Monoamine neurotransmitters and their metabolites in the mature rabbit brain following induction of hydrocephalus.

Functional and behavioral disturbances associated with hydrocephalus may be due in part to altered neurotransmitter function in the brain. Hydrocephalus was induced in adult rabbits by injection of silicone oil into the cisterna magna. These and controls were killed 3 days, 1 and 4 weeks post-injection. Tissue concentrations of norepinephrine, epinephrine, serotonin, dopamine, and the metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3,4-dihydroxyphenylacetic acid (DOPAC) levels were determined in fifteen brain regions using HPLC. There were decreases in hypothalamic and medullary dopamine, transient decreases in basal ganglia serotonin, increases in thalamic noradrenaline, and increases in hypothalamic and thalamic epinephrine. Changes in the primary neurotransmitters may be attributable to damage of their axonal projection systems. Metabolite concentrations increased in the cerebrum. Reduced clearance of extracellular fluid which accompanies cerebrospinal fluid stasis may explain the accumulation of metabolites.

Ependymal development, proliferation, and functions: a review.

A survey of the literature shows that proliferation of ependyma occurs largely during the embryonic and early postnatal periods of development in most species. Differentiation of these cells proceeds along particular regional and temporal gradients as does the expression of various cytoskeletal (vimentin, cytokeratins, glial fibrillary acidic protein) and secretory proteins (S-100). Turnover declines significantly postnatally, and only low levels of residual activity persist into adulthood under normal conditions. Although the reported response of ependyma to injury is somewhat equivocal, only limited regenerative capacity appears to exist and to varying degrees in different regions of the neuraxis. Proliferation has been most often observed in response to spinal cord injury. Indeed, the ependyma plays a significant role in the initiation and maintenance of the regenerative processes in the spinal cord of inframammalian vertebrates. In the human, however, ependyma appears never to regenerate at any age nor re-express cytoskeletal proteins characteristic of immature cells. The functions of ependyma including tanycytes, a specialized form of ependymal cell that persists into adulthood within circumscribed regions of the nervous system, are still largely speculative. Fetal unlike mature ependyma is believed to be secretory and is believed to play a role in neurogenesis, neuronal differentiation/axonal guidance, transport, and support. In the adult brain, mature ependyma is not merely an inert lining but may regulate the transport of ions, small molecules, and water between the cerebrospinal fluid and neuropil and serve an important barrier function that protects neural tissue from potentially harmful substances by mechanisms that are still incompletely understood.

Effects of in utero exposure to low dose ionizing radiation on development in the rat.

Most studies of in utero effects of ionizing irradiation involve high doses and examination at postnatal intervals. Little information is available on the effects of low levels of ionizing radiation on embryogenesis. The developmental effects of in utero exposure to 50 cGy gamma radiation on gestational day-9.5 was investigated using Sprague-Dawley rats. Irradiated rats and appropriate controls were killed at prenatal intervals of 4h, 48h and 10 days after exposure. Fetuses were examined for abnormalities and random samples of tissues were prepared for microscopic study. With the exception of the neuroepithelium, no histopathological changes were observed in embryos 4h after exposure to 50 cGy. In irradiated embryos, mitoses were reduced within the neuro-epithelium; pyknosis and some necrosis of cells were apparent at this gestational interval. Among the gross developmental abnormalities observed in embryos 48h after irradiation, excessive flexion of the embryo and abnormal flexion of the head were the only ones that appeared to be radiation-induced. The mean numerical score (42.3 +/- 0.2, controls; 42.4 +/- 0.1, irradiated) for 17 morphological parameters examined in fetuses at this gestational period compares favorably with other studies. Controls, however, showed greater variability in the extent of development of their forebrain, olfactory system, midbrain, hindbrain, and caudal neural tube. In all cases, there was evidence of slower development in these regions compared to their irradiated counterparts. At term, no significant differences in litter size or resorption rates were observed in irradiated animals compared to the controls, but there was a higher incidence of defective eye development, spinal curvature and visceral anomalies.(ABSTRACT TRUNCATED AT 250 WORDS)

Postnatal development of the rat CNS following in utero exposure to a low dose of ionizing radiation.

In utero exposure to ionizing radiation is of importance because of its potential health risks. The developing nervous system is particularly vulnerable and the consequences of exposure to low levels of radiation (< or = 1 Gy) are not well established. The developmental effects of maternal exposure to 50 cGy gamma-radiation on gestational days (GD) 9.5, 15, and 18 were investigated in Sprague Dawley rats. Rats exposed on GD-9.5 along with appropriate controls were killed at 4 h, 48 h, and 10 days post-irradiation while those irradiated on GD-15 and GD-18 were killed postnatally (PN) on days 7 and 26. All were examined for developmental anomalies and representative samples of brains were processed for microscopic study. No significant developmental differences were observed between irradiated and control embryos killed 48 h after irradiation on GD 9.5. However, in irradiated fetuses a larger number of developmental anomalies were observed at term. Defects of the eye and of spinal curvature were the most common malformations encountered. Mitoses were reduced within the neuroepithelium of embryos irradiated on GD-9.5 and evidence of pyknosis and necrosis was seen 4 h after irradiation. The capacity of surviving primitive neural cells for repair, however, was such that by 48 h after exposure the irradiated nervous system no longer differed from controls. Rats irradiated on GD-15 and GD-18 and examined on PN-26 exhibited clusters of small, dark, pyknotic neurons within the hippocampal and dentate gyri, often bilaterally.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of intracerebroventricular versus intravenous administration of vasopressin on intracranial pressure in the rat.

Arginine vasopressin (AVP) in the CSF has been implicated in the control of intracranial pressure (ICP) and studies have shown that some patients with raised ICP also have elevated levels of AVP in their CSF. Evidence suggests that central AVP has a separate origin and may exert different effects than AVP in the peripheral circulation. The purpose of this study was to compare the effects of intracerebro ventricular (ICV) and intravenous (IV) injection of AVP on ICP and arterial BP. AVP was administered to anaesthetized, ventilated, S/D rats following a 30 min baseline recording period. BP and ICP were recorded continuously for 40 min post-injection. A single ICV injection of 0.125 microgram or 0.5 microgram AVP significantly (p < 0.05) reduced ICP from 5-26% or 0.2-1.0 mmHg for the duration of the recording period. This was accompanied by a corresponding increase in arterial BP of 5-44% or 4-34 mmHg. In contrast, iv injection of 4 ng or 0.05 microgram AVP produced an abrupt but transient rise in BP of 9-171 mmHg accompanied by a 5-23% increase in ICP. Intravenous injection of 0.125 microgram AVP increased BP to 156-171 mmHg exceeding the autoregulatory range and because of this ICP also increased significantly. BP and ICP exhibited a negative linear relationship following ICV administration of both doses of AVP but only after administration of the smaller dose iv. Vehicle alone administered by either route produced no significant changes in ICP of BP.(ABSTRACT TRUNCATED AT 250 WORDS)

Silicone oil-induced hydrocephalus in the rabbit.

Hydrocephalus was induced in adult rabbits by injecting silicone oil into the cisterna magna. Mean intracranial pressure was significantly elevated for approximately 36 h post-injection, during which time maximal ventricular dilatation was attained. Stretching and compression of periventricular tissue and capillaries accompanied dilation of the lateral ventricles. Ventricular dilation promoted mitotic activity among the periventricular astroglia. Ventriculomegaly altered the metabolism of the monoamine neurotransmitters in the cortex, hippocampus, diencephalon, hypothalamus, and brain-stem. Ischemic injury to neurons of the hippocampal formation, particularly the dentate gyrus, was observed when hydrocephalus had persisted for more than 4 weeks. Cerebrospinal fluid shunting effectively reversed the neuropathologic changes only when done in the early stages of hydrocephalus. When hydrocephalus persisted for 8 weeks, rapid reversal of changes in the ependyma and periventricular capillaries was prevented largely by periventricular gliosis.

Circumventricular organ origin of domoic acid-induced neuropathology and toxicology.

The neuroexcitotoxin, domoic acid, was responsible for an episode of mussel poisoning in Eastern Canada in 1987. Severe neurologic impairment and some deaths occurred. We have characterized the nature of domoate-induced neuropathology in the mouse brain. Domoic acid was administered intraperitoneally at doses of 2, 3 or 7 mg/kg to Swiss-Webster mice. Brains were examined at 0.5, 1, 24, 48 or 72 h postinjection for evidence of damage. Significant pathologic changes occurred only after the largest dose of domoic acid. Damage was confined to circumventricular organs lacking a blood-brain barrier and their environs, including the organon vasculosum of the lamina terminalis, subfornical organ, mediobasal hypothalamus and area postrema. The neural damage induced by domoic acid was evident at as early as 30 min after injection and increased by 60 min postinjection. The loci of domoic acid-induced neuropathological changes accounts for several central and peripheral effects and toxicities observed following systemic domoate treatment, these included gastroduodenal lesions, hypodipsia, analgesia, and blood pressure fluctuations.

Afferent connections of the rat's supraoptic nucleus.

Neurons projecting to the supraoptic nucleus (SON) have been identified following stereotaxic injections of either horseradish peroxidase or fast blue into the SON region of adult rats. The subfornical organ, median preoptic nucleus, organum vasculosum of the lamina terminalis and medial septal nucleus were the source of the largest numbers of supraoptic-projecting neurons. Several smaller projections also originate from the ipsilateral locus coeruleus, preoptic area, lateral parolfactorial area, dorsomedial nucleus of the hypothalamus, lateral parabrachial nucleus and ventrolateral medulla. Several other areas appeared to project only to the region immediately dorsal to the SON: lateral septal nucleus, diagonal band of Broca, ventral tegmental nucleus, and the supramamillary nucleus. These areas may influence SON neurosecretory function by way of interneurons found immediately dorsal to SON. Additional areas were identified with retrograde fluorescent label only, and these projected to the area immediately dorsal to SON and/or to SON itself.

Role of endothelium in hypoxic contraction of canine basilar artery.

1. Reversible contraction of canine basilar artery, produced by hypoxia, persisted after mechanical and chemical removal of the endothelium. The removal of endothelium was confirmed by scanning electron microscopy as well as by the abolition or reversal of the relaxant response to acetylcholine or arginine8-vasopressin. 2. Hydroquinone, believed to block selectively endothelium-mediated relaxation, also preferentially attenuated hypoxic contractions even in the absence of endothelium but did not reduce responses to 5-hydroxytryptamine (5-HT) or high external potassium. 3. Contractions induced by red blood cell haemolysate, which occur independently of the endothelium, were also selectively attenuated by hydroquinone. 4. Contractions caused by hypoxia were inhibited by pretreatment with adenosine or by its application after contraction had developed. 5. Hypoxic contraction in canine basilar artery may result partly from a direct effect on smooth muscle as well as through the endothelium. 6. Hydroquinone may have an additional locus of action in smooth muscle cells besides its well known effect on the endothelium.

Changes in periventricular vasculature of rabbit brain following induction of hydrocephalus and after shunting.

Hydrocephalus was induced in rabbits by injection of silicone oil into the cisterna magna. At 1 and 8 weeks postinjection the rabbits were either sacrificed or treated by cerebrospinal fluid shunting for 1 week. Blood vessel profiles in the periventricular neuropil were examined by light microscopy. In the caudate nucleus, septal area, and corpus callosum, hydrocephalus caused a reduction in the number of capillaries but no changes were observed in the number of larger blood vessels. Shunting reduced the size of the ventricles to normal and the number of capillaries increased if hydrocephalus was present for 1 week prior to shunting. If hydrocephalus was present for 8 weeks prior to shunting, the number of capillaries did not increase. These observations support the concept that collapse of capillaries may account for the decreased cerebral blood flow that has been measured in hydrocephalic brains.

Hereditary hydrocephalus in laboratory animals and humans.

Cerebral ventricle dilatation secondary to disturbed flow of CSF has been observed as an inheritable trait in a variety of laboratory animals as well as in humans. In few groups, however, has the neuropathology been adequately elucidated. In most cases, defective development of the cerebral aqueduct or of the subarachnoid space has been observed. Further study is needed to understand the developmental mechanisms that fail and give rise to hydrocephalus in such models.

Neuropathology of congenital hydrocephalus in the SUMS/NP mouse.

The neuropathology of congenital hydrocephalus in SUMS/NP mice was investigated in this study. Hydrocephalus occurred with an incidence of 16.5% and was evident in the form of an enlarged head soon after birth. The condition was progressive; affected mice gradually became noticeably smaller than normals, acquired functional disturbances and died before ever breeding. Hydrocephalic mice exhibited enormous dilatation of the lateral ventricles, thinning of the cortex and compression and distortion of the diencephalon and striatum. Examination of the midbrain in these animals revealed that the proximal cerebral aqueduct was diminished in size, occluded or absent. Evidence of its anomalous development was seen as early as day 15 of foetal development. This is in substantial agreement with previous reports on this strain. Although the mechanism by which this occurs is still unknown, abnormal development of the adjoining diencephalon and/or rostral midbrain is likely to be involved.

Periventricular pathology in hydrocephalic rabbits before and after shunting.

Hydrocephalus was induced in adult rabbits by injection of silicone oil into the cisterna magna. The frontal horns of the lateral ventricles enlarged to the greatest degree and reached maximum size within 3 days. Cilia and microvilli were progressively lost from the ependymal surface primarily over the corpus callosum. Stretching and flattening of ependymal cells was most pronounced over the septal area. Mitotic activity was significantly increased among the ependymal cells and subependymal astrocytes over the caudate nucleus and corpus callosum during the 2 weeks immediately following induction of hydrocephalus. Cerebrospinal fluid shunting returned the ventricles to normal size. Following shunting, however, the periventricular tissue did not resume a normal appearance. Longer durations of hydrocephalus were associated with less recovery of the periventricular tissue following shunting.

Ependyma of the central canal of the rat spinal cord: a light and transmission electron microscopic study.

Ependymal cells of the rat central canal were examined with a view to identifying features that distinguish them regionally and from their counterparts elsewhere in the ventricular system. The results revealed that the lining consisted for the most part of a pseudostratified layer of uniformly organised cuboidal to columnar ependymal cells present in largest numbers in lumbar and sacral segments and in the conus. Two cell variants were identified on the basis of the presence or absence of a radially directed cytoplasmic process originating from the base of the cell. The tanycytic form of ependymal cell was encountered along the entire length of the central canal but with increased frequency in caudalmost segments. Ependymal cells were largely similar in ultrastructural appearance along the length of the cord. Although they were also similar in appearance and orientation to their counterparts in the ventricles they did exhibit some unique features. The most notable were the prominent junctional complexes and associated filaments present along the lateral border of the cells near their apex and the abundance of intermediate filaments in tanycytes. The central canal of the filum differed most markedly from other segments of the cord and resembled in structure the primitive ependymal tube of the caudal cord in lower vertebrates. Ependymal cells of the cord were not sufficiently dissimilar morphologically from their counterparts in the ventricles to account for differences in proliferative capacity in response to localised injury. A factor that merits further study is the difference in numbers of tanycyte ependymal cells in the two locations for they may be the reactive elements that proliferate in response to injury.

Chronic intracranial pressure monitoring in conscious hydrocephalic rabbits.

Epidural intracranial pressure (ICP) was monitored chronically for up to 6 weeks in conscious, unrestrained rabbits. Hydrocephalus was induced by injecting viscous silicone oil into the cisterna magna. Following injection, ICP remained significantly elevated for only 2 days. Thereafter, the baseline ICP of hydrocephalic rabbits returned to control values. During the hydrocephalic period, however, ICP exhibited instability and transient elevations. ICP characteristics of this model of experimental hydrocephalus resemble those of chronically hydrocephalic humans.

Cerebral water content in silicone oil-induced hydrocephalic rabbits.

Specific gravity determinations were made on fresh and desiccated samples of hydrocephalic rabbit brains. There was a density gradient in the normal cortical gray matter. Hydrocephalus was accompanied by significantly increased specific gravity of cortical gray matter at 3 days and 1 and 4 weeks. In the latter two periods, there were also significant increases in the specific gravity of white matter in the corpus callosum. These changes represent water loss throughout the whole cerebrum except at the ventricular surface. The specific gravity of solid tissue brain components changed insignificantly. We conclude that short-term brain volume changes in experimental hydrocephalus were due mainly to loss of tissue water.

Ependyma of the rat fourth ventricle and central canal: response to injury.

The response of ependyma in the fourth ventricle and central canal to injury was investigated in young Sprague-Dawley rats. Animals received either a small unilateral incision in the lateral funiculus of the thoracolumbar (TL) cord or a puncture wound in the dorsolateral medulla. Control and lesioned rats were killed from 2 to 21 days after operation and the tissue encompassing the lesions was processed for light microscopy and transmission electron microscopy. Randomly selected lesioned and control rats received colchicine (0.2 mg/100 g s.c.) 6 h prior to death at postoperative days 1-4. In controls, the central canal of the TL cord was lined by a single layer of uniformly arranged columnar ependymal cells with large basally located nuclei and apically displaced organelles. Prominent membrane fusions and condensations of filaments were consistent features of the apical region of these cells. Their basal poles abutted directly on the subjacent neuropil and occasionally gave rise to radially directed processes. In rats with TL lesions, the lumen of the central canal was collapsed and lined by an irregularly contoured, multilayered appearing ependyma. Ependymal cells were often radially elongated and possessed filament-filled basal processes. Mitotic rates among ependymal cells of lesioned rats reached a maximum of 3.34% on day 2 compared to 0.21 and 0.28% in intact and sham-operated controls, respectively. Mitotic activity declined progressively thereafter and approached control values by day 4. A similar but less pronounced pattern of proliferative activity was seen distal to the cord lesion, however, little activity was observed within the lining of the fourth ventricle of animals with comparable lesions in the medulla.(ABSTRACT TRUNCATED AT 250 WORDS)

Reaction of periventricular tissue in the rat fourth ventricle to chronically placed shunt tubing implants.

The reaction of periventricular tissue to shunt tubing chronically implanted in the fourth ventricle of the rat was investigated by correlative scanning and transmission electron microscopy. Sterile silicone tubing with four 0.4 mm diameter holes was inserted into the fourth ventricle of adult Sprague-Dawley rats through an incision in the atlantooccipital membrane and the animals were killed at postoperative intervals of 5 and 8 weeks. Reactive changes that could be correlated with the extent of contact with the implant occurred in the periventricular tissue. The ependyma lining the ventricle underwent a progressive loss of cilia and microvilli, became attenuated and, in circumscribed areas, was lost entirely. A significant subependymal gliosis accompanied these changes. In regions denuded of ependyma, neurons and glia were exposed directly to the cerebrospinal fluid. Eruptions of periventricular tissue corresponding precisely to the location of holes in the implanted tubing were observed on both the vermal surface of the cerebellum and the floor of the ventricle. Evaginations from the surface of the inferior vermis and the floor of the ventricle were most prevalent at 5 and greatest at 8 weeks postimplantation, respectively. Gliosis combined with mechanical factors are believed to be responsible for development of these periventricular tissue evaginations, which may be a factor in the pathogenesis of cerebrospinal fluid shunt obstruction in treated human hydrocephalus.

Reaction of rabbit lateral periventricular tissue to shunt tubing implants.

The reaction of the periventricular tissue of the lateral ventricle to silicone rubber shunt tubing was studied by scanning and transmission electron microscopy. Nonfunctioning shunt tubing was implanted bilaterally into the frontal horns of rabbits, which were then sacrificed at postoperative intervals of 3 days to 16 weeks. Colchicine was used to study mitotic activity at the 3-day to 4-week postimplantation intervals. Reactive changes that occurred in the periventricular tissue correlated with the degree of contact with the implant and also with the duration of the postoperative period. Ependymal cells underwent progressive attenuation and sloughed completely in the most severely affected areas. Prominent gliosis in the subependyma accompanied the ependymal changes. The ventricular surface directly adjacent to holes in the implant developed ependyma-covered glial evaginations which grew into the implant holes beginning 1 week postimplantation. In the region of the outgrowths, ependymal mitotic activity was significantly increased at 1 and 2 weeks postimplantation. and astroglial mitotic activity was increased at 3 days and 1 week. Proliferation of ependymal and glial cells in the area touching the shunt tubing and mechanical factors contributed to the development of cellular outgrowths which may be a factor in the pathogenesis of shunt obstruction in human hydrocephalus.

Human neonatal hydrocephalus. An electron microscopic study of the periventricular tissue.

An infant of 43 weeks gestational age with severe congenital hydrocephalus was operated on for removal of a subependymal astrocytoma in the region of the foramen of Monro. A biopsy of periventricular tissue was taken from the lateral ventricle for examination by scanning and transmission electron microscopy. The ependyma was largely denuded, with glial cell processes forming most of the ventricular lining. Many of the attenuated ependymal cells, however, had intact junctional complexes at areas of contact with other ependymal cells. Club-shaped unipolar cells, believed to be a previously undescribed form of immature ependymal cells, were found in the ventricular lining. Cerebrospinal fluid edema was present in the neuropil up to 60 microns from the ventricular lumen, but there was no obvious axonal pathology in the tissues examined.