Biomedical subjects
Publications and source records attributed to O T Phillipson.
The anxiolytic lorazepam was studied for its effects on contrast sensitivity to gratings flickering in counterphase in normal volunteers. The drug significantly reduced contrast sensitivity at low spatial frequencies in a dose-related manner. The results are discussed with reference to possible GABA-mediated processes in the retina and lateral geniculate nucleus.
Adrenergic afferents to the thalamus are almost entirely concentrated in the paraventricular thalamic nucleus (PV). The origins of this projection from medullary C1-3 neurones were quantified, using a combination of retrograde fluorescent markers and immunocytochemical localisation for phenylethanolamine N-methyltransferase (PNMT) in the rat. C1 neurones contributed 51%, C2 29% and C3 20% of the total adrenergic input. Many apparently non-adrenergic retrogradely labelled neurones were also found amongst the C1-3 neurones. The C3 region contained the largest adrenergic population (67%) of retrogradely labelled neurones. The neuronal networks associated with PV suggest a role for these adrenergic projections in regulating specific autonomic, locomotor and behavioural events.
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Two experiments were carried out to test the hypothesis, based on anatomical evidence, that contrast gain might be reduced in the retinal periphery in Parkinson's disease. In the first experiment, subjects set contrast thresholds before and after adaptation to a vertical grating of 2 cycles per degree (c/deg), either stationary or oscillating sideways through its spatial period at 8 Hz, presented either in central vision or 7 degrees peripherally. Threshold elevations were similar for central viewing in both patients and controls. However, for peripheral viewing, elevations were greater in the controls, but smaller in the patients, than for central viewing. In the second experiment, a staircase procedure was used to find the contrast of a peripherally viewed grating of either 4 or 1.2 c/deg which apparently matched that of a centrally viewed grating of the same spatial frequency. Patients needed more contrast (about 1.6 times, at both spatial frequencies) than controls for a match. These results suggest that contrast gain may be lowered in the peripheral retina in Parkinson's disease, perhaps because of an abnormality of dopamine amacrine cells, whose density peaks in the peripheral retina.
Previous studies suggest that the tilt aftereffect (TAE) may be used to indicate the site of dopaminergic abnormalities in the human visual system. In this study we investigated the TAE in patients with Parkinson's disease, and in chronic schizophrenic patients receiving depot injections of neuroleptic. The results suggest that the retina may be abnormal in both groups of patients, and that schizophrenic patients may also have cortical changes. The results are discussed in terms of the clinical implications of these visual changes.
Afferent pathways to the rostral reticular thalamic nucleus (Rt) in the rat were studied using anterograde and retrograde lectin tracing techniques, with sensitive immunocytochemical methods. The analysis was carried out to further investigate previously described subregions of the reticular thalamic nucleus, which are related to subdivisions of the dorsal thalamus, in the paraventricular and midline nuclei and three segments of the mediodorsal thalamic nucleus. Cortical inputs to the rostral reticular nucleus were found from lamina VI of cingulate, orbital and infralimbic cortex. These projected with a clear topography to lateral, intermediate and medial reticular nucleus respectively. Thalamic inputs were found from lateral and central segments of the mediodorsal nucleus to the lateral and intermediate rostral reticular nucleus respectively and heavy paraventricular thalamic inputs were found to the medial reticular nucleus. In the basal forebrain, afferents were found from the vertical and horizontal limbs of the diagonal band, substantia innominata, ventral pallidum and medial globus pallidus. Brainstem projections were identified from ventrolateral periaqueductal grey and adjacent sites in the mesencephalic reticular formation, laterodorsal tegmental nucleus, pedunculopontine nucleus, medial pretectum and ventral tegmental area. The results suggest a general similarity in the organisation of some brainstem Rt afferents in rat and cat, but also show previously unsuspected inputs. Furthermore, there appear to be at least two functional subdivisions of rostral Rt which is reflected by their connections with cortex and thalamus. The studies also extend recent findings that the ventral striatum, via inputs from the paraventricular thalamic nucleus, is included in the circuitry of the rostral Rt, providing further evidence that basal ganglia may function in concert with Rt. Evidence is also outlined with regard to the possibility that rostral Rt plays a significant role in visuomotor functions.
The connections of the laterodorsal tegmental nucleus (LDTg) have been investigated using anterograde and retrograde lectin tracers with immunocytochemical detection. Inputs to LDTg were found from frontal cortex, diagonal band, preoptic areas, lateral hypothalamus, lateral mamillary nucleus, lateral habenula; the interpeduncular nucleus, ventral tegmental area, substantia nigra and retrorubral fields; the medial terminal nucleus, interstitial nucleus, supraoculomotor central grey, medial pretectum, nucleus of the posterior commissure, paramedian pontine reticular formation, paraabducens and paratrochlear region; the parabrachial nuclei and nucleus of the tractus solitarius. Terminal labelling from PHA-L injections of LDTg was found in infralimbic, cingulate and hippocampal cortex, lateral septum, septofimbrial and triangular nuclei, horizontal limb of diagonal band and preoptic areas; in the anterior, mediodorsal, reuniens, centrolateral, parafascicular, paraventricular and laterodorsal thalamic nuclei, rostral reticular thalamic nucleus, and zona incerta; the lateral habenula and the lateral hypothalamus. A number of brainstem structures apparently associated with visual functions were also innervated, mainly the superior colliculus, medial pretectum, medial terminal nucleus, paramedian pontine reticular formation, inferior olive, supraoculomotor, paraabducens and supragenual regions, prepositus hypoglossi and nucleus of the posterior commissure. Also innervated were substantia nigra compacta, ventral tegmental area, interfascicular nucleus, interpeduncular nucleus, dorsal and medial raphe, pedunculopontine tegmental region, parabrachial nuclei, and nucleus of the tractus solitarius. These findings suggest the LDTg to be a highly differentiated part of the ascending "reticular activating" system, concerned not only with specific cortical and thalamic regions, especially those associated with the limbic system, but also with the basal ganglia, and visual (particularly oculomotor) mechanisms. Additional links with the habenula-interpeduncular system are discussed in this context.
Contrast thresholds for, and contrast matches between, stationary gratings of three spatial frequencies (0.5, 2, and 8 c/deg) were measured on eight subjects with a history of schizophrenia, just before, and again two to three days after, a therapeutic injection of depot neuroleptic. The drug enhanced sensitivity at the low, and reduced it at the medium and high spatial frequency. After injection, subjects required more contrast to match the apparent contrast of the high, and less contrast to match that of the low, to that of the medium spatial frequency. Pupillary measurements suggested that these effects were not due to drug-induced changes in pupil size. The results are discussed in terms of the functional role of dopamine in the retina, and a possible application in therapy for amblyopia.
The branching pattern of axons arising from cells in the basal forebrain and laterodorsal tegmental nucleus of the pontine grey, was examined using the double retrograde transport of rhodamine- and coumarin-labelled latex microspheres injected into the olfactory bulb and the mediodorsal thalamic nucleus. About 30-50% of basal forebrain neurones were double-labelled, and approximately 30-40% of laterodorsal tegmental neurones were double-labelled ipsilateral to the injections. No contralateral single or double label was observed in the basal forebrain, but approximately 30% of the contralateral laterodorsal tegmental projection was also double-labelled.
Infusion of a low dose (5 microM) of the cell-selective chemical excitant quisqualic acid (QUIS) into rostral ventromedial globus pallidus (GP) had no immediate effect on DA utilization (assessed as [DOPAC]:[DA] and [HVA]:[DA] ratios) in either the medial bank of the prefrontal cortex (FCx) or the agranular insular cortex (AgCx). In contrast, a larger dose (630 microM) of another excitant sodium ibotenate (IBO) produced an immediate bilaterally symmetrical increase in both indices of DA utilization in FCx. There was also a marked trend towards a bilateral increase in these indices of DA utilization in AgCx. In order to determine whether these effects on cortical DA utilization are mediated by a direct cortical route or via the thalamic mediodorsal nucleus (lateral division, MDL), infusions of IBO into GP were repeated in animals with a 1-week-old N-methyl-D-aspartate lesion of MDL. The increase in DA utilization of FCx following infusion of IBO into GP was abolished, although the trend towards increased DA utilization in AgCx was still maintained. Since MDL innervates FCx but not AgCx and since we have previously shown that MDL lesions alone have no effect on DA utilization in either cortical region, the present results suggest that the changes in cortical DA utilization are probably mediated via MD. Thus in addition to the well-documented control exerted by the thalamus over brain DA function, this has now been extended in the present study to include GP, which projects both directly and indirectly to the thalamus.
The effects of unilateral treatments applied to non-dopamine containing output neurones of the thalamic paraventricular nucleus and adjacent midline nuclei (PV-MLT) were observed on dopamine (DA) utilisation of the nucleus accumbens (NAc). The ratios of [metabolite]: [parent amine] were used as indices of DA utilisation. In general, these indices were observed to increase in NAc in a bilaterally symmetrical fashion immediately after infusion of low doses (5 microM) of a cell-selective chemical excitant (quisqualic acid, QUIS) into either rostral or caudal PV-MLT. Moreover, the increases appeared to be entirely due to changes in the tissue content of metabolite. Electrical stimulation of caudal PV-MLT also enhanced DA utilisation ratios in NAc but appeared to do so by decreasing the tissue content of DA itself. Attempts to lesion caudal PV-MLT neurones by infusion of a higher dose of QUIS (50 mM) followed by long-term recovery (7 days) produced ratios of DA utilisation in NAc that were no different from those of controls. DA utilisation ratios in NAc were no different from control values immediately after infusion into caudal PV-MLT of an 'intermediate' dose (10 mM) of another chemical excitant (N-methyl-D-aspartic acid, NMDA). Since DA utilisation ratios in this area were also unaffected by histologically verifiable lesions of caudal PV-MLT neurones produced 7 days after infusion of high doses (100 mM) of NMDA it is argued that the former treatment may lead to an acute firing inactivation of PV-MLT neurones.(ABSTRACT TRUNCATED AT 250 WORDS)
Dopamine (DA) utilisation has been assessed in medial and lateral segments of the caudate-putamen complex (CPM and CPL, respectively) in response to unilateral manipulations aimed at the thalamic mediodorsal nucleus, lateral division (MDL). The ratios of 3,4-dihydroxyphenylacetic acid (DOPAC):DA and 4-hydroxy-3-methoxyphenylacetic acid (homovanillic acid, HVA):DA are used as indices of DA utilisation and, in the case of HVA:DA, may also reflect DA release. Neither electrical stimulation nor ibotenate (IBO) treatment followed by long recovery periods (2 days or 1 week) had any significant effect on DA utilisation in CPM or CPL. Cell-specific activation of neurones produced by short-term (1 h recovery) infusions of IBO aimed unilaterally at MDL (right side) resulted in bilateral increases of DA utilisation in both CP sectors. These changes tended to be slightly more marked in the hemisphere ipsilateral to the side of IBO infusion. Unilateral infusions of IBO were then aimed at MDL of either (1) the left or right hemisphere of animals which had already received a 1-week-old unilateral (right side) prefrontal cortex (FCx) lesion or (2) the right hemisphere of animals which had previously received a 1 week-old bilateral FCx lesion. The pattern of changes, when expressed relative to the 'sham-operated' animals which received the FCx lesion alone, were similar to those described above following intra-MDL infusions of IBO into animals with an intact cortex. The FCx lesions themselves were shown to have no significant effect on DA utilisation in any CP sector. In view of the known neuroanatomical connections, it is likely that the effects observed in CP are not due to activation of MDL neurones themselves but are more likely the result of activation of neurones in the intralaminar nuclei which border MDL. Nevertheless, these findings support the concept that activation of thalamic nuclei will enhance DA function in a variety of forebrain areas in the rat.
Quantitative analysis of the branching pattern of output projections from the prefrontal cortex and the laterodorsal tegmental nucleus of the brainstem, has been carried out using the newly developed method for double retrograde labelling of neurons with fluorescent labelled latex microspheres. At least 34% of cortical mediodorsal projection neurones in lamina VI send collateral axons to the reticular thalamic nucleus, and at least 40% of cortical reticular projection neurones and collateral axons to mediodorsal nucleus. In the brainstem, laterodorsal neurones are also highly collateralized; at least 44% of mediodorsal projection neurones also innervating nucleus reticularis, and at least 47% of reticularis projection neurones innervating the mediodorsal nucleus.
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Dopamine (DA) utilisation has been determined in the medial bank of the prefrontal cortex (FCx) and the agranular insular cortex (AgCx) of the rat in response to a unilateral reduction of gamma-aminobutyric acid (GABA)-mediated inhibition in the thalamic mediodorsal nucleus (MD). The ratios of 3,4-dihydroxyphenylacetic acid (DOPAC): DA and 4-hydroxy-3-methoxyphenylacetic acid (homovanillic acid, HVA): DA were used as indices of DA utilisation. A bilateral increase in both ratios was found in FCx and AgCx following unilateral infusion of GABA antagonists (1 mM) into MDc. When this concentration was infused into one MDL no change was detected in DA utilisation of FCx, although a bilateral increase was observed in AgCx. However, a correspondence with the known anatomical connections was attained following infusion of lower concentrations (0.5 mM) into MDL in that a significant bilateral elevation of DA utilisation was shown in FCx. The changes induced in these ratios by the above treatments were, in general, due to increases in the concentration of metabolite and slight decreases in that of DA. However, unilateral lesions to the presumed GABA-containing neurones of the rostrodorsal thalamic reticular nucleus (TRNd), which topographically innervate MDL, produced increases in both metabolite and DA concentrations in FCx of both hemispheres, whilst those in AgCx were unaffected. Despite the slightly different results obtained using these two experimental approaches, it is argued that a reduction of tonic GABA-mediated inhibition in MD may tend to activate the DA system in cortical target regions.
A method is described for the quantitative analysis of double retrograde labelled neuronal cell bodies following labelling of branched axonal projections. This exploits the known ability of retrograde translocator proteins to transport latex microspheres following their uptake at nerve terminals. Conditions necessary for uptake and transport include small bead diameter (0.05-micron) and carboxylation of the latex particle. Using coumarin- and rhodamine-labelled microspheres a reliable, sensitive, rapid method has been developed, which results in double retrograde cell labelling in branched axonal pathways from the frontal cortex, basal forebrain, and brainstem. The technique has several advantages over currently available double retrograde labelling methods and yields repeatable quantitative estimates of populations of neurones bearing branched axons.
The topography of afferent projections to the mediodorsal thalamic nucleus of the rat has been studied using the retrograde transport of unconjugated wheat germ agglutinin as identified by immunocytochemistry. Inputs were defined according to the lateral, central or medial segments of the nucleus injected, and controlled by additional injections into the habenula, central medial and paraventricular nuclei of the thalamus. Cortical afferents to the lateral segment arose from anterior cingulate and prelimbic areas on the medial surface of the hemisphere, those to the central segment arose mainly from ventral orbital area, whilst those to the medial segment arose from the infra-limbic and agranular insular areas. This strict cortical topography was matched by the organization of afferents from the reticular thalamic nucleus; i.e. lateral, intermediate and medial reticular neurons from the rostral nucleus projected to lateral, central and medial segments of the mediodorsal thalamus respectively. In the basal forebrain ventral pallidum projected only to the medial segment, whilst magnocellular preoptic region projected only to the central segment. Lateral preoptic area projected to lateral and central segments and the diagonal band mainly to central segment. Projections from substantia innominata were found regardless of the area of mediodorsal nucleus injected. The paraventricular nucleus of thalamus, lateral habenula and substantia nigra reticulata projected to the lateral segment only, whilst central gray projected only to the medial segment. Projections from amygdala (mainly basolateral and central nucleus) were found only following central and medial segment injections. All regions of the mediodorsal nucleus injected received input from the lateral hypothalamus, the ventral tegmental area and the dorsal tegmental gray. The results are discussed and particular emphasis is placed on the possible functions of the thalamocortical connections and the role of the reticular thalamic nucleus as a potential regulator of thalamocortical activity.
Afferent projections to the parafascicular nucleus of the rat have been mapped using the retrograde transport of unconjugated wheat germ agglutinin and immunohistochemistry using very short survival times. Retrogradely labelled neurones were found in laminae V and V1 of primary motor cortex, lamina V1 of primary somatosensory cortex, and deep laminae of gustatory cortex; in the reticular thalamic nucleus and zona incerta; and in the caudate-putamen, entopeduncular nucleus, mesencephalic reticular formation and pretectum. Additional label was found in the laterodorsal tegmental nucleus, nucleus tegmenti pedunculopontinus, dorsal and ventral parabrachial nuclei, vestibular nuclei and the lateral cervical, medial and interpositus nuclei of the cerebellum. These results are discussed in the context of the connections of parafascicular nucleus with the motor system, particularly the basal ganglia. Of particular interest are inputs from laterodorsal tegmental nucleus, nucleus reticularis of thalamus, mesencephalic reticular formation, nucleus tegmenti pedunculopontinus, primary motor cortex and deep cerebellar nuclei. These indicate that the parafascicular nucleus lies at an interface between the reticular activating system on the one hand, and the motor system on the other. This result thus enlarges on present concepts of the parafascicular nucleus. Comparison of afferent projections to a variety of non-specific thalamic nuclei, the parafascicular, paraventricular and mediodorsal thalamic nuclei, indicate a remarkable set of topographic parallels from cortical, reticular thalamic, hypothalamic and brainstem sites. These comparisons provide clues as to the organisational principles of these non-specific thalamic nuclei, particularly in the context of the reticular activating system.