Showing papers by "Anders Björklund published in 1985"

Efferent synaptic connections of grafted dopaminergic neurons reinnervating the host neostriatum: a tyrosine hydroxylase immunocytochemical study

Abstract: In adult rats with a unilateral 6-hydroxydopamine-induced destruction of the nigrostriatal dopamine (DA) pathway, grafts of embryonic substantia nigra can establish a new dopaminergic terminal fiber plexus in the previously denervated neostriatum and compensate for some of the behavioral deficits induced by the nigrostriatal lesion. In the present study the synaptic connections of the ingrowing DA fibers from the graft were analyzed ultrastructurally, using immunocytochemical localization of tyrosine hydroxylase (TH), in animals whose lesion-induced motor asymmetry had been completely compensated for by the nigral grafts. In two of the animals, horseradish peroxidase-wheatgerm agglutinin conjugate was injected into the graft in order to trace possible reciprocal afferent connections to the graft from the host striatum. TH-immunoreactive axons from the graft were seen to make abundant symmetric synapses with neuronal elements in the host neostriatum. Between 85 and 90% of these synapses were on dendritic shafts and spines, and the rest were on neuronal perikarya. Two principal targets were identified: dendrites of spiny neurons, the majority of which are likely to be striatal projection neurons; and the cell bodies of giant neurons, most (or perhaps all) of which are known to be cholinergic interneurons. The synapses made on dendritic spines, which constituted about 40% of all TH-positive synapses formed by the TH-positive neurons in the graft, resembled those seen in normal animals, both in that they made contacts with spine necks and in that they invariably were associated with an asymmetric TH-negative synapse contacting the spine head. The innervation of the giant cell perikarya, which constituted about 6% of all TH-positive synapses found, was strikingly abnormal in that the graft-derived TH-positive fibers formed dense pericellular "baskets" selectively around the giant cell bodies. Such arrangements were never seen in the normal striatum, nor did they occur in the intact contralateral striatum in the grafted animals. It is proposed that this apparent dopaminergic hyperinnervation from the graft could provide a powerful inhibition of the cholinergic interneurons in the reinnervated host striatum, and that such an inhibitory mechanism could assist in the graft-induced functional recovery by potentiating the functional effects of DA synapses terminating on the spiny efferent neurons. This dual innervation may thus help to explain why restoration of only a small proportion of the striatal DA innervation by the graft is sufficient to induce complete compensation of, e.g., motor asymmetry in the lesioned rats.(ABSTRACT TRUNCATED AT 400 WORDS)

Cyclosporin A increases survival of cross-species intrastriatal grafts of embryonic dopamine-containing neurons

Abstract: The survival and function of cross-species (mouse-to-rat) grafts of fetal mesencephalic dopamine (DA) neurons, implanted as a cell suspension in the striatum of rats with lesions of the mesostriatal DA system, have been studied in animals with and without immunosuppression induced by Cyclosporin A (CyA). At 6 weeks after grafting 3 out of 7 non-CyA treated animals showed some degree of graft survival and variable functional compensation. In those three animals an average of 92 DA neurons per graft was counted. In the grafted animals treated with daily CyA injections, all grafts survived and produced partial or complete functional compensation, and they had an average of 557 DA neurons per graft. It is concluded that intracerebral graft survival and function can be greatly improved by CyA treatment and that the immunological protection of neural transplants in the brain is only partial.

Cholinergic ventral forebrain grafts into the neocortex improve passive avoidance memory in a rat model of Alzheimer disease

Abstract: The memory dysfunction of Alzheimer disease has been associated with a cortical cholinergic deficiency and loss of cholinergic neurons of the nucleus basalis of Meynert. This cholinergic component of Alzheimer disease can be modeled in the rat by ibotenic acid lesions of the cholinergic nucleus basalis magnocellularis. The memory impairment caused by such unilateral lesions, as reflected in passive avoidance behavior, is reversed by grafts into the deafferented neocortex of embryonic neurons of the cholinergic ventral forebrain, but not by grafts of noncholinergic hippocampal cells.

Unemployment and Mental Health: Some Evidence from Panel Data

Abstract: Microdata are used in this paper to analyze the effects of unemployment on mental health. The analysis is done in two steps. First, cross-section data of labor force participants are analyzed. It appears that the unemployed have worse mental health than the employed. Next, panel data are used to control for "fixed" effects, that is, unobserved omitted variables that are constant over time. The model is also specified to allow both the occurrence of and duration of unemployment to affect mental health. Then we cannot reject the hypothesis that there are no effects of unemployment on mental health. However, some sensitivity tests indicate that the precision of our estimates is rather low.

GABA and neuropeptides in the CNS

Abstract: I. Distribution of neuropeptides in the Central nervous system using biochemical micromethods (M. Palkovits and M.J. Brownstein). II. General morphological features of peptidergic neurons (V.M. Pickel). III. Vasopressin, oxytocin and their related neurophysins (M.V. Sofroniew). IV. LHRH-containing systems (J. Barry, G.E. Hoffman and S. Wray). V. alpha-endorphin, beta-MSH, ACTH, and related peptides (H. Khachaturian, M.E. Lewis, Kang Tsou and S.J. Watson). VI. Distribution of enkephalin-containing neurons in the central nervous system (P. Petrusz, I. Merchenthaler and J.L. Maderdrut). VII. VIP-containing neurons (G.M. Abrams, G. Nilaver and E.A. Zimmerman). VIII. Neurotensin-containing neurons (P.C. Emson, M. Goedert and P.W. Mantyh). IX. Neuronal-cholecystokinin (J.J. Vanderhaeghen). X. An atlas of the distribution of GABAergic neurons and terminals in the rat CNS as revealed by GAD immunohistochemistry (E. Mugnaini and W.H. Oertel). Subject index.

Anatomical and functional consequences of grafting mesencephalic neurons into a peripheral nerve "bridge" connected to the denervated striatum.

Abstract: Adult rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway were tested for amphetamine-induced rotational asymmetry. In animals with functional deficits a fetal mesencephalic transplant was placed intracranially over the superior colliculus within the caudal end of a 2- to 3-cm-long heterologous sciatic nerve segment laid longitudinally on the skull. Two months later the rostral tip of the peripheral nerve graft was cut and inserted through a burr-hole into the denervated striatum. Animals were tested monthly for 5 months for rotational asymmetry and selected rats were sacrificed for histochemical examination. It was shown that the use of a peripheral nerve segment as a bridge between a distant neuronal transplant and a selected region of the adult host brain resulted in the growth of monoaminergic axons into the denervated striatum from the extracerebrally located grafted neurons. The nerve bridge was cut extracranially in rats whose rotational asymmetry had decreased towards normal levels to determine if this behaviour was dependent on axons reaching the striatum through the graft. Each of these animals exhibited an increase in rotational asymmetry one and three weeks after the transection of the nerve. These anatomical and functional observations suggest that the decrease in rotational asymmetry observed in these animals is related to the growth of long axons from the implanted mesencephalic neurons into the denervated host's striatum which traversed the entire peripheral nerve segment.

Functional reactivation of the deafferented hippocampus by embryonic septal grafts as assessed by measurements of local glucose utilization.

Abstract: Transection of the septo-hippocampal connections through fimbria-fornix damage in the rat results in profound hippocampal cholinergic deafferentation, and, when applied bilaterally, leads to severe and long-lasting impairments in learning and memory. Previous studies have shown that intrahippocampal septal grafts can reestablish a new cholinergic innervation in the inititally denervated hippocampal formation and at least partly compensate for the lesion-induced learning impairments in fimbria-fornix lesioned rats. The purpose of the present study was to determine the magnitude of lesion-induced alterations in cerebral function as reflected in local glucose use measured by (14C)-2-deoxyglucose (2-DG) autoradiography, and the degree to which this index of functional activity could be normalized following reinnervation from transplants of fetal cerebral tissue from the primordial septal region. Six months after unilateral fimbriafornix transection the rate of glucose utilization was reduced markedly throughout the ipsilateral hippocampus when compared to the intact contralateral side, while in the neocortex only the cingulate cortex showed long-lasting reductions in glucose use. Rats that received a transplant of fetal septal-diagonal band tissue at the time of fimbria-fornix transection, and were sacrificed 6 months later, displayed significantly greater glucose utilization in the ipsilateral hippocampus and cingulate cortex than was measured in these areas in rats with lesion alone. The recovery in glucose use was paralleled by a significant increase in acetylcholinesterase (AChE) staining in several areas of the ipsilateral hippocampal formation and cingulate cortex. This index of graft-induced cholinergic reinnervation was, moreover, significantly correlated with the rate of glucose use. Thus, in the fimbria-fornix transected animals the magnitude of glucose depression correlated with the extent of reduction in AChE staining, and in the grafted animals the degree of normalization of glucose use was correlated with the graft-induced increase in AChE-staining density. These results thus indicate that the 2-DG autoradiographic technique can provide a unique opportunity to map both altered functional activity in localized areas of the brain following specific lesions and the extent to which transplant-derived reinnervation of the host may induce a return to normal functional levels in the target site.

Neural grafting in animal models of neurodegenerative diseases.

Abstract: Work in amphibians and fish was the first to demonstrate the possibilities for neuronal replacement after damage in the central nervous system. In such species, above all in the visual system, it has been shown that grafted neurons can substitute both structurally and functionally for damaged axonal connections, and that afferent and efferent connections can be established with a high degree of specificity between the grafted neurons and the host. As originally reported by matt he^,^' Stone,sg and S ~ e r r y , ~ ~ vision can be restored in enucleated adult newts or salamanders, or developing frogs, by transplanted or reimplanted whole eye bulbs. These grafts reestablish a new retinotectal pathway with a topographically ordered projection over the contralateral tectum. Similarly, in adult goldfish or developing frogs, grafted or reimplanted tectal tissue can reestablish functional and topographically ordered connections with the regenerating retinotectal axons of

Compensation of Lesion-Induced Changes in Cerebral Metabolism and Behaviour by Striatal Neural Implants in a Rat Model of Huntington’s Disease

Abstract: There now exists ample evidence that the capacity of the adult CNS for functional recovery after large long-term lesions can be promoted by implants of foetal brain tissue (see, e.g., Bjorklund and Stenevi, 1979; Bjorklund et al., 1980; Dunnett et al., 1981a,b, 1982; Perlow et al., 1979; Gash and Sladek, 1979; Freed et al., 1980; Krieger et al., 1980; Gage et al., 1983, 1984; Deckel et al., 1983; Labbe et al., 1983; Isacson et al., 1984; Fine et al., this volume). The use of neural grafting as an experimental technique complements lesion and stimulation experiments in neurobiology. In the assessment of lesion-induced changes in the rat it has been investigated to what extent the grafting of neural tissue to the young lesioned or aged impaired animal can create a sufficient condition for functional recovery (see Bjorklund et al., 1983; Gage et al., 1983, 1984). Functional recovery after lesion-induced changes has been correlated with histological, neurochemical, physiological and metabolic parameters sometimes giving new insights into the mode of operation of certain neural circuitries or transmitter systems.

Brain Transplants: Can They Restore Single Unit Activity in the Hippocampus?

Abstract: Transplants of embryonic septal tissue in rats given fimbria-fornix (Ffx) lesions can either restore maze performance or lead to greater impairments than lesions alone.' The patterns of innervation produced in these two cases are not now distinguishable histologically. The present study investigated the effects of transplants of embryonic septal tissue upon single unit activity in the hippocampus of four groups of rats: normal rats, those given Ffx lesions, those given Ffx lesions and transplants that improved performance on spatial memory tests (trans/smart), and those given Ffx lesions and transplants that impaired maze performance (trans/impaired). Rats were given either sham operations, aspiration lesions of the Ffx, or Ffx lesions and transplants (solid grafts) of embryonic septal tissue into the lesion cavity. Three months after surgery the rats were tested on a water maze that required spatial memory.* Performance on this task distinguished between trans/smart and trans/ impaired rats. Electrodes for single unit recording were implanted surgically after behavioral testing, and recording began one week after surgery. Theta unit activity was recorded from the CA-1 layer of the dorsal hippocampus during two behaviors: an appetitive behavior in which rats walked on an elevated track during recording and a consummatory behavior in which rats drank chocolate milk from a drinking tube. Theta unit activity is characterized by changes in firing frequency and periodicity that vary with behavioral class. In normal rats, high frequency theta unit activity was organized into 7 Hz spike trains during walking, whereas low frequency activity was not organized into periodic spike trains during drinking. In rats given Ffx lesions, firing frequency increased during walking relative to drinking, whereas theta unit activity was never organized into periodic spike trains. In trans/smart rats, overall firing frequency increased during walking relative to drinking, and theta unit activity was somewhat organized into periodic spike trains. In trans/impaired rats, high frequency firing appeared during both behaviors, and theta unit activity did not appear to be organized normally during either behavior. The modulation of theta unit activity was correlated with recovery of performance on the water maze. Unit activity recorded from trans/smart rats resembled that from normal rats, since both frequency and periodicity of theta units were correlated with behavioral class. Only one component of unit activity recorded from Ffx rats were correlated with behavior, since firing frequency, but not periodicity, increased during appetitive behavior. Unit activity recorded from trans/impaired rats was not correlated with behavioral class a t all.

Neuronal Replacement After Traumatic or Age-Dependent Brain Damage

Abstract: During the last few years evidence has accumulated that fetal neurons, implanted into the depth of the brain in adult rats, can reestablish damaged connections in the host brain and substitute functionally for elements lost or damaged as a result of a preceding lesion. This research work has led to the realization that, contrary to traditional views, the adult mammalian CNS has a potential to incorporate new neuronal elements into already established neuronal circuitry and that such implanted neurons can modify the function and behavior of the recipient. For a long time it was thought that the remarkable regenerative and functional potential of CNS tissue grafts that had been demonstrated in cold-blooded vertebrates reflected a fundamental difference in the regenerative properties of central nervous tissue between cold-blooded vertebrates and mammals. During the last few years it has become evident however, that at least certain types of intracerebral neural grafts can perfoum just as well in developing and mammals as in developing or adult submammalian vertebrates.