Clinical and genetic studies of fatal familial insomnia.

We report a 42-year-old man who, for 8 months, had intermittent motor abnormalities and mild difficulty falling asleep. A diagnosis of fatal familial insomnia (FFI) became evident over the next 6 months when he developed progressive insomnia, myoclonus, sympathetic hyperactivity, and dementia. The amyloid or prion protein (PrP) genotype showed features typically seen in FFI, with a 178Asn mutation and a 129Met polymorphism. There was also a deletion of one octapeptide repeat, suggesting that the association of 178Asn mutation with the 129Met polymorphism is not due to "founder effect." Western immunoblot showed a trace of protease-resistant PrP in the thalamus--which had the most significant neuronal loss and gliosis--a moderate amount of PrP in the fronto-temporal area, and no detectable protein elsewhere in the brain. Endocrine studies showed that a circadian modulation of hormonal levels could be maintained despite a near-total absence of sleep. Administration of gamma-hydroxybutyrate induced a remarkable increase in slow-wave sleep.

Asymmetric distribution of cells in the inner nuclear and cone mosaic layers of the goldfish retina.

Cell counts in hematoxylin-stained, flat-mounted retinae revealed that the inner nuclear (INL) and cone mosaic layers (CML) of the goldfish retina contained a high density of cells along the temporal boundary between dorsal and ventral retina. Our findings indicate that the goldfish contains a region situated in the temporal retina in which the density of a wide variety of cell types, that span several retinal layers, is elevated. This study indicates that the dorsotemporal retina, which is the first retinal region to develop, contains the highest density of cells.

Asymmetric distribution of retinal ganglion cells in goldfish.

The distribution of retinal ganglion cells (RGCs) in goldfish was determined by removing an eye and applying cobaltous-lysine to the optic nerve for 24 hr. This procedure allowed the cobalt label to be in continuous contact with the cut ends of the optic axons and thereby backfilled many RGCs. RGC density was determined across three different sizes of retinae by using fish with different eye sizes. Confirming earlier work, we found that RGC density diminished as retinal area increased. However, irrespective of the retinal size, the density of RGCs was elevated along the temporal boundary between the dorsal and the ventral retina. A conservative estimate indicated that the RGC density in the temporal retina was at least 1.8-2.5 times higher than the mean RGC density of the entire retina. Thus, the goldfish retina does not appear to have a homogeneous distribution of RGCs as was previously considered. Small and large retinae differed with respect to the percentage of cells in the RGC layer that was RGCs. In small retinae, even when the noncobalt-filled cells (glia and displaced amacrine cells) were added to the cobalt-filled RGCs, the density of all cell types was elevated in the temporal retina relative to the remainder of the retina. Furthermore, in small retinae, the percentage of cells in the RGC layer that was RGCs (75%) was constant across the radial and circumferential aspects of the retina. In marked contrast, in medium-large retinae, a homogeneous distribution of cells across the entire retina resulted when the noncobalt-filled cells were added to the cobalt-filled cells. However, the percentage of cells that was cobalt-filled RGCs was significantly greater in the temporal retina (50%) than in the remainder of the retina (35%). In large retinae, as in small retinae, the percentage of cells that was RGCs did not vary as a function of distance from the optic disc. These data suggest that, in the course of retinal maturation, cell density in the temporal retina is elevated initially and then declines subsequently to the level of the surrounding retina. Over time, more displaced to the level of the surrounding retina. Over time, more displaced amacrine cells may be added to the tissue surrounding the temporal retina. Alternatively, more RGCs outside the temporal retina may become displaced amacrine cells. Such events could account for the growth-associated, disproportionate decrease in the percentage of cells that is RGCs in the tissue surrounding the temporal retina.(ABSTRACT TRUNCATED AT 400 WORDS)

Retinotopic and chronotopic organization of goldfish retinal ganglion cell axons throughout the optic nerve.

The organization of the retinal ganglion cell (RGC) axons within the goldfish optic nerve head and optic nerve was established by labeling select groups of axons either autoradiographically or with cobaltous lysine. In the optic nerve head, the axons are organized eccentrically with respect to their time of development. Axons of older RGCs are located dorsally and those of younger RGCs are located ventrally. The retinal sectors map across the rostrocaudal axis of the optic nerve head, resulting in four dorsoventrally oriented columns that contain, from rostral to caudal, the axons of ventronasal, dorsonasal, dorsotemporal, and ventrotemporal RGCs. Thus, the optic nerve head is organized into orthogonally oriented laminae. One dimension maps the age of the axons and the other maps the retinal sector of the axons' origin. The optic nerve is organized virtually in the same fashion as the optic nerve head. However, glial septa that invade the optic nerve severely distort, but do not eliminate, the columnar organization of the retinal sectors. These septa deflect many RGC axons and disrupt nearest-neighbor relationships. The distortions produced by the glial septa include folding of the columns and distortion of the chronological lamination. However, the glial septa do not extend into the optic foramen. Therefore, a virtually undistorted columnar organization reappears in the optic foramen. Several roles for the glial septa are discussed.

Simple and complex retinal ganglion cell axonal rearrangements at the optic chiasm.

The rearrangements that retinal ganglion cell (RGC) axons undergo near the optic chiasm were determined by ablating either the nasal, temporal, dorsal, ventral, or peripheral retina. The axons of the remaining intact RGCs were then labelled with cobaltous lysine. RGC axons change their relationship with respect to the axes of the brain and with respect to one another. Toward the caudal end of the optic chiasm, the optic tract begins to rotate axially such that its rostral edge ultimately becomes located medially. Thereby, the column of ventronasal RGC axons shifts from a rostral to a medical position. In addition, columns of axons from other retinal sectors move with respect to one another. Ventrotemporal RGC axons, located initially at the caudal edge of the tract, move toward and come to be positioned laterally to, the column of ventronasal RGC axons. The column of dorsonasal RGC axons moves from the rostral to the lateral side of the column of dorsotemporal RGC axons. Concurrently, the axons within each column reorganize internally. Each chronological lamina of axons within a column twists such that the nasal and temporal axons within each column invert their positions with respect to the edges of the column. All of these reorganizations take place between the caudal end of the optic chiasm and the division of the main optic tract into the optic brachia. Furthermore, the rearrangements that occur do not involve any alterations in the positions of central and peripheral RGC axons with respect to the surface of the diencephalon. The results are discussed with respect to mechanisms that might influence the organization of the visual pathways.

Relationship of ocular pigmentation to the boundaries of dorsal and ventral retina in a nonmammalian vertebrate.

The goldfish eye and retina are partitioned traditionally into dorsal and ventral sectors by a horizontal meridian that passes through the optic disc and is perpendicular to a vertical meridian that extends from the remnant of the choroid fissure through the optic disc. Axons of retinal ganglion cells (RGCs) situated above the horizontal meridian are thought to reach the optic tectum via the ventrolateral optic tract and axons of RGCs situated below the horizontal meridian are thought to reach the optic tectum via the dorsomedial optic tract. When cobaltous-lysine was applied to small temporal retinal slits that were centered on the traditional horizontal meridian, filled fibers were found in the dorsomedial, but not in the ventrolateral, optic tract (Springer and Mednick, '83). Since cobalt-filled axons should have been found in both optic tracts, the traditional horizontal meridian does not indicate the actual boundary between dorsal and ventral retina. We report here that the goldfish iris contains nasal and temporal pigmentation lines (darts) that are each located approximately 21 degrees above the traditional horizontal retinal meridian. Cobalt applied to retinal slits located just above the darts filled RGC axons in the ventrolateral optic tract and cobalt applied to retinal slits just below the darts filled RGC axons in the dorsomedial optic tract. Converging evidence for the reliability of the darts as indicators of the boundary between dorsal and ventral retina was obtained by applying cobalt to severed RGC axons along the dorsomedial edge of the tectum. Cobalt-filled RGCs were found below the nasal dart.(ABSTRACT TRUNCATED AT 250 WORDS)

A quantitative study of the relative contribution of different retinal sectors to the innervation of various thalamic and pretectal nuclei in goldfish.

The contribution of retinal ganglion cells situated in different retinal quadrants to the innervation of eight nontectal, retinorecipient targets was examined in goldfish. In some fish, cobaltous-lysine was used to selectively fill severed intraretinal ganglion cell axons and the number of filled axons within each nucleus was determined. In other fish, either the dorsal or ventral or nasal or temporal retina was ablated and the remaining axons from the intact retina were filled with cobalt. The density of the cobalt-filled axons within the retinorecipient targets was quantified with a microdensitometer. All of the eight targets received different degrees of innervation when the contributions from dorsal and ventral retina were compared. The suprachiasmatic nucleus received axons from ventral, but not from dorsal, retinal ganglion cells (RGCs), while the nucleus opticus dorsolateralis, nucleus opticus commissurae posterior, and nucleus opticus pretectalis dorsalis received more axons from ventral than from dorsal RGCs. The tuberal region, nucleus corticalis, and the accessory optic nucleus received axons from dorsal, but not from ventral, RGCs. The nucleus opticus pretectalis ventralis received more axons from dorsal then from ventral RGCs. Only one target, nucleus corticalis, appeared to receive more axons from nasal than from temporal RGCs. In general, those nuclei that were closest to the dorsal optic tract were innervated exclusively or predominantly by ventral RGC axons, whereas those nuclei that were closest to the ventral optic tract were innervated exclusively or predominantly by dorsal RGC axons. These data indicate that in this particular vertebrate, the dorsal and ventral retinal regions are not homogeneous with respect to their projections to nontectal nuclei. The possible role that the nontectal nuclei play in determining the course of optic axons is discussed.

Topography of the goldfish optic tracts: implications for the chronological clustering model.

Both the dorsal and ventral optic tracts of goldfish have similar shapes when they are sectioned perpendicularly to their longitudinal axes. Each tract is pear-shaped, consisting of a narrow and a deep apex, a wide midspan, and a progressively curved and tapered superficial base. The tracts differ in that the apex of the dorsal optic tract points caudally, while the apex of the ventral optic tract points medially. In addition, upon segregating from the main optic tract, the dorsal optic tract courses dorsally while the ventral optic tract courses caudally. Thus, the two optic tracts have similar shapes and are orthongonal to one another. The topography of the retinal fibers within the optic tracts was determined either by ablating part of the retina and subsequently filling the axons from the intact hemiretina with cobaltous-lysine or by applying cobaltous-lysine to a slit in the retina. Both optic tracts contain a similar arrangement of optic fibers. Axons of central retinal ganglion cells (RGCs) are in the apex of each tract and optic fibers of peripheral RGCs are located along the base of each tract. Axons of temporal RGCs are located dorsally in the ventral optic tract and laterally in the dorsal optic tract, while axons of nasal RGCs are located ventrally in the ventral optic tract and medially in the dorsal optic tract. These findings indicate that the optic axons are organized as laminae. Deeper laminae contain the axons of older annuli of RGCs and superficial laminae contain the axons of younger annuli of RGCs. This type of chronological organization appears to be consistent across vertebrates.(ABSTRACT TRUNCATED AT 250 WORDS)

Topography of the retinal projection to the superficial pretectal parvicellular nucleus of goldfish: a cobaltous-lysine study.

The retinal projection to the superficial pretectal parvicellular nucleus (SPp) of goldfish was examined by filling select groups of optic axons with cobaltous-lysine. The tracer was applied intraocularly to peripheral retinal slits in some fish. In other fish, it was applied to optic axons from an intact hemiretina after one-half of the retina was ablated and the corresponding optic axons had degenerated. The results indicated that SPp is a folded structure, having a dorsal surface innervated by axons from temporal retinal ganglion cells and a ventral surface innervated by axons from nasal retinal ganglion cells. Peripheral retina innervates the anterodorsal and anteroventral edges of SPp, while central retina innervates the posterior genu. Dorsal retina innervates lateral SPp and ventral retina innervates medial SPp. Thus, although SPp is a folded nucleus, the topography of the retino-SPp projection is similar to the topography of the retinotectal projection. That is, the relative position of optic axons within SPp mirrors the retinal location of the ganglion cells that project to SPp. Retino-SPp axons occupy the center of the main optic tract before it divides into the two optic brachia. These axons are topographically arranged, with temporal retino-SPp axons being flanked on both sides by nasal retino-SPp axons. Retino-SPp axons arborize within SPp and then continue to enter the superficial tectal retino-recipient lamina. Thus, these axons innervate both SPp and the optic tectum. These findings are discussed with respect to chemospecific and morphogenetic views of visual system topography.

Retinofugal and retinopetal projections in the cichlid fish Astronotus ocellatus.

The retinofugal and retinopetal projections of the cichlid fish Astronotus ocellatus were studied by applying cobaltous-lysine to the optic nerve. Retinal axons terminate bilaterally in a preoptic-suprachiasmatic region between the base of the third ventricle and the anterior genu of the horizontal commissure and among periventricular cells along the sides of the ventricle. Other retinal axons innervate the tuberal region of the hypothalamus anterior to the infundibulum. Targets innervated in the pretectum include nucleus lateralis geniculatus and dorsal, medial, and ventral pretectal nuclei. Three other targets (nucleus opticus dorsolateralis, nucleus opticus commissurae posterior, nucleus opticus ventrolateralis) are innervated by fibers that leave the medial edge of the dorsal optic tract. Two other targets (basal optic nucleus and accessory optic nucleus) are innervated by fibers from the ventral optic tract. These retinal projections are similar to those previously reported for goldfish in an experiment that used the cobaltous-lysine method (Springer and Gaffney, J. Comp. Neurol. 203:401-424, '81). Retinotectal optic axons were found in a superficial lamina just above the stratum opticum, in the stratum opticum, in three layers of the stratum fibrosum et griseum superficiale, in a lamina just beneath the stratum fibrosum et griseum superficiale, and in the stratum album centrale just above the stratum periventriculare. This result is similar to that previously reported for goldfish; however, the spatial relationships between the various retinorecipient laminae differ for goldfish and Astronotus ocellatus. Efferents to the retina originate in two nuclei and both project contralaterally. The first is the nucleus olfactoretinalis, which is located ventrally between the olfactory lobe and telencephalon. It consists of about 400 cells, of which, approximately 200 cells project to the retina. The second retinopetal nucleus, nucleus thalamoretinalis, is a diffuse group of about 200 cells that project to the retina.

Selective innervation of the goldfish suprachiasmatic nucleus by ventral retinal ganglion cell axons.

The contribution of central, peripheral, dorsal, ventral, nasal and temporal retinal ganglion cells to the innervation of the suprachiasmatic nucleus of goldfish was examined with cobaltous-lysine. The nucleus is innervated by axons from central, peripheral, temporal and nasal retina. However, this innervation originates only from ventral retinal ganglion cell axons. The retinal origin of the innervation may be related to being in an aquatic environment.

Dorsotemporal retinal ganglion cell axons of goldfish are located in the dorsal rather than ventral optic tract.

Cobaltous-lysine was injected into the eyes of goldfish after a slit was made in the temporal retina. Cobalt-filled optic fibers were found in the dorsal optic tract and tracing them to their destinations revealed that they terminated rostrally in the peripheral edges of both the dorsal and ventral aspects of the optic tectum. Hence, axons from ganglion cells in the dorsotemporal retina are in the dorsal optic brachium rather than in the ventral optic brachium as was previously assumed.