5. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript limbic and autonomic brain circuits. 21,22,24,43 CRH-producing neurons are widely but specifically distributed in the brain, 49 including a substantial CRH-expressing neuronal population located in the central nucleus of the amygdala (ACe), 22,53 a region considered as a major source for extra-endocrine CRH-mediated neurotransmission. 24 Abundant target neurons for CRH, expressing cognate receptors, have been demonstrated in the hippocampus. 2,13,15 In addition, physiological effects of CRH on hippocampal neuron...