Retinal pathology in Alzheimer's disease. I. Ganglion cell loss in foveal/parafoveal retina.

Morphometric analysis of the numbers of neurons in the ganglion cell layer (GCL) of the central retina (fovea/foveola/parafoveal retina) in eyes from 9 Alzheimer's disease (AD) and 11 age-matched control cases revealed an overall decrease of 25% in total numbers of neurons in AD as compared with control eyes. Detailed analyses of GCL neurons at various eccentricities from the foveola showed that the greatest decrease in neuronal density (43% decrease) occurred in the central 0-0.5 mm (foveal region), while at 0.5-1 mm and at 1-1.5 mm eccentricities, neuronal loss amounted to 24 and 26%, respectively. The temporal region of the central retina appeared most severely affected, with up to 52% decrease in neuronal density near the foveola (central 0-0.5 mm eccentricity). There was close agreement between fellow eyes analyzed separately for three AD and three control cases. Analysis of neuronal sizes showed that all sizes of neurons were similarly affected in AD. In the GCL of control retinas, neurons decreased with age (coefficient of correlation = -0.67), while in AD retinas no such relationship was evident. Since in the central 0-2 mm region of the retina 97% of neurons in the GCL are ganglion cells (while the remaining 3% consist of displaced amacrine cells), these results demonstrate extensive ganglion cell loss in the central retina in AD.

Retinal pathology in Alzheimer's disease. II. Regional neuron loss and glial changes in GCL.

Detailed analyses of neuronal and astrocyte cell numbers in the ganglion cell layer (GCL) of whole-mounted peripheral retinas from 16 Alzheimer's disease (AD) and 11 control eyes (11 and 9 cases, respectively) demonstrate extensive neuronal loss throughout the entire retina in AD as compared to control eyes. The observed neuronal loss is most pronounced in the superior and inferior quadrants, ranging between 40 and 49% throughout the midperipheral regions, and reaching 50-59% in the far peripheral inferior retina, while the overall neuronal loss throughout the entire retina amounts to 36.4% (p < 0.004). Although the 16% increase in astrocyte numbers is not significant, the ratio of astrocytes to neurons is significantly higher (82%; p < 0.0008) in AD as compared to normal retina (0.238 +/- 0.070 vs. 0.131 +/- 0.042). These results are strengthened by the close agreement (within +/- 15% of respective means) found between fellow eyes. Analysis of glial fibrillary acidic protein immunoreactivity (GFAP-ir) in sections of retinas from an additional 12 AD and 19 control cases show increased GFAP-ir with more extensive labeling of astrocytes in the GCL as well as increased labeling of Müller cell end-feet and radial processes in AD as compared to control retinas. The extensive loss of neurons documented in these retinas, accompanied by an increased astrocyte/neuron ratio, provides further support for the substantial involvement of the retina in AD.

Nonretinal projections to the medial terminal accessory optic nucleus in rabbit and rat: a retrograde and anterograde transport study.

The distribution and density of the nonretinal projections to the rabbit medial terminal accessory optic nucleus (MTN) have been studied after injections of horseradish peroxidase (HRP) into the MTN in seven rabbits, and confirmation for the presence of certain of these projections has been made in the rabbit or rat by utilizing anterograde transport of tritiated leucine or leucine/proline after appropriate injections into cerebral cortical areas and brainstem nuclei. In seven cases studied by the retrograde axonal transport method, HRP-labeled neurons have been identified: (A) In four visual or preoculomotor nuclei in which available autoradiographic brain series have confirmed the presence of projections to the MTN: (1) The nucleus of the optic tract/dorsal terminal accessory optic nucleus, (2) the interstitial nucleus of the superior fasciculus (posterior fibers), (3) the periaqueductal gray (including its supraoculomotor portion), and (4) the medial division of the deep mesencephalic nucleus. (B) Within the ventral lateral geniculate nucleus, from which a projection to the MTN has been confirmed autoradiographically in the rat by other workers. (C) In brainstem nuclei and cerebral cortical areas in which available autoradiographic brain series fail to confirm the presence of afferents to the MTN: (1) The nucleus reticularis pontis, pars oralis and pars caudalis, (2) the intermediate interstitial nucleus of the medial longitudinal fasciculus, (3) the nucleus raphe pontis, and (4) five cerebral cortical areas (the area retrosplenialis granularis dorsalis, the striate area, the parietal area 3, the subicular cortex, and the regio praecentralis granularis). Finally, we report retrograde labeling which, on the basis of published connectional data, we believe to result from the spread to and uptake from axons en passant. The false-positive labeling in this category is likely to result from spread of HRP into ventral tegmental nuclei or tracts adjacent to the MTN. Thus, as a result, in the medulla and pons, labeled neurons are found in the medial, lateral, and superior vestibular nuclei, the medullary reticular formation including the nucleus reticularis gigantocellularis, the lateral reticular nucleus, the nucleus raphe magnus, the spinal nucleus of V, the nucleus gracilis/nucleus cuneatus, the dorsal and ventral divisions of the parabrachial nucleus, the central pontine gray, the nucleus K of Meessen and Olszewski, and the dorsal nucleus of the lateral lemniscus.(ABSTRACT TRUNCATED AT 400 WORDS)

Anatomical studies on the nucleus reticularis tegmenti pontis in the pigmented rat. I. Cytoarchitecture, topography, and cerebral cortical afferents.

The nucleus reticularis tegmenti pontis (NRTP) is a precerebellar reticular nucleus that has been found to be related to cerebropontocerebellar pathways and, more recently, to eye movements. The present study investigates the cytoarchitecture, the topography, and the cerebral cortical projections to the NRTP in the pigmented rat. The cytoarchitecture and topography of the NRTP was determined by examination of Nissl-stained material sectioned in the transverse and sagittal planes. Two cytoarchitectonically distinct portions of the NRTP are apparent; a central subdivision (NRTPc) composed of large multipolar, small spherical, and fusiform neurons, and a pericentral subdivision (NRTPp) composed of loosely packed small fusiform and spherical neurons. The NRTPc is located dorsal to the medial lemniscus and pyramidal tracts over the caudal two-thirds of the pons. It extends caudodorsally to the region just rostral and ventral to the abducens nucleus. The NRTPp is adjacent to the lateral margins of the NRTPc, rostrally, and lies ventral to the caudal portions of the NRTPc. Large injections of horseradish peroxidase (HRP) were made into the cerebellum in order to determine the degree to which each subdivision of the NRTP contributes to the cerebellar projection. A high percentage of NRTPc neurons and a lower percentage of NRTPp neurons were labeled. These differences in labeling density and neuronal morphology noted above confirm the appropriateness of subdividing the NRTP into central and pericentral subdivisions. The cerebral cortical afferents to the NRTP were examined by placing small iontophoretic injections of HRP into the NRTPc and NRTPp. A systematic examination of all cortical areas revealed that the HRP-labeled neurons are entirely localized within pyramidal layer V of three major cortical areas: the ipsilateral prefrontal cortex (Brodmann areas 8, 8a, 11, and 32); the ipsilateral motor and somatosensory cortices (Brodmann areas 2, 4, 6, and 10), and the bilateral cingular cortex (Brodmann areas 24a, 24b, 29c, and 29d). By far, the heaviest cortical labeling with HRP injections into the medial NRTPc is within the cingular cortex that may, in the rat, be homologous to the frontal eye field of the cat and monkey. In contrast, injections involving the lateral NRTPc or the NRTPp produced labeling within wide regions of the cortex with the greatest number in the somatomotor cortex.(ABSTRACT TRUNCATED AT 400 WORDS)

Anatomical studies on the nucleus reticularis tegmenti pontis in the pigmented rat. II. Subcortical afferents demonstrated by the retrograde transport of horseradish peroxidase.

The subcortical nuclear groups projecting to the nucleus reticularis tegmenti pontis (NRTP) were studied in pigmented rats with the aid of the retrograde horseradish peroxidase (HRP) technique. Small iontophoretic injections of HRP were placed in the medial regions of the NRTP, an area that has been shown in several species to be involved in eye movements. Other large injections in the NRTP or small injections placed just outside the nucleus were used to clarify the projections to the NRTP. Results indicate that the NRTP receives afferents from visual relay nuclei, including the nucleus of optic tract, the superior colliculus, and the ventral lateral geniculate nucleus; oculomotor-associated structures including the zona incerta, the H1 and H2 fields of Forel, the nucleus subparafasciculus, the interstitial nucleus of Cajal, the visual tegmental relay zone of the ventral tegmental area of Tsai, the mesencephalic, pontine, and medullary reticular formations, the nucleus of the posterior commissure, and a portion of the periaqueductal gray termed the supra-oculomotor periaqueductal gray; cerebellar and pontomedullary nuclei, including the superior, lateral, and medial vestibular nuclei, the deep cerebellar nuclei, and NRTP interneurons, and nuclei related to limbic functions including the lateral habenula, the mammillary nuclei, the hypothalamic nuclei, the preoptic nuclei, and the nucleus of diagonal band of Broca. A surprisingly large number of afferents to the medial regions of the NRTP arise from visual- or eye-movement-related nuclei. The projection from the nucleus of the optic tract (NOT) confirms previous anatomical and physiological studies on the pathways involved in horizontal optokinetic nystagmus, but the number of NOT afferents is small in relation to other areas potentially related to visuomotor pathways such as the zona incerta, ventral lateral geniculate nucleus, fields of Forel, perirubral area, and subparafasciculus. The NRTP may also relay information related to vertical visuomotor reflexes (e.g., vertical optokinetic nystagmus) given the strong projections from the medial terminal nucleus of the accessory optic system, visual tegmental relay zone, supra-oculomotor periaqueductal gray, interstitial n. of Cajal, and midbrain reticular formation. The presence of significant NRTP projections from the superior colliculus and the mesencephalic and pontine reticular formations suggests that these nuclei may provide the pathways for the noted saccade-related activity of NRTP neurons. In addition, projections from the vestibular nuclei were found that provide the anatomical basis for head velocity signals recorded in NRTP neurons.(ABSTRACT TRUNCATED AT 400 WORDS)

Pretectal and brain stem projections of the medial terminal nucleus of the accessory optic system of the rabbit and rat as studied by anterograde and retrograde neuronal tracing methods.

The projections of the medial terminal nucleus (MTN) of the accessory optic system have been studied in the rabbit and rat following injection of 3H-leucine or 3H-leucine/3H-proline into the MTN and the charting of the course and terminal distribution of the MTN efferents. The projections of the MTN, as demonstrated autoradiographically, have been confirmed in retrograde transport studies in which horseradish peroxidase (HRP) has been injected into nuclei shown in the autoradiographic series to contain fields of terminal axons. The following projections of the MTN have been identified in the rabbit and rat. The largest projection is to the ipsilateral nucleus of the optic tract and dorsal terminal nucleus (DTN) of the accessory optic system. Labeled axons course through the midbrain reticular formation and the superior fasiculus, posterior fibers of the accessory optic system, to reach the nucleus of the optic tract and the DTN in both rabbit and rat. Axons also run forward to traverse the lateral thalamus and to distribute to rostral portions of the nucleus of the optic tract in rat only. A second, large projection is to the contralateral dorsolateral portion of the nucleus parabrachialis pigmentosus of the ventral tegmental area together with an adjacent segment of the midbrain reticular formation. The patchy terminal field observed has been named the visual tegmental relay zone (VTRZ). This fiber projection courses within the posterior commissure and along its path to the VTRZ, provides terminals to the interstitial nucleus of Cajal and the nucleus of Darkschewitsch, both bilaterally. A third, large MTN projection distributes ipsilaterally to the deep mesencephalic nucleus, pars medialis, and the oral pontine reticular formation. Further, this projection also supplies input to the medial nucleus of the periaqueductal gray matter, bilaterally in the rabbit and rat, and in the rabbit also to the ipsilateral superior and lateral vestibular nuclei. A fourth projection crosses the midline and courses caudally to reach, contralaterally, the dorsolateral division of the basilar pontine complex and the above nuclei of the vestibular complex. A fifth projection of the MTN utilizes the medial longitudinal fasciiculus to reach the rostral medulla, in which its axons distribute ispilaterally to the dorsal cap, its ventrolateral outgrowth, and the beta nucleus of the inferior olivary complex. There is also a contralateral contingent of this projection that leaves the medial longitudinal fasciculus to innervate a small rostral segment of the contralateral dorsal cap.(ABSTRACT TRUNCATED AT 400 WORDS)

Projections of the dorsal and lateral terminal accessory optic nuclei and of the interstitial nucleus of the superior fasciculus (posterior fibers) in the rabbit and rat.

The projections of the dorsal and lateral terminal accessory optic nuclei (DTN and LTN) and of the dorsal and ventral components of the interstitial nucleus of the superior fasciculus (posterior fibers; inSFp have been studied in the rabbit and rat by the method of retrograde axonal transport following injections of horseradish peroxidase into oculomotor-related brainstem nuclei. The projections of the ventral division of the inSFp have been further investigated in rabbits with the anterograde axonal transport of 3H-leucine. The data show that the projections of the DTN, LTN, and inSFp are remarkably similar in rabbit and rat. The DTN projects heavily to the ipsilateral medial terminal accessory optic nucleus (MTN), nucleus of the optic tract, and dorsal cap of the inferior olive. The DTN projects sparsely to the ipsilateral visual tegmental relay zone and to the contralateral superior and lateral vestibular nuclei. The LTN and dorsal component of the inSFp are found to share the same basic connections; both project heavily to the ipsilateral nucleus of the optic tract and visual tegmental relay zone and send a moderately sized projection to the ipsilateral MTN. However, while the dorsal component of the inSFp sends significant ipsilateral projections to both rostral and caudal portions of the dorsal cap, only a few LTN neurons appear to follow this example and only by projecting to the rostral part of the dorsal cap. In addition, both the LTN and dorsal component of the inSFp send sparse contralateral projections to the MTN, nucleus of the optic tract, and visual tegmental relay zone; and the dorsal component of the inSFp also provides a sparse contralateral projection to both rostral and caudal portions of the dorsal cap. The ventral component of the inSFp projects heavily to the ipsilateral visual tegmental relay zone and moderately to the ipsilateral MTN and nucleus of the optic tract. The ventral inSFp projects sparsely to the contralateral MTN, the nucleus of the optic tract, and the visual tegmental relay zone. A few of its neurons target the ipsilateral dorsal cap of the inferior olive. Unlike the DTN (present study) and the MTN (Giolli et al.: J. Comp. Neurol. 227:228-251, '84; J. Comp. Neurol. 232:99-116, '85a), the LTN and the inSFp of the rabbit and rat lack projections to the superior and lateral vestibular nuclei.(ABSTRACT TRUNCATED AT 400 WORDS)

Projections of medial terminal accessory optic nucleus, ventral tegmental nuclei, and substantia nigra of rabbit and rat as studied by retrograde axonal transport of horseradish peroxidase.

Projections of the medial terminal nucleus (MTN) of the accessory optic system, the ventral tegmental area of Tsai, and the substantia nigra of the rabbit and the rat have been studied by the method of retrograde axonal transport of horseradish peroxidase. The data show that MTN projections are remarkably similar in the rabbit and rat. The MTN projects heavily to the ipsilateral nucleus of the optic tract and dorsal terminal nucleus of the accessory optic system and to a portion of the contralateral ventral tegmental area of Tsai that we have termed the visual tegmental relay zone (VTRZ). Further, the MTN sends projections to the ipsilateral mesencephalic (deep mesencephalic nucleus, pars medialis) and pontine (nucleus reticularis pontis oralis) reticular formations; the contralateral dorsolateral division of the basal pontine complex; the superior and lateral vestibular nuclei (contralateral in rat; bilateral in rabbit); and the ipsi- and contralateral interstitial nucleus of Cajal, nucleus of Darkschewitsch, and supraoculomotor-periaqueductal gray. The findings also indicate that the MTN has a small bilateral, but mainly ipsilateral, projection to the dorsal cap, its ventrolateral outgrowth, and the B division of the inferior olivary complex. This study further reveals that ventral tegmental nuclei (n. parabrachialis pigmentosus and n. paranigralis) and subdivisions of the substantia nigra (pars compacta and pars reticulata) project to many brain stem targets of the MTN. Thus, the VTRZ projections are similar to those of the MTN in both distribution and density except that the VTRZ projection to the inferior olive is substantially stronger. The nucleus parabrachialis pigmentosus sends a small contralateral projection to the VTRZ and a moderate-sized bilateral projection to the supraoculomotor-periaqueductal gray. The nucleus paranigralis sends a moderate number of axons to the ipsilateral deep mesencephalic nucleus, pars medialis, and the nucleus reticularis pontis oralis and provides a strong bilateral projection to the supraoculomotor-periaqueductal gray. The pars compacta of the substantia nigra provides a sparse input to the ipsilateral deep mesencephalic nucleus, pars medialis, and nucleus reticularis pontis oralis, and to the contralateral VTRZ and sends a moderate number of axons, bilaterally, to the supraoculomotor-periaqueductal gray. The pars reticulata of the substantia nigra sends an ipsiateral projection of moderate size to the intermediate and deep layers of the superior colliculus, sparse ipsilateral projections to the deep mesencephalic nucleus, pars medialis, and nucleus reticularis pontis oralis, and a sparse bilateral projection to

Pattern of striate cortical projections to the pretectal complex in the guinea pig.

The primary goal of this study was to determine whether the striate cortex (Oc 1) of the guinea pig projects to the pretectal nucleus of the optic tract (NOT), the first postretinal station of the horizontal optokinetic pathway, and, if so, to analyze the anatomical organization of this cortico-NOT projection. Other goals of this investigation are to identify other pretectal nuclear projections from the visual cortex in the guinea pig, and to determine whether there is any visuotopic organization in this pathway. Axonal tracers (biocytin or 3H-leucine) were injected into the striate cortex (Oc 1), and the tissue processed with histochemical or light autoradiographic techniques. All subcortical terminal labeling is ipsilateral in the basal ganglia and thalamic nuclei. Furthermore, projections are traced to the ipsilateral brainstem, including two areas of the pretectal complex: (1) one in the NOT, extending in some cases to the adjacent lateral portion of the posterior pretectal nucleus (PPN), and (2) one in the pars compacta of the anterior pretectal nucleus (APNc). The terminal fields in the APN are consistently located rostrally in the dorsolateral portion of the nucleus, independently of the injection site in Oc 1, whereas in the NOT the terminal fields shift slightly after injections placed in different locations in the striate cortex. A correlation of the injection sites in Oc 1 and terminal fields in the NOT reveals a loose topographic organization in the cortico-NOT projection; accordingly, the rostrocaudal axis of the striate cortex projects to the lateromedial axis of the NOT, with a 90 degrees rotation, whereas lateral parts of the striate cortex project diffusely throughout the rostrocaudal extent of the NOT. These data show for the first time that the NOT in the guinea pig receives a substantial projection from the visual cortex. Given the fact that in the guinea pig the optokinetic nystagmus shares some of the characteristics found in cat and monkey (i.e., consistent initial fast rise in the slow phase velocity and reduced asymmetry in monocular stimulation), the present findings lend support to the hypothesis that a cortical input to the NOT is a necessary condition for these oculomotor properties to be present.

Projections from visual areas of the cerebral cortex to pretectal nuclear complex, terminal accessory optic nuclei, and superior colliculus in macaque monkey.

The purpose of this study was to analyze the projections from visually related areas of the cerebral cortex of rhesus monkey to subcortical nuclei involved in eye-movement control; i.e., the pretectal nuclear complex, the terminal nuclei of the accessory optic system (AOS), and the superior colliculus (SC). The anterograde tracer 3H-leucine was pressure injected bilaterally into the cortex of six monkeys (for a total of 12 cases) involving the primary visual cortex (area 17); the medial prestriate cortex (medial 18/19); dorsomedial area 19; the caudal portion of the cortex of the superior temporal sulcus, upper bank (cytoarchitectural area OAa) and lower bank (area PGa); the lower bank of the caudal lateral intraparietal sulcus (area POa); and the inferior parietal lobule (area 7). The results revealed that the pretectal nucleus of the optic tract received inputs from medial prestriate cortex, dorsomedial part of area 19, OAa, and PGa. The posterior pretectal nucleus received sparse projections from area 7 and the cortex lining the intraparietal sulcus (dorsomedial part of area 19 and POa). The pretectal olivary nucleus was targeted by neurons in cortex of dorsomedial area 19, and the anterior pretectal nucleus was targeted by neurons in both dorsomedial 19 and area 7. The nuclei of the AOS (dorsal terminal; lateral terminal; and interstitial nuclei of the superior fasciculus, posterior and medial fibers) received projections exclusively from areas OAa and PGa. Furthermore, in one case with PGa injection, the medial terminal nucleus, dorsal portion, was also labeled. The visual cortical areas studied projected differentially upon the SC laminae. The primary visual area 17 projected only to the superficial laminae, i.e., stratum zonale (SZ), stratum griseum superficiale (SGS), and stratum opticum (SO). On the other hand, the medial portion of the prestriate cortex and caudal OAa and PGa targeted the superficial and intermediate laminae, i.e., SZ, SGS, SO, and stratum griseum intermediale (SGI), whereas caudal area POa projected primarily to the intermediate layer SGI. Rostral area 7 (mainly 7b) neurons terminated in the stratum album intermediale (SAI); no SC terminals were found in a case in which caudal area 7 (mainly 7a) was injected.

GABAergic and non-GABAergic projections of accessory optic nuclei, including the visual tegmental relay zone, to the nucleus of the optic tract and dorsal terminal accessory optic nucleus in rat.

This study examines the non-gamma-amino butyric acid (GABA)ergic (group I neurons) and GABAergic neurons (group II neurons) of the accessory optic system projecting to the nucleus of the optic tract (NOT)/dorsal terminal nucleus (DTN) of the accessory optic system in rat. These nuclei include the dorsal (MTNd) and ventral (MTNv) divisions of the medial terminal nucleus, the lateral terminal nucleus, the interstitial nucleus of the superior fasciculus, the posterior fibers, and the visual tegmental relay zone. GABAergic neurons of these nuclei that do not target the NOT/DTN (group III neurons) have also been observed. The fluorescent retrograde tracer fluoro-gold was injected into the pretectum, targeting the NOT/DTN and the tissue prepared immunocytochemically to reveal neurons containing the neurotransmitter GABA. Three groups of neurons (groups I, II, and III neurons) were examined in terms of their distribution, density, and percentage present. Group I neurons are single-labeled with fluoro-gold and represent non-GABAergic neurons projecting to the NOT/DTN. These neurons are of the highest density in the lateral terminal nucleus (204 neurons/mm2). Their densities are also substantial in the MTNv (120 neurons/mm2), interstitial nucleus of the superior fasciculus, posterior fibers (96 neurons/mm2), and visual tegmental relay zone (93 neurons/mm2). Group II neurons are double-labeled with fluoro-gold and GABA. They form a system of GABAergic neurons projecting to the NOT/DTN, which are exceedingly dense in the MTNd (78 neurons/mm2) but are also dense in both the visual tegmental relay zone (49 neurons/mm2) and MTNv (33 neurons/mm2). Group III neurons are GABAergic neurons that do not target the NOT/DTN but must project to other brain nuclei and/or be interneurons. These are of extremely high concentration in the visual tegmental relay zone (316 neurons/mm2) and are also of substantial densities in the MTNd (77 neurons/mm2), lateral terminal nucleus (72 neurons/mm2), and MTNv (44 neurons/mm2). The MTNd has the highest percentage of GABAergic neurons projecting to the NOT/DTN (72%). GABAergic neurons also form significant percentages of the projections to the NOT/DTN from the visual tegmental relay zone (34%) and MTNv (21%). The percentage of the total GABAergic neurons that project to the NOT/DTN is the highest in the MTNd (50%) and MTNv (42%). The described GABAergic afferents to the NOT/DTN may function to process information concerned with the compensation for retinal slip.

Projections of the lateral terminal accessory optic nucleus of the common marmoset (Callithrix jacchus).

The connections of the lateral terminal nucleus (LTN) of the accessory optic system (AOS) of the marmoset monkey were studied with anterograde 3H-amino acid light autoradiography and horseradish peroxidase retrograde labeling techniques. Results show a first and largest LTN projection to the pretectal and AOS nuclei including the ipsilateral nucleus of the optic tract, dorsal terminal nucleus, and interstitial nucleus of the superior fasciculus (posterior fibers); smaller contralateral projections are to the olivary pretectal nucleus, dorsal terminal nucleus, and LTN. A second, major bundle produces moderate-to-heavy labeling in all ipsilateral, accessory oculomotor nuclei (nucleus of posterior commissure, interstitial nucleus of Cajal, nucleus of Darkschewitsch) and nucleus of Bechterew; some of the fibers are distributed above the caudal oculomotor complex within the supraoculomotor periaqueductal gray. A third projection is ipsilateral to the pontine and mesencephalic reticular formations, nucleus reticularis tegmenti pontis and basilar pontine complex (dorsolateral nucleus only), dorsal parts of the medial terminal accessory optic nucleus, ventral tegmental area of Tsai, and rostral interstitial nucleus of the medial longitudinal fasciculus. Lastly, there are two long descending bundles: (1) one travels within the medial longitudinal fasciculus to terminate in the dorsal cap (ipsilateral >> contralateral) and medial accessory olive (ipsilateral only) of the inferior olivary complex. (2) The second soon splits, sending axons within the ipsilateral and contralateral brachium conjunctivum and is distributed to the superior and medial vestibular nuclei. The present findings are in general agreement with the documented connections of LTN with brainstem oculomotor centers in other species. In addition, there are unique connections in marmoset monkey that may have developed to serve the more complex oculomotor behavior of nonhuman primates.

Autoradiographic pattern of 3H-fucose incorporation in the developing mouse retina.

Light microscopic autoradiography was used to study the pattern of glycoprotein labeling following intravitreal injection of 3H-fucose in the developing mouse retina. Autoradiograms from three postnatal age groups (7-day, 12-day, and adult) were examined. Distinct labeling patterns were observed in all three age groups which followed the general scheme of incorporation into cell bodies followed by localization in the synaptic layers. Thus, 1 to 2 hr after injection, the label was present in all layers but concentrated within the cell bodies of amacrine, ganglion, and horizontal cells in P7 and P12 animals and amacrine and ganglion cells in the adult animals. In all age groups, the synaptic layers showed increased incorporation compared to nuclear layers and a greater retention of glycoproteins. The major differences noted during development were that the turnover rate of 3H-fucose was faster in 7-day animals than in the P12 or adult animals.

Retinal degeneration in the macula of patients with Alzheimer's disease.

Recent reports (Hinton et al. 1986; Blanks et al. 1989) document the involvement of the retina in the constellation of neurodegenerative changes present in Alzheimer's disease (AD). These studies demonstrate the degeneration of large numbers of optic nerve axons and loss of retinal ganglion cells (RGCs) in patients with AD, but the quantitative changes in the retina of patients with AD compared with age-matched controls have not been examined. An important question is whether the lesion affects the macula, the area of highest visual acuity and the region of the greatest density of cone photoreceptor cells and RGCs. Additionally, it is unknown if patients with AD have a uniform thinning of cells in the ganglion cell layer (GCL) or if there is a differential loss of the medium- to large-sized cells, as suggested earlier (Bassi et al. 1987) and documented histopathologically in some areas of the central nervous system of patients with AD (Kemper 1984). If patients with AD were to show a differential loss of large versus small RGCs with characteristic differences in density, distribution, central projections, and physiologic properties (see review by Rowe and Stone 1977), then a loss of the visual functions normally ascribed to these classes of mammalian RGCs might be expected. This quantitative study of the retinal lesions in the macula of patients with AD provides important data on the progression of the disease and may eventually be the basis for diagnostic procedures for assessing the severity of AD.

A mechanism for type III vestibular responses of frog cerebellar Purkinje cells.

Type III Purkinje cells (P-cells), which are excited with both directions of horizontal rotation, are found in high numbers in the frog auricular lobe and adjacent cerebellar areas. To examine the mechanisms underlying these responses, recordings were made from P-cells in curarized animals during rotational stimulation of the horizontal canals. The horizontal canal input to these cells was then modified unilaterally by VIIth nerve section, intraperilymphatic injection of local anesthetic, or by caloric stimulation. Control recordings were also obtained from peripheral canal neurons. Type III responses were abolished by unilateral lesions or reversible blockage of the VIIIth nerve with local anesthetic. The remaining responses were attributable only to the unaffected horizontal canal, ie. only type II or type I responses were observed upon interruption of the ipsi-or contralateral nerve, respectively. The level of spontaneous activity of cerebellar input fibers was low and during rotation produced 'cell silencing' response waveform asymmetries (facilitation greater than disfacilitation). When the level of peripheral resting activity was increased (warm water irrigation), thereby increasing horizontal canal response symmetry, type III responses were reduced in magnitude or abolished. Conversely, cold water irrigation, which decreases the resting rate and response symmetry of input fibers, enhanced type III response magnitudes. On the basis of these results, it is suggested that type III responses result from the fact that single P-cells receive a facilitatory input from both horizontal canals. Since these inputs are 180 degrees phase-reversed and their response waveforms asymmetrical, their resulting postsynaptic effect is a net excitation during both portions of the stimulus cycle.

Orientation of the semicircular canals in rat.

The orientation of the rat semicircular canals was determined using one of two techniques. Null point analysis was used to define physiologically the planar equations of the anterior (n = 15) and posterior canals (n = 15); equations for the horizontal canal (n = 19) were determined using an anatomical dissection technique. Canal orientation was defined with respect to stereotaxic coordinate system and, for comparison, relative to head position during freeze (startle) behavior. Results show that ipsilateral canal planes are orthogonal within 4-8 degrees, and pairs of right-left synergistic pairs are essentially co-planar. The horizontal canals are inclined upwards 35 degrees with respect to the horizontal plane, but a head position of 43 degrees nose-down was determined to produce near optimal horizontal canal and minimal vertical canal activation with horizontal rotation. Finally, a loud or unexpected auditory stimulus initiates a freeze (startle) response in rat characterized by an transient followed by a sustained head position lasting several seconds. Transients are complete within 300-400 ms. Thereafter, the head becomes momentarily stabilized in the startle position which averaged 14 +/- 8 degrees (nose-down with respect to horizontal stereotaxic zero) across the population (n = 14). The response habituated only slightly, but the final position was sufficiently variable so as to limit the usefulness of the freeze (startle) position as a reference of semicircular canal position in the rat.

The human accessory optic system.

The accessory optic system (AOS) has been extensively studied among vertebrates, including primates. It has never clearly been identified in man, and it has not been considered functionally important by clinicians. Because of a lack of a suitable neuroanatomical tract-tracing technique, anatomical demonstration of a retinofugal pathway to the human AOS had previously not been feasible. A modified osmium impregnation method has been shown to permit the tracing of degenerated fibers in man even after long survival periods. This technique employs p-phenylene diamine (PPD) as a marker of myelin and products of axonal degeneration. We applied the PPD method in the examination of one monkey brain (Cynomolgus) and two human autopsy brains with previous visual system lesions. The lateral, dorsal, and medial terminal accessory optic nuclei and the interstitial nucleus of the superior fasciculus, posterior fibers (LTN, DTN, MTN, and inSEp) in the monkey and the LTN, the DTN, and the inSEp in the human all showed degenerated axons and preterminal axonal profiles indicative of direct retinal input. The ventral midbrain tegmentum including the MTN area was not available for study in either of the human brains. The accessory optic projections in both the monkey and human brains proved to be bilateral but primarily crossed. The human visual system thus shares similarities with the simian, in the location and number of the AOS fiber bundles and terminal nuclei and in the organization of the retinofugal projections to these nuclei.

Planar relationships of the semicircular canals in rhesus and squirrel monkeys.

The technique of principal-component analysis was used to define anatomically the semicircular canal planes of the rhesus and squirrel monkeys with respect to the stereotaxic coordinate system. The analyses were performed on a series of points obtained from the dissected osseous labyrinths. A planar equation was defined for each canal plane in the stereotaxic coordinate system and angles were calculated between the 3 ipsilateral canal planes, between synergistic canal pairs and between each canal plane and the stereotaxic planes. The data from both species are similar: the ipsilateral canal planes are nearly orthogonal; synergistic pairs of canal planes are approximately parallel with angles of 2 degrees-12 degrees between pairs in the rhesus monkey and 13 degrees-16 degrees between pairs in the squirrel monkey. The horizontal canal planes form angles of 22 degrees and 18 degrees with the horizontal stereotaxic plane in the rhesus and squirrel monkeys, respectively. A head position of 15 degrees (pitch nose-down) was calculated to produce an optimal head position in both species for maximally stimulating the horizontal canals and minimally stimulating the vertical canals during horizontal angular acceleration. The radii of curvature (R) of the horizontal, anterior and posterior canals were also measured for both species using a calibrated reticle. These measurements indicate that the anterior canal of both species has the largest radius of curvature. This anatomical information is discussed in relation to the available physiological data.

Cat efferent vestibular system: weak suppression of primary afferent activity.

Efferent vestibular neurons identified electrophysiologically in the brain stem do not receive a short latency synaptic input from the ipsilateral labyrinth. Central electric stimulation of these neurons influenced the resting discharge of only 8% of the primary afferent vestibular neurons. Caloric or electric stimulation of the vestibular input was ineffective in changing the spontaneous activity of contralateral primary afferent vestibular neurons.

Semicircular canal radii of curvature (R) in cat, guinea pig and man.

The radii of curvature (R) of the horizontal (Rh), anterior (Ra) and posterior (Rp) semicircular canals were measured by a new technique (called ROTA) for cat, guinea pig and man. For each canal, data points from the osseous canal were rotated and plotted by computer such that the plane of the sheet of computer plot corresponded to the plane best fitting that canal. The radius of each osseous canal was determined and where necessary, the radius of the arc of data points was corrected for thickness of the absent tissue. For cat, guinea pig and man there are differences in R between canals within a labyrinth suggesting that if other things are equal there could be differences in the average mechanical sensitivity of the canals, which is consistent with physiological recordings from primary vestibular neurons in the cat. The Rs determined by ROTA are compared with Rs determined by conventional histological means.