Lesioned Side Research Articles

Human neural stem cell transplants improve motor function in a rat model of Huntington's disease.

The present study investigated the neuroanatomical and behavioral effects of human stem cell transplants into the striatum of quinolinic acid (QA)-lesioned rats. Twenty-four rats received unilateral QA (200 nM/microl) injections into the striatum. One week later, rats were transplanted with stem cells derived from human fetal cortex (12 weeks postconception) that were either 1) pretreated in culture media with the differentiating cytokine ciliary neurotrophic factor (CNTF; n = 9) or 2) allowed to grow in culture media alone (n=7). Each rat was injected with a total of 200,000 cells. A third group of rats (n=8) was given a sham injection of vehicle. Rats transplanted with human stem cells performed significantly better over the 8 weeks of testing on the cylinder test compared with those treated with vehicle (P < or = 0.001). Stereological striatal volume analyses performed on Nissl-stained sections revealed that rats transplanted with CNTF-treated neurospheres had a 22% greater striatal volume on the lesioned side compared with those receiving transplants of untreated neurospheres (P = 0.0003) and a 26% greater striatal volume compared with rats injected with vehicle (P < or = 0.0001). Numerous human nuclei-positive cells were visualized in the striatum in both transplantation groups. Grafted cells were also observed in the globus pallidus, entopeduncular nucleus, and substantia nigra pars reticulata, areas of the basal ganglia receiving striatal projections. Some of the human nuclei-positive cells coexpressed glial fibrillary acidic protein and NeuN, suggesting that they had differentiated into neurons and astrocytes. Taken together, these data demonstrate that striatal transplants of human fetal stem cells elicit behavioral and anatomical recovery in a rodent model of Huntington's disease.

Changes of high-affinity choline transporter CHT1 mRNA expression during degeneration and regeneration of hypoglossal nerves in mice

The high-affinity choline transporter CHT1 works for choline uptake in the presynaptic terminals of cholinergic neurons. We examined its expression in the hypoglossal nucleus after unilateral hypoglossal nerve transection in mice by fluorescent in situ hybridization. One week after axotomy, CHT1 mRNA expression was lost in all hypoglossal motoneurons in the lesioned side. Two weeks after axotomy, CHT1 mRNA started to be re-expressed in a few motoneurons that recovered connections to tongue muscles as revealed by retrograde labeling with Fast Blue. After 4 weeks, most of axotomized hypoglossal motoneurons were reconnected and re-expressed CHT1 mRNA as strongly as control neurons, and the regenerating cholinergic axons established mature neuromuscular junctions. These results suggest that the establishment of motor innervation is critical for CHT1 mRNA expression in hypoglossal neurons after axotomy.

Phrenic rehabilitation and diaphragm recovery after cervical injury and transplantation of olfactory ensheathing cells

Functional respiratory recovery was evaluated by recording diaphragm and phrenic nerve activity several months after cervical cord hemisection followed by olfactory ensheathing cell (OEC) transplantation. The intact side was taken as a control in each rat. Sham-transplanted rats did not recover respiratory activity from the ipsilateral lesioned side. By contrast, ipsilateral phrenic and diaphragmatic activities recovered in transplanted rats amounted to 80.7% and 73% of their controls, respectively. After contralateral acute C1 section eliminating any contralateral influence from crossed compensatory pathways, the ipsilateral phrenic activity remained at 57.5% of the control, indicating that the phrenic recovery originated from the ipsilateral side. Supralesional stimulation in these rats elicited sublesional ipsilateral postsynaptic phrenic responses showing that transplantation helped ipsilateral fibers to again transmit nervous messages to the phrenic target, leading to substantial functional recovery. The origin of mechanisms involved in respiratory recovery (regeneration, resurrection, sprouting, sparing, demasking of latent pathways) is discussed.

11β-Hydroxysteroid Dehydrogenase Type 1 Activity in Medial Vestibular Nucleus and Cerebellum after Unilateral Vestibular Deafferentation in the Rat

In the early stages of vestibular compensation (VC) (the behavioural recovery that follows unilateral vestibular deafferentation), neurons in the medial vestibular nucleus (MVN) on the lesioned side develop a sustained up-regulation of their intrinsic excitability. This plasticity is dependent on the activation of glucocorticoid receptors, which presumably occurs during the acute stress response that accompanies the vestibular deafferentation symptoms. Recent studies have established that the access of glucocorticoids to their intracellular receptors in brain is potently modulated by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which catalyses the generation of active glucocorticoids from their inert 11-keto forms. In this study, we investigated the presence of 11β-HSD1 bioactivity, and possible changes in activity in the early stage after vestibular deafferentation, in the cerebellar nodulus and uvula, the flocculus/paraflocculus (F/PF) complex and the MVN of the rat. 11β-HSD1 activity was found in each of these brain areas, with especially high levels of activity in the F/PF complex. No differences were found in the level of 11β-HSD1 activity in these brain areas between control rats, sham-operated rats and rats that underwent VC for 4 h after unilateral vestibular deafferentation. These findings demonstrate 11β-HSD1 bioactivity in the MVN and vestibulocerebellum, but exclude the possibility that changes in 11β-HSD1 activity occur in the early period after deafferentation, over the time when changes in MVN neuronal properties take place.

Microwave-assisted immunostaining: a new approach yields fast and consistent results

Advances in microwave technology permitted the development of new antigen labeling techniques. The recent microwave development of a true variable wattage unit designed for laboratory use and an apparatus for dampening standing wave radiation patterns have allowed investigators to better control the conditions within a microwave cavity. Thus, operating limits thought to be endemic to microwave-assisted protocols could be effectively mitigated. Standard protocols for histochemistry call for prolonged incubations and numerous rinses that add considerable time to the procedure. Here, we present microwave-assisted staining protocols for floating rat brain sections and cultured rat hippocampal cells. Acetylcholinesterase (ACHE) histochemistry and immunocytochemistry were conducted inside a specially designed and configured laboratory microwave oven. As a control additional tissue sections were stained on the bench and treated in the same manner as those in the microwave. Labeling was minimal in the control tissue, but specific, high contrast staining was present in the microwave group. Tissues were evenly stained with minimal background, and anatomical structures were easily detected. Also, the differences between lesioned and intact sides of the brain were obvious and agreed with previous observations. Microwave-assisted methods resulted in significantly shorter protocol times (∼10-fold) resulting in staining patterns of equal or superior quality to those obtained using conventional methods.

Gait instability in patients with acoustic neuroma

ObjectiveTo investigate pathological gait in patients with unilateral acoustic neuroma using tactile sensors placed under both feet.Material and MethodsForty-three patients were enrolled in the study. They were categorized into two groups: the small tumor group had tumors<2 cm from the porus acousticus without any brainstem compression and the large tumor group had tumors>2 cm from the porus acousticus with brainstem compression. Eighteen healthy subjects served as controls. Subjects were asked to walk freely with eyes open or closed for a distance of nearly 8 m. The coefficients of variation (CVs) of stance, swing and double support were calculated. The stability of the trajectories of the center of force and the foot pressure difference were also studied.ResultsThe CVs of stance, swing and double support were significantly greater with eyes closed and, with the exception of double support, these differences were greater in the tumor groups. The instability of the trajectories of the center of force was significantly greater in the tumor group, and in the large tumor group the horizontal component of sway movement of the trajectories of the center of force of the foot on the same side as the lesion was greater than that on the intact side with eyes closed. Regarding foot pressure differences between the two feet, the large tumor group had a greater foot pressure for the foot on the same side as the lesion than for the foot on the intact side, especially with eyes closed. No significant difference was found in the small tumor group.ConclusionThe presence of acoustic neuroma may cause unstable gait, and steady gait is considerably dependent on visual input. Larger tumors may produce shifts in the body's center of gravity to the lesioned side during gait, especially under conditions of visual deprivation. These abnormalities may reflect some influences on gait control systems such as phase and muscular tonus control systems.

Large Vestibular Evoked Myogenic Potentials in Response to Bone-Conducted Sounds in Patients with Superior Canal Dehiscence Syndrome

Dehiscence of the superior semicircular canal is a ‘new’ vestibular entity. Among these patients, the vestibular evoked myogenic potentials (VEMP) in response to air-conducted sounds are large. In the present study, VEMP in response to bone-conducted sounds were studied in 5 normal subjects, in 3 patients after (unilateral) labyrinthectomy and in 4 patients with (unilateral) superior canal dehiscence syndrome. The bone-conducted sound stimulus was a 250- and a 500- tone burst delivered monaurally on the mastoid using standard bone conductors. Among the normals, bone-conducted sounds delivered monaurally caused VEMP bilaterally. There was, however, a transcranial attenuation for the 500-Hz stimulus, but less so for the 250-Hz stimulus. Among the patients with labyrinthectomy there were VEMP on the healthy side, but not on the lesioned side, irrespective of whether the bone-conducted sounds were presented behind the healthy or the operated ear. Among the patients with superior canal dehiscence syndrome, the VEMP on the affected side were larger than on the healthy side. This suggests that there is also vestibular hypersensitivity for bone-conducted sounds in these patients.

Lipoprotein lipase and endothelial lipase expression in mouse brain: regional distribution and selective induction following kainic acid-induced lesion and focal cerebral ischemia

Lipoprotein and endothelial lipases are members of the triglyceride lipase gene family. These genes are expressed in the brain, where the encoded proteins are fulfilling functions that have yet to be elucidated. In this study, we examined the distribution of their respective mRNAs in the C57BL/6 mouse brain by in situ hybridization. In control mice, we observed widespread expression of lipoprotein lipase (LPL) mRNA mainly in pyramidal cells of the hippocampus (CA1, CA2 and CA3 areas), in the striatum and in several cortical areas. Endothelial lipase (EL) mRNA expression was restricted to CA3 pyramidal cells of the hippocampus, to ependymal cells in the ventral part of the third ventricle and to some cortical cell layers. To gain insight into the role played by lipases in the brain, neurodegeneration was induced by intraperitoneal injection of kainic acid (KA) or by occlusion of the middle cerebral artery (MCA). Upon injection of KA, a rapid increase in EL mRNA expression was observed in the piriform cortex, hippocampus, thalamus and neocortex. However, the levels of LPL mRNA were unaffected by KA injection. Remarkably, after focal cerebral ischemia, the expression of EL was unaffected whereas a dramatic increase in LPL expression was observed in neocortical areas of the lesioned side of the brain. These results show that LPL and EL transcripts are selectively upregulated in function of the type of brain injury. LPL and EL could thus fulfill a function in the pathophysiological response of the brain to injury.

Entorhinal cortex lesioning promotes neurogenesis in the hippocampus of adult mice

Hippocampal neurogenesis in adult mammals is influenced by many factors. Lesioning of the entorhinal cortex is a standard model used to study injury and repair in the hippocampus. Here we use bromodeoxyuridine (BrdU) labeling combined with immunohistochemical identification using cell type specific markers to follow the fate of neural progenitors in the hippocampus following entorhinal cortex lesioning in mice. We show that unilateral entorhinal cortex lesioning does not alter the rate of neural progenitor proliferation in the ipsilateral dentate gyrus during the first 3 days after lesioning. However it enhances cell survival at 42 days post-lesioning leading to an increased number of β-III tubulin and calbindin-immunoreactive neurons being produced. By contrast, when BrdU was administered 21 days post-lesioning, the number of surviving cells 21 days later was similar on the lesioned and non-lesioned sides. Thus, acutely entorhinal cortex lesioning promotes neurogenesis by enhancing survival of either neural progenitors or their progeny. However, this stimulus to neurogenesis is not sustained into the recovery period.

Extrapyramidal motor symptoms versus striatal infarction volume after focal ischemia in mongolian gerbils

Few behavioral tests are available to evaluate extrapyramidal dysfunctions after focal cerebral ischemia in rodents, although extrapyramidal motor dysfunctions are often observed clinically in patients with cerebral infarction. We evaluated the methamphetamine (MP)-induced rotation test for the detection and quantification of extrapyramidal motor dysfunction induced by striatal infarction in gerbils after focal cerebral ischemia. Mongolian gerbils ( n=79) underwent the left common carotid artery occlusion (CCAO) for 10, 15, or 20 min. Spontaneous and MP-induced rotation tests were repeated postischemia, and the results compared with the extent of ischemic tissue injury. The density of dopaminergic neurons immunostained with a tyrosine hydroxylase antibody in the substantia nigra pars compacta (SNpc) also was measured. Histological examination revealed selective neuronal death of the hippocampal cornu ammonis 1 (CA1) sector in 10-min CCAO animals, infarction confined to the striatum and hippocampal neuronal death in 15-min CCAO animals, and widespread hemispheric infarction in 20-min CCAO animals. Dopaminergic neurons in the SNpc were preserved in 10- and 15-min CCAO animals but were significantly reduced in 20-min CCAO animals. In MP-induced rotation tests, 15-min CCAO animals showed biased rotation ipsilateral to the lesioned side. Biased rotation persisted 4 weeks postischemia, and the number of rotations significantly correlated with the regional infarction volume of the striatum. Twenty-minute CCAO animals showed biased rotation contralateral to the lesioned side; rotation number was not correlated with the infarction volume. Our results show that biased rotation behavior is a sensitive parameter of the extent of striatal injury after focal cerebral ischemia provided the lesion is not extended to the ipsilateral cortex. MP-induced rotation in rodents probably coordinates with the extrapyramidal motor dysfunction after striatal infarction in patients with vascular Parkinsonism.

Evolving metabolic changes during the first postoperative year after subthalamotomy.

Short-term benefit from unilateral subthalamotomy for advanced Parkinson disease (PD) is associated with metabolic alterations in key targets of subthalamic nucleus (STN) and globus pallidus (GP) output. In this study positron emission tomography (PET) scanning was used to assess these changes and their relation to long-term benefits of subthalamotomy. To determine whether the early postoperative changes persisted at longer-term follow up, the authors assessed six patients with advanced PD by using [18F]fluorodeoxyglucose-PET at 3 and 12 months postsurgery. The authors compared each of the postoperative images with baseline studies, and assessed interval changes between the short- and long-term follow-up scans. Clinical improvement at 3 and 12 months was associated with sustained metabolic decreases in the midbrain GP internus (GPi), thalamus, and pons of the lesioned side (p < 0.01). The activity of a PD-related multiregional brain network, which correlated with bradykinesia and rigidity, was reduced at both postoperative time points (p < 0.05). Comparisons of 3- and 12-month images revealed a relative metabolic increase in the GP externus (GPe) (p < 0.001), which was associated with worsening gait, postural stability, and tremor at long-term follow up. These findings indicate that subthalamotomy may have differential effects on each of the functional pathways that mediate parkinsonian symptomatology. Sustained relief of akinesia and rigidity is associated with suppression of a pathological network involving the GPi and its output. In contrast, the recurrence of tremor may relate to changes in the function of an STN-GPe oscillatory network.

Walking performance of vestibular-defective patients before and after unilateral vestibular neurotomy

The present study investigated goal-directed linear locomotion in nine Menière’s patients before and after (1 week, 1 and 3 months) a curative unilateral vestibular neurotomy (UVN). Experiments were done using a 3D motion analysis system in subjects walking eyes open (EO) and eyes closed (EC) towards a real or memorized target, respectively. Locomotor pattern (velocity, step length, step frequency and walk ratio) and walking trajectory deviations were evaluated for normal and fast speeds of locomotion and compared to those recorded in 10 healthy subjects. Before UVN, patients showed no walking deviation but gait pattern changes characterized by slower walks compared to the controls, mainly due to step length and step frequency reductions for both visual conditions and locomotion speeds. In the acute stage after UVN, locomotor pattern impairments were significantly accentuated. On the other hand, patients showed strong walking deviations towards the lesioned side with EC. Opposite lateral deviation towards the intact side were observed with EO for normal speed only. Recovery from impaired locomotor pattern was achieved within 1 month for normal speed but remained uncompensated 3 months post-lesion for fast speed particularly in EC condition. Finally, the walking trajectory deviation towards the lesioned side in the dark was maintained up to 3 months after UVN. The results show that central processing of visual and vestibular cues contributes to an accurate locomotor pointing. They argue for an increased weight of visual reference frame on locomotor functions when vestibular function is unilaterally impaired.

Neurokinin-1 receptor-expressing cells regulate depressor region of rat ventrolateral medulla

Intraparenchymal injection of the saporin conjugate [Sar9, Met (O2)11] substance P-saporin (SSP-SAP) into the ventrolateral medulla (VLM) destroys neurokinin-1 receptor-immunoreactivity (NK1R-ir) neurons selectively. This treatment attenuates the hypotension caused by injection of DL-homocysteic acid (DLH) into the caudal VLM (CVLM). Here we ask whether SSP-SAP creates this deficit by destroying the CVLM GABAergic interneurons that mediate the sympathetic baroreflex (baroactivated depressor neurons) or by destroying other VLM neurons. Two weeks after unilateral SSP-SAP treatment (97% loss of VLM NK1R-ir neurons) DLH-induced hypotension and sympathetic tone inhibition were blunted on the lesioned side. Unlesioned or unilaterally lesioned rats received phenylephrine (PE) while awake to identify CVLM baroactivated depressor neurons by the presence of Fos-ir nuclei. Although CVLM Fos-ir cells were not NK1R-ir, their number was reduced approximately 60-70% on the SSP-SAP-injected side. SSP-SAP spared VLM neurons devoid of NK1R-ir, such as the catecholaminergic cells and the precerebellar glutamatergic neurons. In the pre-Bötzinger region of the VLM the toxin killed glutamatergic neurons while sparing glycinergic and GABAergic inhibitory neurons. In the CVLM region approximately 26% of the inhibitory cells were destroyed. In conclusion, the baroactivated depressor neurons of the CVLM do not appear to express NK1Rs but their activity is probably modulated by a population of excitatory NK1R-ir cells located in the VLM. The results also suggest that a region located below the CVLM (subCVLM) may contain an unrelated population of GABAergic depressor neurons that are NK1R-ir but are either not barosensitive or do not express Fos during baroreceptor stimulation.

Neurotrophic factors expressed in both cortex and spinal cord induce axonal plasticity after spinal cord injury.

We reported recently that overexpression of neurotrophin-3 (NT-3) by motoneurons in the spinal cord of rats will induce sprouting of corticospinal tract (CST) axons (Zhou et al. [2003] J. Neurosci. 23:1424-1431). We now report that overexpression of brain-derived neurotrophic factor (BDNF) or glial cell-derived neurotrophic factor (GDNF) in the rat sensorimotor cortex near the CST neuronal cell bodies together with overexpression of NT-3 in the lumbar spinal cord significantly increases axonal sprouting compared to that induced by NT-3 alone. Two weeks after unilaterally lesioning the CST at the level of the pyramids, we injected rats with saline or adenoviral vectors (Adv) carrying genes coding for BDNF (Adv.BDNF), GDNF (Adv.GDNF) or enhanced green fluorescent protein (Adv.EGFP) at six sites in the sensorimotor cortex, while delivering Adv.NT3 to motoneurons in each of these four groups on the lesioned side of the spinal cord by retrograde transport from the sciatic nerve. Four days later, biotinylated dextran amine (BDA) was injected into the sensorimotor cortex on the unlesioned side to mark CST axons in the spinal cord. Morphometric analysis of axonal sprouting 3 weeks after BDA injection showed that the number of CST axons crossing the midline in rats treated with Adv.BDNF or Adv.GDNF were 46% and 52% greater, respectively, than in rats treated with Adv.EGFP or PBS (P < 0.05). These data demonstrate that sustained local expression of neurotrophic factors in the sensorimotor cortex and spinal cord will promote increased axonal sprouting after spinal cord injury, providing a basis for continued development of neurotrophic factor therapy for central nervous system damage.

Transplantation of neural stem cells modulates apolipoprotein E expression in a rat model of stroke

The expression of apolipoprotein E (apoE) after ischemic brain damage has been associated with plasticity involved in promoting functional recovery. We therefore examined the expression and distribution of apoE in rats that received intraparenchymal grafts of the conditionally immortal stem cell line MHP36 either ipsilateral or contralateral to the lesion or intraventricular grafts 4 months after transplantation. ApoE immunoreactivity was highly expressed in the striatum, somatosensory cortex, and thalamus of the lesioned hemisphere in all rats subjected to middle cerebral artery occlusion. Only in rats with intraparenchymal grafts, apoE was significantly upregulated in the contralateral hemisphere, whereas levels and distribution in rats with intraventricular grafts resembled those of ischemic controls. In ischemic rats, apoE was seen in both astrocytes and neurons on the lesioned side, and in grafted rats, apoE was present in host and transplanted neurons and astrocytes. Previously we have shown that intraparenchymal grafts reduced sensorimotor asymmetry, whereas intraventricular grafts improved cognitive dysfunction, with transplanted cells being widely distributed in cortex, striatum, and corpus callosum on both sides of the brain in all grafted groups. Thus, stem cells grafted in the parenchyma are not only capable of limited expression of apoE in the host brain but also trigger a robust increase on the side contralateral to stroke damage where this does not normally occur. Findings that parenchymal, but not ventricular, grafts facilitated sensorimotor recovery suggests that apoE might contribute to plastic changes in relevant pathways, possibly on both sides of the brain. In contrast, no evidence was found for an association between apoE and recovery of cognitive function in rats with intraventricular grafts.

Rapid increase of Nurr1 expression in the substantia nigra after 6-hydroxydopamine lesion in the striatum of the rat.

Nurr1 is a transcription factor essential for the genesis of ventral dopaminergic neurons. In this study, we investigated the expression of Nurr1 protein and mRNA in the adult rat brain by using immunohistochemistry and in situ hybridization, respectively. Another aim of our study was to investigate Nurr1 expression in substantia nigra after dopamine depletion induced by the injection of 6-hydroxydopamine in the striatum. We observed that Nurr1 mRNA and protein are expressed in several brain regions, including cortex, hippocampus, substantia nigra, and ventral tegmental area, in agreement with previous reports using in situ hybridization. Additionally, we found that Nurr1 is expressed in brain regions that have not been previously reported, such as striatum, septum, and superior colliculus. Highest levels of expression were found in cortex, medial septum, dentate gyrus, some hypothalamic nuclei, and substantia nigra. Interestingly, we observed that, in the superior colliculus, Nurr1 protein is localized in the cytoplasm of cells, whereas, in other regions, it was localized mainly in the nuclei, suggesting that Nurr1 subcellular localization is regulated and may have functional implications. Dopamine depletion induced by an injection of 6-hydroxydopamine into the striatum produced an increase in the number of cells expressing Nurr1 mRNA and protein in both substantia nigra compacta and substantia nigra reticulata, ipsilateral and contralateral to the lesioned side, measured 24 hr after the 6-hydroxydopamine injection. These results suggest that Nurr1 may be involved in many neuronal functions in the adult central nervous system and, in particular, might be related to the compensation processes that take place in dopaminergic cells in order to normalize extracellular dopamine levels in the striatum.

Remodeling of synaptic connections in the deafferented vestibular nuclear complex

To determine if synaptic remodeling in the vestibular nuclear complex (VNC) may be involved in vestibular compensation, expressions of growth-associated protein-43 (GAP-43) and synaptosome-associated protein of 25 kDa (SNAP-25) were examined by immunoblotting and immunocytochemistry after unilateral vestibular ganglionectomy (UVG) in rats. GAP-43 expression increased bilaterally in the VNC after UVG, but more rapidly on the lesioned side, and remained high through 60 days. It was mainly associated with boutons at all survival times but was also present in some axonal processes and, at 7 days after UVG, in some somata. SNAP-25 expression also increased bilaterally, more rapidly on the lesioned side, but decreased bilaterally after peaking at 14 days. Its distribution in the VNC resembled that of GAP-43 but was more completely localized to boutons. Comparisons were made with auditory centers of the same rats, since the lesion also deafferented that system. Our results combined with those of previous studies suggest that degeneration of the vestibular nerve fibers is required for increased expression of GAP-43 in the VNC. The results suggest that axonal sprouting and synaptogenesis are involved in synaptic remodeling bilaterally in the rat VNC after UVG.

Sensorimotor deficits in a unilateral intrastriatal 6-OHDA partial lesion model of Parkinson’s disease in marmoset monkeys

Animal studies investigating the efficacy of neurotrophic factors as treatments for Parkinson’s disease (PD) ideally require partial dopamine (DA) lesion models. The intrastriatal 6-hydroxydopamine (6-OHDA) lesion model may be suitable for this purpose. Although this model has been well characterized in rodents, it has not previously been used in monkeys. The goal of the present study was to characterize the behavioral effects of unilateral injections of 6-OHDA in the basal ganglia of common marmoset monkeys ( Callithrix jacchus). Cell counts from tyrosine hydroxylase immunochemistry 5 months postlesion revealed DA cell loss in the substantia nigra on the lesioned side to ∼46% of relative to the unlesioned side. 6-OHDA lesioned monkeys showed a variety of behavioral deficits. Apomorphine induced rotation and simple sensorimotor measures (head position bias and PD disability rating score) were most affected by the lesion. The largest deficits were seen at 1 or 2 weeks postsurgery but had recovered by week 10. 6-OHDA lesioned monkeys took longer to complete a more complex sensorimotor staircase task. At 3.5 months postlesion, 6-OHDA monkeys also showed deficits on an object retrieval task designed to measure sensorimotor planning and skilled hand use. α-Methyl- p-tyrosine, a tyrosine hydroxylase inhibitor, reinstated those deficits which had undergone recovery in the lesioned animals and also exacerbated the deficits on the staircase task. This model has potential in assessing treatments for PD aimed at curtailing disease progression such as continuous delivery of neurotrophic factors.

Inflammatory Response Associated with Axonal Injury to Spinal Motoneurons in Newborn Rats

Axonal injury in peripheral nerve results in massive motoneuron loss during development. The purpose of this study was to examine the response of phagocytic populations (brain macrophages, BMOs, versus microglia) after different types of axonal lesions (distal axotomy or avulsion) in newborn rats. The morphology, spatial location and activation state of these inflammatory cells were observed. Following spinal root avulsion, BMOs were signaled rapidly and specifically to the location of dying motoneurons in the spinal cord. A large number of BMOs were observed around the avulsed motoneurons on the lesioned side of the spinal cord 1 day following the lesion. These BMOs were large, round, and intensely stained by both antibodies against ED1 and OX-42. The number of BMOs decreased by 3 days and disappeared by 5 days after injury. At the same time, reactive microglia appeared in the lesioned area and rapidly reached the peak level by the 5th day following avulsion. These reactive microglia were medium in size with retracted cellular processes and were also intensely stained by both ED1 and OX-42 antibodies. The number and staining intensity of reactive microglia declined sharply by day 7 after the lesion. In contrast, after distal axotomy only microglia but not BMOs were observed in the lesioned area. These microglial cells were small in size with long and fine-branched processes. They were ED1-negative but OX-42-positive.

Dopamine release rather than content in the caudate putamen is associated with behavioral changes in the iron rat model of parkinson’s disease

The effects of intranigral iron injection on dopamine (DA) release and content in the caudate putamen (CPu) and their relationship to DA-related behavioral response were investigated in rats. Different concentrations of FeCl 3 (10, 20, and 40 μg) and saline were injected separately into the left substantia nigra. In some experiments, rats were pretreated with desferrioxamine or saline before iron injection. After 3 weeks, changes in behavioral response, DA release, and DA content in the CPu were determined. In all iron injection groups (10, 20, and 40 μg), DA content in the lesioned side of the brain was significantly decreased, showing a significant linear correlation ( R 2 = 0.981, P = 0.01), and DA turnover ratio significantly increased (both P = 0.01, 0.01 and 0.001 vs unlesioned sides, respectively). However, injection dosages of 10 or 20 μg of iron did not lead to significant changes in DA release in the CPu or in behavioral response. At the 40-μg dosage, it was found that DA release in the lesioned side and rearing activity both were significantly reduced (all P = 0.01 vs unlesioned side or control) and apomorphine-induced rotation was observed. Pretreatment with desferrioxamine significantly inhibited the effect of iron on DA release and content. These results demonstrate that iron injection can damage dopaminergic neurons and suggest that DA release, rather than DA content, in the CPu is associated with DA-related behavioral changes in this PD model.