Quantitative analyses of GFRalpha-1 and GFRalpha-2 mRNAs and tyrosine hydroxylase protein in the nigrostriatal system reveal bilateral compensatory changes following unilateral 6-OHDA lesions in the rat

Copy numbers of mRNAs for GFRalpha-1 and GFRalpha-2, the preferred receptors for glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN) were determined by real-time quantitative RT-PCR (QRT-PCR). Receptor expression was assessed in striatum (ST) and substantia nigra (SN) of normal rats and rats acutely or progressively lesioned by 6-OHDA injected into the medial forebrain bundle or ST, respectively. GFRalpha-1 mRNA was clearly detected in normal ST. In normal SN, significantly higher expression of both receptors was observed. At 4 weeks after acute lesion, GFRalpha-2 mRNA was markedly decreased in SN bilaterally, whereas GFRalpha-1 mRNA in SN and ST was not affected. A progressive lesion resulted in a progressive decrease of GFRalpha1 mRNA in ST bilaterally. In SN, levels of GFRalpha-1 mRNA were not significantly affected by a progressive lesion, whereas GFRalpha-2 mRNA was markedly decreased bilaterally. Quantitative western blotting standardized against tyrosine hydroxylase (TH) protein from PC12 cells revealed the expected decrease in TH protein in lesioned SN, but also significant increases in TH protein in contralateral, unlesioned SNs at 4 weeks after both acute and progressive lesions. These data suggest that previously unrecognized compensatory changes in the nigrostriatal system occur in response to unilateral dopamine depletion. Since the changes observed in receptor expression did not always parallel loss of dopamine neurons, cells in addition to the nigral dopamine neurons appear to be affected by a 6-OHDA insult and are potential targets for the neurotrophic factors, GDNF and NTN.     

Neutral endopeptidase-24.11, μ and δ opioid receptors after selective brain lesions: an autoradiographic study

The cellular localization of the rat brain neutral endopeptidase (NEP, EC 3.4.24.11) was investigated by quantitative autoradiography of the enzyme inhibitor [3H]N-[(2RS)-3-hydroxyaminocarbonyl-2-benzyl-1-oxopropyl]glycine ([3H]HACBO-Gly) after lesions of the striatum, nigrostriatal and corticostriatal pathways. The effect of these lesions on NEP levels was compared with that on delta and mu opioid receptors, selectively labeled with [3H]Tyr-D-Thr-Gly-Leu-Thr ([3H]DTLET) and [3H]Tyr-D-Ala-Gly-MePhe-Glycinol ([3H]DAGO), respectively. Twenty-one days after injection of kainate in the caudate putamen (CP), the NEP level was locally decreased (52%) but the time course of this decrease was different from that of mu and delta opioid receptors: [3H]DAGO binding was diminished by 40% from day 2 whereas that of [3H]DTLET was reduced by 51% from day 7. Kainic acid injection in the CP induced in the globus pallidus (GP) and substantia nigra (SN) a distant reduction of the 3 opioid markers. Likewise after injection of colchicine in the CP, [3H]HACBO-Gly binding was decreased in the GP (60%) and SN (58%), [3H]DTLET binding was reduced by 54 and 55% in the GP and SN, respectively and [3H]DAGO labeling was diminished by 49% in the GP, and 58% in the SN. Finally, lesion of the nigrostriatal dopamine pathway by 6-hydroxydopamine did not induce any change of NEP level in the CP and GP whereas delta and mu opioid receptor levels were diminished respectively by 25 and 29% in the CP, and 45 and 39% in the GP, a new finding of the present study. Taken together these data suggest that NEP is in part associated with striatal intrinsic neurons. In the GP and SN, a large part of NEP seems to be presynaptically associated with nerve terminals endowed with mu and delta opioid receptors, which originate from efferent striatal neurons. In contrast to opioid receptors in the CP, the NEP appears not to be associated with dopaminergic nerve terminals originating from the SN. Cortical ablation did not affect any of the opioid markers.     

Glial cell line-derived neurotrophic factor (GDNF) gene delivery protects dopaminergic terminals from degeneration

Previously, we observed that injection of an adenoviral (Ad) vector expressing glial cell line-derived neurotrophic factor (GDNF) into the striatum, but not the substantia nigra (SN), prior to a partial 6-OHDA lesion protects dopaminergic (DA) neuronal function and prevents the development of behavioral impairment in the aged rat. This suggests that striatal injection of AdGDNF maintains nigrostriatal function either by protecting DA terminals or by stimulating axonal sprouting to the denervated striatum. To distinguish between these possible mechanisms, the present study examines the effect of GDNF gene delivery on molecular markers of DA terminals and neuronal sprouting in the aged (20 month) rat brain. AdGDNF or a control vector coding for beta-galactosidase (AdLacZ) was injected unilaterally into either the striatum or the SN. One week later, rats received a unilateral intrastriatal injection of 6-OHDA on the side of vector injection. Two weeks postlesion, rats injected with AdGDNF into either the striatum or the SN exhibited a reduction in the area of striatal denervation and increased binding of the DA transporter ligand [(125)I]IPCIT in the lesioned striatum compared to control animals. Furthermore, injections of AdGDNF into the striatum, but not the SN, increased levels of tyrosine hydroxylase mRNA in lesioned DA neurons in the SN and prevented the development of amphetamine-induced rotational asymmetry. In contrast, the level of T1 alpha-tubulin mRNA, a marker of neuronal sprouting, was not increased in lesioned DA neurons in the SN following injection of AdGDNF either into the striatum or into the SN. These results suggest that GDNF gene delivery prior to a partial lesion ameliorates damage caused by 6-OHDA in aged rats by inhibiting the degeneration of DA terminals rather than by inducing sprouting of nigrostriatal axons.     

PSA-NCAM distinguishes reactive astrocytes in 6-OHDA-lesioned substantia nigra from those in the striatal terminal fields

6-hydroxydopamine (6-OHDA) lesion of the substantia nigra (SN) causes the appearance of reactive astrocytes not only in the SN but also in the striatal terminal fields, as measured by increased size of the cells and their processes, as well as enhanced expression of glial fibrillary acidic protein (GFAP) and an epitope recognized by monoclonal antibody 19D1. We now demonstrate that polysialylated neural cell adhesion molecule (PSA-NCAM) is induced on reactive astrocytes, as well as on large neurons, on the ipsilateral side of the 6-OHDA-lesioned SN. Colocalization of GFAP and PSA-NCAM was confirmed for reactive astrocytes using a confocal laser scanning microscope. Negligible amounts of PSA-NCAM reactivity were detected contralaterally, although colocalization was noted on astrocytes with sparse, significantly thinner processes. In contrast to the increase of GFAP in the lesioned striatum, few striatal astrocytes expressed PSA-NCAM. In agreement with these results, PSA-NCAM was detected on cultured reactive astrocytes from SN but not reactive striatal astrocytes. Double immunohistochemistry for proliferating cell nuclear antigen (PCNA), a marker of dividing cells, and GFAP demonstrated that reactive astrocytes in lesioned SN were PCNA-positive whereas those in striatum were not. Although NG2 chondroitin sulfate proteoglycan expression also increased in the lesioned SN, NG2 was not colocalized with PSA-NCAM, was not expressed on astrocytes, and labeled only oligodendrocyte precursor cells. Our results suggest that PSA-NCAM can act as a marker for reactive astrocytes only at the site of the lesion and not in the terminal fields, probably because it is reexpressed only when astrocytes divide.     

An evaluation of the possible protective effects of neonatal striatal transplants against kainic acid-induced lesions.

The present study examined the recent report that transplantation of neonatal striatal tissue into kainic acid (KA) lesioned striatum protected the contralateral striatum from a subsequent KA lesion. We did not find a significant difference in the survival rate of animals that received neonatal striatal transplants into a KA lesioned striatum followed by a subsequent lesion of the contralateral striatum compared to those animals that received bilateral KA-induced striatal lesions alone. The tissue transplants did not protect against the degeneration of striatal neurons induced by KA. Indeed, the survival rate was very low (25%) in the transplant groups. A second experiment was also performed to examine whether a neonatal striatal transplant might reduce the severe syndrome of aphagia and adipsia associated with KA lesions of the striatum. Animals that received the neonatal striatal transplants showed increased aphagia and adipsia compared to animals only receiving the KA lesion. Again, the transplant group had a very low survival rate (10%). The present study was unable to confirm that neonatal striatal transplants protect against KA lesions either by themselves or in conjunction with a recent KA lesion.     

Lesion-induced increase of BDNF is greater in the striatum of young versus old rat brain

Young (4-5 month old) and old (32-34 month old) Brown Norway/F344 hybrid rats were given unilateral 6-OHDA lesions of the nigrostriatal pathway. Four weeks later tissue from the lesioned or intact striatum or ventral midbrain was dissected and analyzed for brain-derived neurotrophic factor (BDNF) protein levels using an enzyme-linked immunosorbent assay. BDNF protein content was greater in the lesioned striatum than in the intact striatum for all young rats, and the increased BDNF content in the lesioned striatum of young rats was directly correlated with severity of lesion as determined by rotational scores. BDNF content in the lesioned striatum increased in less than half of the old rats and was not significantly different than BDNF content in the intact striatum. BDNF content in the lesioned substantia nigra/ventral tegmental area (SN/VTA) was greater than BDNF content in the intact SN/VTA for both young and old rats. These data suggest that an age-related difference in activity of at least one neurotrophic factor, BDNF, occur within the denervated striatum following a neurotoxic lesion of the nigrostriatal pathway.     

In vivo release of [H]GABA in cat caudate nucleus and substantia nigra. II. Involvement of different thalamic nuclei in the bilateral changes induced by a nigral application of muscimol

The contribution of motor and intralaminar thalamic nuclei to the changes of [3H]GABA release evoked in both caudate nuclei (CN) and both substantia nigra (SN) by a unilateral nigral application of muscimol (10(-6) M) was investigated on halothane-anaesthetized cats. Acute lesions were performed on one side of the thalamus at the level of either the ventralis medialis and ventralis lateralis (motor nuclei) or the centralis lateralis and paralamellar zone of the medialis dorsalis (intralaminar nuclei). The release of [3H]GABA neosynthesized from [3H]glutamine was measured by perfusing continuously a [3H]glutamine-enriched physiological medium through a push-pull cannula implanted in the 4 structures under investigation. After two hours of superfusion, muscimol (10(-6) M) was delivered for 60 min through the nigral push-pull cannula implanted ipsilaterally to the thalamic lesion. Evoked changes of [3H]GABA release were analyzed either in motor or intralaminar nuclei lesioned cats and compared to those observed in intact animals. Whatever the localization of the thalamic lesions was, an increased release of [3H]GABA was elicited locally in the SN and distally in the ipsilateral CN as in intact animals, suggesting that the responses induced ipsilaterally did not require nigro-thalamic pathways. On the contrary, in the contralateral CN changes of [3H]GABA release evoked by the nigral muscimol application were reversed by both types of thalamic lesion. Instead of a decreased release of [3H]GABA observed in intact cats, an increased release of [3H]GABA was detected in lesioned animals. In the contralateral SN, the response was reversed only after the intralaminar nuclei lesion. In this situation nigral muscimol application induced a decreased release of [3H]GABA in contrast to the enhanced release observed in intact and motor thalamic lesioned cats. The parallel increased release of [3H]GABA observed in the contralateral CN and SN in motor thalamic nuclei lesioned cats suggests an activation of the striatonigral cells by the nigral muscimol treatment. The asymmetrical changes of [3H]GABA release measured in the contralateral CN and SN in intact and intralaminar nuclei lesioned cats could indicate a presynaptic modulation of the [3H]GABA release acting either at the CN or the SN levels. The possible pathways involved in the interhemispheric transfer of information originating from one SN to the contralateral basal ganglia components are also discussed.     

Use of aminopeptidase M as a hypotensive agent in spontaneously hypertensive rats.

The present investigation determined that a commercially available aminopeptidase M (AmM, Sigma Chemical) can be utilized to lower blood pressure in normotensive and hypertensive rats. In vitro analyses indicated that the predominant peptidase present in this preparation was AmM; however, it also contained some aminopeptidase A (AmA) and less DAP IV. Although no DAP IV-mediated metabolism of angiotensin II (AII) or angiotensin III (AIII) was measured, both AmM and AmA metabolized AII and AIII. Upon further examination, it appeared that AII could be converted to AIII by either AmM or AmA; however, Arg was cleaved from the N-Terminal of AIII predominantly by AmM. The aminopeptidase inhibitors actinonin (AC), amastatin (AM), and bestatin (BE) effectively blocked the AmM-induced hydrolysis of the Asp-Arg bond of AII, and the Arg-Val bond of AIII. The activity of AmA was inhibited by AM but was relatively resistant to inhibition by AC and BE. Next, exogenous aminopeptidase replacement was employed in the anesthetized spontaneously hypertensive rat (SHR) in an attempt to temporarily correct a hypothesized brain deficiency of receptor-associated peptidases and lower blood pressure. Third-ventricle infusion of AmM produced significant drops in blood pressure and heart rate in both SHRs and Wistar-Kyoto normotensive controls. Pretreatment with AC or BE was particularly effective at interfering with the subsequent AmM-induced hypotensive effect, while AM was less effective. The central mechanisms underlying these effects are in need of further investigation; however, they are at least partially dependent upon the brain angiotensin system.     

Changes in the activity of gamma-glutamyl transpeptidase induced by kainic acid and surgical lesions of the hippocampal formation in young rats

To study possible functional involvement of gamma-glutamyl transpeptidase (GGT) in glutamate transmitter metabolism we lesioned putative glutamatergic structures of the rat hippocampal formation by intracerebroventricular (i.c.v.) injection of kainic acid (KA) or by surgical CA3 axotomy. Unilateral injection of KA into the left lateral cerebral ventricle of 30-day-old rats resulted in decreased GGT activity in hippocampal areas CA3, Ca1 ipsilaterally, and in the contralateral area CA1, four hours after the induction of the chemical lesion. Four days after the injection, the enzyme activity was decreased in all hippocampal areas with the exception of the contralateral dentate gyrus. Four days after bilateral i.c.v. injection of KA, lower GGT levels were found than was seen after bilateral surgical lesion of the CA3 pyramidal cell axons (Schaffer's collaterals). The surgical lesion was followed by a decrease of GGT only in the stratum pyramidale and stratum radiatum of area CA1. In contrast to the effects in 30-day-old rats, unilateral i.c.v. injection of KA on postnatal day 12 did not alter the GGT activity in any studied hippocampal area presumably because of incomplete maturation of structures required for KA vulnerability.     

Neovascularization in kainic acid-induced lesions of rat striatum. An immunohistochemical study with laminin

Vascular changes occurring after stereotaxic injection of the excitatory neurotoxin kainic acid (KA) into the rat striatum were studied at various time intervals after the lesion using laminin immunohistochemistry. Laminin immunohistochemistry revealed marked vascular changes, including presumed neovascularization, in the lesioned striatum. Vessels with increased laminin immunoreactivity were demonstrated from 2 days up to at least 5 months following the injection. The majority was capillary vasculature, which was distributed throughout the lesioned striatum, sometimes being arranged densely along the needle tract. Fine spike-like sprouts called streamers were also loaded with laminin immunoreactivity. In contrast, laminin immunoreactivity in vessels in the control striatum was negligible. Vascular changes detected by laminin immunohistochemistry preceded but then almost paralleled gliosis demonstrated by glial fibrillary acidic protein immunohistochemistry. These results indicate that striatal injection of KA causes marked vascular changes including neovascularizations which are demonstrable by laminin immunohistochemistry.     

Major histocompatibility complex antigen expression on rat microglia following epidural kainic acid lesions

Vigorous expression of major histocompatibility complex (MHC) class I and class I surface glycoproteins was observed on reactive microglia but not on astrocytes in the rat brain following lesions induced by epidural kainic acid (KA) on the cerebral cortex. The monoclonal antibodies used were OX18 against MHC class I, OX6 against MHC class II, OX1 against leukocyte common antigen (LCA), and W3/13 against pan-T lymphocytes. Astrocytes were marked by antibodies to glial fibrillary acidic protein (GFA) and S100b protein. The lesion differentially affected four zones: the central area of the lesion where most cells died; the peripheral zone surrounding the lesion where selective damage occurred; projection tracts from the lesioned area; and terminal fields of damaged neurons. In nonlesioned animals, class I expression was confined to vascular endothelial cells and some small glial cells. Following KA treatment, class I-positive round cells appeared in the central zone at day 1, peaked about day 5, and then slowly declined. In the peripheral zone, class I-positive microglia were present fron day 2 on. They demonstrated classical morphology for such cells, and in some cases arranged themselves in pyramidal profiles surrounding neurons. Reactive microglia were also class I positive along tracts of damaged neurons and in the terminal areas. The reaction was reduced to control levels 16-20 weeks after lesioning although some vascular endothelial cells and a few round cells still stained positively in the cystic area, which was the remnant of the central zone. Class II antigen expression first appeared in the form of round cells in the central zone of the lesion on day 1. These peaked at 5-7 days and declined thereafter. In the peripheral zone on day 5, some positive round or ameboid cells were found intermingled with typical reactive microglia. This reaction peaked at about 1-2 weeks and decreased thereafter. Class II-positive microglia appeared in fiber tracts and in the terminal areas on day 5, peaked after 2-3 weeks, and declined thereafter. Double immunostaining for class I and II antigens showed that there were significantly fewer class II- than class I-positive cells, but the morphology of the two groups was similar. No astrocytes stained positively for either group I or group II antigen. In both the primary and secondary lesioned areas, LCA staining was observed on the surface of reactive microglia. In the primary lesions there were also LCA-positive round cells in the central zone, but these were rare in the peripheral zone and the secondary lesioned areas.(ABSTRACT TRUNCATED AT 400 WORDS)     

Gender differences in spontaneous and MK-801-induced activity after striatal lesions

At different times post-lesion, the excitotoxically lesioned striatum has been shown to undergo significant neuroanatomical and neurochemical changes, which could be expressed behaviorally. Gender and dose of excitotoxin are other variables that may modify the behavioral effects of the lesion. Consequently, the purpose of this study was to determine the effect of dose, gender, and time post-lesion on spontaneous and drug-induced locomotor behavior after intrastriatal KA lesions. Results showed that dose and time post-lesion had a significant effect on the deficits observed. Hyperactivity induced by the lesion with KA (5 nm) subsided as time post-lesion increased. Both the pattern of spontaneous and MK-801-induced locomotor activity were different for male and female rats. In female animals with KA lesions (5 nm), MK-801 did not stimulate ambulatory activity nor reduce vertical activity. Both female and male rats lesioned with KA (5 nm) showed an exaggerated response to amphetamine, at a time when spontaneous locomotor activity was reduced to control levels. Haloperidol significantly reduced locomotor activity in all groups.     

Partial, graded losses of dopamine terminals in the rat caudate-putamen: an animal model for the study of compensatory adaptation in preclinical parkinsonism

Procedures to lesion dopamine (DA) neurons innervating the rat caudate-putamen (CP) in a partial, graded fashion are described in this study. The goal is to provide a lesion model that supports intra-animal comparisons of voltammetric recordings used to investigate compensatory adaptation of DA neurotransmission. Lesions exploited the topography of mesostriatal DA neurons, microinjections of the neurotoxin 6-hydroxydopamine (6-OHDA) into the medial and lateral edges of the ventral mesencephalon containing DA cell bodies and microdissection of the CP into six regions. Analysis of tissue DA content in these regions by HPLC-EC demonstrated that 6-OHDA injected into the lateral substantia nigra results in a significantly greater loss of DA in lateral versus medial regions of the CP. The direction of the graded loss of DA was reversed (i.e. a medial to lateral lesion gradient) by the injection of 6-OHDA into the ventral tegmental area near the medial SN. Extracellular concentrations of electrically evoked DA could be measured across the mediolateral axis of the CP in a single animal using the technique of in vivo voltammetry. More importantly, graded decreases in the amplitude of evoked DA levels generally followed the direction of the tissue DA gradient in lesioned animals. These results suggest that the graded loss of DA terminals in the CP, coupled to a spatially and temporally resolved technique for monitoring extracellular DA, is a viable tool for investigating compensatory adaptation in the mesostriatal DA system.     

Structural alteration and possible growth of afferents after kainate lesion in the adult rat thalamus

Afferents to the thalamic ventrobasal complex (VB) originating from the spinal cord, the dorsal column nuclei, and the somatosensory cortex were anterogradely labeled by WGA-HRP 30 days after an injection of kainic acid (KA), which produced a complete unilateral neuronal loss in the VB, the opposite side being used as a control. At the light microscopic level, there was no obvious rerouting of spinal afferents away from the lesioned areas towards unlesioned parts of VB. There was an apparent decrease in the number of lemniscal afferents to the lesioned side, which may indicate a progressive retrograde degeneration. At higher magnification, all three afferent systems studied demonstrated morphological changes, predominantly manifested by terminal swellings that reached up to 25 micron in diameter. Control experiments suggested that these morphological alterations were related neither to a direct action of the excitotoxin nor to the absence of a different afferent system but to the loss of neuronal postsynaptic targets. At the electron microscopic level, the normal ultrastructural features of VB were not observed after a KA lesion. No neuronal somata, dendrites, or normal presynaptic elements were observed. Neural elements, some of which were labeled from the somatosensory cortex or the dorsal column nuclei, were essentially of two types: varicosities and unmyelinated axonal profiles. Varicosities could be separated into two broad classes: The majority were large structures derived from large, sometimes myelinated, axons and containing a wealth of organelles. Since they were not completely surrounded by glial elements, we have denoted them unensheathed varicosities. Among the organelles, the most obvious features were vesicles and tubules of smooth endoplasmic reticulum, microtubules, mitochondria, and various lysosome-like inclusions. These unensheathed varicosities gave rise to large, mound-like protrusions containing large vacuoles and thin long protrusions either filled with neurofilaments or resembling unmyelinated axonal profiles. Others were completely surrounded by a glial sheet and were therefore called ensheathed varicosities. These ensheathed varicosities presented several characteristics typical of degenerating profiles, including neurofilamentous proliferation and morphological alterations of the mitochondria. Unmyelinated axonal profiles occupied a substantial territory in the lesioned area. They were most often grouped in bundles sometimes wrapped by glial processes.(ABSTRACT TRUNCATED AT 400 WORDS)     

NG2 proteoglycan-expressing cells of the adult rat brain: possible involvement in the formation of glial scar astrocytes following stab wound

Stab wound lesion to the adult central nervous system induces strong proliferative response that is followed by the formation of a dense astroglial scar. In order to determine the origin of those astrocytes composing the glial scar, the cell proliferation marker bromodeoxyuridine (BrdU) was administered to lesioned rats that were fixed 3 h or 6 days later. At 3 h after the BrdU administration, labeled nuclei were frequently associated with either NG2(+) cells or microglia/macrophages, but rarely with astrocytes expressing glial fibrillary acidic protein (GFAP). Six days later, by contrast, numerous BrdU-labeled nuclei were associated with astrocytes located along the lesion borders. After the injection of a viral vector of the green fluorescent protein (GFP) into the lesional cavity, GFP was preferentially detected within NG2- or GFAP-labeled cells when lesioned animals were fixed 1 or 6 days after the injections, respectively. The combined detection of glial markers within cells present in the lesioned area indicated that, although they rarely express GFAP, the marker of mature astrocytes, NG2(+) cells located along the lesion borders frequently express nestin and vimentin, i.e., two markers of immature astrocytes. Lastly, chronic treatment of lesioned rats with dexamethasone was found to inhibit the proliferation of NG2(+) cells present within the lesioned area and to subsequently alter the formation of a dense astroglial scar. Taken together, these data strongly suggest that following a surgical lesion, at least a portion of the astrocytes that constitute the glial scar are issued from resident NG2(+) cells.     

Basic fibroblast growth factor expression and tenascin C immunoreactivity after partial unilateral hemitransection of the rat brain

Basic fibroblast growth factor (bFGF) gene expression as well as its immunoreactivity were studied after partial unilateral hemitransection of the rat brain during a time course of 24 h, 72 h, 7 and 14 days. The mechanical injury resulted in a global increase of bFGF gene expression at the 24-h time interval. This global increase was seen at the ipsilateral site at the level of the lesion as well as rostral to the lesion in the ipsilateral hemisphere. The upregulation in bFGF gene expression was in most of the areas investigated due to an upregulation in glial cells as seen by means of nonradioactive in situ hybridization compared with immunocytochemistry for glial fibrillary acidic protein (GFAP). Basic FGF immunoreactivity (IR) was increased around the lesion in glial cell nuclei 7 days after the injury. This increase was also detected in GFAP positive glial cells surrounding small vessels in the lesioned area. Moreover, in the present paper we demonstrate increased tenascin immunoreactivity in the lesioned area 7 days after injury. The tenascin IR was increased at the edges of the lesion as well as in vessel like structures. The tenascin IR was partially codistributed with GFAP IR in the lesioned area. The lesion was also characterized by an increase in vimentin IR as well as in laminin IR. It is suggested that the observed changes in the expression of bFGF, matrix proteins (laminin, tenascin) and intermediate filaments (vimentin) are involved in (a) tissue repair, (b) protection of neuronal cells from excitotoxic influences and (c) formation of new vessels in the lesioned area.     

Intraparenchymal fetal striatal transplants and recovery in kainic acid lesioned rats

Striatal kainic acid (KA) lesions induce behavioral and biochemical deficits which resemble symptoms encountered in patients suffering from Huntington's disease. In rats with KA lesions, fetal striatal transplants have shown to reverse the pervasive nocturnal hyperactivity induced by the lesion. In the present study 4.6 mm3 of fetal striatal tissue were delivered bilaterally into the anterodorsal portion of the lesioned caudate nucleus. Care was taken to deliver the transplant within the host parenchyma and away from the lateral ventricles. Locomotor behavior analyzed using the Digiscan animal activity monitors before and after the transplants demonstrated a reversal of the hyperactivity following transplants in 70% of lesioned animals. Microinjections of horseradish peroxidase delivered into the globus pallidus and substantia nigra of a small group of functionally recovered transplanted animals, did not reveal evidence for reinnervation between host nigra or pallidum and the transplant at 10 weeks post-transplantation. Other laboratories have reported anatomical connections by 6 months post-transplantation. Ventricular/brain ratios demonstrated that intraparenchymal transplants significantly reduced the ventricular dilation following KA lesion. These results suggest that functional recovery can be obtained when the transplant is immersed into the host's striatal parenchyma regardless of the existence of long-range anatomical connections.     

Hemispheric asymmetries in spontaneous firing characteristics of substantia nigra pars reticulata neurons following a unilateral 6-hydroxydopamine lesion of the rat nigrostriatal pathway

Single unit activity of substantia nigra pars reticulata (SNR) neurons was recorded bilaterally in rats subjected to unilateral 6-hydroxydopamine lesions of the ascending mesostriatal dopaminergic pathway, resulting in an almost complete loss of dopaminergic neurons in the ipsilateral SN pars compacta. Firing rate and firing pattern of SNR neurons in lesioned rats were compared with respective data from sham-lesioned rats and naive controls. In lesioned rats, the mean firing rate of SNR neurons at the lesioned side was significantly reduced and there was an increase in the occurrence of bursting activity. In contrast, firing rate in the contralateral SNR was significantly increased without change in the frequency of bursting neurons. This asymmetrical change in spontaneous firing characteristics of SNR neurons following the lesion could be involved in the complex behavioral changes seen in this model of Parkinson's disease.