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G W Arbuthnott

Publications and source records attributed to G W Arbuthnott.

At least 19 recordsLinked to original sources
PubMed2005

Evidence of a breakdown of corticostriatal connections in Parkinson's disease.

Dendritic spines are important structures which receive synaptic inputs in many regions of the CNS. The goal of this study was to test the hypothesis that numbers of dendritic spines are significantly reduced on spiny neurones in basal ganglia regions in Parkinson's disease as we had shown them to be in a rat model of the disease [Exp Brain Res 93 (1993) 17]. Postmortem tissue from the caudate and putamen of patients suffering from Parkinson's disease was compared with that from people of a similar age who had no neurological damage. The morphology of Golgi-impregnated projection neurones (medium-sized spiny neurones) was examined quantitatively. The numerical density of dendritic spines on dendrites was reduced by about 27% in both nuclei. The size of the dendritic trees of these neurones was also significantly reduced in the caudate nucleus from the brains of PD cases and their complexity was changed in both the caudate nucleus and the putamen. Dendritic spines receive crucial excitatory input from the cerebral cortex. Reduction in both the density of spines and the total length of the remaining dendrites is likely to have a grave impact on the ability of these neurones to function normally and may partly explain the symptoms of the disorder.

Aged↗
PubMed2004

Death of dopaminergic neurones in the rat substantia nigra can be induced by damage to globus pallidus.

Parkinson's disease is a debilitating disorder that results from the death of dopaminergic neurones in the substantia nigra. Subthalamic nucleus neurones use glutamate as their neurotransmitter and send excitatory projections to the substantia nigra. Changes in both the mean firing rate and firing pattern of neurones of the subthalamic nucleus have been found in patients with this disease. This has led to the suggestion that hyperactivity of the subthalamic nucleus may be involved in the pathology of the dopaminergic neurones. Subthalamic nucleus lesions or treatment with glutamatergic antagonists can be neuroprotective in animal models of Parkinson's disease but until now there has been no direct evidence that hyperactivity of subthalamic nucleus neurones can lead to downstream cell death. Here we show that lesions of the rat globus pallidus (a treatment that has been shown to increase subthalamic nucleus neuronal activity) result in a significant reduction of the number of dopaminergic neurones in the substantia nigra.

Animals↗
PubMed2001

Identification of the source of the bilateral projection system from cortex to somatosensory neostriatum and an exploration of its physiological actions.

Microinjections of cholera toxin B subunit were made into the area of the neostriatum that receives input from the primary somatosensory barrel cortex (SI) in the rat. Studies of the cortices then allowed retrograde identification of the cortical cells supplying the striatal input. When injections were restricted to the neostriatum, retrograde labelling was found in layer V of both SI cortices. Ipsilateral to the injection, cells were retrogradely filled with toxin in all parts of the barrel field, in adjacent parietal cortex, in the motor cortex and in prefrontal areas. A similar distribution across cortical areas was seen contralaterally; however, the stained cells in the SI were between rather than within barrel columns. An earlier anterograde study suggested two inputs from the SI to the neostriatum. The present results indicate that one input to the somatosensory area of the neostriatum arises bilaterally from neurons between the barrels of the SI, while the topographic pathway from below the barrels is present only ipsilaterally. These anatomical results indicate that separate stimulation of the two corticostriatal pathways from the barrel cortex is possible. Electrical stimulation of the contralateral cortex will activate the bilateral pathway, while electrical stimulation of the whisker pads activates the barrels and hence the topographic pathway. Neurons in the somatosensory region of the striatum responded to stimuli in the contralateral cortex and in the contralateral whisker pad. In spite of very different path lengths, stimuli via the two routes gave rise to excitatory postsynaptic potentials in the striatal cells with similar latencies. The excitatory postsynaptic potentials to whisker pad stimulation had a rapid rise time and usually resulted in at least one action potential. Responses to stimulation of the contralateral cortex rose to a peak more slowly and were more variable in latency, but also gave rise to an action potential in the majority of cases. All the neurons had the physiological characteristics of medium-sized densely spiny cells and after intracellular filling with biocytin had the appropriate morphology. In summary, we propose that two corticostriatal pathways arise from layer V cells in the barrel area of the somatosensory cortex; one is bilateral and arises from cells mainly below the septa, while a topographical pathway arises from cells below the barrels. Both pathways can raise the spiny output cells of the striatum to firing threshold. The latencies from the contralateral cortex imply slowly conducting fibres with considerably more temporal dispersion than the pathway from below the barrels, which we excited from the contralateral periphery.

Animals↗
PubMed2000

Corticofugal axons from adjacent 'barrel' columns of rat somatosensory cortex: cortical and thalamic terminal patterns.

The cortical representations of the vibrissae of the rat form a matrix in which each whisker has its own area of cortex, called a 'barrel'. The afferent pathways from the periphery travel first to the trigeminal nuclei and thence via the ventroposteromedial thalamus (VPM) to the cortical barrels have been described in detail. We have studied the output from barrels by filling adjacent areas of the primary somatosensory cortex (SI) with either Phaseolus vulgaris leucoagglutinin (PHA-L) or biotinylated dextran amine (BDA) and demonstrating the course and terminations of the axons that arise within the barrel fields. The method not only dramatically illustrates the previously described corticothalamic pathway to VPM but also demonstrates a strict topography in the cortical afferents to the thalamic reticular nucleus (RT). Cells supplying the RT projection are found below the barrels in layer IV. Connections to the posterior thalamus, on the other hand, have no discernible topography and are derived from cortical areas surrounding the barrels. Thus the outputs of these 'septal' areas return to the region from which they receive thalamic input. The corticocortical connections are also visible in the same material. Contralateral cortical connections arise from the cells of the septa between barrels. The projections to secondary somatosensory area (SII) are mirror images of the barrel pattern in SI with rather more overlap but nonetheless a recognisable topography.

Animals↗
PubMed2000

Dopamine and synaptic plasticity in the neostriatum.

After the unilateral destruction of the dopamine input to the neostriatum there are enduring changes in rat behaviour. These have been ascribed to the loss of dopamine and the animals are often referred to as 'hemiparkinsonian'. In the denervated neostriatum, we have shown that not only are the tyrosine hydroxylase positive boutons missing, but also the medium sized densely spiny output cells have fewer spines. Spines usually have asymmetric synapses on their heads. In a recent stereological study we were able to show that there is a loss of approximately 20% of asymmetric synapses in the lesioned neostriatum by 1 mo after the lesion. Current experiments are trying to establish the specificity of this loss. So far we have evidence suggesting that there is no obvious preferential loss of synapses from either D1 or D2 receptor immunostained dendrites in the neostriatum with damaged dopamine innervation. These experiments suggest that dopamine is somehow necessary for the maintenance of corticostriatal synapses in the neostriatum. In a different series of experiments slices of cortex and neostriatum were maintained in vitro in such a way as to preserve at least some of the corticostriatal connections. In this preparation we have been able to show that cortical stimulation results in robust excitatory postsynaptic potentials (EPSPs) recorded from inside striatal neurons. Using stimulation protocols derived from the experiments on hippocampal synaptic plasticity we have shown that the usual consequence of trains of high frequency stimulation of the cortex is the depression of the size of EPSPs in the striatal cell. In agreement with similar experiments by others, the effect seems to be influenced by NMDA receptors since the unblocking of these receptors with low Mg++ concentrations in the perfusate uncovers a potentiation of the EPSPs after trains of stimulation. Dopamine applied in the perfusion fluid round the slices has no effect but pulsatile application of dopamine, close to the striatal cell being recorded from, and in temporal association with the cortical trains, leads to a similar LTP like effect. The reduction of K+ channel conductance in the bath with TEA also has the effect of making cortical trains induce potentiation of corticostriatal transmission. TEA applied only to the cell being recorded from has no similar effect; the cortical stimulation again depresses the EPSP amplitude, so the site of action of TEA may well be presynaptic to the striatal cell. The morphological and physiological experiments may not necessarily be related but it is tempting to suggest that dopamine protects some corticostriatal synapses by potentiating them but that in the absence of dopamine others simply disconnect and are no longer detectable on electron microscopy.

Animals↗
PubMed1999

Double anterograde tracing of outputs from adjacent "barrel columns" of rat somatosensory cortex. Neostriatal projection patterns and terminal ultrastructure.

The sensory input to the neostriatum from groups of cortical cells related to individual facial vibrissae has been investigated at both light- and electron-microscopic resolution. The purpose of the study was to establish the extent to which corticostriatal input maintains the anatomical coding of spatial information that is present in cortex. A double anterograde tracing method was used to identify the output projections from groups of adjacent neurons in different barrel columns, so that the anatomical relationships between two groups could be studied throughout their length. Adjacent whiskers are represented in adjoining cortical barrels and an examination of corticostriatal projections from these reveals two patterns of projection. In one, the anatomical topography is partially preserved; the barrels are represented in adjoining, discrete, areas of the somatosensory neostriatum. In the second projection pattern, the neostriatal innervation is diffuse and adjacent barrels are represented in overlapping regions of the neostriatum. Moreover, the fibres are thinner, have smaller boutons, and are present in both the ipsilateral and contralateral neostriatum. The two systems also enter the neostriatal neuropile separately. The discrete topographic system enters the adjacent neostriatum as collaterals which leave the descending corticofugal fibres at right angles, while the diffuse system enters directly from the corpus callosum at an acute angle. Examination of the neostriatal terminal fields by correlated light and electron microscopy, shows that characteristic axospinous terminals on spiny neurons are made by both groups of cortical fibres, although they differ in their size and morphology. It is concluded that at least two corticostriatal pathways arise from the barrel cortex. One connection maintains some of the anatomical code implicit in the barrel pattern of primary somatosensory cortex, but another, more diffuse, system is overlaid upon it which may carry different information from this complex area of cortex.

3,3'-Diaminobenzidine↗
PubMed1998

Plasticity of synapses in the rat neostriatum after unilateral lesion of the nigrostriatal dopaminergic pathway.

In the 6-hydroxydopamine model of Parkinson's disease in the rat, there is a significant reduction in the number of dendritic spines on the principal projection neurons in the neostriatum, presumably attributable to loss of the nigrostriatal dopamine input. These spines invariably receive input from terminals forming asymmetric synapses that originate mainly from the cortex. The object of the present study was to determine the fate of those terminals after the loss of dendritic spines. Unbiased estimates of synaptic density and absolute numbers of synapses in a defined volume of the neostriatum were made using the "disector" and Cavalieri techniques. Numerical synaptic density of asymmetric synaptic contacts was 17% lower in the neostriatum deprived of dopamine innervation and, in absolute terms, there were 3 billion (19%) fewer contacts. The numerical density of a subpopulation of asymmetric contacts on dendritic spines that have complex or perforated synaptic specializations and normally make up 9% of the asymmetric population was 44% higher on the experimental side. Asymmetric synapses were found to be enriched in glutamate using postembedding immunogold labeling. The present observations demonstrate that the loss of spines previously reported after 6-hydroxydopamine lesions is accompanied by a loss of asymmetric synapses rather than by the movement of synapses from spines to other postsynaptic targets. The study also demonstrates that there is an increase in complex synaptic interactions that have been implicated in synaptic plasticity in other regions of the CNS after experimental manipulations.

Animals↗
PubMed1997

Plasticity of striatopallidal terminals following unilateral lesion of the dopaminergic nigrostriatal pathway: a morphological study.

In Parkinson's disease the dopaminergic nigrostriatal pathway degenerates, resulting in an imbalance in activity of two pathways of information flow through the basal ganglia. In animal models of the disease, the striatonigral pathway becomes underactive and the striatopallidal pathway becomes overactive. In the present study immunocytochemistry for enkephalin and GABA and anterograde labelling were used to investigate whether morphological plasticity occurs in striatopallidal terminals following unilateral removal of the nigrostriatal dopaminergic pathway. Pallidal terminals were immunostained to reveal enkephalin and examined in the electron microscope (n=399). Immunoreactive synaptic bouton profiles were on average 64% larger on the experimental side 26 days after the lesion. Analysis of their shape revealed that those on the dopamine-depleted side of the brain were more irregular in profile and that their synaptic specialisations were more complex in shape but not significantly different in length. Striatopallidal terminals were also identified by GABA immunocytochemistry combined with anterograde labelling (n=20). Double-labelled boutons were significantly larger in cross-sectional area on the experimental side (57%). Analysis of terminals that were simply labelled by the immunogold method to reveal GABA (n=278) showed no significant differences in size between terminals from the dopamine-depleted and control side. This suggests that a substantial number of GABAergic terminals in the globus pallidus do not belong to the striatopallidal population of terminals. These morphological changes correlate with previous studies suggesting striatopallidal boutons are more active after destruction of dopaminergic input to the neostriatum.

Animals↗
PubMed1996

Dopamine reverses the depression of rat corticostriatal synapses which normally follows high-frequency stimulation of cortex in vitro.

Learning deficits resulting from dopamine depletion suggest that striatal dopamine release is crucial for reinforcement. Recently described firing patterns of dopamine neurons in behaving monkeys show that transient increases in dopamine release are brought about by reinforcement. We describe an enduring change in the strength of synaptic transmission following pulsatile application of dopamine intended to mimic the transient increases associated with reinforcement. Intracellular records were made from neurons in slices of the rat corticostriatal system. Neurons having the properties of the medium-sized spiny neurons responded to cortical stimulation with depolarizing potentials (peak amplitude 12.0 +/- 1.3 mV; latency 9.2 +/- 0.1 ms; mean +/- S.D., n = 19), which had the properties of monosynaptic excitatory postsynaptic potentials. After trains of stimuli to the cortex had been applied in conjunction with intracellular depolarizing current, the size of these excitatory postsynaptic potentials was reduced (-27% at 20 min). Application of dopamine (approximately 30 microM) in a solution containing KCl concomitant with depolarization and presynaptic activation increased the subsequent excitatory postsynaptic potentials (+21% at 20 min) without significant lasting change in the membrane properties of the postsynaptic cell. This suggests that dopamine has an enduring, activity-dependent action on the efficacy of corticostriatal transmission, which may be a cellular basis for the learning-related effects of the nigrostriatal system.

Animals↗
PubMed1996

Morphological changes in met(5)-enkephalin-immunoreactive synaptic boutons in the rat neostriatum after haloperidol decanoate treatment.

The morphological plasticity of an identified population of synaptic boutons in the rat neostriatum was investigated 24 h (short-term treatment) or 14 days (long-term treatment) after administration of the depot neuroleptic, haloperidol decanoate. Specific methionine(5)-enkephalin antiserum was used to label bouton profiles in the dorsal neostriatum. The size and shape of these boutons was subsequently analysed with quantitative methods at the ultrastructural level. Immunoreactive synaptic bouton profiles were found to have a larger cross-sectional area, to be less circular in shape and to have a longer maximum diameter after long-term neuroleptic treatment. These parameters were not significantly affected by short-term neuroleptic treatment. The morphological parameters indicate that methionine(5)-enkephalin-immunoreactive boutons become enlarged, probably by elongating. This suggests that boutons containing methionine(5)-enkephalin increase their potential synaptic efficacy in the long term after neuroleptic treatment.

Animals↗
PubMed1995

In vivo detection of immunoreactive neurokinin A release within rat substantia nigra and its dependency on a dopaminergic input.

In the striatum, the tachykinin peptide neurokinin A (NKA) is thought to coexist with substance P in the gamma-aminobutyric acid-containing spiny neurones which project to the substantia nigra. We have used in vivo antibody-coated microprobes to directly monitor the release of NKA-like immunoreactivity (NKA-LI) within substantia nigra during various pharmacological manipulations. The data clearly illustrates a basal or resting extracellular presence of NKA-LI restricted to substantia nigra reticulata which was found to be largely dependent on a dopaminergic input. Acute administration of haloperidol (0.1-0.2 mg/kg i.p.) considerably reduced this basal NKA-LI whereas depot administration (14 mg/kg i.m. released over 2 weeks) produced a less substantial reduction. Lesion of nigro-striatal dopamine neurones with the neurotoxic agent 6-hydroxydopamine produced significant reductions in the nigral NKA-LI detected. However, d-amphetamine administration (4 mg/kg i.p.) did not alter the pattern of NKA-LI release for up to 4 h posttreatment. These results indicate that changes in peptide mRNA levels do not necessarily reflect changes in peptide release and suggest that NKA may be the more physiologically relevant tachykinin within the substantia nigra of the rat.

Amphetamine↗
PubMed1995

Identified cholinergic neurones in the adult rat brain are enriched in GAP-43 mRNA: a double in situ hybridisation study.

The cellular expression of growth associated protein-43 mRNA by identified choline acetyl transferase mRNA positive cells was investigated in the mature rat brain using a combined radioactive and non-radioactive in situ hybridisation technique. Cellular sites of growth associated protein-43 mRNA were detected using a 35S-oligonucleotide while choline acetyl transferase mRNA positive neurones were identified using two alkaline phosphatase-labelled probes. In the cholinergic cells of the corpus striatum, basal forebrain and laterodorsal tegmental nucleus a specific growth associated protein-43 hybridisation signal (silver grains) was detected, demonstrating that these choline acetyl transferase mRNA positive cells are enriched in growth associated protein-43 gene transcripts. By contrast, the large cholinergic cells of the motor nucleus of the trigeminal nerve did not express growth associated protein-43 mRNA. Quantification of the growth associated protein-43 hybridisation signal expressed by identified choline acetyl transferase mRNA positive cells showed regional variations in the relative cellular abundance of this transcript; cholinergic cells in the laterodorsal tegmental nucleus and corpus striatum expressed the strongest cellular hybridisation signal. Mean cross-sectional somatic area measurements of these growth associated protein-43/cholinergic positive cells confirmed the identity of these neurones as belonging to the cholinergic phenotype. A strong 35S-growth associated protein-43 hybridisation signal was detected also in numerous other non-choline acetyl transferase mRNA positive nerve cells in other regions of the brain, although the chemical phenotypes of these neurones were not determined. Our data reveal that expression of the growth-associated protein GAP-43 is maintained in identified cholinergic neurones in the postnatal rat brain, suggesting that this protein may subserve important functions in cholinergic and other neurones of the adult mammalian brain.

Animals↗
PubMed1995

Inhibition of neuronal nitric oxide synthase by 7-nitroindazole: effects upon local cerebral blood flow and glucose use in the rat.

The novel nitric oxide synthase inhibitor 7-nitroindazole (7-NI) is relatively specific for the neuronal isoform of the enzyme and in this study we have used this compound to investigate the physiological role of perivascular nitric oxide-containing nerves in the cerebrovascular bed. Following injection of 7-NI (25 or 50 mg/kg, i.p.), cerebral blood flow and glucose utilization were measured in the conscious rat using the fully quantitative [14C]iodoantipyrine and 2-[14C]deoxyglucose techniques, respectively. Neither dose of the drug produced any change in arterial blood pressure, confirming a lack of effect upon the endothelial isoform of the enzyme, although there was a pronounced decrease in heart rate (-28% by 10 min postinjection). Throughout the brain 25 mg/kg 7-NI i.p. resulted in decreases in blood flow of between -20% in the hippocampus and -58% in the substantia nigra. Increasing the dose to 50 mg/kg resulted in a further generalized decrease, to almost -60% in parts of the thalamus and hippocampus, but in every animal this higher dose of 7-NI also produced randomly distributed areas of relative hyperaemia, which were most commonly found in those areas where the most intense hypoperfusion was otherwise in evidence. Despite these changes in blood flow, in all but a very few areas of the brain no significant decrease in glucose use was measured at either of the two doses of 7-NI. Thus despite the greater specificity of 7-NI for neuronal nitric oxide synthase, the cerebrovascular effects of the drug in vivo are very similar to that reported for the arginine analogues. However, these data do suggest that nitric oxide-releasing neurones in the brain may have an important role to play in the regulation of cerebral blood flow.

Amino Acid Oxidoreductases↗
PubMed1994

Cerebrovascular autoregulation in response to hypertension induced by NG-nitro-L-arginine methyl ester.

Local neocortical blood flow and glucose utilization were measured in conscious rats using [14C]iodoantipyrine and [14C]2-deoxyglucose quantitative autoradiography, respectively, following intravenous injection of the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (30 mg/kg). The dose of NG-nitro-L-arginine methyl ester was chosen so as to produce a level of hypertension equivalent to that produced in a parallel group of rats by the infusion of angiotensin-II (5 micrograms/ml at 0.5-2.0 ml/h). In those animals in which angiotensin-induced hypertension did not exceed 150 mmHg (mean arterial blood pressure), there were no significant effects upon cortical blood flow when compared to controls, but at higher pressures (157 +/- 1 mmHg), blood flow was significantly increased in circumscribed areas of cortex, most notably in parietal (from 204 +/- 10 to 780 +/- 44 ml/100 g per min) and occipital cortex (from 175 +/- 5 to 600 +/- 46 ml/100 g per min), whilst other cortical areas (e.g. temporal and frontal areas) were unchanged. Despite the fact that NG-nitro-L-arginine methyl ester increased blood pressure to levels (164 +/- 1 mmHg) which were in excess of the highest produced by angiotensin, there was no evidence of focal hyperaemia; indeed blood flow was significantly reduced in every cortical region except parietal area 1. No significant differences in glucose use were evident between any of the groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1993

Dendritic domains of medium spiny neurons in the primate striatum: relationships to striosomal borders.

Medium spiny neurons are the projection neurons of the striatum. They receive the majority of striatal afferents, and they make up the vast majority of all neurons in the striatum. These densely spiny cells thus constitute a major substrate for input-output processing in the striatum. In the experiments described here we analyzed the dendritic fields of spiny neurons in the squirrel monkey striatum and plotted their orientations with respect to the borders between striosomes and matrix. Medium-sized spiny neurons in the caudate nucleus were filled intracellularly in a fixed-slice preparation with the fluorescent dye Lucifer Yellow. Dendritic arbors were reconstructed following immunostaining of the injected neurons with antiserum to Lucifer Yellow and counterstaining for striosome/matrix compartments. A majority of the medium spiny neurons studied had dendritic arborizations that remained within their compartment of origin. Thus the striosome/matrix subdivision not only partitions neurotransmitter molecules and extrinsic striatal connections into two domains in the primate caudate nucleus, but also constrains the dendritic arbors of many projection neurons there. Other medium spiny neurons, however, in both striosomes and matrix, had dendrites that crossed from one compartment into the other. About a quarter of the spiny neurons reconstructed had at least one such crossing dendrite. These results suggest that compartmentalization of afferent and efferent processing by projection neurons in the primate striatum is not absolute. For a subpopulation of spiny neurons in striosomes and matrix, inputs to one compartment could have a direct influence on output cells of the other.

Animals↗