Selective decline of 5-HT1A receptor binding sites in rat cortex, hippocampus and cholinergic basal forebrain nuclei during aging

The effect of aging on 5-HT_1A receptor binding in several forebrain areas associated with the basal forebrain cholinergic system was investigated in rats of 3-, 24- and 30-months-old by receptor autoradiography and biochemical binding assay using [³H]8-OH-DPAT as a ligand. Autoradiographic measurements demonstrated a marked region-specific decline of ligand binding in: (i) regions of the basal forebrain cholinergic cell groups, i.e. the medial septum, diagonal band nuclei and magnocellular nucleus basalis, (ii) the frontal and parietal neocortex and (iii) the dentate gyrus of the hippocampus. No change or only a slight decrease of the 5-HT_1A receptor density was found in other areas investigated: the CA1 and CA3 sectors of hippocampus, the cingular and perirhinal cerebral cortex and the lateral septum. The autoradiographic findings were substantiated by the biochemical binding assay, which revealed a comparable loss of 5-HT_1A receptor in the hippocampus and neocortex at the age of 30 months. The results clearly show that with increasing age the decrement of 5-HT_1A receptor binding in the rat forebrain is remarkably region-selective and particularly affects the cholinergic cell groups that innervate cortex and hippocampus. This phenomenon appears to be especially significant in relation to the neuronal substrates underlying the age-related alterations of mood and cognition.     

Cognitive potentials in the basal ganglia—frontocortical circuits. An intracerebral recording study

We studied cognitive functions related to processing sensory and motor activities in the basal ganglia (BG), specifically in the putamen and in cortical structures forming the BG-frontocortical circuits. Intracerebral recordings were made from 160 brain sites in 32 epilepsy surgery candidates. We studied P3-like potentials in five different tests evoked by auditory and visual stimuli, and two sustained potentials that are related to cognitive activities linked with movement preparation: BP (Bereitschaftspotential) and CNV (contingent negative variation). We compared the presence of a potential with a phase reversal or an amplitude gradient to the absence of a generator. All of the studied cognitive potentials were generated in the BG; the occurrence in frontal cortical areas was more selective. The frequency of all but one potential was significantly higher in the BG than in the prefrontal and in the cingulate cortices. The P3-like potentials elicited in the oddball paradigm were also more frequent in the BG than in the motor/premotor cortex, while the occurrence of potentials elicited in motor tasks (BP, CNV, and P3-like potentials in the CNV paradigm) in the motor cortex did not significantly differ from the occurrence in the BG. The processing of motor tasks fits with the model by Alexander et al. of segregated information processing in the motor loop. A variable and task-dependent internal organisation is more probable in cognitive sensory information processing. Cognitive potentials were recorded from all over the putamen. The BG may play an integrative role in cognitive information processing.     

Primate basal ganglia activity in a precued reaching task: preparation for movement

Single cell activity was recorded from the primate putamen, caudate nucleus, and globus pallidus during a precued reaching movement task. Two monkeys were trained to touch one of several target knobs mounted in front of them after an LED was lighted on the correct target. A precue was presented prior to this target go cue by a randomly varied delay interval, giving the animals partial or complete advance information about the target for the movement task. The purpose of this design was to examine neuronal activity in the major structures of the basal ganglia during the preparation phase of limb movements when varying amounts of advance information were provided to the animals. The reaction times were shortest with complete precues, intermediate with partial precues, and longest with precues containing no information, demonstrating that the animals used precue information to prepare partly or completely for the reaching movement before the target go cue was given. Changes in activity were seen in the basal ganglia during the preparatory period in 30% of neurons in putamen, 31% in caudate nucleus, and 27% in globus pallidus. Preparatory changes were stronger and more closely linked to the time of movement initiation in putamen than in caudate nucleus. Although the amount of information contained in the precues had no significant effect on preparatory activity preceding the target go cue, a directional selectivity during this period was observed for a subset of neurons with preparatory changes (15% in putamen, 11% in caudate nucleus, 14% in globus pallidus) when the precue contained information about the upcoming direction of movement. A smaller subset of neurons showed selectivity for the preparation of movement amplitude. A larger number of preparatory changes showed selectivity for the direction or amplitude of movement following the target go cue than in the delay period before the cue. The intensity of preparatory changes in activity in many cases depended on the length of the delay interval preceding the target go cue. Even following the target go cue, the intensity of the preparatory changes in activity continued to be significantly influenced by the length of the preceding delay interval for 11% of changes in putamen, 8% in caudate nucleus, and 18% in globus pallidus. This finding suggests that preparatory activity in the basal ganglia takes part in a process termed motor readiness. Behaviorally, this process was seen as a shortening of reaction time regardless of precue information for trials in which the delay interval was long and the animals showed an increased readiness to move. Preparatory activity in putamen following the target go cue was most intense in trials with a short delay interval, in which motor readiness had not achieved its maximum level prior to the go cue. The results of this study indicate that the basal ganglia are involved in multiple aspects of preparatory processing for limb movement. Preparatory processing is therefore unlikely to be divided anatomically along the functional lines examined in this study. In the basal ganglia, preparatory processing reflects both preparation for target selection and control of timing the onset of movement (motor readiness). These characteristics can be integrated in a functional scheme in which the basal ganglia are predominantly responsible for the automated execution of well-trained behavior.     

Topographic projections from the basal ganglia to the nucleus tegmenti pedunculopontinus pars compacta of the cat with special reference to pallidal projections

Summary Projections from the basal ganglia to the nucleus tegmenti pedunculopontinus pars compacta (TPC) were studied by using anterograde and retrograde tracing techniques with horseradish peroxidase conjugated with wheat germ agglutinin (WGA-HRP) in the cat. Following WGA-HRP injections into the medial TPC area, a substantial number of retrogradely labeled cells were seen in the entopeduncular nucleus (EP) and medial half of the substantia nigra pars reticulata (SNr), whereas following WGA-HRP injections into the lateral TPC area, labeled cells were marked in the caudal half of the globus pallidus (GP) and lateral half of the SNr. To confirm the retrograde tracing study, WGA-HRP was injected into the EP or the caudal GP, and anterograde labeling was observed in the TPC areas. Terminal labeling was located in the medail TPC area in the EP injection case, while terminal labeling was observed in the lateral TPC area in the caudal GP injection case. Projections from the striatum to the pallidal complex (the EP and the caudal GP) were also studied autoradiographically by injecting amino acids into various parts of the caudate nucleus and the putamen. Terminal labeling was distributed over the whole extent of the EP and the rostral GP following injections into the rostral striatum (the head of the caudate nucleus or the rostral part of the putamen), while terminal labeling was distributed over the caudal GP following injections into the caudal striatum (the body of the caudate nucleus or the caudal part of the putamen). From these findings, we conclude that there exists a medio-lateral topography in the projection from the basal ganglia to the TPC: The EP receives afferent projections from the rostral striatum and projects to the medial TPC area, whereas the caudal GP receives projections from the caudal striatum and sends fibers to the lateral TPC area.Abbreviations BC brachium conjunctivum - CD caudate nucleus - CP cerebral peduncle - DBC decussation of the brachium conjunctivum - EP entopeduncular nucleus - GP globus pallidus - IC internal capsule - ICo inferior colliculus - LH lateral habenular nucleus - ML medial lemniscus - PN pontine nuclei - PUT putamen - SCo superior colliculus - SI substantia innominata - SN substantia nigra - SNc substantia nigra pars compacta - SNr substantia nigra pars reticulata - STN subthalamic nucleus - TH thalamus - TPC nucleus tegmenti pedunculopontinus pars compacta     

The effect of increasing extracellular potassium concentration on the resting heat rate of the isolated rat papillary muscle

The effect of elevating extracellular K⁺ concentration on the basal metabolism of the isolated rat left ventricular papillary muscle has been investigated. The preparation was mounted on a thermopile and connected to a force transducer, to allow simultaneous measurement of muscle heat production and force. The resting heat rate (RHR) of the quiescent preparation was measured as an index of basal metabolism. Throughout all of the experiments, the muscles were maintained under a resting force of 10 mN and all measurements of RHR were made at times when there was no active force present above this passive level. Elevating the extracellular K⁺ concentration from 5.9 to 20, 40, then 80 mM produced graded increases in the RHR. The increase in RHR produced by 40 mM K⁺ was observed to be time-dependent, its effect being significantly greater at 5–7 h than at 2–4 h after cardiectomy. Averaged over all times, the percentage increases in RHR produced by 20, 40, and 80 mM K⁺ in the presence of 2 mM Ca²⁺ were 6.4±2.0%, 28.7±2.3%, and 51.3±8.9% (mean±SEM) respectively. The high K⁺-induced increase in basal metabolism was also shown to be Ca²⁺-dependent, the increase in RHR produced by 40 mM K⁺ being greater the higher the extracellular Ca²⁺ concentration (0.5–8.0 mM). The addition of verapamil was found to partially inhibit the K⁺-induced increase in resting metabolism. These results show that elevation of the extracellular K⁺ concentration produces a graded increase in the RHR that is Ca²⁺-dependent. It is suggested that the increases in RHR observed in this investigation are in part associated with elevated levels of myoplasmic free Ca²⁺ which stimulate the internal Ca²⁺ pumps.     

The timing of arm-trunk coordination is deficient and vision-dependent in Parkinson's patients during reaching movements

The role of the basal ganglia in the coordination of different body segments and utilization of motor synergies was investigated by analyzing reaching movements to remembered three-dimensional (3D) targets in patients with Parkinson's disease (PD). Arm movements were produced alone or in combination with a forward bending of the trunk, with or without visual feedback. Movements in PD patients were more temporally segmented, as evidenced by irregular changes in tangential velocity profiles. In addition, the relative timing in the onsets and offsets of fingertip and trunk motions were substantially different in PD patients than in control subjects. While the control subjects synchronized both onsets and offsets, the PD patients had large mean intervals between the onsets and offsets of the fingertip and trunk motions. Moreover, PD patients showed substantially larger trial-to-trial variability in these intervals. The degree of synchronization in PD patients gradually increased during the movement under the influence of visual feedback. The mean and variability of the intersegmental intervals decreased as the fingertip approached the target. This improvement in timing occurred even though the separate variability in the timing of arm and trunk motions was not reduced by vision. In combined movements, even without vision, the PD patients were able to achieve normal accuracy, suggesting they were able to use the same movement synergies as normals to control the multiple degrees of freedom involved in the movements and to compensate for the added trunk movement. However, they were unable to recruit these synergies in the stereotyped manner characteristic of healthy subjects. These results suggest that the basal ganglia are involved in the temporal coordination of movement of different body segments and that related timing abnormalities may be partly compensated by vision. Abnormal intersegmental timing may be a highly sensitive indicator of a deficient ability to assemble complex movements in patients with basal-ganglia dysfunction. This abnormality may be apparent even when the overall movement goal of reaching a target is preserved and normal movement synergies appear to be largely intact.     

Effects of ACTH4--10 on self-stimulation behavior in the rat

The threshold current evoking self-stimulation or multiples of this current was used to investigate the effect of ACTH_4–10 on response performance for brain stimulation reward in the medial septum (MS) and the medial forebrain bundle (MFB). ACTH_4–10 in a dose of 50 μg administered SC enhanced bar-pressing for low intensity stimulation but failed to change self-stimulation rates when the base-line rate exceeded 100 responses per 6 min. The peptide lowered the threshold for producing self-stimulation but only in the MS. When an ascending sequence of threshold multiples was used within a session, ACTH_4–10 treatment resulted in an increase in response rate at 1.2 and 1.5 threshold multiples and a decrease at 3.0 times the threshold but only in the MS. The results indicate that ACTH_4–10 facilitated response performance at a low response rate by enhancing the rewarding effect of brain stimulation. Furthermore, the peptide changed the response pattern which normally followed reinforcement shift in the MS.     

The congenital basal cell adenoma of salivary glands Contribution to the differential diagnosis of congenital salivary gland tumours

Congenital epithelial tumours of the salivary glands are very rare. The Salivary Gland Registry maintained in the Department of Pathology, University of Hamburg, contains only three cases among a total of 6,646 salivary gland tumours from the years 1965–1994. The three cases were classified as congenital basal cell adenoma, two of the parotid gland and one of the submandibular gland. Histologically, the three adenomas were similar in structure to the adult counterpart of basal cell adenoma with solid, trabecular or tubular (duct-like) patterns. In some cystic spaces of the duct-like structures PAS- and Astra blue-positive substances were secreted. On immunocytochemistry, the luminal duct-like cells showed membranous expression of cytokeratins 3, 5, 6, 7, 13 and 19. In the isomorphic basaloid cells of the solid and trabecular cell nests few cells expressed cytokeratin. On the outside of the solid cell nests there were smaller elongated myoepithelial-like cells, which expressed cytokeratin 14 and vimentin. Cytokeratins 1, 2, 4 and 18 were not expressed. The pattern of expression reflects the different stages of maturity of the tumour cells and is related to the development of the salivary glands until the end of the 3rd embryonal month with an arrest of further cell differentiation. No acinic cells, invasive growth, recurrence or metastases were observed. The differential diagnosis includes other congenital salivary gland tumours, such as hybrid basal cell adenoma-adenoid cystic carcinoma, sialoblastoma or embryoma, carcinoma, hamartoma and teratoma.     

Postsynaptic dorsal column neurons in the cat: a study with retrograde transport of horseradish peroxidase

Summary In situ hybridization histochemistry and RNA blots were used to study the expression of glutamic acid decarboxylase (GAD) mRNA in rats with or without a unilateral lesion of midbrain dopamine neurons. Two populations of GAD mRNA positive neurons were found in the intact caudate-putamen, substantia nigra and fronto-parietal cortex. In caudate-putamen, only one out of ten of the GAD mRNA positive neurons expressed high levels, while in substantia nigra every second of the positive neurons expressed high levels of GAD mRNA. Relatively few, but intensively labelled neurons were found in the intact fronto-parietal cerebral cortex. In addition, one out of six of the GAD mRNA positive neurons in the fronto-parietal cortex showed a low labeling. On the ipsilateral side, the forebrain dopamine deafferentation induced an increase in the number of neurons expressing high levels of GAD mRNA in caudateputamen, and a decrease in fronto-parietal cortex. A smaller decrease was also seen in substantia nigra. However, the total number of GAD mRNA positive neurons were not significantly changed in any of these brain regions. The changes in the levels of GAD mRNA after the dopamine lesion were confirmed by RNA blot analysis. Hence, midbrain dopamine neurons appear to control neuronal expression of GAD mRNA by a tonic down-regulation in a fraction of GAD mRNA positive neurons in caudate-putamen, and a tonic up-regulation in a fraction of GAD mRNA positive neurons in fronto-parietal cortex and substantia nigra.