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O Isacson

Publications and source records attributed to O Isacson.

At least 127 records · Page 7Linked to original sources
PubMed1988

Intracerebral neuronal grafting in experimental animal models of age-related motor dysfunction.

The combined morphological, biochemical, electrophysiological, and behavioral data summarized above show that implanted embryonic nerve cells in some cases can substitute quite well for a lost intrinsic neuronal system in mammals. The intracerebral implants probably exert their effects in several ways. The functional effects seen with grafts placed into one of the cerebral ventricles (such as those described in the studies of Perlow et al., Freed et al., and Gash et al.) are thus probably explained on the basis of a diffuse release of an active amine or peptide into the host CSF and adjacent brain tissue. In other instances, as in animals with DA-rich grafts reinnervating the neostriatum, we believe that the available data provide quite substantial evidence that the behavioral recovery is caused by the ability of the grafted neurons to reinnervate relevant parts of the host brain. This is illustrated by the studies mentioned above that show that the degree of functional recovery in 6-OHDA-lesioned rats with nigral transplants is directly correlated with the extent of striatal DA reinnervation and that the "profile" of functional recovery is dependent on that area of the striatal complex that is reinnervated by the graft. This point is particularly well illustrated in a further study in which rats with electrodes implanted into the center of intracortical nigral grafts were allowed to "self-stimulate" via the graft. The results show that the graft can indeed sustain self-stimulation behavior and that the rate of lever-pressing is related to the proximity between the electrode tip and the DA-containing neurons in the graft. This strongly supports the notion that the implanted DA neurons can transmit behaviorally meaningful and temporally organized information to the host brain via their efferent connections. To what extent the intracerebral implants can be functionally integrated with the host brain is still poorly known, though, and it therefore remains an interesting question for further investigation. The chances for extensive integration may be greatest for neuronal suspension grafts implanted as deposits directly into the depth of the brain, but even solid grafts inserted as whole pieces into the brain have, in several cases, been seen to become reinnervated from the host brain in adult and developing recipients. Nevertheless, a recent HRP study failed to detect any host afferents to intracortical solid nigral grafts, despite the fact that these grafts had themselves formed extensive DA connections in the host striatum and had produced behavioral recovery.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗
PubMed1987

Astroglial response in the excitotoxically lesioned neostriatum and its projection areas in the rat.

The anatomical distribution of the astrocytic glial reactions, following ibotenic acid-induced neuronal degeneration of the neostriatum in the rat, has been studied immunohistochemically using an antibody directed against the astrocytic marker, glial fibrillary acidic protein. The acute astroglial response to the excitotoxic lesion, determined 7 days post lesion, was compared with a sham-operated group and a chronic group that had received the excitotoxic lesion 6 months prior to histological evaluation. Total doses of 16-20 micrograms ibotenic acid injected unilaterally into the head of the neostriatum caused not only a marked neuronal cell loss but was also accompanied by a large increase in the number and size (about 5 times) of glial fibrillary acidic protein-stained astrocytes throughout the neostriatum by 7 days after lesion. Reactive astrocytes were also observed in the major neostriatal projection areas, the globus pallidus and the substantia nigra pars reticulata, at 7 days post lesion, although no neuronal cell loss could be detected in these regions using regular Cresyl Violet staining. Previous studies of lesions identical to the ones used here have shown that globus pallidus and substantia nigra are deafferented as a result of the neostriatal neuronal degeneration. The reactive astrocytes in the striatal projection areas had a 3-5 times larger size than control astrocytes from the same anatomical region. In animals that received a larger dose of ibotenic acid into the neostriatum (25 micrograms), neuronal cell loss was also observed in the neocortex and reactive glial fibrillary acidic-stained astrocytes were found in the entire neocortex of the injected hemisphere. In the chronic group, 6 months after the excitotoxic lesion, the astroglial response was clearly diminished or absent in the major neostriatal projection areas, but was still present within the lesioned neostriatum. The results suggest that focal neuronal destruction can result in widespread astrocytic glial reactions which follow the anatomical connectivity of the lesioned area. This may have implications for the understanding of the multifocal distribution of glial reactions seen in patients with striatal degeneration as a result of Huntington's disease.

Animals↗
PubMed1987

Neural grafting in a rat model of Huntington's disease: striosomal-like organization of striatal grafts as revealed by acetylcholinesterase histochemistry, immunocytochemistry and receptor autoradiography.

Grafts of fetal striatum were implanted in the form of a cell suspension into the brains of rats with prior ibotenic acid lesions of the caudate-putamen. The grafts were placed in three different sites: the lesioned caudate-putamen, or the denervated (but otherwise undamaged) globus pallidus and substantia nigra. After 3-6 months survival the grafts were investigated by means of immunohistochemistry and receptor autoradiography in combination with routine histology and acetylcholinesterase histochemistry. The grafts placed within the lesioned caudate-putamen were at least 10-fold larger larger than those placed in the substantia nigra region, with the grafts placed in the globus pallidus being of intermediate size. In all locations the acetylcholinesterase staining had an uneven, patchy distribution, which was most pronounced in the grafts located within the caudate-putamen. These patches did not bear any obvious relationship to variations in density of the neuronal perikarya within the grafted tissue. Many of the neuropeptide-immunoreactive neuron types present in the normal striatum, such as those containing substance P, [Met]enkephalin, somatostatin, cholecystokinin and neuropeptide Y were also detected in the grafted striatum along with acetylcholinesterase-positive staining. Acetylcholinesterase-positive, [Met]enkephalin-positive, substance P-positive and tyrosine hydroxylase-positive markers all showed uneven, patchy distributions in the grafts. This was also the case for the distribution of dopamine D2 and opiate receptors (as revealed by [3H]spiroperidol and [3H]diprenorphine autoradiography, respectively), whereas muscarinic receptor binding was even throughout the grafts. As is the case in the so-called striosomal patches (neurochemically defined compartments) in the immature intact striatum during the early postnatal period, patches of high acetylcholinesterase staining in the grafts showed partial correspondence with patches of high [Met]enkephalin fibre staining, and dopamine receptor density, and (although to a lesser degree) also with patches of high opiate receptor density and high substance P-immunoreactivity. This correspondence of patches also occurred between tyrosine hydroxylase fibre staining and acetylcholinesterase staining as revealed by grafts placed into the substantia nigra. These results suggest that the fetal striatal cell suspension grafts will give rise to a fairly normal range of striatal neuron and receptor types and that they develop at least some of the striosomal features characteristic for the normal striatum.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetylcholinesterase↗
PubMed1986

Cortical grafts prevent atrophy of cholinergic basal nucleus neurons induced by excitotoxic cortical damage.

Damage to the neocortex, here induced by the excitotoxin kainic acid in the rat, is known to induce cell shrinkage, without actual loss of cells, in the part of the cholinergic basal nucleus projecting to the damaged area. Fetal cortical tissue, implanted into the neuron-depleted cortex in the form of a dissociated cell suspension, completely prevented this degenerative change of the basal nucleus cholinergic neurons. Choline acetyltransferase biochemistry and acetylcholinesterase fiber staining of the transplants indicated a substantial ingrowth from the cholinergic host neurones into the graft. It is proposed that the basal forebrain cholinergic neurons normally receive a trophic influence from their target areas and that grafted neocortex can substitute for the loss of such trophic influence in cortex-damaged animals.

Alzheimer Disease↗
PubMed1986

Effects of dopamine-rich grafts on conditioned rotation in rats with unilateral 6-hydroxydopamine lesions.

To assess the capacity of dopamine-rich grafts to ameliorate conditioned behavioural deficits induced by dopamine depleting lesions, rats with unilateral 6-hydroxydopamine lesions and intrastriatal grafts were compared with rats with lesions alone and with unoperated control rats in learning a conditioned turning response ('conditioned rotation') for water. The lesions impaired conditioned contralateral rotation and the grafts ameliorated the impairment. By contrast, the grafts introduced an ipsilateral impairment which was not apparent in the rats with lesions alone. The results show that some aspects of graft function are adaptive, but that other aspects of function are not well controlled by the host brain, and so may be maladaptive.

Animals↗
PubMed1986

The rotating 6-hydroxydopamine-lesioned mouse as a model for assessing functional effects of neuronal grafting.

Mice were first administered intrastriatal injections of 6-hydroxydopamine and subsequently a sub-group was given neural cell suspension grafts prepared from 14-day-old fetal ventral mesencephalic mouse tissue. Six and 8 weeks after transplantation the mice in the grafted group exhibited a significant reduction in amphetamine-induced turning behaviour towards the lesioned side compared to non-grafted lesioned controls. Six of the 7 mice that had surviving grafts containing histofluorescent dopamine neurons eventually showed a reversed motor side bias with more amphetamine-induced turning in a direction away from the transplant.

Amphetamine↗
PubMed1986

In vivo measurement of spontaneous release and metabolism of dopamine from intrastriatal nigral grafts using intracerebral dialysis.

Spontaneous release and metabolism of dopamine (DA) from intrastriatal grafts of fetal mesencephalic DA neurons was measured by intracerebral dialysis. Mesencephalic DA cell suspensions were implanted into the head of the caudate-putamen in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the mesostriatal DA pathway. Four months later, when tests for amphetamine-induced turning behaviour showed that the grafts had become functional, loops of dialysis tubing were implanted into the striatum on the grafted side and the contralateral non-lesioned side of the grafted rats, and in a similar position in the denervated caudate-putamen of 6-OHDA lesioned control rats. Dialysis perfusates collected from the 6-OHDA lesioned striata showed a reduction of about 95-98% in DA and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). In the grafted animals these levels had recovered to about 40% of control for DA and to 12-16% of control for HVA and DOPAC. In addition, the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) was increased in the grafted striata compared to both the lesioned and non-lesioned controls. Amphetamine had little or no effect on DA release in the 6-OHDA lesioned rats, but caused a marked increase in DA release in the grafted rats, this response being proportional to that seen in intact striata. Since the subsequent histochemical analysis showed that the dialysis probe had been located in the transplant-reinnervated part of the caudate-putamen, the results provide additional evidence that the grafted DA neurons exert their functional effects through a continuous active transmitter release from their newly-established terminals in the reinnervated host target.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1986

Afferent and efferent connections of striatal grafts implanted into the ibotenic acid lesioned neostriatum in adult rats.

The afferent and efferent connections of grafts of fetal caudate-putamen, implanted into the ibotenic acid (IA)-lesioned striatum of adult rats, have been studied with wheat germ agglutinin conjugated horseradish peroxidase (WGA-HRP) as a combined retrograde and anterograde tracer, and with aldehyde fluorescence histochemistry for the visualisation of dopamine-containing nigrostriatal afferents from the host. The WGA-HRP was deposited in crystalline form (within a capillary tip) either into the depth of the graft tissue, or into the IA lesioned host striatum as a control. Labelling was only evaluated in specimens where the WGA-HRP deposit was entirely confined within the graft. Retrogradely labelled neurons were most consistently found in the ipsilateral host substantia nigra and the spared portions of the host CP, and in one case also in the midline and intralaminar thalamic nuclei normally projecting to the striatum. Some neurons, although weakly labelled, occurred in the deep layers of the frontal cortex in all grafted rats. Signs of anterograde WGA-HRP labelling in the host were found in one of the five animals in the ipsilateral globus pallidus and substantia nigra, pars reticulata. Fluorescence histochemistry revealed extensive ingrowth of dopamine-containing fibres from the host striatum into the grafted striatal tissue. The ingrowing fibres formed distinct and partly interconnected patches, most prominently in the peripheral regions of the grafts. The results provide evidence that intrastriatal grafts of fetal striatal tissue receive extensive dopaminergic afferents from the host substantia nigra, and that they may be capable of establishing connections also with thalamus, neocortex and globus pallidus of the host, as well as with the spared portions of the host caudate-putamen. The afferent connections from the thalamus and neocortex were notably more variable and sparse. However, since the control WGA-HRP deposits (into the lesioned host striatum) labelled the cortical and thalamic afferent neurons only poorly, it appears that the cortico-striatal and thalamo-striatal afferents (in contrast to the nigro-striatal ones) had undergone substantial degenerative changes (atrophy and/or cell death) in the long-term (6-11 months) IA-lesioned rats. The sparse thalamic and cortical afferent connections to the grafts may thus reflect an inability of the grafted striatal tissue to prevent the course of degenerative changes in these striatal input systems.

Animals↗
PubMed1986

Intrastriatal grafting of dopamine-containing neuronal cell suspensions: effects of mixing with target or non-target cells.

The effects of target and non-target cells on the growth and function of intrastriatal grafts of mesencephalic dopamine neurons have been studied in rats with unilateral 6-hydroxydopamine-induced lesions of the nigrostriatal dopamine pathway. Cell suspensions of ventral mesencephalon from 14-15-day-old rat fetuses (rich in developing dopamine neurons) were either grafted alone or grafted after mixing with equivalent numbers of cells obtained from the striatum (a major dopamine target area) or spinal cord (a non-target area for the mesencephalic dopamine neurons). The combined mesencephalic and striatal grafts gave rise to a greater area of dense innervation in the host caudate-putamen than grafts of mesencephalic cells alone or grafts of mesencephalic cells mixed with spinal cord cells. The number of surviving catecholamine-containing neurons did not differ significantly in the different types of grafts. In addition, there was an altered outgrowth pattern in the combined mesencephalic-striatal grafts consisting of small round islands of intensely fluorescent catecholamine-containing fibres, often in close association with the grafted dopamine neurons. In a subsequent biochemical study it was found that combined mesencephalic-striatal grafts exhibited dopamine levels and turnover that did not differ from grafts containing mesencephalic cells only. The mesencephalic-striatal cografts showed a trend toward enhanced behavioural effect, in terms of greater reduction in amphetamine-induced rotation asymmetry, when compared to other graft groups. It is suggested that the addition of embryonic striatal target cells can exert stimulatory effects on morphological development, and possibly functional parameters, of fetal dopamine cells also in vivo after intrastriatal grafting.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1986

Graft-induced behavioral recovery in an animal model of Huntington disease.

Bilateral ibotenic acid lesions of the anteromedial neostriatum produce neuropathological and behavioral changes in rats that are characterized by locomotor hyperactivity and severe maze learning impairments, which can be viewed as analogous to changes seen in Huntington disease. Grafts of fetal striatal neurons, implanted either into the lesioned striatum or into the denervated globus pallidus, reduced both the learning impairments and the locomotor hyperactivity, probably via different mechanisms. The results demonstrate the capacity of neural implants for functional neuronal replacement and promotion of functional recovery after damage to a major telencephalic structure participating in complex cognitive and motoric behaviors.

Animals↗
PubMed1985

Survival of intracerebrally grafted rat dopamine neurons previously cultured in vitro.

Fetal rat dopamine (DA) neurons were cultured in vitro for a 6-day period and transported, after redissociation, for 2 days prior to being grafted to the neostriatum of adult rats with 6-hydroxydopamine lesions of the ascending nigrostriatal pathway. In 2 of the 5 graft recipients that were tested for amphetamine-induced motor asymmetry, the grafts eliminated the lesion-induced turning behaviour within 3-6 weeks after transplantation. Fluorescence histochemistry revealed surviving grafts in all 6 recipients at 7 weeks after transplantation, containing between 42 and 125 DA neurons. The number of surviving DA neurons in the 3 non-compensated rats was below the minimum number of cells previously found to be necessary for functional effects on turning behaviour to occur.

Animals↗
PubMed1985

Rat fetal brain tissue grafts survive and innervate host brain following five day pregraft tissue storage.

Freshly dissected fetal basal forebrain tissue rich in cholinergic neurons was either dissociated into a cell suspension and injected into the cholinergically denervated hippocampus of adult rats, or stored in a preservative medium at 4 degrees C. Five days later the stored tissue was dissociated into a cell suspension and injected in the denervated hippocampus in another group of animals. Six weeks later the grafts were evaluated with acetylcholinesterase histochemistry for the assessment of graft survival, graft tissue volume and extent of reinnervation of the denervated hippocampus. All grafts in both the freshly dissociated and the 'stored' group survived. The stored grafts were on the average 1/5 in volume but had an appropriate and extensive laminated reinnervation pattern within the denervated hippocampus. This method of storing cells for extended periods prior to grafting allows for experimental manipulation of fetal tissue as well as long distance transportation prior to intracerebral grafting.

Animals↗