Seizures induced by fever are the most prevalent age-specific seizures in infants and young children. Whether they result in long-term sequelae such as neuronal loss and temporal lobe epilepsy is controversial. Prospective studies of human febrile seizures have found no adverse effects on the developing brain. However, adults with temporal lobe epilepsy and associated limbic cell loss frequently have a history of prolonged febrile seizures in early life. These critical issues may be resolved using appropriate animal models. Published models of hyperthermic seizures have used 'adolescent' and older rats, have yielded a low percentage of animals with actual seizures, or have suffered from a high mortality, rendering them unsuitable for long-term studies. This article describes the establishment of a model of febrile seizures using the infant rat. Hyperthermia was induced by a regulated stream of mildly heated air, and the seizures were determined by both behavioral and electroencephalographic (EEG) criteria. Stereotyped seizures were generated in 93.6% of 10-11-day-old rats. EEG correlates of these; seizures were not evident in cortical recordings, but were clearly present in depth recordings from the amygdala and hippocampus. Prolonged febrile seizures could be induced without bums, yielding a low mortality (11%) and long-term survival. In summary, an infant rat paradigm of EEG-confirmed, hyperthermia-induced seizures which is suitable for long-term studies is described. This model should be highly valuable for studying the mechanisms and sequelae of febrile seizures.
Neuroendocrine correlates of chronic stress in human infants have not been established. The goal of the present study was to create an animal model of continuous chronic stress using the immature rat to measure basal plasma corticosterone, and secretion of plasma corticosterone in response to an acute stress. This was achieved by modulation of the cage environment for rat pups and their mothers. During postnatal days 2-9, pups were maintained in three groups: (1) handled, (2) not handled and with ample bedding; and (3) not handled with limited bedding. On postnatal day 9, some pups from each group were subjected to acute cold-separation stress and were killed 90, 240, or 360 min later along with unstressed controls. The group not handled and with limited bedding manifested increased plasma corticosterone output even without cold exposure and a sustained increase of plasma corticosterone after cold-separation stress. Plasma corticosterone interanimal variability was increased and body weight was decreased in these pups, typical of a state of chronic stress. The first model of continuous stress in infant rats in which upregulation of hypothalamic-pituitary-adrenal axis is achieved without maternal separation is presented. This paradigm may more closely approximate the human situation of chronically stressed, neglected infants.
Corticotropin-releasing hormone (CRH) administered into the cerebral ventricles of rats during the first postnatal week caused a specific and stereotyped behavior sequence: rhythmic chewing and licking (jaw myoclonus) were followed by 'litnbic'-type seizures. The onset of the seizures was much more rapid (2-45 min vs 3-7 h) than in adult rats, and the convulsant doses were much lower (50 × 10 −12 mol per gram brain weight vs 750 × 10 −12 mol per gram brain weight in adults). CRH potency in inducing seizures varied inversely with age. CRH-induced seizures occurred prior to any changes in serum corticosterone, and were eliminated by the administration of a CRH antagonist, as well as of phenytoin. Electrocorticographic correlates of CRH-induced behaviors in the infant rat were inconsistent, suggesting a subcortical origin of CRH-induced paroxysmal events in the immature brain.
The neuroanatomical substrate of seizures induced by picomolar amounts of corticotropinreleasing hormone in infant rats was investigated. Electrographic and behavioral phenomena were monitored in 42 rat pups aged 5 to 22 days. Rat pups carried bipolar electrodes implanted in subcortical limbic structures, as well as cortical electrodes and intracerebroventricular cannulae. The administration of corticotropin-releasing hormone produced age-specific seizures within minutes, which correlated with rhythmic amygdala discharges. Paroxysmal hippocampal and cortical discharges developed subsequently in some rats. Corticotropin-releasing hormone-induced electrographic and behavioral seizures originate in the amygdala.Corticotropin-releasing hormone (CRH) is a 41-amino acid neuropeptide, isolated originally from the mammalian hypothalamus [1], It has since been shown to be distributed nonrandomly in the central nervous system, and to perform roles other than the control of secretion of ACTH and endorphins from the anterior pituitary [2]. Specifically, central transduction of stress, anxiety, depression, and anorexia have been demonstrated [2,3].CRH activates neurons both in vivo and in vitro [4][5][6][7][8][9]. The peptide increases both spontaneous and evoked spike discharge from locus ceruleus neurons in vivo [4], CRH induces neuronal depolarization in CA1 and CA3 hippocampal pyramidal cells in the slice preparation in vitro [5]. CRH administered into the cerebral ventricles of adult rats causes epileptiform discharges in the amygdala after a 1-to 3-hour delay, which spread to the dorsal hippocampus [6]. These discharges progress over 3 to 7 hours to behavioral and electrographic seizures. The doses needed for frank seizure generation in adult rats axe 1-5 to 3-75 × 10 −9 mol (0.75-1.88 × 10 −9 mol/gm of brain weight) [6][7][8].We have previously shown that CRH is a far more rapid and potent convulsant in the neonatal rat [10]. Seizures occur with a latency of as little as 2 minutes and with CRH doses as low as 7.5 × 10 −12 mo! or 0.05 × 10 −9 mol/gm of brain weight [10]. The present study was designed to define the neurobiological matrix of the behavioral and electrographic effects of the neuropeptide. We used infant rats, starting on postnatal day 5. Materials and Methods AnimalsTimed-pregnancy Sprague-Dawley-derived rats were obtained from Zivic-Miller (Zelionplc, PA). They were housed under a 12-hour light/dark cycle and fed ad libitum. Copyright © 1992 Delivery times were monitored and were accurate to within 12 hours. The day of birth was considered day zero. The pups were kept with the mothers, and litters were culled to 12 pups. Infant rats were subjected to surgery 24 hours before recording and returned to their mothers. CRH was always administered between 9 and 10:30 AM, to minimize diurnal variations in seizure susceptibility [11] and in endogenous CRH levels [12]. Surgical ProcedureElectrodes were implanted under halothane anesthesia, using an infant rat stereotaxic apparatus as previously describe...
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