Biomedical subjects

D I Finkelstein

Publications and source records attributed to D I Finkelstein.

At least 37 records · Page 2Linked to original sources

PubMed2000

Axonal sprouting following lesions of the rat substantia nigra.

Parkinson's disease is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Symptoms do not appear until most nigral neurons are lost, implying that compensatory mechanisms are present. Sprouting has been proposed as one of these mechanisms. This study quantified the extent of compensatory axonal sprouting following injury of dopaminergic neurons within the substantia nigra pars compacta. Specifically, the extent of the axonal arbour and axonal varicosity morphology was measured after partial destruction (with 6-hydroxydopamine) of the substantia nigra of the adult male rat. Four months later, the substantia nigra was injected with the anterograde neuronal tracer dextran-biotin to trace the full extent of individual axons. An unbiased estimate of neuron number was performed in each animal. This demonstrated nigral neuronal loss ranging from 10 to 90% on the side that received the injection whilst a 7% reduction was observed in the side contralateral to the lesion. Coincident with this loss, some nigral neurons lose tyrosine hydroxylase expression. Vigorous axonal sprouting was observed in the terminal arbours of lesioned animals and was associated with an increased axonal varicosity size. Axonal varicosities and branching points were primarily confined to the dorsal 1.5mm of the caudate-putamen, an area predominantly innervated by nigral neurons. It appears that dopaminergic neurons were responsible for this sprouting because the density of dopamine transporter immunoreactive varicosities in the caudate-putamen was maintained until about a 70% loss of neurons. It was concluded that substantial compensation in the form of sprouting and new dopaminergic synapse formation occurs following lesions of the substantia nigra pars compacta.

Adrenergic Agents↗

PubMed2000

Early direct and transneuronal effects in mice with targeted expression of a toxin gene to D1 dopamine receptor neurons.

The neurochemical profile was examined at postnatal day 3-4 in mutant mice generated by in vivo Cre mediated activation of an attenuated diphtheria toxin gene inserted into the D1 dopamine receptor gene locus. An earlier study of this model had shown that D1 dopamine receptor, substance P and dynorphin were not expressed in the striatum. Quantitative in situ hybridization analysis showed an increase in D2 dopamine receptor and enkephalin messenger RNA expression. The nigrostriatal pathway in the mutant pups was intact with a normal number of dopaminergic neurons in the substantia nigra and the ventral tegmental area in addition to a normal pattern of striatal dopamine transporter and tyrosine hydroxylase immunoreactivity. Quantitative analysis of striatal dopamine transporter density using [3H]mazindol showed a reduction of 26% suggesting a degree of transneuronal down-regulation. There was also a 49% reduction of striatal GABA receptor binding and a 36% reduction of striatal muscarinic receptor binding in mutant pups. The number of healthy striatal neuropeptide Y-containing interneurons was also substantially down-regulated in the mutant striatum. In contrast, there was an increase in the number of striatal cholinergic interneurons. Down-regulated cortical GABA receptor and muscarinic receptor binding was also observed in addition to subtle morphological changes in the neuropeptide Y-expressing population of cortical neurons. The changes reflect the early cascade of events which follows the ablation of D1 dopamine receptor-positive cells. Although extensive changes in a number of striatal and cortical neurons were demonstrated, only subtle transneuronal effects were seen in the nigrostriatal pathway.

Animals↗

PubMed1999

Sprouting of dopaminergic axons after striatal injury: confirmation by markers not dependent on dopamine metabolism.

Striatal injury increases dopamine metabolism in the nigrostriatal system but it is unclear whether this response is due to increased synthesis and activation of tyrosine hydroxylase within existing dopamine terminals and/or branching and sprouting of new terminals. While monitoring the density of tyrosine hydroxylase immunoreactive fibers suggests that sprouting occurs, this technique alone cannot adequately answer this question since the intensity of staining and thus the visibility of individual fibers are intimately linked to dopaminergic activity. However, by examining axons and their branches using markers that are independent of dopamine metabolism it is possible to determine whether dopaminergic sprouting does in fact take place. One month after using a Scouten wire knife to create a small lesion in the left striatum of normal C57/bl-6 mice, silver staining revealed an increase in the total number of neuronal fibers throughout the injured striatum. This was accompanied by intense staining of tyrosine hydroxylase-positive fibers around the wound and an increased density of striatal fibers labeled with dextran-biotin after injection of this neuronal tracer into the substantia nigra 1 month after striatal surgery and 5 days prior to sacrifice. The increase in tyrosine hydroxylase immunoreactivity confirms previous observations of increased dopaminergic activity after striatal injury. The increases in silver staining and dextran-biotin transport provide independent evidence that this increase in dopaminergic activity occurs because of sprouting of new fibers originating in the substantia nigra.

Animals↗

PubMed1999

Nitrergic stimulation of the locus coeruleus modulates blood pressure and heart rate in the anaesthetized rat.

To investigate whether nitric oxide is involved in the cardiovascular responses mediated via the locus coeruleus, the effects of microinjections of L-arginine and L-glutamate into the locus coeruleus on blood pressure and heart rate were investigated in sodium pentobarbitone-anaesthetized rats. Unilateral microinjection of L-arginine (25, 50 nmol) elicited dose-related depressor (-17 +/- 4, -25 +/- 4 mmHg) and bradycardic (13 +/- 3, 24 +/- 6 b.p.m.) effects. Furthermore, these effects were attenuated by prior local microinjection of N(G)-nitro-L-arginine (40 nmol). Peripheral muscarinic receptor blockade with atropine methyl nitrate (1 mg/kg, i.v.) attenuated the bradycardic but not the depressor responses to L-arginine. L-Glutamate (2 nmol) microinjections also mediated depressor (-27 +/- 6 mmHg) and bradycardic (53 +/- 23 b.p.m.) effects that were attenuated by microinjections of dizocilpine maleate (1 nmol) into the locus coeruleus. In addition, pretreatment with N(G)-nitro-L-arginine (40 nmol) also significantly attenuated the depressor response elicited by L-glutamate. These results suggest that nitrergic and glutamatergic pathways are operative within the locus coeruleus to modulate cardiovascular function, and also that a functional interaction may exist between the nitrergic and glutamatergic systems within the rat locus coeruleus.

Anesthesia, General↗

PubMed1998

Targeted expression of a toxin gene to D1 dopamine receptor neurons by cre-mediated site-specific recombination.

Idiopathic Parkinson's disease involves the loss of midbrain dopaminergic neurons, resulting in the presynaptic breakdown of dopaminergic transmission in the striatum. Huntington's disease and some neurodegenerative diseases with Parkinsonian features have postsynaptic defects caused by striatal cell death. Mice were generated in which an attenuated form of the diphtheria toxin gene (tox-176) was expressed exclusively in D1 dopamine receptor (D1R)-positive cells with the aim of determining the effect of this mutation on development of the basal ganglia and on the locomotor phenotype. Transgenic mice expressing Cre, a site-specific DNA recombinase, were crossed with a second line in which a transcriptionally silenced tox-176 gene was inserted into the D1R gene locus by homologous recombination. Young doubly transgenic mutant mice expressing the tox-176 gene displayed bradykinesia, dystonia, and had falls caused by myoclonic jerks. The mutant brain had evidence of apoptosis and reactive gliosis and, consistent with the D1R expression pattern, the striatum was reduced in volume, and the Islands of Calleja were absent. In contrast, the cortex was of normal thickness. D1Rs were not detectable in mutants by in situ hybridization or ligand autoradiography, whereas D2 dopamine receptor (D2R) mRNA and protein was present in the striatum. In addition, substance P and dynorphin, neuropeptides known to be expressed in D1R-positive striatonigral projection neurons were not detectable. Enkephalin, a marker found in D2-positive striatopallidal projection neurons was expressed in the mutant brain. The mutant represents a novel neurodegenerative disease model with a dramatic extrapyramidal phenotype.

Animals↗

PubMed1998

Regional distribution of low affinity kainate receptors in brain of Macaca fascicularis determined by autoradiography using [3H](2S,4R)-4-methylglutamate.

Binding of [3H](2S,4R)-4-methylglutamate, a novel low affinity kainate receptor agonist, was studied in brain sections of a Macaca fascicularis monkey. In cerebellar sections, [3H](2S,4R)-4-methylglutamate bound to a single population of sites (KD = 20 nM) and was inhibited by various glutamate receptor ligands: kainate > 6-cyano-7-nitroquinoxaline-2,3-dione > L-glutamate >> AMPA. (S)-5-lodowillardiine and (RS)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propanoic acid (ATPA), drugs selective for the GluR5 subunit, displaced 50% and 40% of binding, respectively. Autoradiography revealed topographic binding of [3H](2S,4R)-4-methylglutamate. Binding in cortex was highest in layer 5 and restricted to CA2/3 in hippocampus. Levels of binding were high in septum and hypothalamus. Moderate densities of binding were found in caudate-putamen, cerebellar granular layer, nucleus tractus solitarius, cuneate nucleus and area postrema. Binding in spinal cord was concentrated in dorsal horn. [3H](2S,4R)-4-Methylglutamate shows differential binding throughout primate brain and is a valuable new ligand for low affinity kainate receptors.

Animals↗

PubMed1998

Neuronal activity in the monkey ventrolateral thalamus following perturbations of voluntary wrist movements.

Extracellular single-cell recordings were made from the cerebellar thalamus (89 neurones) and the VPLc (53 neurones) of three conscious monkeys. The animals were trained to perform wrist movement paradigms including: (a) visually triggered skilled, voluntary movements; (b) 100-ms duration torque pulse perturbations applied during a hold period (termed Pa perturbations); (c) 100-ms perturbations that commenced 100 ms after the visual trigger but during preparation before a skilled, voluntary movement (termed Pb perturbations); and (d) 100-ms perturbations during the skilled, voluntary movement (termed Pm perturbations). These Pb and Pm perturbations were used to identify central and peripheral influences on patterns of neuronal discharge in the ventrolateral thalamus. There was no systematic difference between the responses to Pb and Pm perturbations of neurones in the cerebellar thalamus and those in VPLc. The responses of VPLc and cerebellar thalamic neurones to Pa perturbations were considered to represent transduction of peripheral afferent input, and these responses were compared with the responses to the other types of perturbations. Up to 40% of neurones in cerebellar thalamus and VPLc responded to Pb and Pm perturbations in a similar pattern to that which followed Pa perturbations, and therefore most likely represented faithful transduction of peripheral input. However, the response of over half the neurones in VPLc and cerebellar thalamus to Pb or Pm perturbations differed from Pa perturbations in a manner suggesting that central influences had gated the peripheral input. The short-latency response in cerebellar thalamus which was modified by central influences is appropriately timed to contribute to the "intended" response to perturbations of motor cortical neurones.

Afferent Pathways↗

PubMed1997

A comparison of methods used to detect changes in neuronal discharge patterns.

The discharge pattern of two thalamic neurones was recorded from a conscious monkey performing voluntary movements about the wrist joint. The neuronal discharge was displayed as a raster centred on movement of the wrist. The discharge patterns of both neurones was very strongly correlated with movement. Three experienced researchers were asked to examine the data and to classify every part of each trial as background discharge, 'on' (increased firing rate) or 'off' (decreased or zero firing rate) and to mark the times that neuronal discharge changed state. A 'standard output' was made from these classifications. A back-propagation artificial Neural Network (the Network) was used to model the standard output and cumulative sums (CUSUMs) and maximum likelihood was then performed on the data and compared with the Network. There was a high correlation between the output of each observer (r > 0.61) and the standard output and between the Network and the standard output (r > 0.99). However the correlation between standard output and CUSUMs (r = 0.06) and standard output and maximum likelihood (r = 0.36) was much lower. The Network could be trained with as few as 12 trials, indicating a high degree of constancy in the methods employed by the observers. The Network was also highly efficient at detecting changes in state of neuronal activity (r > 0.99). In summary, when used on single trial data, visual inspection is a reliable method for detecting timing of change neuronal discharge and is superior to CUSUM and maximum likelihood. As well it is capable of detecting neuronal discharge state: that is whether firing rate is increased, normal or decreased. Neural Networks promise to be a useful method of confirming the consistency of visual inspection as a means of detecting changes in neuronal discharge pattern.

Action Potentials↗

PubMed1996

On the distribution of cholecystokinin B receptors in monkey brain.

In view of recent evidence for a role for the B subtype of cholecystokinin (CCKB) receptor in panic and anxiety, the distribution of CCKB receptors in the forebrain of a Rhesus macaca monkey was examined by receptor autoradiography employing [125I]D-Tyr25(Nleu28,31)-CCK25-33S. CCKB receptors were widely and topographically distributed in cortex. Other structures with notable labelling included the basal ganglia, presubiculum, amygdala, mamillary bodies, cerebellar cortex and pineal gland. The distribution of CCKB receptors further supports roles for this peptide in behavioural processes.

Animals↗

PubMed1996

The relationship between monkey ventrolateral thalamic nucleus activity and kinematic parameters of wrist movement.

Extracellular recordings were made from single neurones in the cerebellar thalamus (75 neurones) and the VPLc (44 neurones) of four conscious moving monkeys. The experiment was designed to establish the discharge of ventrolateral thalamic neurones encodes information about kinematic parameters. The animals were trained to resist unexpected perturbations of the wrist and to perform skilled, voluntary wrist movements, producing stereotyped reflex and active movements with a wide range of durations and amplitudes. Statistical analysis of the discharge pattern associated with individual trials of movement was performed. In various maintained wrist positions there was a significant correlation (P < 0.05) between frequency of tonic discharge and joint position in 40% of the cerebellar thalamic neurones and in 54% of VPLc neurones. The phasic neuronal discharge associated with stereotyped movement often appeared "velocity-or acceleration-like'. However, statistical analyses revealed that the phasic discharge of only a small percentage of cerebellar thalamic and VPLc neurones was correlated with duration of movement, peak velocity or acceleration. The percentage of cerebellar thalamic neurones with discharge correlated to kinematic parameters was much greater when an unexpected change in the gain between joint angle and screen display led to errors in tracking the target. It is concluded that the cerebello-thalamo-cortical (CTC) pathway, carries information regarding maintained joint position but not velocity or acceleration of movement during a stereotyped task. However, the CTC pathway has a greater capacity to signal information about movement velocity and acceleration when there is a mismatch between the intended and actual movement.

Animals↗

PubMed1996

Leukemia inhibitory factor is a myotrophic and neurotrophic agent that enhances the reinnervation of muscle in the rat.

The effects of leukemia inhibitory factor (LIF) on muscle atrophy and the reinnervation of muscle were investigated. The rat medial gastrocnemius (MG) nerve was either cut (denervation groups), crushed (reinnervation group) or left intact (normal group). Muscles were injected with LIF in phosphate buffered saline (PBS) containing pluronic gel, the contralateral control muscles were injected with the vehicle alone. The muscles from the LIF-injected denervation groups were analysed for muscle fibre area; this was found to be significantly larger than controls. The greatest change was observed in the reinnervation group, where the muscle fibre area following LIF treatment was 53% (Type 1) and 84% (Type 2) greater. In addition, nerve fibre diameters were analysed in the reinnervation-treated group and these were also significantly larger. However, LIF injected into normally innervated muscle resulted in a decrease in muscle fibre area. These results show that LIF ameliorates denervation-induced muscle atrophy and improves regeneration of muscle and nerve.

Animals↗

PubMed1996

An electron microscopic tracer study of the projections from entopeduncular nucleus to the ventrolateral nucleus of the rat.

The entopeduncular (EP) nucleus is considered to be the major outflow nucleus of the basal ganglia (BG). The anterograde tracer dextran biotin was injected into EP to investigate its connections with the thalamus. Terminals from EP were found in the ipsilateral ventroanterior-ventrolateral (VAL) and ventromedial thalamic nuclei (VM), lateral habenular and centromedian-parafascicular complex. Electron microscopy of the terminals in VAL/VM revealed densely labelled small synapses that had prominent post-synaptic densities and round vesicles. Synapses were observed onto dendrites and dendritic spines but not onto other synapses or somas. No symmetrical synapses with pleomorphic vesicles were labelled. It is concluded that the synaptic contacts between EP and thalamus are Gray type 1. These findings have implications regarding current theories of BG pathophysiology.

Animals↗

PubMed1994

Projections from the lateral and interposed cerebellar nuclei to the thalamus of the rat: a light and electron microscopic study using single and double anterograde labelling.

The lateral and interposed cerebellar nuclei may have different functions in the control of movement. Efferent fibres from both nuclei project predominantly to areas of the thalamus, which in turn project to the motor cortex. In this study, single and double anterograde-tracing techniques have been used to examine and compare the pathways from the lateral and interposed nuclei to the thalamus in the rat by using both light and electron microscopy to look for evidence of organisational or structural features that may underlie the proposed functional differences between these nuclei. Terminals from the lateral nucleus were found to be located most medially in the thalamus, predominantly in the ventral lateral nucleus and the rostral pole of the posterior nuclear group. Terminals from the posterior interposed nucleus were located slightly rostral and lateral to those from the lateral nucleus, mainly around the border between the ventral lateral nucleus and the ventral posterior medial nucleus. Terminals from the anterior interposed nucleus were located slightly rostral and lateral to those from the posterior interposed nucleus, predominantly in the rostral pole of the ventral posterior lateral nucleus. Terminals from the lateral and interposed nuclei were also found in double anterograde-tracing experiments to be nonoverlapping in the regions between these main areas of termination. The structure of terminals from the lateral and interposed nuclei, however, as well as their synaptic relationship with thalamic neurones, were found to be similar. The terminals are large and form synapses with proximal dendrites of thalamic neurones. They contained round vesicles and formed multiple synaptic contacts with dendritic shafts, as well as dendritic spines. The findings indicate that information from the lateral and interposed nuclei is processed in separate regions of the thalamus but that the mode of synaptic transfer to thalamic neurones is likely to be similar for the two projections.

Animals↗

PubMed1993

Recovery of muscle after different periods of denervation and treatments.

Three aspects of reinnervation and recovery of skeletal muscle following various periods of denervation were investigated: (1) the effect of duration of denervation; (2) the effect of hyperthyroidism on recovery; and (3) whether the muscle or the nerve limits recovery. The rat medial gastrocnemius (MG) nerve was cut and then resutured after 0, 3, 7, 21, or 56 days. In a second group of animals, the MG muscle was denervated and, in addition, the animal received triiodothyronine (T3) supplementation during reinnervation. The third group of animals had the denervated MG muscle reinnervated by a larger number of newly transected foreign axons. The force produced by the reinnervated muscle depends on the period that the muscle was denervated. Recovery was impaired when the period of denervation exceeded 7 days. T3 treatment did not benefit the return of force production, nor did providing the muscle with a larger number of newly transected axons.

Animals↗

PubMed1992

Immunity to nerve growth factor and the effect on motor unit reinnervation in the rabbit.

The trophic effects of nerve growth factor (NGF) on sympathetic, peripheral afferent, and other neural crest-derived cells have been intensively investigated. More recently, NGF has been shown to have an influence on motoneurons. This study was undertaken to investigate whether NGF had any influence on the mechanical or histological properties of reinnervated motor units. Three groups of rabbits were used: normal rabbits, rabbits in which the nerve to medial gastrocnemius (MG) was cut and allowed to reinnervate for 56 days, and rabbits in which the MG nerve reinnervated in the presence of immunity to NGF. Immunity to NGF did not affect the ability of motor axons to reinnervate a muscle, nor were the contractile characteristics of the motor units altered. The size of horseradish peroxidase-labeled motoneurons was not influenced by immunization against NGF; however, the distribution of afferent neuron sizes was altered. Conduction velocity of motor axons proximal to the neuroma was significantly faster after immunization against NGF. Transection and subsequent reinnervation by a peripheral nerve normally causes an increase in myelin thickness proximal to the neuroma. However, immunization against NGF appeared to decrease the magnitude of myelin thickening. It was concluded that immunization against NGF affects motor axonal conduction velocity via an influence on the neural crest-derived Schwann cells.

Animals↗

PubMed1992

Developmental changes in hindlimb muscles and diaphragm of sheep.

In this study, plasma thyroxine, contractile and histochemical (adenosinetriphosphatase and NADH) characteristics of soleus (SOL), medial gastrocnemius (MG), and extensor digitorum longus (EDL) were examined in 140-day-gestation fetal sheep and in 2-, 5-, and 30-day-old lambs and adult ewes. Electrophoretic separation of myosin heavy chains was also done on all muscles and the diaphragm. There were no differences in the twitch contraction and relaxation times of MG and EDL at the different ages; in contrast SOL contraction times were significantly shorter in the fetus and newborn than in the adult. Fast glycolytic fibers first appeared in EDL, MG, and diaphragm at 5, 30, and 5 days after birth, respectively. The proportion of slow oxidative fibers decreased after birth and with postnatal development in EDL, whereas they increased in MG and diaphragm. Plasma thyroxine concentrations were higher in the fetus and day-old lambs than in 2-, 5-, and 30-day-old lambs or adult sheep. It is suggested that contractile specialization of the fast-twitch diaphragm, MG, and EDL is largely achieved in utero and is probably mediated by thyroid hormone. In contrast, SOL changed postnatally, probably influenced by the altered neural drive.

Aging↗

PubMed1991

Functional and structural changes of rat plantaris motoneurons following compensatory hypertrophy of the muscle.

The conduction velocity and histological structure of motoneurons innervating normal and hypertrophied rat plantaris muscles were investigated. Hypertrophy was produced by ablation of synergist muscles. Single motor units were obtained by ventral root dissection and conduction velocities measured. The structure of neurons was investigated following retrograde labeling with horseradish peroxidase. A combined silver, gold and cholinesterase staining method was developed to study the motor endplate. In addition, the peripheral nerve was fixed, embedded in Araldite, and sectioned for determination of axonal size and myelin thickness. Conduction velocity of motor axons decreased following hypertrophy of the skeletal muscle (control CV = 75.8 +/- 8.9 m s-1, n = 94, hypertrophy CV = 69.0 +/- 12.3 m s-1, n = 84). However, no alteration in the size of motor axons or myelin thickness could account for this alteration in conduction velocity. Mean motoneuronal soma size decreased following muscle hypertrophy (soma diameter: control 36.1 +/- 4.6 microns, n = 283, hypertrophy 32.9 +/- 4.5 microns, n = 294). The complexity of the motor endplate increased following hypertrophy with an increased occurrence of nodal sprouts. In addition, the area of cholinesterase staining increased following hypertrophy (control 588.1 +/- 297.2 microns 2, n = 269, hypertrophy 857.7 +/- 357.0 microns 2, n = 269). This study found that both the morphological and physiological parameters of motoneurons innervating a hypertrophied muscle were shifted toward those of normal rat slow motor units.

Adaptation, Physiological↗

PubMed1991

Effects of thyroidectomy on development of skeletal muscle in fetal sheep.

The influence of the thyroid gland on the functional and histochemical development of fast- and slow-twitch skeletal muscle of fetal sheep has been studied in euthyroid fetal sheep (n = 6) and athyroid fetuses (n = 4) surgically thyroid-ectomized at 70-75 days of gestation. Two fast-twitch muscles, the medial gastrocnemius and extensor digitorum longus, and the slow-twitch soleus muscle were studied at the fetal age of 140 days gestation. The athyroid fetuses had significantly slower twitch contraction and relaxation times in both the medial gastrocnemius and extensor digitorum longus muscles compared with the euthyroid fetuses. Twitch contraction and relaxation times of the soleus were not different in the two groups. Thyroidectomy resulted in an increase in the proportion of fast (type II) muscle fibers and myosin, as shown histochemically and by gel electrophoresis of heavy-chain myosins. These results indicate that the functional maturation of the fast-twitch muscles of sheep is influenced by the presence of an intact thyroid gland from at least 70 days of gestation. In contrast, the slow-twitch soleus muscle fiber diameter and twitch contraction and relaxation times were not different in the two groups.

Animals↗