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U Stenevi

Publications and source records attributed to U Stenevi.

At least 91 records · Page 5Linked to original sources
PubMed1982

Functional activity of substantia nigra grafts reinnervating the striatum: neurotransmitter metabolism and [14C]2-deoxy-D-glucose autoradiography.

Dopaminergic innervation of the caudate nucleus in adult rats can be partially restored by the grafting of embryonic substantia nigra into the overlying parietal cortex with concomitant compensation of certain behavioral abnormalities. In this study the function of such grafts was investigated neurochemically by quantification of transmitter metabolism and glucose utilization in the reinnervated target. Rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal bundle received a single graft to the dorsal caudate-putamen and were screened for rotational behavior following 5 mg/kg methamphetamine. The grafts restored dopamine concentrations in the caudate-putamen from initially less than 0.5% to an average of 13.6% of normal in rats with behavioral compensation. The ratio of 3,4-dihydroxyphenylacetic acid to dopamine, which is a measure of the rate of transmitter turnover, were equivalent in transplanted and normal control rats. Moreover, measurements of DOPA accumulation for a 30-min period after DOPA decarboxylase inhibition indicated similar fractional dopamine turnover rates in normal and transplant-reinnervated tissues. Correlations between rotational behavior and dopamine concentrations showed that reinnervation to only 3% of normal was sufficient to counterbalance the motor asymmetry. Measurements of glucose utilization by [14C]deoxyglucose autoradiography indicated equivalent metabolic rates for the grafted tissue and the intact substantia nigra. 6-Hydroxydopamine denervation of the caudate-putamen had no significant effect on neuronal metabolism in that region, nor did subsequent reinnervation from a graft. Grafts, however, were associated with a 16% reduction of glucose uptake in the ipsilateral globus pallidus, indicating a significant transsynaptic influence of the nigral transplants on neuronal metabolism in the host brain. Overall the results indicate that behaviorally functional neuronal grafts spontaneously metabolize dopamine and utilize glucose at rates characteristic of the intact nigrostriatal system. This provides further evidence that ectopic intracortical nigral transplants can reinstate dopaminergic neurotransmission in regions of the host brain initially denervated by the 6-hydroxydopamine lesion.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1981

Cerebral circulatory response to hypercapnia: effects of lesions of central dopaminergic and serotoninergic neuron systems.

The present study explores the possibility that the central dopaminergic and serotoninergic neuron systems influence CBF under normocapnic and hypercapnic conditions. In the first part of the study the effect of unilateral 6-hydroxydopamine lesion of the nigrostriatal dopamine pathway on local cerebral blood flow (1-CBF) was measured autoradiographically with [14C]iodoantipyrine as the diffusible tracer. The lesion caused no major effect on CBF under normocapnic or hypercapnic conditions. However, the circulatory response to hypercapnia was slightly enhanced (about 10%) in the denervated caudate-putamen. It is suggested that under hypercapnic conditions the pronounced increase in blood flow in the caudate-putamen is normally modulated by a slight vasoconstriction caused by dopamine release from the nigrostriatal system. In the second part of the study the effect of intraventricular 5,7-dihydroxytryptamine on cerebral metabolic rate for oxygen (CMRO2) and CBF was evaluated using a 133xenon modification of the Kety-Schmidt inert gas technique. The lesion, which removed about 90% of cortical 5-hydroxytryptamine, had no effect on the circulatory response to hypercapnia, not did it alter CMRO2. Under normocapnic conditions, though, the lesion seemed to induced a minor increase in CMRO2, which indicates that the serotoninergic system exerts a depressant resting tone on metabolic rate in the brain.

Animals↗
PubMed1981

In vivo evidence for a hippocampal adrenergic neuronotrophic factor specifically released on septal deafferentation.

Denervation of the hippocampal formation in adult rats through lesions of the septohippocampal pathway was found to induce a trophic growth response in intracortical grafts of sympathetic superior cervical ganglia, and to stimulate regeneration of the intrinsic locus coeruleus adrenergic neurons following chemically induced axotomy. The grafted sympathetic adrenergic neurons grew very poorly into the adjacent hippocampus in animals with the septohippocampal pathways intact. A lesion of the ipsilateral fimbria-fornix or of the medial septum-diagonal band area caused a massive stimulation of axonal growth from the transplanted ganglionic neurons into the denervated hippocampus. This increase was more than 100-fold by 1 month after lesion and about 10-fold by 3 months after lesion. Fluorescence histochemistry revealed that the lesion-induced ingrowth occurred primarily into those areas of the dentate gyrus and hippocampus which were denervated of their septal cholinergic afferents. In addition, the septal and fimbria-fornix lesions induced a marked increase in size and noradrenaline fluorescence of the grafted sympathetic neurons, without any clear-cut effects on the numbers of surviving neurons in the graft. This lesion-induced trophic growth response (increases in axonal outgrowth, cell body size and noradrenaline content) was specific for lesions of the septal (probably primarily cholinergic) innervation of the hippocampus. Thus, extensive denervations induced by lesions of the commissural or perforant path afferents, as well as selective lesions of the intrinsic adrenergic afferents from the locus coeruleus, had no clear-cut effects. The intrinsic central adrenergic neurons were also found to be responsive to the lesion-induced growth-stimulating mechanism. Thus, lesions of the fimbria-fornix or the medial septum-diagonal band area had a marked stimulatory effect on the regeneration of the locus coeruleus noradrenergic neurons after selective chemical axotomy (induced by 5,7-dihydroxytryptamine; 5,7-DHT). Thus, the adrenergic reinnervation of the initially denervated hippocampus was significantly accelerated by 3 weeks after the fimbria-fornix or septal lesions, and the increase persisted for at least 8-10 months after transplantation. These results provide evidence for an adrenergic neuronotrophic factor whose production in the hippocampus normally is under the control of non-adrenergic (probably cholinergic) afferents originating in the septal-diagonal band area. The actions of this putative factor on sympathetic adrenergic neurons resemble those induced by nerve growth factor (NGF). Interestingly, however, the results obtained after 5,7-DHT-induced axotomy indicate that central and peripheral adrenergic neurons are equally responsive, and thus that the putative central adrenergic neuronotrophic factor may play a normal physiological role in the regulation of axonal growth and regeneration within the central nervous system.

Adrenergic Fibers↗
PubMed1981

Behavioural recovery following transplantation of substantia nigra in rats subjected to 6-OHDA lesions of the nigrostriatal pathway. II. Bilateral lesions.

Rats with a unilateral transplant of embryonic substantia nigra, placed in a cortical cavity overlying the caudate-putamen, were compared with control animals on a range of behavioral tests following bilateral 6-OHDA lesions of the ascending dopaminergic nigrostriatal pathway. Tests designed to reveal behavioural asymmetry--such as spontaneous, tail-pinch and amphetamine-induced rotation, sensorimotor orientation, and side preference in a T-maze--revealed that the rats with bilateral 6-OHDA lesions and a unilateral transplant are similar to unilaterally lesioned animals with one intact nigrostriatal pathway. Both transplanted and bilaterally lesioned control rats became spontaneously akinetic after the second 6-OHDA lesion. This akinesia could be reversed by a low dose of amphetamine (0.5 mg/kg) in the transplanted but not in the non-transplanted control rats. The attenuated effects of apomorphine and L-DOPA on activity and rotation suggest that the nigral transplant produced a partial reversal of receptor supersensitivity following the 6-OHDA lesion on the same side as the transplant. However, other effects of the bilateral 6-OHDA lesion, including the development of aphagia, adipsia and akinesia, were not reversed by the presence of the transplant. The transplants were shown by fluorescence histochemistry to have densely reinnervated the dorsal parts of the denervated caudateputamen on the side ipsilateral to the transplant. The results show that intracortical nigral grafts reinnervating parts of the dorsal caudate-putamen can reverse some, but not all, functional impairments associated with bilateral destruction of the nigrostriatal pathway.

Animals↗
PubMed1981

Grafts of embryonic substantia nigra reinnervating the ventrolateral striatum ameliorate sensorimotor impairments and akinesia in rats with 6-OHDA lesions of the nigrostriatal pathway.

Previous studies have shown that transplants of embryonic substantia nigra, which reinnervate the dorsal neostriatum, can compensate for certain, but not all, behavioural deficits induced by unilateral or bilateral destruction of the nigrostriatal dopamine pathways in adult rats. The present study shows the nigral transplants which are placed in the lateral cortex so as to reinnervate ventral and lateral parts of the neostriatum, give an entirely different pattern of behavioural recovery. Thus, the laterally placed grafts were more efficient than the previous dorsally placed ones in compensating for the sensorimotor asymmetry in unilaterally lesioned animals, and the akinesia seen after bilateral lesions. Conversely, the drug-induced motor asymmetry which was completely abolished by the dorsal grafts was not significantly affected in the present animals. These results support the idea of topographic heterogeneity with respect to striatal functions, and suggest that the technique can be used as a tool for more detailed analysis of the functional organization of the meso-telencephalic dopamine systems and the functional heterogeneity of the dopaminergically innervated striatal-based forebrain regions.

Animals↗
PubMed1981

Reformation in adult rats of functional septo-hippocampal connections by septal neurons regenerating across an embryonic hippocampal tissue bridge.

Implants of embryonic hippocampus, placed into a cavity transecting the septo-hippocampal pathway in adult rats, have previously been shown to promote the regeneration of the lesional septo-hippocampal axons across the cavity. The present study provides electrophysiological evidence that these regenerating acetylcholinesterase-containing axons are able to re-establish atropine-sensitive excitatory synaptic connections in the grafted hippocampus as well as in the dorsal part of the initially denervated host hippocampus, thus demonstrating that intracerebral tissue implants can promote true, functional regeneration across a major tissue defect in the adult mammalian CNS.

Acetylcholinesterase↗
PubMed1981

Intracerebral grafting of dissociated CNS tissue suspensions: a new approach for neuronal transplantation to deep brain sites.

Suspensions of central nervous tissue, prepared by dissociation of selected embryonic brain regions, may be viably transplanted by intraparenchymal injection into a variety of sites in the depth of adult rat host brains. Such grafted neurons can mediate considerable reinnervation of a previously denervated brain region, and they can replace neurons intrinsic to a particular target, such as the caudate-putamen, previously damaged by the neurotoxin kainic acid. The present technique should open entirely new possibilities for experiments on neuronal reconstruction following brain lesions.

Animals↗
PubMed1981

Behavioural recovery following transplantation of substantia nigra in rats subjected to 6-OHDA lesions of the nigrostriatal pathway. I. Unilateral lesions.

The ability of embryonic substantia nigra transplants to compensate for behavioural deficits induced by unilateral destruction of the nigrostriatal dopamine pathway has been investigated in adult rats. Six days following unilateral 6-OHDA lesions of the nigrostriatal pathway, the adequacy of the lesion was assessed by measurement of the intensity of ipsilateral amphetamine-induced rotation. All rats then received surgical cavities in the cortex overlying the head of the caudate-putamen on the lesioned side. In 51 rats, transplants of embryonic substantia nigra were placed on the dorsal surface of the caudate-putamen, and the remaining 19 rats served as unilateral lesioned controls. Behavioural testing was conducted approximately 3 months after transplantation: (a) the transplant animals alone showed a marked reduction in ipsilateral rotation induced by 5 mg/kg amphetamine ('compensation'); (b) although both transplanted and control rats expressed equal contralateral rotation at a dose of 0.25 mg/kg apomorphine, the transplant animals alone showed a marked reduction in rotation at a lower dose of 0.05 mg/kg; (c) the transplanted rats showed less asymmetry in spontaneous rotational behaviour than controls, and the asymmetry was further reduced by mild tailpinch; (d) when tested for spontaneous choice behaviour in a T-maze, control rats showed 97% selection of the arm ipsilateral to the 6-OHDA lesion, whereas the transplanted rats that were well compensated on the amphetamine rotation test turned to the contralateral side on 30-40% of choices; (e) no transplant-induced changes were found in contralateral sensory inattention on a sensorimotor test battery, whether tested spontaneously or under mild tailpinch-induced activation. The results support the conclusion that dopaminergic reinnervation of the dorsal neostriatum is capable of inducing functional recovery in many, but not all, behavioural tests which involve side choice or bias, not only after pharmacological activation but also in the spontaneously behaving animal.

Amphetamine↗
PubMed1981

Effects of methamphetamine on blood flow in the caudate-putamen after lesions of the nigrostriatal dopaminergic bundle in the rat.

Methamphetamine was given to rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal dopaminergic bundle. In these animals local cerebral blood flow, measured autoradiographically with [14C]iodoantipyrine as the diffusible tracer, was more than twice as high in the denervated caudate-putamen as compared to control. Measurements of local glucose consumption with the [14C]deoxyglucose technique showed no corresponding change in local metabolic rate. In fact, glucose consumption was lower in the caudate-putamen on the lesion side. The results show that the amphetamine-induced increase in cerebral blood flow does not require an inact nigrostriatal dopaminergic system. Furthermore, dopamine released by amphetamine seems to constrict the vessels and reduce the blood flow in the caudate-putamen.

Animals↗
PubMed1981

Innervation of embryonic hippocampal implants by regene-rating axons of cholinergic septal neurons in the adult rat.

The regeneration of the septal cholinergic system in adult rats has been studied in animals bearing transplants of hippocampus taken from 20-40 mm rat fetuses (approximately 17-21 days of gestation). The septal axons located within the fimbria and the dorsal fornix were lesioned and a cavity was prepared at the rostral end of the hippocampus. The embryonic tissue was placed adjacent to the severed end of the fornix-fimbria. The time-course of ingrowth of cholinergic fibers into the transplant was monitored by acetylcholine esterase (AChE) histochemistry and the determination of the levels of choline acetyltransferase (ChAT). Both methods indicate that there is a progressive ingrowth into the transplant of cholinergic fibers up to 3 months after transplantation. The newly-formed AChE-positive fibers in the transplant remain beyond one year after transplantation and are thus presumably permanent. Both horseradish peroxidase (HRP) injections into the implant and radiofrequency lesions of the septal-diagonal band area indicate that the principal source of these fibers is the AChE-positive neurons of the medial septum and the nucleus of the diagonal band which normally form the septohippocampal cholinergic projection. The results suggest: (1) that implants of a normal embryonic target tissue can promote axonal regeneration in mature neurons of the mammalian central nervous system; (2) that some neurons in the adult mammalian CNS retain at least part of their embryonic capacity to generate axons and recognize specific postsynaptic targets in developing CNS tissue; and (3) that this host-implant interaction can result in the formation of quite specific innervation patterns in the implanted target tissue.

Acetylcholine↗
PubMed1981

Regeneration of the septohippocampal pathways in adult rats is promoted by utilizing embryonic hippocampal implants as bridges.

The ability of embryonic hippocampal tissue to promote regeneration of cholinergic axons in the septohippocampal system has been studied in adult rats. Strips of embryonic hippocampus, taken from 7-40 mm rat fetuses, were implanted into a 2-3 mm wide cavity which completely transected the septal cholinergic axons innervating the intrinsic hippocampus. The ingrowth of cholinergic fibres into the denervated host hippocampal formation was monitored by measuring the activity of the enzyme, choline acetyltransferase (ChAT), and by acetylcholine esterase (AChE) histochemistry. The results demonstrated a gradual, partial return of both ChAT enzyme activity and AChE-positive fibres in the initially denervated hippocampal formation of the adult recipient. Time-course studies indicated that this ingrowth progressed from the implant into the rostral tip of the host hippocampus, and continued caudally to cover the entire dorsal hippocampus by 3-6 months postoperative. Although the regenerating AChE-positive fibres reached the hippocampal target in the recipient along abnormal routes, they reinnervated selectively the appropriate terminal areas within the host hippocampus and dentate gyrus, suggesting the presence of quite specific mechanisms to guide the regenerating axons back to their original targets. Lesions of the medial septum-diagonal band area of the host and horseradish peroxidase (HRP) injections into the host hippocampus, caudal to the implant, indicated that the origin of the regenerating axons was predominately from the ipsilateral ventral medial septum and diagonal band area of the host. The results provide evidence that axonal regeneration and reinnervation of a denervated target zone can be promoted by utilizing implants of embryonic CNS tissue to bridge a tissue defect between the target and the lesioned axonal stumps.

Acetylcholinesterase↗
PubMed1981

Cerebral blood flow and oxygen consumption in the rat brain after lesions of the noradrenergic locus coeruleus system.

The effect of lesions of the locus coeruleus neuron system on cerebral metabolic rate for oxygen (CMRO2) and blood flow (CBF) was evaluated in paralyzed and mechanically ventilated rats, using a 133xenon modification of the Kety-Schmidt inert gas technique. Bilateral electrothermic lesions of its ascending bundle caused no significant change in CBF or CMRO2. The 6-hydroxydopamine lesions did not influence the CBF and CMRO2 responses to hypercapnia and hypoxia. It is concluded that the locus coeruleus does not exert any resting tone on CBF and CMRO2 and that no influence on the CBF and CMRO2 responses to hypercapnia and hypoxia is mediated via its ascending projections.

Animals↗
PubMed1981

Functional reactivation of the deafferented neostriatum by nigral transplants.

Functional deficits following brain lesions can be due not only to the disruption of conduction in specific input and output pathways passing through the site of injury, but also to the loss of important regulatory systems controlling the functional state of neuronal circuitries in areas distant from the lesion. For example, the behavioural disturbances that result from lesions of the nigrostriatal dopamine (DA) pathways can be reversed by administration of dopamine receptor-activating drugs, such as L-dopa or apomorphine. This suggests that the lesioned dopaminergic system, rather than conveying specific input and output signals, is normally acting on neuronal machineries whose activity levels are set by the activity at the dopaminergic synapses. Thus the neurological deficits resulting from these lesions are due to functional inactivation of otherwise intact neostriatal circuitries. Previous studies have shown that intracerebral transplants of embryonic substantia nigra can compensate for drug-induced as well as spontaneous asymmetric motor behaviour (expressed as a tendency to move in circles towards the lesioned side), whereas the sensorimotor asymmetry, which is pronounced in rats with a unilateral lesion of the nigrostriatal DA pathway, was unaffected by the transplant. We report here that restoration of striatal dopaminergic neurotransmission by nigral transplants in animals with bilateral, complete lesions of the nigral transplants in animals with bilateral, complete lesions of the nigrostriatal DA pathways can reinstate not only certain aspects of spontaneous motor behavior, but also sensorimotor orientation and sensory attention on the side of the body contralateral to the graft.

Animals↗
PubMed1980

Reinnervation of the denervated striatum by substantia nigra transplants: functional consequences as revealed by pharmacological and sensorimotor testing.

Embryonic substantia nigra (SN) was transplanted to the neostriatum in adult rats subjected to a unilateral or serial bilateral destruction of the nigrostriatal dopamine (DA) pathway. The survival of the graft and the growth of DA-containing fibers from the graft into the host brain was studied by fluorescence histochemistry and micro-fluorometry. The motor asymmetry, and the contralateral 'sensory neglect' induced by a unilateral destruction of the nigrostriatal DA pathway, were monitored in the transplanted rats and in non-transplanted controls through repeated measurements of the amphetamine-and apomorphine-induced rotational behaviour, and through analysis of the rats performance in a number of sensorimotor tests. Finally, the development of aphagia and adipsia after a serial bilateral destruction of both nigrostriatal DA pathways were followed in rats bearing bilateral SN transplants and in lesioned non-transplanted controls. The results show that large parts of the dorsal neostriatum can be reinnervated by DA-containing axons from the intracortical transplant and that this new DA input can fully compensate for the amphetamine-induced motor assymmetry that resulted from the initial destruction of the innate nigrostriatal DA pathway. The fluorescence microscopical observations provide strong evidence that the compensation of the amphetamine-induced rotational response was specifically related to the re-establishment of a new DA input to the denervated neostriatum, and that the degree of rotational compensation was well correlated to the magnitude of ingrowth into the neostriatum. Subsequent surgical removal of the SN transplant reinstated the initial rotational behaviour. In sharp contrast to the marked compensation in motor asymmetry, the transplanted rats showed no tendency to recover in their sensorimotor performance. Thus, while the sensorimotor deficit had recovered in the control group a marked contralateral 'sensory neglect' remained in the transplanted animals. Furthermore, removal of the transplant produced a significant improvement in their sensorimotor performance within 3 days. In the bilaterally transplanted animals the presence of the transplants did not prevent the development of severe adipsia, aphagia and akinesia following the destruction of the remaining contralateral nigrostriatal pathway. In fact, the recovery from the consummatory deficits tended to be better in the lesioned control rats than in the transplanted ones. It is concluded that SN transplants reinnervation the dorsal part of the neostriatum are able to replace the innate SN in normalizing some aspects of the rats motor behaviour, while their sensorimotor deficits and deficits in consummatory behaviour were unaffected. It is suggested that this dissociation of transplant-induced recovery is due to the failure of the SN transplants to reinnervate those parts of the neostriatum which are most directly implicated in sensorimotor and consummatory behaviour.

Animals↗
PubMed1980

Differentiation of embryonic hypothalamic transplants cultured on the choroidal pia in brains of adult rats.

Hypothalmic tissue from 16 to 18-day fetal rats was transplanted onto the choridal pia overlying the superior colliculus in adult female rats. After survival periods of 2 weeks to 19 months, brains containing transplants were processed for monoamine fluorescence histochemistry, immunohistochemistry for three neuropeptides (LHRH, somatostatin, neurophysin), or for autoradiography in ovariectomized hosts that received [3 H] estradiol. Most of the transplants survived and retained or increased in size; 14 of 25 transplants examined by fluorescence histochemistry were found to contain median eminence-like structures. In almost all of the transplants that were stained for neuropeptides, beaded processes and occasional cell bodies were observed. Although immunoreactive fibers were found near blood vessels, no palisade arrangement typical of the normal median eminence was evident. Each of the hypothalamic transplants on which steroid autoradiography was performed contained clusters of estrophilic neurons, the intensity of labeling of which was comparable to that seen in the host hypothalamus. These results indicate that many characteristic morphological and chemical features of the hypothalamus, which are not evident in the 16 to 18-day fetus, are elaborated in transplants during the survival period in the host. Transplantation of fetal hypothalamus to adult choridal pia thus appears to be a valuable approach for studying the factors, humoral or neural, that regulate the differentiation of this brain region.

Animals↗