Csaba Leranth
, New Haven

Anatomy, Cell Biology, Endocrinology

M.D., Ph.D.
44.37

Publications

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    ABSTRACT: Bisphenol-A (BPA) is widely used in the manufacture of plastics, epoxy resins and certain paper products. A majority of the population in the developed world is routinely exposed to BPA from multiple sources and has significant circulating levels of BPA. Although BPA is categorized as an endocrine disruptor with a growing literature on adverse effects, it is uncertain whether cognitive dysfunction is induced in humans by exposure to BPA. The present study examined the impact of BPA in primate brain by exposing adult male vervet monkeys for 4 weeks continuously to circulating levels of BPA that were in the range measured in studies of humans environmentally exposed to BPA. This regimen of exposure to BPA decreased both working memory accuracy and the number of excitatory synaptic inputs on dendritic spines of pyramidal neurons in two brain regions that are necessary for working memory (prefrontal cortex and hippocampus). These observed behavioral and synaptic effects were ameliorated following withdrawal from BPA. As Old World monkeys (e.g., vervets) and humans share some uniquely primate morphological, endocrine, and cognitive traits, this study indicates the potential for significant cognitive disruption following exposure of humans to BPA. This article is protected by copyright. All rights reserved.
    No preview · Article · Dec 2014 · The Journal of Comparative Neurology
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    ABSTRACT: . Cognitive deficits are a core symptom of schizophrenia, yet they remain particularly resistant to treatment. The model provided by repeatedly exposing adult non-human primates to phencyclidine (PCP) has generated important insights into the neurobiology of these deficits, but it remains possible that administration of this psychotomimetic agent during the pre-adult period - when the dorsolateral prefrontal cortex (DLPFC) in human and non-human primates is still undergoing significant maturation - may provide a greater understanding of schizophrenia-related cognitive deficits. . The effects of repeated PCP treatment on spine synapse number, DA turnover and BDNF expression in DLPFC and on working memory accuracy wereexamined in pre-adultmonkeys. . One week following PCP treatment, juvenile and adolescent male monkeys demonstrated a greater loss of spine synapses in DLPFC than adult male monkeys. Further studies indicated that in juvenile malesa cognitive deficit existed at 4 weeks following PCP treatment and this impairment was associated with decreased dopamine turnover,decreased BDNF mRNA, and a loss of dendritic spine synapses in DLPFC. In contrast, female juvenile monkeys displayed no cognitive deficit at 4 weeks after PCP treatment, and no alteration indopamine turnover or BDNF mRNA or spine synapse number in DLPFC. In the combined group of male and female juvenile monkeys, significant linear correlations were detected between dopamine turnover, spine synapse number and cognitive performance. . As the incidence of schizophrenia is greater in males than females, these findings support the validity of the juvenile primate PCP model and highlight its potential usefulness in understanding the deficits in DLPFC in schizophrenia and developing novel treatments for the cognitive deficits associated with schizophrenia. © The Author 2014. Published by Oxford University Press on behalf of CINP.
    No preview · Article · Oct 2014 · The International Journal of Neuropsychopharmacology
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    ABSTRACT: Transplanted multipotent human fetal neural stem cells (hfNSCs) significantly improved the function of parkinsonian monkeys in a prior study primarily by neuroprotection, with only 3%-5% of cells expressing a dopamine (DA) phenotype. In this paper, we sought to determine whether further manipulation of the neural microenvironment by overexpression of a developmentally critical molecule, glial cell-derived neurotrophic factor (GDNF), in the host striatum could enhance DA differentiation of hfNSCs injected into the substantia nigra and elicit growth of their axons to the GDNF-expressing target. hfNSCs were transplanted into the midbrain of 10 green monkeys exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine. GDNF was delivered concomitantly to the striatum via an adeno-associated virus serotype 5 vector, and the fate of grafted cells was assessed after 11 months. Donor cells remained predominantly within the midbrain at the injection site and sprouted numerous neurofilament-immunoreactive fibers that appeared to course rostrally toward the striatum in parallel with tyrosine hydroxylase-immunoreactive fibers from the host substantia nigra but did not mature into DA neurons. This work suggests that hfNSCs can generate neurons that project long fibers in the adult primate brain. However, in the absence of region-specific signals and despite GDNF overexpression, hfNSCs did not differentiate into mature DA neurons in large numbers. It is encouraging, however, that the adult primate brain appeared to retain axonal guidance cues. We believe that transplantation of stem cells, specifically instructed ex vivo to yield DA neurons, could lead to reconstruction of some portion of the nigrostriatal pathway and prove beneficial for the parkinsonian condition.
    Full-text · Article · Apr 2014 · STEM CELLS TRANSLATIONAL MEDICINE
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    ABSTRACT: Gonadal hormones induce significant changes in cognitive function, associated with alterations in the structure of the hippocampus. We have previously shown that androgens increase the number of spine synapses in the CA1 stratum radiatum of the monkey hippocampus. Recent evidence, however, suggests that loss of testicular hormone production may have variable effects on neuroplasticity in different regions of the hippocampus. To test this hypothesis, we examined the effects of orchidectomy in the dentate gyrus and CA3 subfield of the hippocampus in male St. Kitts vervet monkeys (Chlorocebus aethiops sabaeus). Spine synapse density was significantly reduced (39%) after orchidectomy in the dentate gyrus, consistent with previously published reports in CA1 (40%). However, in CA3 orchidectomy induced a much smaller (22%) reduction in synapse density, which did not reach the limits of statistical significance. These results suggest that orchidectomy exerts heterogeneous effects on hippocampal spine synapse density, the CA3 subfield being relatively spared compared to CA1 and the dentate gyrus. This heterogeneity may contribute to the mixed functional responses observed in males following loss of testicular hormone secretions.
    No preview · Article · Nov 2013 · Neuroscience Letters
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    Ari L Mendell · Neil J Maclusky · Csaba Leranth
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    ABSTRACT: Dehydroepiandrosterone (DHEA), the most abundant adrenal androgen in primates, is also synthesized from cholesterol in the brain. Like testosterone, DHEA induces spine synapse formation in the hippocampus. In female rats, this re-sponse is blocked by co-administration of an inhibitor of aromatase, the enzyme responsible for estrogen biosynthesis. In males, by contrast, the hippocampal synaptic response to DHEA is unaffected by treatment with an aromatase in-hibitor. We hypothesized that this sex difference might reflect differential dependence of the hippocampal responses on subcortical afferents from the basal forebrain. To test this hypothesis, we examined the effects of unilateral fimbria/ fornix transection (FFX) on DHEA-induced synapse formation in the cornu ammonis 1 (CA1) hippocampal subfield of gonadectomized female and male rats. In ovariectomized females, CA1 spine synapse density after DHEA treatment was reduced by more than 60% ipsilateral to FFX. In males, however, unilateral FFX transection had no effect on spine synapse density after DHEA treatment. These results suggest that sex differences in the dependence on local estrogen biosynthesis of the CA1 synaptic response to androgen may at least in part be the result of sex differences in the relative contributions of afferents to the hippocampus from the basal forebrain.
    Full-text · Article · Sep 2013 · Neuroscience & Medicine
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    ABSTRACT: We combined viral vector delivery of human glial-derived neurotrophic factor (GDNF) with the grafting of dopamine precursor cells from fetal ventral mesencephalon to determine whether these strategies would improve the anti-Parkinson's effects in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys, an animal model for Parkinson's disease. Both strategies have been reported as individually beneficial in animal models of Parkinson's disease, leading to clinical studies. GDNF delivery has also been reported to augment ventral mesencephalic tissue implants but no combined studies have been done in monkeys. Monkeys were treated with MPTP and placed into four balanced treatment groups receiving only rAAV5/huGDNF, only fetal dopamine precursor cells, both together, or a buffered saline solution (control). The combination of fetal precursors with rAAV5/huGDNF showed significantly higher striatal dopamine concentrations compared with the other treatments, but did not lead to greater functional improvement in this study. For the first time under identical conditions in primates, we show that all three treatments lead to improvement compared with control animals.Molecular Therapy (2013); doi:10.1038/mt.2013.180.
    Full-text · Article · Aug 2013 · Molecular Therapy
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    ABSTRACT: A human embryonic stem cell (HESC) line, (H1), was studied after differentiation to adopaminergic phenotype in vitro in order to carry out in vivo studies in parkinsonianmonkeys. To identify morphological characteristics of transplanted donor cells, HESCs weretransfected with a GFP lentiviral vector. Gene expression studies were performed at eachstep of a neural rosette based dopaminergic differentiation protocol by RT-PCR. In vitroimmunofluorescence revealed that >90% of the differentiated cells exhibited a neuronalphenotype by β-III-tubulin immunocytochemistry, with 17% of the cells co-expressing tyrosinehydroxylase prior to implantation. Biochemical analyses demonstrated dopamine release inculture in response to potassium chloride induced membrane depolarization, suggesting thatthe cells synthesized and released dopamine. These characterized, HESC-derived neuronswere then implanted into the striatum and midbrain of MPTP (1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine)-exposed monkeys which were triple immunosuppressed. Here wedemonstrate robust survival of transplanted HESC derived neurons after six weeks, as wellas morphological features consistent with polarization, organization, and extension ofprocesses that integrated into the host striatum. Expression of the dopaminergic markertyrosine hydroxylase was not maintained in HESC derived neural grafts in either the striatumor substantia nigra, despite a neuronal morphology and expression of β-III-tubulin. Theseresults suggest that dopamine neuronal cells derived from neuroectoderm in vitro will notmaintain the correct midbrain phenotype in vivo in non-human primates, contrasted withrecent studies showing dopamine neuronal survival using an alternative floor-plate method.
    Full-text · Article · Apr 2013 · Cell Transplantation
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    ABSTRACT: Prevalent use of bisphenol-A (BPA) in the manufacture of resins, plastics and paper products has led to frequent exposure of most people to this endocrine disruptor. Some rodent studies have suggested that BPA can exert detrimental effects on brain development. However as rodent models cannot be relied on to predict consequences of human exposure to BPA during development, it is important to investigate the effects of BPA on non-human primate brain development. Previous research suggests that BPA preferentially targets dopamine neurons in ventral mesencephalon and glutamatergic neurons in hippocampus, so the present work examined the susceptibility of these systems to low dose BPA exposure at the fetal and juvenile stages of development in non-human primates. Exposure of pregnant rhesus monkeys to relatively low levels of BPA during the final 2 months of gestation, induced abnormalities in fetal ventral mesencephalon and hippocampus. Specifically, light microscopy revealed a decrease in tyrosine hydroxylase-expressing (dopamine) neurons in the midbrain of BPA-exposed fetuses and electron microscopy identified a reduction in spine synapses in the CA1 region of hippocampus. In contrast, administration of BPA to juvenile vervet monkeys (14-18 months of age) was without effect on these indices, or on dopamine and serotonin concentrations in striatum and prefrontal cortex, or on performance of a cognitive task that tests working memory capacity. These data indicate that BPA exerts an age-dependent detrimental impact on primate brain development, at blood levels within the range measured in humans having only environmental contact with BPA.
    No preview · Article · Jan 2013 · NeuroToxicology
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    ABSTRACT: Parkinson's disease is usually characterized as a movement disorder; however, cognitive abilities that are dependent on the prefrontal cortex decline at an early stage of the disease in most patients. The changes that underlie cognitive deficits in Parkinson's disease are not well understood. We hypothesize that reduced dopamine signalling in the prefrontal cortex in Parkinson's disease is a harbinger of detrimental synaptic changes in pyramidal neurons in the prefrontal cortex, whose function is necessary for normal cognition. Our previous data showed that monkeys exposed to the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), but not exhibiting overt motor deficits (motor-asymptomatic), displayed cognitive deficits in prefrontal cortex-dependent tasks. The present results demonstrate that motor-asymptomatic MPTP-treated monkeys have a reduced dopamine concentration and a substantially lower number (50%) of asymmetric (excitatory) spine synapses in layer II/III, but not layer V, of the dorsolateral prefrontal cortex, compared to controls. In contrast, neither dopamine concentration nor asymmetric synapse number was altered in the entorhinal cortex of MPTP-treated monkeys. Together, these findings suggest that the number of asymmetric spine synapses on dendrites in the prefrontal cortex is dopamine-dependent and that the loss of synapses may be a morphological substrate of the cognitive deficits induced by a reduction in dopamine neurotransmission in this region.
    Full-text · Article · Sep 2012 · The International Journal of Neuropsychopharmacology
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    ABSTRACT: We have recently reported that in the learned helplessness model of depression, the less hippocampal spine synapses rats have, the more helpless they become. It remains unclear, however, whether the observed synaptic changes are associated with the loss of CA1 pyramidal cells. Cell bodies in the CA1 pyramidal layer are very densely packed, making cell counting difficult in this hippocampal subregion. To address this issue, we developed a new approach that (1) yields excellent preservation of the three-dimensional tissue structure; (2) utilizes osmium tetroxide to unambiguously label nucleoli; and (3) facilitates and accelerates unbiased, reliable counting of densely packed cell bodies. Our method provides an improved tool for studies aiming to evaluate hippocampal atrophy and cell loss, the most characteristic features in many neurodegenerative diseases, such as Alzheimer's disease, temporal lobe epilepsy and ischemia, as well as in several psychiatric disorders. Using this new method, we demonstrated no significant changes in the number of CA1 pyramidal cells in the rat learned helplessness paradigm. In addition, volumes of the CA1 pyramidal cell layer and the entire CA1 subfield remained unchanged among treatment groups. We conclude that previously observed synaptic alterations in helpless rats are not associated with CA1 pyramidal cell loss. This finding suggests that behavioral outcome in the learned helplessness paradigm is related to plastic events at the synaptic level, rather than at the level of principal cells.
    Full-text · Article · Mar 2012 · Journal of Neuroscience Methods
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    ABSTRACT: Schizophrenia patients, long-term abusers of phencyclidine (PCP), and monkeys treated with PCP all exhibit enduring cognitive deficits. Evidence indicates that loss of prefrontal cortex spine synapses results in cognitive dysfunction, suggesting the presence of synaptic pathology in the monkey PCP model; however, there is no direct evidence of such changes. In this study we use the monkey PCP model of schizophrenia to investigate at the ultrastructural level whether remodelling of dorsolateral prefrontal cortex (DLPFC) asymmetric spine synapses occurs following PCP. Subchronic PCP treatment resulted in a decrease in the number of asymmetric spine synapses, which was greater in layer II/III than layer V of DLPFC, compared to vehicle-treated controls. This decrease may contribute to PCP-induced cognitive dysfunction in the non-human primate model and perhaps in schizophrenia. Thus, the synapse loss in the PCP model provides a novel target for the development of potential treatments of cognitive dysfunction in this model and in schizophrenia.
    Full-text · Article · Jun 2011 · The International Journal of Neuropsychopharmacology
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    ABSTRACT: Enduring cognitive deficits exist in schizophrenic patients, long-term abusers of phencyclidine (PCP), as well as in animal PCP models of schizophrenia. It has been suggested that cognitive performance and memory processes are coupled with remodeling of pyramidal dendritic spine synapses in prefrontal cortex (PFC), and that reduced spine density and number of spine synapses in the medial PFC of PCP-treated rats may potentially underlie, at least partially, the cognitive dysfunction previously observed in this animal model. The present data show that the decrease in number of asymmetric (excitatory) spine synapses in layer II/III of PFC, previously noted at 1-week post PCP treatment also occurs, to a lesser degree, in layer V. The decrease in the number of spine synapses in layer II/III was sustained and persisted for at least 4 weeks, paralleling the observed cognitive deficits. Both acute and chronic treatment with the atypical antipsychotic drug, olanzapine, starting at 1 week after PCP treatment at doses that restore cognitive function, reversed the asymmetric spine synapse loss in PFC of PCP-treated rats. Olanzapine had no significant effect on spine synapse number in saline-treated controls. These studies demonstrate that the effect of PCP on asymmetric spine synapse number in PFC lasts at least 4 weeks in this model. This spine synapse loss in PFC is reversed by acute treatment with olanzapine, and this reversal is maintained by chronic oral treatment, paralleling the time course of the restoration of the dopamine deficit, and normalization of cognitive function produced by olanzapine.
    Full-text · Article · Jun 2011 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
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    Tamir S Aldad · Nora Rahmani · Csaba Leranth · Hugh S Taylor
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    ABSTRACT: To evaluate the effect of bisphenol-A (BPA), a xenoestrogen endocrine disruptor, on endometrial P receptor (PR) expression in nonhuman primates and human cells. Controlled trial in primates. University. African green monkeys. After oophorectomy, BPA (50 μg/kg/d), E(2), both, or vehicle control were administered. Estradiol and BPA were used in Ishikawa cells. Progesterone receptor expression using immunohistochemistry and quantitative polymerase chain reaction. Progesterone receptor expression was increased in E(2)-treated primates compared with controls. Exposure to the combination of E(2) and BPA resulted in decreased PR expression compared with E(2) exposure alone. In Ishikawa cells treated with E(2), PR expression increased 5.1-fold; however, when Ishikawa cells were simultaneously treated with E(2) and BPA, PR expression was decreased to 0.6-fold that of cells treated with E(2) alone. Bisphenol-A alone functions as a weak estrogen. However, when administered with E(2), BPA diminishes E(2)-induced PR expression. The estrogen-like effect of BPA reported in exposed humans may be mediated by PR blockade and a resultant decrease in the estrogen inhibition normally imparted by P. Diminished PR expression may underlie previous reports linking BPA exposure to endometrial dysfunction in humans.
    Preview · Article · Apr 2011 · Fertility and sterility
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    Tibor Hajszan · Csaba Leranth
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    ABSTRACT: The potential adverse effects of Bisphenol A (BPA), a synthetic xenoestrogen, have long been debated. Although standard toxicology tests have revealed no harmful effects, recent research highlighted what was missed so far: BPA-induced alterations in the nervous system. Since 2004, our laboratory has been investigating one of the central effects of BPA, which is interference with gonadal steroid-induced synaptogenesis and the resulting loss of spine synapses. We have shown in both rats and nonhuman primates that BPA completely negates the ∼ 70-100% increase in the number of hippocampal and prefrontal spine synapses induced by both estrogens and androgens. Synaptic loss of this magnitude may have significant consequences, potentially causing cognitive decline, depression, and schizophrenia, to mention those that our laboratory has shown to be associated with synaptic loss. Finally, we discuss why children may particularly be vulnerable to BPA, which represents future direction of research in our laboratory.
    Preview · Article · Oct 2010 · Frontiers in Neuroendocrinology
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    Full-text · Article · Feb 2010 · Toxicological Sciences
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    ABSTRACT: Vectors derived from adeno-associated virus (AAV) are promising candidates for neural cell transduction in vivo because they are nonpathogenic and achieve long-term transduction in the central nervous system. AAV serotype 2 (AAV2) is the most widely used AAV vector in clinical trials based largely on its ability to transduce neural cells in the rodent and primate brain. Prior work in rodents suggests that other serotypes might be more efficient; however, a systematic evaluation of vector transduction efficiency has not yet been performed in the primate brain. In this study, AAV viral vectors of serotypes 1–6 with an enhanced green-fluorescent protein (GFP) reporter gene were generated at comparable titers, and injected in equal amounts into the brains of Chlorocebus sabaeus. Vector injections were placed in the substantia nigra (SN) and the caudate nucleus (CD). One month after injection, immunohistochemistry for GFP was performed and the total number of GFP+ cells was calculated using unbiased stereology. AAV5 was the most efficient vector, not only transducing significantly more cells than any other serotype, but also transducing both NeuN+ and glial-fibrillary-acidic protein positive (GFAP+) cells. These results suggest that AAV5 is a more effective vector than AAV2 at delivering potentially therapeutic transgenes to the nigrostriatal system of the primate brain.
    Full-text · Article · Dec 2009 · Molecular Therapy
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    ABSTRACT: Despite the fact that women are twice as likely to develop depression as men, our understanding of depression neurobiology in female subjects is limited. We have recently reported in male rats that development of helpless behavior is associated with a severe loss of hippocampal spine synapses, which is reversed by treatment with the antidepressant desipramine. Considering that estradiol has a hippocampal synaptogenic effect similar to those of antidepressants, the presence of estradiol during the female reproductive life might influence behavioral and synaptic responses to stress and depression. With electron microscopic stereology, we analyzed hippocampal spine synapses in association with helpless behavior in ovariectomized female rats (n = 70), under different conditions of estradiol exposure. Stress induced an acute and persistent loss of hippocampal spine synapses, whereas subchronic treatment with desipramine reversed the stress-induced synaptic loss. Estradiol supplementation given either before stress or before escape testing of nonstressed animals increased the number of hippocampal spine synapses. Correlation analysis demonstrated a statistically significant negative correlation between the severity of helpless behavior and hippocampal spine synapse numbers. These findings suggest that hippocampal spine synapse remodeling might be a critical factor underlying learned helplessness and, possibly, the neurobiology of depression.
    Full-text · Article · Oct 2009 · Biological psychiatry
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    ABSTRACT: In spite of partial success in treating Parkinson's disease by using ectopically placed grafts of dopamine-producing cells, restoration of the original neuroanatomical circuits, if possible, might work better. Previous evidence of normal anatomic projections from ventral mesencephalic (VM) grafts placed in the substantia nigra (SN) has been limited to neonatal rodents and double grafting or bridging procedures. This study attempted to determine whether injection of a potent growth-promoting factor, glial cell line-derived neurotrophic factor (GDNF), into the target regions or placement of fetal striatal co-grafts in the nigrostriatal pathway might elicit neuritic outgrowth to the caudate nucleus. Four adult St. Kitts green monkeys received embryonic VM grafts into the rostral mesencephalon near the host SN, and injections of adeno-associated virus 2 (AAV2)/GDNF or equine infectious anemia virus (EIAV)/GDNF into the caudate. Three adult monkeys were co-grafted with fetal VM tissue near the SN and fetal striatal grafts (STR) 2.5 mm rostral in the nigrostriatal pathway. Before sacrifice, the striatal target regions were injected with the retrograde tracer Fluoro-Gold (FG). FG label was found in tyrosine hydroxylase-labeled neurons in VM grafts in the SN of only those monkeys that received AAV2/GDNF vector injections into the ipsilateral striatum. All monkeys showed FG labeling in the host SN when FG labeling was injected on the same side. These data show that grafted dopaminergic neurons can extend neurites to a distant target releasing an elevated concentration of GDNF, and suggest that grafted neurons can be placed into appropriate loci for potential tract reconstruction.
    Full-text · Article · Jul 2009 · The Journal of Comparative Neurology

  • No preview · Article · Jan 2009 · Cell Transplantation
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    Preview · Article · Dec 2008 · Proceedings of the National Academy of Sciences

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