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I J Mitchell

Publications and source records attributed to I J Mitchell.

53 records · Page 3Linked to original sources
PubMed1988

Responses resembling defensive behaviour produced by microinjection of glutamate into superior colliculus of rats.

Electrical stimulation of the superior colliculus in rats elicits not only orienting movements, as it does in other mammals, but also behaviours resembling such natural defensive responses as prolonged freezing, cringing, shying, and fast running and jumping. To investigate the location of the cells mediating these behaviours, the superior colliculus was systematically mapped with microinjections of sodium L-glutamate (50 mM, 200 nl), and the resultant behavioural changes as assessed in an open field were analysed for defence-like responses. The main regions that gave defensive behaviour were (i) rostromedial superior colliculus (all layers), and (ii) both medial and lateral parts of the caudal deep layers. Cells in these areas project into the ipsilateral descending pathway. However, the cells of origin of this pathway are also found in collicular regions, such as rostral intermediate gray and parts of far caudal colliculus, that did not give defensive movements in response to glutamate stimulation. It is unclear whether this is because only parts of the ipsilateral pathway mediate defensive behaviours, or because glutamate is a relatively inefficient stimulating agent for these systems. An unexpected feature of the results was that at a number of collicular sites the nature of the defensive response changed with successive (up to three) injections of glutamate, often appearing to become more intense. Whether the mechanism underlying this potentiation is related to the conditioning of natural defensive behaviour is unknown.

Animals↗
PubMed1988

Chorea and myoclonus in the monkey induced by gamma-aminobutyric acid antagonism in the lentiform complex. The site of drug action and a hypothesis for the neural mechanisms of chorea.

Experiments are described in which the gamma-aminobutyric acid (GABA) antagonist bicuculline was injected into the lentiform complex of conscious monkeys. Injections into either the lateral segment of the globus pallidus, or the medial part of the putamen, gave rise to chorea of the contralateral limbs and/or orofacial region. Control injections of vehicle alone were without effect. Injections of bicuculline into the lateral part of the putamen gave rise to contralateral myoclonus. The chorea produced by lateral pallidal or medial putaminal injections was virtually indistinguishable from the dyskinesia (chorea/ballism) which has been shown, in previous studies, to be induced by injection of GABA antagonists into the subthalamic nucleus. It is proposed that the primary site of action of the GABA antagonist in producing chorea, in the present studies, was the lateral segment of the globus pallidus. The mode of action is suggested to be interruption of GABAergic transmission from the striatum to the lateral pallidal segment. Since this also occurs in Huntington's disease, it is proposed that experimental chorea induced by this method in the monkey may be a useful model of the dyskinesia seen in Huntington's disease in man. Loss of influence of inhibitory striatopallidal fibres would lead to abnormally increased activity of lateral pallidal neurons. These in turn project to the subthalamic nucleus, upon which they have an inhibitory action. Dyskinesia is thus produced by physiological inhibition of the subthalamic nucleus, whose destruction, both in man and the monkey, is known to produce ballism. It is proposed that ballism and chorea share common neural mechanisms, both involving the loss of influence of the subthalamic nucleus on the medial segment of the globus pallidus.

Animals↗
PubMed1987

Further evidence for segregated output channels from superior colliculus in rat: ipsilateral tecto-pontine and tecto-cuneiform projections have different cells of origin.

Two of the targets of the ipsilateral descending pathway from the superior colliculus are the cuneiform area (immediately ventral to the inferior colliculus), and the dorsolateral basilar pons. The cells of origin of the projections to these targets in rat were studied with a retrograde double-labelling technique, using the fluorescent tracers True blue and Diamidino yellow. Although many tectal cells were single-labelled by injections into basilar pons or the cuneiform area, less than 5% were double-labelled. The two projections thus appear to arise mainly from separate populations of cells within the superior colliculus.

Animals↗
PubMed1987

Descending projections from the superior colliculus in rat: a study using orthograde transport of wheatgerm-agglutinin conjugated horseradish peroxidase.

Despite extensive behavioural work on the rat superior colliculus, its descending efferent pathways have not been fully characterised with modern anatomical tract-tracing techniques. To investigate these pathways, wheatgerm-agglutinin conjugated with horseradish peroxidase (1%) was injected at various locations within the superior colliculus of hooded rats. Label judged to be transported orthogradely was plotted on coronal sections modified from the atlas of Paxinos and Watson (1982). Two major descending pathways were identified. (i) The bulk of the fibres in the ipsilateral descending pathway leave the superior colliculus ventrolaterally, and course around the lateral margin of the midbrain reticular formation. Caudally, projecting fibres leave the main bundle to innervate the cuneiform nucleus, and parts of the pontomedullary reticular formation. Terminal fields associated with the major bundle of fibres are found in an area medial to the brachium of the inferior colliculus; the parabigeminal nucleus and adjacent tegmentum; the ventrolateral midbrain reticular formation; and the lateral pontine nuclei. (ii) The fibres of the main contralateral descending pathway leave the superior colliculus ventromedially, to cross midline in the dorsal tegmental decussation. They immediately turn caudally to join the predorsal bundle, in which they run the length of the brainstem to reach the cervical spinal cord. Major terminal fields occur in nucleus reticularis tegmenti pontis; the pedunculopontine/parabrachial area; paramedian pontomedullary reticular formation; and inferior olive. In addition there is lighter labelling in many areas of the pontomedullary reticular formation and in the cervical spinal cord. There was also a much sparser contralateral descending projection that crossed midline in the tectal commissure, and sent terminals to the contralateral cuneiform area and adjoining regions. These results suggest that the distribution of the descending efferent pathways from the superior colliculus in rats is similar to those described in other species. The fact that the two major pathways project to quite different terminal areas, together with previous findings that they have separate cells of origin within the tectum, suggests that they may also be functionally distinct.

Animals↗
PubMed1987

Levodopa-induced dyskinesia and response fluctuations in primates rendered parkinsonian with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).

Six non-human primates received doses of MPTP sufficient to produce a severe parkinsonian syndrome. Levodopa therapy reversed parkinsonian features in all animals, but resulted in dose-dependent choreoathetoid movements of the lower limbs of 3, together with akathisia and dystonia in 2. 'End-of-dose deterioration' was common to all animals, although 'on-off' periods were only seen in 3. Preliminary observations using a clinical rating scale and automatic activity counters demonstrate that both the motor response to levodopa and the complications of therapy are readily quantifiable. We suggest that this is a useful experimental model for testing new strategies in the management of idiopathic Parkinson's disease, particularly with regard to the prevention of drug-induced involuntary movements.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1987

Autoradiographic analysis of [3H]kainic acid binding in primate brain.

The distribution of [3H]kainic acid binding sites was studied in the primate brain using semiquantitative autoradiography. The highest levels of binding were observed in the hippocampal area CA3 and the dentate gyrus. The deep layers of pyriform, cingulate and insular cortex, the central nucleus of the amygdala and the caudate nucleus also displayed high levels of [3H]kainic acid binding. Although these areas receive putative excitatory amino acid-containing afferents, other regions containing a similar input displayed low levels of binding. Some similarities were apparent between the distribution of binding sites and pathological changes in human neurodegenerative disorders such as temporal lobe epilepsy.

Animals↗
PubMed1986

Neural mechanisms mediating 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine-induced parkinsonism in the monkey: relative contributions of the striatopallidal and striatonigral pathways as suggested by 2-deoxyglucose uptake.

The neural mechanisms which mediate parkinsonian symptoms have been investigated in the monkey by application of the 2-deoxyglucose (2-DG) metabolic mapping technique to animals rendered parkinsonian by systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The results show that 2-DG uptake was dramatically increased in the globus pallidus, but not the substantia nigra pars reticulata, in parkinsonian monkeys compared to controls. This observation has been interpreted as indicating increased synaptic activity in the putaminopallidal, but not the caudatonigral, pathway which suggests a relatively greater involvement of the putaminopallidal pathway in relation to the motor manifestations of parkinsonism.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1986

A semi-quantitative atlas of 5-hydroxytryptamine-1 receptors in the primate brain.

The regional distribution of 5-hydroxytryptamine-1 receptors in the primate brain was studied by semi-quantitative autoradiographic analysis of tritiated ligand binding. Areas showing the highest density of 5-hydroxytryptamine-1 receptors (greater than 200 fmol [3H]5-hydroxytryptamine bound per mg tissue), included the cerebral cortex (laminae I-II), claustrum, posterior cell group of the basal nucleus of Meynert, the infracommissural part of the globus pallidus, cortical amygdaloid nucleus, hippocampal formation (CA1-subiculum region, the anterior CA2, CA3 and CA4 regions and the molecular layer of the dentate gyrus), thalamic nuclei (parafascicular, parataenial, paraventricular and superior central lateral nuclei), substantia nigra pars reticulata, dorsal raphe nucleus and choroid plexus. The distribution of 5-hydroxytryptamine-1 receptors is compared to the distribution of both 5-hydroxytryptamine receptors and terminal fields of serotonergic projections as previously described in subprimates.

Amygdala↗
PubMed1986

N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in the monkey: neurochemical pathology and regional brain metabolism.

Systemic administration of the neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to macaque monkeys induced a profound parkinsonian state marked by hypokinesia/bradykinesia, rigidity and tremor. Postmortem studies revealed severe pathological changes in the substantia nigra, pars compacta and in the ventral tegmental area. The levels of dopamine and its major metabolites were reduced by about 90% in the neostriatum, including the nucleus accumbens, when compared to controls. In one animal, the locus coeruleus showed severe pathological changes in association with a reduction in forebrain noradrenaline. 2-deoxyglucose uptake studies suggested that in experimental parkinsonism there if a profound change in the activity of the striatopallidal pathway, but not necessarily in the striatonigral pathway.

Animals↗
PubMed1985

Sites of the neurotoxic action of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in the macaque monkey include the ventral tegmental area and the locus coeruleus.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces a profound parkinsonian state when systemically administered in monkeys and man. Previous studies have shown MPTP to be toxic to only the dopamine (DA) cells in the substantia nigra pars compacta and not to other catecholamine (CA)-containing cells. The data presented here suggest that MPTP also has a specific neurotoxic effect on the DA-containing cells of the ventral tegmental area and the noradrenaline-containing cells of the locus coeruleus in macaque monkeys with a moderate-to-severe parkinsonian syndrome. The results suggest that MPTP-induced parkinsonism in the monkey more closely replicates the neurochemical changes seen in idiopathic Parkinson's disease than previously thought.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1985

Common neural mechanisms in experimental chorea and hemiballismus in the monkey. Evidence from 2-deoxyglucose autoradiography.

The autoradiographic 2-deoxyglucose uptake technique was used to visualise local cerebral metabolic activity in the monkey in recently developed models of chorea and hemiballismus. Unilateral dyskinesia was induced by injection of a gamma-aminobutyric acid antagonist into the corpus striatum (in the case of chorea) or subthalamic nucleus (in the case of hemiballismus). Patterns of 2-deoxyglucose uptake suggest that during both forms of experimental dyskinesia the subthalamic nucleus and its projection to the globus pallidus are abnormally hypoactive.

Animals↗
PubMed1985

Regional brain uptake of 2-deoxyglucose in N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in the macaque monkey.

This preliminary report describes application of the 2-deoxyglucose (2DG) autoradiographic technique to study regional changes in brain metabolism in experimental parkinsonism, induced in the monkey by administration of the neurotoxin MPTP. In one monkey, rendered severely parkinsonian by MPTP, there was a marked increase in the uptake of 2DG in the globus pallidus (both medial and lateral segments) and in the ventral anterior and ventral lateral thalamic nuclei, in comparison to non-parkinsonian animals. Increased uptake of 2DG in the globus pallidus may reflect increased activity of striatopallidal synapses secondary to loss of nigrostriatal dopaminergic neurones. The findings are in sharp contrast to our observations on regional brain metabolism in experimental choreiform dyskinesia in the monkey.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1985

Subcortical changes in the regional uptake of [3H]-2-deoxyglucose in the brain of the monkey during experimental choreiform dyskinesia elicited by injection of a gamma-aminobutyric acid antagonist into the subthalamic nucleus.

Hemichorea/hemiballismus was induced in monkeys by localized injections of a gamma-aminobutyric acid antagonist into the contralateral subthalamic nucleus. During active dyskinesia, [3H]-2-deoxyglucose was administered and, subsequently, regional cerebral metabolic activity was examined by autoradiographic exposure of brain sections. The results indicate that during dyskinesia there was an overall decrease in local cerebral glucose utilization in a number of structures on the side of the brain contralateral to the abnormal movements (ipsilateral to the drug injection). These structures included the injected subthalamic nucleus, both medial and lateral segments of the globus pallidus, the substantia nigra, and the ventral anterior and ventral lateral nuclei of the thalamus. On the basis of evidence that changes in the energy requirement of neurons are due mainly to changes in synaptic activity, the autoradiographic findings are interpreted as indicating that during experimental hemichorea/hemiballismus there was an overall decrease in synaptic activity of subthalamopallidal, subthalamonigral and pallidothalamic pathways on the side of the brain contralateral to the dyskinesia. This interpretation is discussed in relation to current theories of the pathophysiology of choreiform dyskinesias.

Animals↗
PubMed1985

The organisation of the efferent projections of the zona incerta.

The hypothesis that the six cytoarchitectonically distinct subdivisions of the zona incerta send efferent projections to different parts of the brain was tested using retrograde fluorescent tracing techniques. Injections of tracer in the superior colliculus, pontomesencephalic tegmentum, thalamus or spinal cord resulted in characteristic and distinctive patterns of labelling in the zona incerta, suggesting that the different subdivisions of the zona incerta give rise to different sets of efferent projections. Thus, injections into the deep layers of the superior colliculus resulted in retrogradely labelled neurons predominantly in the zona incerta pars ventralis, whereas injections into the pontomesencephalic tegmentum, avoiding the superior colliculus, labelled neurons mostly in the zona incerta pars dorsalis. Parafascicular thalamic injections resulted in labelled neurons in the zona incerta pars rostropolaris, pars dorsalis, pars caudalis and a few in the pars ventralis. The spinal cord injections labelled predominantly the magnocellular cells of the zona incerta. The results of the double labelling experiment also give support to the conclusion that different areas of the zona incerta give rise to largely individual sets of efferent projections. Combined injections of tracers into the superior colliculus and thalamus resulted in the labelling of two essentially independent cell groups, the tectal projecting cells being found mainly in the zona incerta pars ventralis and the thalamic projecting cells being found in the zona incerta pars rostropolaris, pars dorsalis and pars caudalis. However, a small number of double labelled cells was found. These cells, which presumably send collateral projections to both the tectum and the thalamus, were found mainly in the dorsal part of the zona incerta pars ventralis, immediately next to the pars dorsalis. In the light of these findings it would appear that the zona incerta may be organised into largely distinct subdivisions, each of which has its own set of cytoarchitectonic and efferent projection characteristics.

Animals↗
PubMed1984

In defence of optical density ratios in 2-deoxyglucose autoradiography.

The use of optical density ratios to describe changes in [14C]2-deoxyglucose uptake in neuroanatomical mapping experiments has recently been criticized. It has been argued that a fixed ratio of tissue isotope concentration does not yield a constant optical density ratio but is dependent on the exposure time and the absolute amounts of isotope used. Here it is demonstrated that such variations in optical density ratios are due to an artifact in calculating the optical density ratio, which can easily be corrected provided that the film is not approaching saturation and not due to the non-linearity of an exposure-density curve as has previously been suggested.

Animals↗