Calculation of the Density of States Using Discrete Variable Representation and Toeplitz Matrices

A direct and exact method for calculating the density of states for systems with localized potentials is presented. The method is based on explicit inversion of the operator $E-H$. The operator is written in the discrete variable representation of the Hamiltonian, and the Toeplitz property of the asymptotic part of the obtained {\it infinite} matrix is used. Thus, the problem is reduced to the inversion of a {\it finite} matrix

Effects of maternal and sibling deprivation on basal and stress induced hypothalamic-pituitary-adrenal components in the infant rat.

Prolonged maternal deprivation during early infancy increases basal- and stress-induced corticosterone (CORT) levels, but the underlying mechanism is not clear. In general, stressors activate the hypothalamic-pituitary-adrenal (HPA) axis, with secretion and compensatory synthesis of hypothalamic cortcotropin-releasing hormone (CRH). In the infant rat, we have demonstrated that maximally tolerated acute cold stress induced a robust elevation of plasma CORT throughout the first 2 postnatal weeks. However CRH messenger RNA (CRH-mRNA) abundance 4 h subsequent to cold stress was enhanced only in rats aged 9 days or older. This suggests a developmental regulation of the CRH component of the HPA-response to this stressor. The present study examined whether increased basal and cold stress-induced CORT levels after 24 h of maternal deprivation were due to enhanced CRH-mRNA abundance in the hypothalamic paraventricular nucleus (PVN). CRH-mRNA abundance, and basal- and cold-induced plasma CORT levels were measured in maternally deprived 6 and 9-day-old pups compared to non-deprived controls. Maternal deprivation increased basal and cold-induced CORT levels on both 6 and 9-day-old rats. CRH-mRNA abundance in the PVN of deprived rats did not differ from that in non-deprived rats. Our results indicate that the enhanced basal and stress-induced plasma CORT observed after 24 h maternal deprivation is not due to increased CRH-mRNA abundance in the PVN

Neurobiology of the stress response early in life: evolution of a concept and the role of corticotropin releasing hormone.

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

Developmental profile of messenger RNA for the corticotropin-releasing hormone receptor in the rat limbic system.

The ontogeny of corticotropin-releasing hormone (CRH) receptor messenger ribonucleic acid (mRNA) in rat brain, using in situ hybridization, is the focus of this study. The developmental profile of CRH receptor using binding assays and receptor autoradiography has been reported, but may be confounded by the presence of a binding protein. The recent cloning of the rat CRH receptor gene has permitted the use of in situ hybridization histochemistry to map the distribution of cells expressing CRH receptor mRNA in the developing brain. We used antisense 35S-labeled oligodeoxynucleotide probes for the two reported splice-variants of the CRH receptor mRNA, which yielded essentially identical localization patterns. CRH receptor mRNA was clearly detectable in infant brain starting on the second postnatal day. Signal in hippocampal CA1, CA2 and CA3a increased to 300-600% of adult levels by postnatal day 6 with a subsequent gradual decline. In the amygdala, in contrast, CRH receptor mRNA abundance increased steadily between the second and the ninth postnatal days, to levels twice higher than those in the adult. In the cortex, CRH receptor mRNA levels were high on postnatal day 2 and decreased to adult levels by day 12. Transient signal over the hypothalamic paraventricular nucleus, observed on the second postnatal day, was not evident at older ages. These results demonstrate robust synthesis of CRH receptor as early as on the second postnatal day and unique region-specific developmental profiles for CRH receptor gene expression

Corticotropin releasing factor receptor type II (CRF2) messenger ribonucleic acid levels in the hypothalamic ventromedial nucleus of the infant rat are reduced by maternal deprivation.

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

Cerebellar mutism in children: report of six cases and potential mechanisms.

Cerebellar mutism is a rare finding associated with resection of posterior fossa tumors or cerebellar hemorrhages. We reviewed the medical records of six children, aged 6 to 12 years, who developed cerebellar mutism after resection of a posterior fossa mass or as a result of posterior fossa trauma. From 1989 to 1994, 210 children underwent posterior fossa resection at our institution, and four developed mutism (an incidence of 1.6%). All four patients had primitive neuroectodermal tumors. The fifth patient experienced trauma, and another patient had an arteriovenous malformation (AVM). In four children, hydrocephalus developed as a result of their tumor or AVM. Four developed cerebellar mutism 24 to 48 hours after surgery or trauma, and one developed cerebellar mutism 5 days after surgery, coincident with hydrocephalus. In one, mutism occurred after a second resection was performed for a recurrence of his posterior fossa tumor. Cerebellar mutism lasted 10 days in one patient and 2 to 8 weeks in the other four. Dysarthria was apparent in four patients during the recovery phase. We suggest trauma to the dentate nucleus and/or its outflow tract, the superior cerebellar peduncle, as a cause of reversible mutism. Because posterior fossa tumors are common in children, mutism should be recognized as an important side effect of surgery

ACTH treatment of infantile spasms: mechanisms of its effects in modulation of neuronal excitability.

The efficacy of ACTH, particularly in high doses, for rapid and complete elimination of infantile spasms (IS) has been demonstrated in prospective controlled studies. However, the mechanisms for this efficacy remain unknown. ACTH promotes the release of adrenal steroids (glucocorticoids), and most ACTH effects on the central nervous system have been attributed to activation of glucocorticoid receptors. The manner in which activation of these receptors improves IS and the basis for the enhanced therapeutic effects of ACTH--compared with steroids--for this disorder are the focus of this chapter. First, a possible "common excitatory pathway," which is consistent with the many etiologies of IS and explains the confinement of this disorder to infancy, is proposed. This notion is based on the fact that all of the entities provoking IS activate the native "stress system" of the brain. This involves increased synthesis and release of the stress-activated neuropeptide, corticotropin-releasing hormone (CRH), in limbic, seizure-prone brain regions. CRH causes severe seizures in developing experimental animals, as well as limbic neuronal injury. Steroids, given as therapy or secreted from the adrenal gland upon treatment with ACTH, decrease the production and release of CRH in certain brain regions. Second, the hypothesis that ACTH directly influences limbic neurons via the recently characterized melanocortin receptors is considered, focusing on the effects of ACTH on the expression of CRH. Experimental data showing that ACTH potently reduces CRH expression in amygdala neurons is presented. This downregulation 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 downregulation of CRH expression, providing direct evidence for the involvement of these receptors in the mechanisms by which ACTH exerts this effect. Thus, ACTH may reduce neuronal excitability in IS by two mechanisms of action: (1) by inducing steroid release and (2) by a direct, steroid-independent action on melanocortin receptors. These combined effects may explain the robust established clinical effects of ACTH in the therapy of IS