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ABSTRACT: Background: Deep brain stimulation (DBS) in the ventral tuberal hypothalamus (VTH) is currently under investigation for the treatment of severe obesity. Stimulation impact on a number of closely related hypothalamic neural systems could potentially influence normal hypothalamic function and thereby generate adverse side effects. Objective: To assess the feasibility and safety of VTH DBS in a non-primate large animal model. Methods: In the VTH of 6 Göttingen minipigs, quadropolar leads were implanted bilaterally (n = 2) or unilaterally (n = 4), using optimized MRI sequences allowing identification of major diencephalic landmarks. Heart rate, weight, behavior and nighttime locomotor activity were recorded throughout the study period. Two of the unilaterally implanted minipigs were examined with [(15)O]H(2)O positron emission tomography (PET) scans performed in DBS-off and DBS-on mode. Results: VTH DBS elicited an amplitude-dependent increase in heart rate and transient aggressive behavior. PET demonstrated that VTH DBS caused a global increase in cerebral blood flow velocities and decreased mean transit time. Conclusions: VTH DBS results in behavioral and physiological changes, which may derive from activation of closely related limbic and autonomic networks. Caution and further studies of longer length should be requested before this procedure is used more widely in humans.
Stereotactic and Functional Neurosurgery 07/2012; 90(5):281-291. · 1.85 Impact Factor
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J C Sørensen,
M S Nielsen,
F Rosendal,
D Deding,
K S Ettrup,
K N Jensen,
R L Jørgensen,
A N Glud,
K Meier,
L M Fitting,
A Møller,
A K O Alstrup,
L Ostergaard,
C R Bjarkam
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ABSTRACT: The Göttingen minipig has been established as a translational research animal for neurological and neurosurgical disorders. This animal has a large gyrencephalic brain suited for examination at sufficient resolution with conventional clinical scanning modalities. The large brain, further, allows use of standard neurosurgical techniques and can accommodate clinical neuromodulatory devises such as deep brain stimulation (DBS) electrodes and encapsulated cell biodelivery devices making the animal ideal for basic scientific studies on neuromodulation mechanisms and preclinical tests of new neuromodulation technology for human use. The use of the Göttingen minipig is economical and does not have the concerns of the public associated with the experimental use of primates, cats, and dogs, thus providing a cost-effective research model for translation of rodent data before clinical trials are initiated.
Progress in brain research 01/2011; 194:97-103. · 3.04 Impact Factor
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ABSTRACT: Large animal neuroscience enables the use of conventional clinical brain imagers and the direct use and testing of surgical procedures and equipment from the human clinic. The greater complexity of the large animal brain additionally enables a more direct translation to human brain function in health and disease. Economical, ethical, scientific and practical issues may on the other hand hamper large animal neuroscience. Large animal neuroscience should therefore either be performed in order to examine large animal species dependent problems or to complement promising small animal basic studies by constituting an intermediate research system, bridging small animal CNS research to the human CNS. We have, accordingly, during the last ten years used the Gottingen minipig to examine neuromodulatory treatment modalities such as stem cell transplantation and deep brain stimulation directed towards Parkinson disease. This has been accomplished by the development of a MPTP-based large animal model of Parkinson disease in the Gottingen minipig and the development of stereotaxic and surgical approaches needed to manipulate the Gottingen minipig CNS. The instituted changes in the CNS can be evaluated in the live animal by brain imaging (PET and MR), cystometry, gait analysis, neurological evaluation and by post mortem examination based on histology and stereological analysis.
British Journal of Neurosurgery 02/2008; 22 Suppl 1:S9-12. · 0.88 Impact Factor
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ABSTRACT: This study describes the pathological findings in the brain of a patient with Parkinson's disease (PD) treated with bilateral subthalamic high-frequency deep brain stimulation (STN DBS) for 29 months prior to death. After routine neuropathological examination, tissue blocks containing the electrode tracts, the subthalamic nucleus (STN), the substantia nigra and the pre-frontal cortex were paraffin embedded and cut into 5-microm-thick serial sections and stained with several conventional staining methods and immunohistochemistry. Bilateral nigral depigmentation, cell loss and Lewy body formation confirmed the diagnosis of PD. Microscopic evaluation furthermore confirmed the location of the electrodes in the STN. The electrode tracts were surrounded by a 150-microm-wide glial fibrillary acidic protein (GFAP)-positive capsule consisting of a thin collagen layer lining the lumen of the tract, whilst an area with few cells and axons constituted the capsule wall towards the surrounding normal brain tissue. The brain tissue appeared normal outside the capsule boundaries with no difference in areas of stimulation compared with areas of no stimulation. Our results correspond with previous studies performed after fewer months of STN DBS and indicate mild histopathological changes in the vicinity of the electrode tract, appearing to result from the electrode placement and not from the electrical stimulation.
European Journal of Neurology 03/2007; 14(2):132-8. · 3.69 Impact Factor
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ABSTRACT: Twenty percent of the patients immunosuppressed with cyclosporine A (CsA) develop neurological side effects such as tremor, paresthesias, headache, seizures, visual disorders, paresis, and coma-CsA encephalopathy. The encephalopathy resolves on CsA discharge; autopsies of recovered patients are normal. Characteristic lesions are seen on magnetic resonance imaging (MRI) during the period of encephalopathy. MRI of asymptomatic patients receiving CsA as well as most recovered patients are normal. Several theories of pathogenesis have been proposed, but none has been firmly established. The current placebo-controlled study, blinded to the investigator, was accordingly initiated to elucidate histopathological changes in the brain. Twelve adult Göttingen minipigs were randomized into two groups treated with either low-dose CsA (10 mg/kg/d) or no treatment for 6 months. Behavior, blood pressure, and blood parameters were measured throughout the study. All animals had a cerebral MRI before sacrifice. Three control pigs and one CsA-treated pig died during observation and were excluded from the study. None of the remaining eight pigs displayed behavioral signs or MRI-visible lesions characteristic of CsA encephalopathy. The brains appeared all normal on the gross pathological examination, but microscopy revealed perivascular, meningeal, and neuronal tissue infiltration with granulocytes and mononuclear cells in one CsA-treated pig, while the remaining pigs were without histopathological lesions. Pathological changes were noticed in one out of five CsA-treated animals, corresponding to the percentage of patients treated with CsA who develop CsA encephalopathy. To pursue this finding, two studies, one using CsA 20 mg/kg/d for 6 months and one using CsA 10 mg/kg/d for 12 months, have been initiated.
Transplantation Proceedings 11/2005; 37(8):3305-8. · 1.00 Impact Factor
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ABSTRACT: We present a nonmagnetic Plexiglas stereotaxic localizer box that can be fitted directly to the pig skull by aluminum screws, allowing stereotaxic MRI or ventriculography and subsequent high-precision stereotaxic procedures. The localizer box was used to target the subthalamic nucleus (STN) bilaterally in five female Göttingen minipigs. Stereotaxic markers were inserted in the pig skull, the head fixated in the localizer box by aluminum screws inserted bilaterally in the zygoma bone with the hard palate locked on a horizontal palate holder. MRI was obtained on a 3T-MR-imager revealing the relation between the inserted markers and the estimated STN-position, and thus the target coordinates. After the MRI, a stereotaxic frame with attached micromanipulator was locked on to the localizer box converting it into a stereotaxic device. The stereotaxic markers were exposed and used as starting point for the stereotaxic procedure, whereby a microelectrode for electrolytic lesioning was inserted in the STN. Postmortem histological analysis revealed 70% correct STN-targeting. The average distance from the lesion center to the STN center was 1.2 mm with a S.D. of 1.1 mm. The most displaced lesion being 3.6 mm from the STN center. We conclude that the described localizer box secure firm head fixation, allowing stereotaxic MRI and subsequent conversion into a stereotaxic device for high-precision stereotaxic procedures.
Journal of Neuroscience Methods 11/2004; 139(2):293-8. · 1.98 Impact Factor
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ABSTRACT: Suprapontine neural integration during the storage phase is decisive for the timing of voiding. Neurological disorders like Parkinson's disease are thus frequently complicated by bladder dysfunction. The aim of the present study was to investigate the effect of high frequency deep brain stimulation on the urine storage and voiding function in conscious Parkinsonian minipigs.
Five Goettingen minipigs had a Parkinsonism-like state induced by intoxication with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). An electrode for chronic stimulation was placed unilaterally in the subthalamic nucleus. The effect of stimulation was determined by the outcome of transurethral cystometries performed with the stimulation in on- and off-mode.
Of 20 planned cystometry-sessions 18 were completed. Six incomplete voidings occurred in stimulation on-mode and five in off-mode. Interruption of the stimulation for 2 days was followed by a significant increase in pressure rise on filling to cystometric capacity, from 7 to 21 cmH(2)O (P = 0.005), and an insignificant reduction in cystometric capacity from 30 to 26 ml/kg bodywt. (P = 0.370), leading to a significant decrease in bladder compliance from 124 to 34 ml/cmH(2)O (P = 0.013).
Transurethral cystometry was a feasible examination technique in pigs. The findings demonstrate that high frequency deep brain stimulation changes the bladder characteristics in the storage phase. Since bladder pressure and capacity responded differently to interruption of stimulation distinct neural mechanisms must be involved in the modulation of sensory information on bladder tension and stretch.
Neurourology and Urodynamics 02/2004; 23(3):265-72. · 2.96 Impact Factor
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ABSTRACT: A new autometallographic (AMG) technique for staining myelin in formaldehyde- or paraformaldehyde- (PFA) fixed tissue is presented. The tissue sections were exposed to AMG development without prior treatment with silver salts. The method was examined on PFA-fixed tissue from mouse, rat, pig, and formaldehyde-fixed human autopsy material. Samples from brain, spinal cord, cranial, and spinal nerves were either cut on a vibratome, frozen and cryostat sectioned, or embedded and microtome sectioned, before AMG development and counterstaining. The AMG-myelin technique results in a specific black/dark-brown staining of myelin in all parts of the CNS and PNS. It works on all species examined, independent of the histological preparation techniques applied. The AMG staining is stable, stays unchanged through decades, allows counterstaining, and has previously been used with immunohistochemical techniques. On perfusion-fixed tissue the technique works without further fixation, but the intensity of the AMG-myelin staining is increased by increased postfixation time. Additionally, immersion fixation has to last for days depending on the size of the tissue block in order to obtain proper myelin staining. The most feasible explanation of the chemical events underlying the AMG-myelin technique is that nano-sized clusters of metallic silver are formed in the myelin as a result of chemical bounds with reducing capacity, exposed or created by the formaldehyde molecule. The AMG method is simple to perform and as specific as the conventional osmium and luxol fast blue stainings. The present technique is thus an effective, simple, inexpensive, and quick myelin staining method of formaldehyde- or PFA-fixed tissue.
Histology and histopathology 11/2003; 18(4):1125-30. · 2.48 Impact Factor
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ABSTRACT: We present a newly developed brain slicing machine and technique for tissue embedding, which enable orientation of fresh or fixed brain tissue from small laboratory animals, in any given position, and subsequent tissue sectioning into slabs with an optional thickness between 0.5 and 20 mm. The oriented tissue slabs may be analysed directly, or processed further on a cryostat or vibratome, into thin stainable histological sections, and aligned to MR-images or brain atlases, depending on the reference used for the initial orientation. Additionally, we describe a new embedding medium (HistOmer) which is an alginate cold polymer ready for instant use after mixing with water. HistOmer allows accurate positioning of the tissue during embedding, and at the same time supports and protects the embedded tissue during sectioning. HistOmer is, therefore, described comprehensively and compared with other commonly used embedding media. This novel slicing technique may also, as illustrated, be used to perform isotropic random orientation of the embedded tissue, before sectioning into tissue slabs of the same thickness. The technique thereby fulfills the requirements for optimal tissue sampling and preparation needed for an unbiased stereologic analysis.
Journal of Neuroscience Methods 08/2001; 108(2):153-9. · 1.98 Impact Factor
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P Cumming,
E H Danielsen,
M Vafaee,
L Falborg,
E Steffensen, J C Sørensen,
N Gillings,
D Bender,
K Marthi,
F Andersen,
O Munk,
D Smith,
A Møller,
A Gjedde
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ABSTRACT: As part of the DaNeX study, the uptake and binding of several positron emitting tracers was recorded in brain of healthy Göttingen minipigs, in minipigs with a syndrome of parkinsonism due to MPTP intoxication, and in parkinsonian minipigs which had received intrastriatal grafts of mesencephalic neurons from fetal pigs. The specific binding of [11C]NS 2214 to catecholamine uptake sites was reduced by two thirds in striatum of the intoxicated animals, while the rate constant for the decarboxylation of [18F]fluorodopa was reduced by 50% in the intoxicated animals. Several months after grafting, both pre-synaptic markers of dopamine fibres were normal in striatum. Dopamine depletion or grafting were without effect on the cerebral perfusion rate, measured with [15O]-water, did not alter the rate of oxygen metabolism (CMRO2) in brain, and did not alter the binding potential of tracers for dopamine D1 or D2 receptors in pig striatum. However, the grafting was associated with a local increase in the binding of [11C]PK 11195, a tracer for reactive gliosis, suggesting that an immunological reaction occurs at the site of graft, which might potentially have reduced the graft patency. However, this apparent immunological response did not preclude the re-establishment of normal [18F]fluorodopa and [11C]NS 2214 uptake in the allografted striatum.
Acta Neurologica Scandinavica 06/2001; 103(5):309-15. · 2.47 Impact Factor
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ABSTRACT: We present a new method allowing direct comparison between images obtained by present digital scanning modalities and histological sections from the same object. More specifically the paper illustrates how to orientate, embed, and section large irregular tissue blocks after magnetic resonance imaging (MRI) in such a way that accurate correlation of the digital data sets to histological sections is possible. The functionality and capability of the described procedure and slicing machine is illustrated by results from the pig brain. Accordingly, three pigs were MR-scanned, followed by perfusion fixation. The brains were removed, oriented according to the MR scans, embedded in alginate, and cut on a newly developed slicing machine. The tissue blocks were then stained to reveal grey and white matter and photographed before final sectioning on a cryostat into 80 microm thick sections which were Nissl-stained with toluidine. The results demonstrate how our method enables direct comparison between the pig brain MR images and the later obtained histological sections. The alginate embedding method and slicing machine offer the same possibilities for other parenchymateous organs and soft tissues and may, in addition, be of use in stereological analysis.
Journal of Neuroscience Methods 01/2001; 104(1):93-8. · 1.98 Impact Factor
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ABSTRACT: Patients with Parkinson's disease suffering from severe fluctuations, i.e. dyskinesias and on-off periods and/or severe tremor, who cannot be improved by adjustment of the medical treatment, can be treated with deep brain stimulation via leads implanted bilaterally into the subthalamic nuclei.
Nine patients with advanced idiopathic Parkinson's disease were treated with stereotactic and bilateral implantation of leads into the subthalamic nuclei. All patients had levodopa responsive Parkinson's disease and levodopa induced fluctuations in the form of on-off periods and dyskinesias. The mean age was 61 years and the mean duration of disease 15 years. The patients were followed for 12 months and evaluated with the Unified Parkinson's Disease Rating Scale off and on medications before and after lead implantation.
The Hoehn & Yahr stage fell from 3.9/2.8 before lead implantation and off/on medication to 3.0/2.3 with lead stimulation turned on and off/on medication. The activity of daily living (ADL) index was significantly improved and reduced from 27/13 before lead implantation and off/on medication to 12/7 with the stimulation turned on and off/on medication i.e. with 55%/46% on stimulation. The motor score was likewise significantly improved and reduced from 55/28 to 24/17 i.e. with 56%/39% on stimulation. The most important results of deep brain stimulation in the subthalamic nuclei is the significant reduction of the motor fluctuations. On stimulation off periods were reduced from 30% to 6% and the dyskinesias were significantly reduced from 47% to 14% of the daytime. The mean dose of levodopa equivalent medication was reduced with 26%.
In conclusion, patients with advanced Parkinson's disease and levodopa induced fluctuations can be successfully treated with bilateral high frequency electric stimulation of leads implanted into the subthalamic nuclei.
Ugeskrift for laeger 11/2000; 162(41):5491-6.
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ABSTRACT: The authors tested the hypothesis that oxygen metabolism is the key factor linking the long-term viability of ischemic brain tissue to the magnitude of residual blood flow during the first 6 hours following a stroke.
Eleven anesthetized pigs underwent a series of positron emission tomography studies to measure cerebral blood flow (CBF) and metabolism before and for 7 hours after the animals were subjected to permanent middle cerebral artery (MCA) occlusion. The extent of collateral blood supply was assessed using angiography. Abnormal metabolism of the ischemic tissue progressed as a function of time in inverse proportion to the magnitude of residual CBF, and the volume of the infarct grew in inverse proportion to the residual blood supply. Ten hours after occlusion of the MCA, the infarct topographically matched the tissue with a cerebral metabolic rate of oxygen consumption below 50% of values measured on the contralateral side. This was also the threshold for the decline of the oxygen extraction fraction below normal, which was critical for the prediction of nonviable ischemic tissue. Mildly ischemic tissue (CBF > 30 ml/100 g/min) did not reach the cerebral metabolic rate of oxygen threshold of viability during the first 6 hours after MCA occlusion; moderately ischemic tissue (CBF 12-30 m1/100 g/ min) reached the threshold of viability in 3 hours; and severely ischemic tissue (CBF < 12 ml/100 g/min) remained viable for less than 1 hour.
The relationship between the residual CBF and both oxygen metabolism and extraction is critical to the evolution of metabolic deficiency and lesion size after stroke.
Journal of Neurosurgery 10/2000; 93(4):647-57. · 2.96 Impact Factor
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ABSTRACT: Zinc-positive neurons and terminals, known to be associated with the glutamatergic projections in the brain, can be demonstrated by the histochemical Timm method and later modifications thereof. The adult rat neocortex contain a uniform lamination of zinc-positive cells with specific projections to, e.g., the striatum. We have previously reported that fetal neocortical grafts implanted in the adult rat neocortex combined with rearing in an enriched environment can improve behavioral functions and reduce the secondary atrophy of thalamus after cortex infarction in adult rats. In order to examine whether the expression of zinc positivity is ontogenetically inherent to neocortical neurons we grafted fetal neocortical tissue to aspiration or ischemic lesions of the frontoparietal neocortex of adult rats, followed by histochemical visualization of the vesicular zinc pool by selenite or sulfide. One further aim of the study was to elucidate to what extent the distribution of zinc-containing neurons and terminals in the grafts depended on rearing under different environmental conditions. The foremost finding of the present study was that the overall density of zinc-containing terminals in fetal cortical transplants placed in brain infarcts of adult spontaneously hypertensive rats is higher when the rats are reared in an enriched environment. Moreover, the presence and expression of zinc-positive neurons and terminals do not seem to be ontogenetically inherent to the cortical neurons as the fetal neocortical grafts placed in aspiration lesions contained no zinc-selenide-positive neurons and few or no zinc-selenide-positive terminals. The presence or expression of zinc-positive cells may thus be induced by ingrowth of fibers and terminals from the host brain as transplants placed in the ischemic lesions expressed both zinc-positive neurons and terminals.
Experimental Neurology 08/2000; 164(1):176-83. · 4.70 Impact Factor
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ABSTRACT: The ontogenetic development of the neocortical projections to the striatum was studied in postnatal rats by sensitive anterograde tracing with biocytin. The developmental status of this mainly glutamatergic pathway is important as it plays a major role in regulation of striatal maturation and induction of excitotoxic striatal neurodegeneration resembling the type found in Huntington's disease. Biocytin pelletts were injected into the motorcortex caudal forelimb area of newborn rats and of rats aged 3, 6, 13, 27 and 61 days followed by sacrifice and visualisation of the tracer 24 h later, at P1, P7, P14, P28 and P62, respectively. Biocytin pellets were also injected into the motorcortex jaw-lip-tongue area and into the cingulate cortex of newborn and 6-day-old rats. The biocytin pellets produced intense anterograde labelling of corticofugal projection fibres from the injection sites, as well as a local Golgi-like labelling of neurons. From postnatal day 1 into adult age efferent fibres from the motorcortex caudal forelimb area displayed a progressively denser innervation of the ipsilateral and contralateral, dorsolateral striatum. The terminating fibres were most dense in the ipsilateral striatum. In the dorsolateral striatum the corticostriatal fibres displayed a patch/matrix-like arrangement from postnatal day 14 onwards. Injections into the motorcortex jaw-lip-tongue area at postnatal days 0 and 6 displayed a progressive, denser innervation of the ipsilateral and contralateral ventrolateral striatum. The cingulate corticostriatal fibre projection, was more developed at birth than the projection from the motorcortex and increased its fibre density in the ipsilateral dorsomedial striatum up to at least day 7. In conclusion: the ipsilateral corticostriatal projections from the rat motorcortex and cingulate areas are present in newborn rats. During postnatal life the pathway develops further and specialisation of the terminating fibres into a patch/matrix like arrangement can be identified by postnatal day 14.
Anatomy and Embryology 08/1999; 200(1):73-80. · 1.42 Impact Factor
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ABSTRACT: Neuroleptic-induced oral dyskinesias in rats, a putative analogue to human tardive dyskinesia, may be due to excitotoxic degeneration within the striatum. Haloperidol treatment for 34 weeks increased the optical density of preproenkephalin messenger RNA in individual striatal neurons and enkephalin peptide in the neuropil, regardless of the level of oral dyskinesia produced. However, using unbiased stereological methods, an increased number of striatal neurons expressing preproenkephalin messenger RNA was observed only in rats that did not develop pronounced oral dyskinesias during haloperidol treatment. Said in another manner, the haloperidol-treated animals that developed pronounced oral dyskinesias, failed to produce an increase in the number of neurons expressing preproenkephalin messenger RNA. These results indicate that the mechanism by which neuroleptics induce oral dyskinesias in rats, and perhaps tardive dyskinesia in humans, involves a functional disturbance or even damage to a subpopulation of enkephalinergic neurons in the striatum.
Neuroscience 02/1999; 88(1):27-35. · 3.38 Impact Factor
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ABSTRACT: The study was undertaken to determine if the levels of vesicular zinc in neuronal terminals would decrease in response to focal brain ischemia. The middle cerebral artery was occluded distal to the striatal branches in male spontaneously hypertensive rats. At 7, 15, 30, 45, 60, 90, 120 min; 3, 6, 12, 24, 48 h and 7 days later the animals were sacrificed and the brains were stained for zinc-sulfides, cell bodies and AChE-positive cholinergic fibers. The density of zinc positive terminals significantly decreased in the neocortical ischemic zone 7 min after middle cerebral artery occlusion (MCAO). In the neocortical layers II and III most zinc positive neuronal terminals disappeared at 7 min after MCAO whereas the zinc positive terminals in layers V and VI remained positive at least 2 h. Beginning at 1 h after MCAO and progressing to 24 h a significant decrease in the density of zinc positive terminals was observed in the dorsolateral striatum, and ventrobasal thalamic nucleus, both major projection areas of the sensorimotor cortex. The disappearance of zinc positive neuronal terminals in the ischemic neocortex and related areas, is most likely due to a neuronal release of vesicular zinc in response to hypoxia. The high extracellular concentration of zinc is thought to be both neuroprotective by blocking the NMDA receptor and neurotoxic by activating neuronal influx of Ca2+ through voltage gated calcium channels. It seems evident that the latter effect of zinc is contributing to the neuronal death in focal brain ischemia.
Brain Research 12/1998; 812(1-2):265-9. · 2.73 Impact Factor
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ABSTRACT: The purpose of this study was to evaluate whether grafting of fetal neocortical tissue 1 week after focal brain ischemia improved behavioral outcome and reduced secondary thalamic atrophy.
One week after distal ligation of the right middle cerebral artery in spontaneously hypertensive male rats, blocks of fetal neocortex (embryonic day 17) were homografted to rats housed in standard or enriched environments. Control infarcted nongrafted rats were housed in the enriched environment. Behavioral outcome was repeatedly tested until the rats were killed 20 weeks after the ligation. Ten days earlier, a mixture of 2% Fluoro-Gold and 10% biotinylated dextran amine was injected into the transplants for retrograde and anterograde tracing of graft-host connections.
Grafted and nongrafted rats with enriched housing performed significantly better than grafted rats with standard housing on a rotating pole and a prehensile traction test. Grafted "enriched" rats were moreover significantly better than grafted "standard" rats and nongrafted enriched rats in a rotation test and a postural and locomotor tail position test. In the latter test, nongrafted enriched rats performed significantly better than grafted standard rats. The lesion-induced atrophy in posterior thalamus with its major sensorimotor cortex relay nuclei was significantly reduced in grafted enriched rats compared with nongrafted enriched rats. Afferent and efferent graft-host connections were identified in both grafted groups. Graft volumes did not differ.
Neural grafting enhanced functional outcome and reduced thalamic atrophy only when combined with housing in enriched environments.
Stroke 07/1997; 28(6):1225-31; discussion 1231-2. · 5.73 Impact Factor
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ABSTRACT: The aim of the present study was to demonstrate the morphology and distribution of the serotonergic neurons in the brainstem of the New Zealand white rabbit by using a highly specific immunocytochemical procedure. It was possible to divide the serotonergic neurons into a rostral group, which is situated in the mesencephalon and the rostral part of the pons containing four serotonergic nuclei, and a caudal group, which is located in the medulla and the caudal part of the pons containing five serotonergic nuclei. The localization of the serotonergic neurons is presented in a detailed brainstem atlas, and the distribution of the serotonergic neurons is in accordance with results obtained by other authors in different species. Special emphasis was given to the fact that many of the serotonergic neurons were distributed in more lateral parts of the brainstem. The laterally orientated neurons, which were large and multipolar, were morphologically different from the serotonergic neurons in the midline, which were mostly small and relatively nonpolar. The serotonergic system of the New Zealand white rabbit has undergone a major lateralization, like the serotonergic system of man and higher primates, and it may therefore be excellently suited for experimental procedures directed towards the serotonergic system. The difference between serotonergic neurons localized in the midline and those situated laterally may reflect functional differences based on dissimilarity in connectivity and morphology, and this possible subspecialization of the serotonergic system is discussed in the context of present knowledge of serotonergic anatomy and function.
The Journal of Comparative Neurology 05/1997; 380(4):507-19. · 3.81 Impact Factor
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ABSTRACT: Thalamic neuronal degeneration after neocortical lesions involve both anterograde and retrograde components. This study deals with the thalamic microglial response after neocortical aspiration lesions, using fluorogold fluorescent prelabeling, to identify retrogradely degenerating thalamocortical neurons, combined with histochemical or immunohistochemical staining of microglial cells. Adult male Wistar rats were injected with the retrograde fluorescent tracer fluorogold, in the right sensorimotor cortex (forepaw area) in order to retrogradely label thalamic neurons projecting to this area. After 1 week, the fluorogold injection site was removed by aspiration, axotomizing at the same time the thalamic projection neurons now retrogradely labeled with fluorogold. After 3, 7, 14, and 28 days the animals were killed and processed for nucleoside diphosphatase histochemistry or complement type 3 receptor immuno-histochemistry and class I and II major histocompatibility complex immunohistochemistry using OX42, OX18, and OX6 antibodies. The histological analysis showed a prominent and progressive nucleoside diphosphatase-, OX42-, and OX6-positive microglial cell response in the ventrolateral, posterior, and ventrobasal thalamic nuclei with ongoing retrograde and anterograde neuronal degeneration. Initially the reactive microglia had a bushy morphology and were succeeded by ameboid microglia and microglial cluster cells as the reaction progressed. However, in the reticular thalamic nucleus, which suffered exclusively anterograde neuronal degeneration, a different picture was seen with only bushy microglia. The neurons undergoing retrograde degeneration in the ventrolateral, posterior, and ventrobasal thalamic nuclei were retrogradely labeled by the fluorogold tracer. Individual nucleoside diphosphatase-, OX42-, or OX6-positive microglial cells extended long cytoplasmic processes surrounding fluorogold-labeled neurons and had in some cases apparently phagocytized these. Several microglial cells were thus double-labeled with nucleoside diphosphatase or OX42 and fluorogold. In addition, small nucleoside diphosphatase-positive, fluorogold-labeled perivascular cells were observed in the neocortex near the fluorogold-injected and ablated neocortical areas and in the ipsilateral thalamus. This study demonstrates: (1) that the microglial response to thalamic degeneration after neocortical lesion is graded with a limited reaction to the well-known massive anterograde axonal degeneration and a more extended reaction to the axotomy-induced retrograde cell death; and (2) that also perivascular cells and possibly macrophages may contribute to this reaction, as seen by uptake of fluorogold from axotomized neurons in the degenerating thalamic nuclei.
Experimental Brain Research 12/1996; 112(2):203-12. · 2.39 Impact Factor
