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Striatal Neurons (striatal + neuron)
Selected AbstractsExtracellular matrix molecules and synaptic plasticity: immunomapping of intracellular and secreted Reelin in the adult rat brainEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 2 2006Tania Ramos-Moreno Abstract Reelin, a large extracellular matrix glycoprotein, is secreted by several neuron populations in the developing and adult rodent brain. Secreted Reelin triggers a complex signaling pathway by binding lipoprotein and integrin membrane receptors in target cells. Reelin signaling regulates migration and dendritic growth in developing neurons, while it can modulate synaptic plasticity in adult neurons. To identify which adult neural circuits can be modulated by Reelin-mediated signaling, we systematically mapped the distribution of Reelin in adult rat brain using sensitive immunolabeling techniques. Results show that the distribution of intracellular and secreted Reelin is both very widespread and specific. Some interneuron and projection neuron populations in the cerebral cortex contain Reelin. Numerous striatal neurons are weakly immunoreactive for Reelin and these cells are preferentially located in striosomes. Some thalamic nuclei contain Reelin-immunoreactive cells. Double-immunolabeling for GABA and Reelin reveals that the Reelin-immunoreactive cells in the visual thalamus are the intrinsic thalamic interneurons. High local concentrations of extracellular Reelin selectively outline several dendrite spine-rich neuropils. Together with previous mRNA data, our observations suggest abundant axoplasmic transport and secretion in pathways such as the retino-collicular tract, the entorhino-hippocampal (,perforant') path, the lateral olfactory tract or the parallel fiber system of the cerebellum. A preferential secretion of Reelin in these neuropils is consistent with reports of rapid, activity-induced structural changes in adult brain circuits. [source] Modulatory action of acetylcholine on striatal neurons: microiontophoretic study in awake, unrestrained ratsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 3 2003François Windels Abstract Cholinergic interneurons innervate virtually all medium spiny striatal cells, but the relevance of this input in regulating the activity and afferent responsiveness of these cells remains unclear. Studies in anaesthetized animals and slice preparations have shown that iontophoretic acetylcholine (ACh) either weakly excites or inhibits striatal neurons. These differential responses may reflect cholinergic receptor heterogeneity but may be also related to the different activity states of recorded units and different afferent inputs specific in each preparation. Single-unit recording was combined with iontophoresis in awake, unrestrained rats to examine the effects of ACh and selective muscarinic (oxotremorine M or Oxo-M) and nicotinic agonists (nicotine or NIC) on dorsal and ventral striatal neurons. These effects were tested on naturally silent, spontaneously active and glutamate-stimulated units. We found that iontophoretic ACh primarily inhibited spontaneously active and glutamate-stimulated units; the direction of the ACh response, however, was dependent on the firing rate. The effects of ACh were generally mimicked by Oxo-M and, surprisingly, by NIC, which is known to excite units in most central structures, including striatal neurons in anaesthetized preparation. Given that NIC receptors are absent on striatal cells but located primarily on dopamine terminals, we assessed the effects of NIC after complete blockade of dopamine receptors induced by systemic administration of a mixture of D1 and D2 antagonists. During dopamine receptor blockade the number of NIC-induced inhibitions dramatically decreased and NIC had mainly excitatory effects on striatal neurons. Thus, our data suggest that under physiologically relevant conditions ACh acts as a state-dependent neuromodulator, and its action involves not only postsynaptic but also presynaptic cholinoreceptors located on dopamine- and glutamate-containing terminals. [source] Tonically active neurons in the primate striatum and their role in the processing of information about motivationally relevant eventsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2002Paul ApicellaArticle first published online: 11 DEC 200 Abstract Analysis of recordings of single neuronal activity in the striatum of monkeys engaged in behavioural tasks has shown that tonically active neurons (TANs) can be distinguished by their distinct spontaneous firing and functional properties. As TANs are assumed to be cholinergic interneurons, the study of their physiological characteristics allows us to gain an insight into the role of a particular type of local-circuit neuron in the processing of information at the striatal level. In monkeys performing various behavioural tasks, the change in the activity of TANs, unlike the diversity of task-related activations exhibited by the phasically active population of striatal neurons, involves a transient depression of the tonic firing related to environmental events of motivational significance. Such events include primary rewards and stimuli that have acquired a reward value during associative learning. These neurons also respond to an aversive air puff, indicating that their responsiveness is not restricted to appetitive conditions. Another striking feature of the TANs is that their responses can be modulated by predictions about stimulus timing. Temporal variations in event occurrence have been found to favour the responses of TANs, whereas the responses are diminished or abolished in the presence of external cues that predict the time at which events will occur. These data suggest that the TANs respond as do detectors of motivationally relevant events, but they also demonstrate that these neurons are influenced by predictive information based on past experience with a given temporal context. TANs represent a unique subset of striatal neurons that might serve a modulatory function, monitoring for temporal relationships between environmental events. [source] Characterization of the mouse adenylyl cyclase type VIII gene promoter: regulation by cAMP and CREBEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 7 2002Jennifer R. Chao Abstract Adenylyl cyclase (AC) type VIII has been implicated in several forms of neural plasticity, including drug addiction and learning and memory. In the present study, we directly examined the role for the transcription factor CREB (cAMP response element binding protein) in regulating ACVIII expression by cloning a 5.2 kilobase region upstream of the translation start site of the mouse ACVIII gene. Analysis of this fragment revealed consensus elements for several transcription factors, including a canonical cAMP response element (CRE) in close proximity to the transcription initiation region. Next, ACVIII promoter activity was studied in two neural-derived cell lines and in primary cultures of rat striatal neurons. Activation of the cAMP pathway by forskolin treatment increased promoter activity, and a series of deletion and point mutants demonstrated that this activation is mediated specifically via the canonical CRE site. Gel shift assays confirmed that this site can bind CREB and several CREB family proteins. Further, activation of the ACVIII promoter by forskolin was potentiated by expression of a constitutively active form of CREB, CREB-VP16, whereas it was inhibited by expression of a dominant-negative form of CREB, A-CREB. Finally, over-expression of CREB in vivo, by viral-mediated gene transfer, induced ACVIII promoter activity in the brains of ACVIII-LacZ transgenic mice. These results suggest that the ACVIII gene is regulated by CREB in vitro and in vivo and that this regulation may contribute to CREB-dependent neural plasticity. [source] Dopamine transporter knock-out mice are hypersensitive to 3-nitropropionic acid-induced striatal damageEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 12 2002Pierre-O. Abstract Evidence suggests that dopamine is involved in the modulation of striatal excitotoxic processes. To further investigate this issue, we studied the effects of systemic ,low-dose' (total dose, 340 mg/kg in 7 days) 3-nitropropionic acid (3-NP) intoxication in dopamine transporter knock-out mice (DAT,/,) compared to wildtype (DAT+/+) mice. Systemic ,low-dose' 3-NP induced a significant impairment in a rotarod task only in DAT,/, mice. Histopathology also demonstrated a significant reduction of the striatal volume (,7%, P < 0.05), neuronal density (,12.5%, P < 0.001) and absolute number estimates of striatal neurons (,11.5%, P < 0.001) in DAT,/, compared to DAT+/+ mice, with increased glial activation, independent of the degree of succinate dehydrogenase inhibition. These findings strengthen the hypothesis for dopamine modulation of excitotoxicity within the nigrostriatal system. [source] Differential sensitivity of medium- and large-sized striatal neurons to NMDA but not kainate receptor activation in the ratEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 10 2001Carlos Cepeda Abstract Infrared videomicroscopy and differential interference contrast optics were used to identify medium- and large-sized neurons in striatal slices from young rats. Whole-cell patch-clamp recordings were obtained to compare membrane currents evoked by application of N -methyl- d -aspartate (NMDA) and kainate. Inward currents and current densities induced by NMDA were significantly smaller in large- than in medium-sized striatal neurons. The negative slope conductance for NMDA currents was greater in medium- than in large-sized neurons and more depolarization was required to remove the Mg2+ blockade. In contrast, currents induced by kainate were significantly greater in large-sized neurons whilst current densities were approximately equal in both cell types. Spontaneous excitatory postsynaptic currents occurred frequently in medium-sized neurons but were relatively infrequent in large-sized neurons. Excitatory postsynaptic currents evoked by electrical stimulation were smaller in large- than in medium-sized neurons. A final set of experiments assessed a functional consequence of the differential sensitivity of medium- and large-sized neurons to NMDA. Cell swelling was used to examine changes in somatic area in both neuronal types after prolonged application of NMDA or kainate. NMDA produced a time-dependent increase in somatic area in medium-sized neurons whilst it produced only minimal changes in large interneurons. In contrast, application of kainate produced significant swelling in both medium- and large-sized cells. We hypothesize that reduced sensitivity to NMDA may be due to variations in receptor subunit composition and/or the relative density of receptors in the two cell types. These findings help define the conditions that put neurons at risk for excitotoxic damage in neurological disorders. [source] Mice transgenic for exon 1 of the Huntington's disease gene display reduced striatal sensitivity to neurotoxicity induced by dopamine and 6-hydroxydopamineEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 9 2001Åsa Petersén Abstract Huntington's disease is an autosomal dominant hereditary neurodegenerative disorder characterized by severe striatal cell loss. Dopamine (DA) has been suggested to play a role in the pathogenesis of the disease. We have previously reported that transgenic mice expressing exon 1 of the human Huntington gene (R6 lines) are resistant to quinolinic acid-induced striatal toxicity. In this study we show that with increasing age, R6/1 and R6/2 mice develop partial resistance to DA- and 6-hydroxydopamine-mediated toxicity in the striatum. Using electron microscopy, we found that the resistance is localized to the cell bodies and not to the neuropil. The reduction of dopamine and cAMP regulated phosphoprotein of a molecular weight of 32 kDa (DARPP-32) in R6/2 mice does not provide the resistance, as DA-induced striatal lesions are not reduced in size in DARPP-32 knockout mice. Neither DA receptor antagonists nor a N -methyl- d -aspartate (NMDA) receptor blocker reduce the size of DA-induced striatal lesions, suggesting that DA toxicity is not dependent upon DA- or NMDA receptor-mediated pathways. Moreover, superoxide dismutase-1 overexpression, monoamine oxidase inhibition and the treatment with the free radical scavenging spin-trap agent phenyl-butyl-tert-nitrone (PBN) also did not block DA toxicity. Levels of the antioxidant molecules, glutathione and ascorbate were not increased in R6/1 mice. Because damage to striatal neurons following intrastriatal injection of 6-hydroxydopamine was also reduced in R6 mice, a yet-to-be identified antioxidant mechanism may provide neuroprotection in these animals. We conclude that striatal neurons of R6 mice develop resistance to DA-induced toxicity with age. [source] Differential modulation of AMPA receptors by cyclothiazide in two types of striatal neuronsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 8 2000Vladimir S. Vorobjev Abstract The modulation of ,-amino-3-hydroxy-5-methyl-4-isoxazol-propionate (AMPA) receptor-mediated currents by cyclothiazide was investigated in acutely isolated cells from rat striatum with whole-cell patch-clamp recording. Single-cell reverse transcriptase-polymerase chain reaction (RT-PCR) was used to identify medium spiny and giant aspiny neurons and to determine their AMPA receptor subunit composition mostly in separate experiments. After pretreatment with cyclothiazide, kainate-induced AMPA responses were more strongly potentiated in medium spiny than in giant aspiny neurons; cyclothiazide induced a ninefold leftward shift in the kainate concentration,response curve for medium spiny neurons (not giant aspiny neurons). The EC50s for the cyclothiazide potentiation did not differ substantially between medium spiny neurons and giant aspiny neurons. The recovery of kainate-activated currents from modulation by cyclothiazide was slower for medium spiny neurons than for giant aspiny neurons. Medium spiny neurons expressed GluR-A, GluR-B and GluR-C, but not GluR-D subunits in both flip and flop splice variants. All giant aspiny neurons expressed GluR-A and GluR-D, exclusively in the flop form, half of them also expressed GluR-B and GluR-C. This is in keeping with slow and fast desensitization kinetics in medium spiny neurons and giant aspiny neurons, respectively, and differences in cyclothiazide modulation. The rate of cyclothiazide dissociation from the AMPA receptor, activated by glutamate, was ,,90 times slower in medium spiny neurons than in giant aspiny neurons. In giant aspiny neurons (not medium spiny neurons) this rate was strongly dependent on the presence of an agonist; 1 m m glutamate increased it 30-fold. Thus, two major cell groups in the striatum display distinct AMPA receptor compositions carrying specific properties of glutamate responses. Excitatory transmission will thus be differentially affected by cyclothiazide-type compounds. [source] RGS9-2 mediates specific inhibition of agonist-induced internalization of D2 -dopamine receptorsJOURNAL OF NEUROCHEMISTRY, Issue 3 2010Jeremy Celver J. Neurochem. (2010) 114, 739,749. Abstract Regulator of G protein signaling 9-2 (RGS9-2), a member of the RGS family of GTPase accelerating proteins, is expressed specifically in the striatum, a brain region involved in controlling movement, motivation, mood and addiction. RGS9-2 can be found co-localized with D2 -class dopamine receptors in medium spiny striatal neurons and altered functioning of both RGS9-2 and D2 -like dopamine receptors have been implicated in schizophrenia, movement disorders and reward responses. Previously we showed that RGS9-2 can specifically co-localize with D2 -dopamine receptors (D2R). Here we provide further evidence of the specificity of RGS9-2 for regulating D2R cellular functions: the expression of RGS9-2 inhibits dopamine-mediated cellular internalization of D2R, while the expression of another RGS protein, RGS4, had no effect. In addition, the agonist-mediated internalization of the G protein coupled delta opioid receptor was unaffected by RGS9-2 expression. We utilized mutant constructs of RGS9-2 to show that the RGS9-2 DEP (for Disheveled, EGL-10, Pleckstrin homology) domain and the GTPase accelerating activity of RGS9-2 were necessary for mediating specific inhibition of D2R internalization. [source] Protective up-regulation of CK2 by mutant huntingtin in cells co-expressing NMDA receptorsJOURNAL OF NEUROCHEMISTRY, Issue 3 2008Mannie M. Y. Fan Abstract Huntington's disease is caused by a polyglutamine expansion in the huntingtin (htt) protein, and previous data indicate that over-activation of NMDA receptors (NMDARs) may be involved in the selective degeneration of cells expressing NR1/NR2B NMDARs. We used KinetworksÔ multi-immunoblotting screens to examine expression of 76 protein kinases, 18 protein phosphatases, 25 heat shock/stress proteins, and 27 apoptosis proteins in human embryonic kidney 293 cells transfected with NR1/NR2B and htt containing 15 (htt-15Q; wild-type) or 138 (htt-138Q; mutant) glutamine repeats. Follow-up experiments revealed several proteins involved in the heat-shock response pathway to be up-regulated in the soluble fraction from cells expressing htt-138Q, including protein phosphatase 5 and cyclin-dependent kinase 5. Increased expression in the soluble fraction of htt-138Q-expressing cells was also noted for the stress- and calcium-activated protein-serine/threonine kinase casein kinase 2, a change which was confirmed in striatal tissue of yeast artificial chromosome transgenic mice expressing full-length mutant htt. Inhibition of casein kinase 2 activity in cultured striatal neurons from these mice significantly exacerbated NMDAR-mediated toxicity, as assessed by labeling of apoptotic nuclei. Our findings are consistent with up-regulation of components of the stress response pathway in the presence of polyglutamine-expanded htt and NR1/NR2B which may reflect an attempt at the cellular level to ameliorate the detrimental effects of mutant htt expression. [source] Frontal cortical afferents facilitate striatal nitric oxide transmission in vivo via a NMDA receptor and neuronal NOS-dependent mechanismJOURNAL OF NEUROCHEMISTRY, Issue 3 2007Stephen Sammut Abstract Striatal nitric oxide (NO) signaling plays a critical role in modulating neural processing and motor behavior. Nitrergic interneurons receive synaptic inputs from corticostriatal neurons and are activated via ionotropic glutamate receptor stimulation. However, the afferent regulation of NO signaling is poorly characterized. The role of frontal cortical afferents in regulating NO transmission was assessed in anesthetized rats using amperometric microsensor measurements of NO efflux and local field potential recordings. Low frequency (3 Hz) electrical stimulation of the ipsilateral cortex did not consistently evoke detectable changes in striatal NO efflux. In contrast, train stimulation (30 Hz) of frontal cortical afferents facilitated NO efflux in a stimulus intensity-dependent manner. Nitric oxide efflux evoked by train stimulation was transient, reproducible over time, and attenuated by systemic administration of either the NMDA receptor antagonist MK-801 or the neuronal NO synthase inhibitors 7-nitroindazole and NG -propyl- l -arginine. The interaction between NO efflux evoked via train stimulation and local striatal neuron activity was assessed using dual microsensor and local field potential recordings carried out concurrently in the contralateral and ipsilateral striatum, respectively. Systemic administration of the non-specific NO synthase inhibitor methylene blue attenuated both evoked NO efflux and the peak oscillation frequency (within the delta band) of local field potentials recorded immediately after train stimulation. Taken together, these observations indicate that feed-forward activation of neuronal NO signaling by phasic activation of frontal cortical afferents facilitates the synchronization of glutamate driven oscillations in striatal neurons. Thus, NO signaling may act to amplify coherent corticostriatal transmission and synchronize striatal output. [source] Pivotal role of early B-cell factor 1 in development of striatonigral medium spiny neurons in the matrix compartmentJOURNAL OF NEUROSCIENCE RESEARCH, Issue 10 2008Mary Kay Lobo Abstract The mammalian striatum plays a critical function in motor control, motor and reward learning, and cognition. Dysfunction and degeneration of the striatal neurons are implicated in major neurological and psychiatric disorders. The vast majority of striatal neurons are medium spiny neurons (MSNs). MSNs can be further subdivided into distinct subtypes based on their physical localization in the striatal patch vs. matrix compartments and based on their axonal projections and marker gene expression (i.e., striatonigral MSNs vs. striatopallidal MSNs). Despite our extensive knowledge on the striatal cytoarchitecture and circuitry, little is known about the molecular mechanisms controlling the development of the MSN subtypes in the striatum. Early B-cell factor 1 (Ebf1) is a critical transcription factor implicated in striatal MSN development. One study shows that Ebf1 is critical for the differentiation of MSNs in the matrix, and our separate study demonstrates that Ebf1 is selectively expressed in the striatonigral MSNs and is essential for their postnatal differentiation. In the present study, we further validate the striatonigral MSN deficits in Ebf1,/, mice using multiple striatonigral MSN reporter mice. Moreover, we demonstrate that the striatonigral MSN deficits in these mice are restricted to those in the matrix, with relative sparing of those in the patch. Finally, we demonstrate that Ebf1 deficiency also results in reduced expression of another striatonigral-specific transcription factor, zinc finger binding protein 521 (Zfp521), which is a known Ebf1 functional partner. Overall, our study reveals that Ebf1 may play an essential role in controlling the differentiation of the striatonigral MSNs in the matrix compartment. © 2008 Wiley-Liss, Inc. [source] Functional anatomy of the basal gangliaMOVEMENT DISORDERS, Issue S3 2002J. Yelnik MD Abstract Four organizational levels of the basal ganglia that could be particularly determinant in terms of functional properties are reviewed: (1) macroscopic anatomy, which is characterized by a dramatic decrease of cerebral tissue volume from the cerebral cortex to the deepest portions of the basal ganglia; (2) connectivity, which consists of both complex loops and a partition into three territories, sensorimotor, associative, and limbic (which process motor, cognitive, and emotional information, respectively); (3) neuronal morphology, characterized by a dramatic numeric and geometric convergence of striatal neurons onto pallidonigral neurons; and (4) dopaminergic innervation of the basal ganglia, which is organized as a dual system that is supposed to have opposite effects on the activity of the system. Current models of the basal ganglia are discussed. © 2002 Movement Disorder Society [source] Human neural stem cells genetically modified for brain repair in neurological disordersNEUROPATHOLOGY, Issue 3 2004Seung U. Kim Existence of multipotent neural stem cells (NSC) has been known in developing or adult mammalian CNS, including humans. NSC have the capacity to grow indefinitely and have multipotent potential to differentiate into three major cell types of CNS, neurons, astrocytes and oligodendrocytes. Stable clonal lines of human NSC have recently been generated from the human fetal telencephalon using a retroviral vector encoding v-myc. One of the NSC lines, HB1.F3, carries normal human karyotype of 46XX and has the ability to self-renew, differentiate into cells of neuronal and glial lineages, and integrate into the damaged CNS loci upon transplantation into the brain of animal models of Parkinson disease, HD, stroke and mucopolysaccharidosis. F3 human NSC were genetically engineered to produce L-dihydroxyphenylalanine (L-DOPA) by double transfection with cDNA for tyrosine hydroxylase and guanosine triphosphate cylohydrolase-1, and transplantation of these cells in the brain of Parkinson disease model rats led to L-DOPA production and functional recovery. Proactively transplanted F3 human NSC in rat striatum, supported the survival of host striatal neurons against neuronal injury caused by 3-nitropro-pionic acid in rat model of HD. Intravenously introduced through the tail vein, F3 human NSC were found to migrate into ischemic lesion sites, differentiate into neurons and glial cells, and improve functional deficits in rat stroke models. These results indicate that human NSC should be an ideal vehicle for cell replacement and gene transfer therapy for patients with neurological diseases. In addition to immortalized human NSC, immortalized human bone marrow mesenchymal stem cell lines have been generated from human embryonic bone marrow tissues with retroviral vectors encording v-myc or teromerase gene. These immortalized cell lines of human bone marrow mesenchymal stem cells differentiated into neurons/glial cells, bone, cartilage and adipose tissue when they were grown in selective inducing media. There is further need for investigation into the neurogenic potential of the human bone marrow stem cell lines and their utility in animal models of neurological diseases. [source] R6/2 neurons with intranuclear inclusions survive for prolonged periods in the brains of chimeric miceTHE JOURNAL OF COMPARATIVE NEUROLOGY, Issue 6 2007Anton Reiner Abstract The R6/2 mouse possesses mutant exon 1 of human Hdh, and R6/2 mice with 150 CAG repeats show neurological abnormalities by 10 weeks and die by 15 weeks. Few brain abnormalities, however, are evident at death, other than widespread ubiquitinated neuronal intranuclear inclusions (NIIs). We constructed R6/2t+/t, , wildtype (WT) chimeric mice to prolong survival of R6/2 cells and determine if neuronal death and/or neuronal injury become evident with longer survival. ROSA26 mice (which bear a lacZ transgene) were used as WT to distinguish between R6/2 and WT neurons. Chimeric mice consisting partly of R6/2 cells lived longer than pure R6/2 mice (up to 10 months), with the survival proportional to the R6/2 contribution. Genotypically R6/2 cells formed NIIs in the chimeras, and these NIIs grew only slightly larger than in 12-week pure R6/2 mice, even after 10 months. Additionally, neuropil aggregates formed near R6/2 neurons in chimeric mice older than 15 weeks. Thus, R6/2 neurons could survive well beyond 15 weeks in chimeras. Moreover, little neuronal degeneration was evident in either cortex or striatum by routine histological stains. Nonetheless, striatal shrinkage and ventricular enlargement occurred, and striatal projection neuron markers characteristically reduced in Huntington's disease were diminished. Consistent with such abnormalities, cortex and striatum in chimeras showed increased astrocytic glial fibrillary acidic protein. These results suggest that while cortical and striatal neurons can survive nearly a year with nuclear and extranuclear aggregates of mutant huntingtin, such lengthy survival does reveal cortical and striatal abnormality brought on by the truncated mutant protein. J. Comp. Neurol. 505:603,629, 2007. © 2007 Wiley-Liss, Inc. [source] Neurokinin B-producing projection neurons in the lateral stripe of the striatum and cell clusters of the accumbens nucleus in the ratTHE JOURNAL OF COMPARATIVE NEUROLOGY, Issue 2 2004Ligang Zhou Abstract Neurons producing preprotachykinin B (PPTB), the precursor of neurokinin B, constitute 5% of neurons in the dorsal striatum and project to the substantia innominata (SI) selectively. In the ventral striatum, PPTB-producing neurons are collected mainly in the lateral stripe of the striatum (LSS) and cell clusters of the accumbens nucleus (Acb). In the present study, we first examined the distribution of PPTB-immunoreactive neurons in rat ventral striatum and found that a large part of the PPTB-immunoreactive cell clusters was continuous to the LSS, but a smaller part was not. Thus, we divided the PPTB-immunoreactive cell clusters into the LSS-associated and non-LSS-associated ones. We next investigated the projection targets of the PPTB-producing ventral striatal neurons by combining immunofluorescence labeling and retrograde tracing. After injection of Fluoro-Gold into the basal component of the SI (SIb) and medial part of the interstitial nucleus of posterior limb of the anterior commissure, many PPTB-immunoreactive neurons were retrogradely labeled in the LSS-associated cell clusters and LSS, respectively. When the injection site included the ventral part of the sublenticular component of the SI(SIsl), retrogradely labeled neurons showed PPTB-immunoreactivity frequently in non-LSS-associated cell clusters. Furthermore, these PPTB-immunoreactive projections were confirmed by the double-fluorescence method after anterograde tracer injection into the ventral striatum containing the cell clusters. Since the dorsalmost part of the SIsl is known to receive strong inputs from PPTB-producing dorsal striatal neurons, the present results indicate that PPTB-producing ventral striatal neurons project to basal forebrain target regions in parallel with dorsal striatal neurons without significant convergence. J. Comp. Neurol. 480:143,161, 2004. © 2004 Wiley-Liss, Inc. [source] Slowed progression in models of huntington disease by adipose stem cell transplantation,ANNALS OF NEUROLOGY, Issue 5 2009Soon-Tae Lee MD Objective Adipose-derived stem cells (ASCs) are readily accessible and secrete multiple growth factors. Here, we show that ASC transplantation rescues the striatal pathology of Huntington disease (HD) models. Methods ASCs were isolated from human subcutaneous adipose tissue. In a quinolinic acid (QA)-induced rat model of striatal degeneration, human ASCs (1 million cells) were transplanted into the ipsilateral striatal border immediately after the QA injection. In 60-day-old R6/2 mice transgenic for HD, ASCs (0.5 million cells) were transplanted into each bilateral striata. In in vitro experiments, we treated mutant huntingtin gene-transfected cerebral neurons with ASC-conditioned media. Results In the QA model, human ASCs reduced apomorphine-induced rotation behavior, lesion volume, and striatal apoptosis. In R6/2 transgenic mice, transplantation of ASCs improved Rota-Rod performance and limb clasping, increased survival, attenuated the loss of striatal neurons, and reduced the huntingtin aggregates. ASC-transplanted R6/2 mice expressed elevated levels of peroxisome proliferator-activated receptor , coactivator-1, (PGC-1,) and reactive oxygen defense enzymes and showed activation of the Akt/cAMP-response element-binding proteins. ASC-conditioned media decreased the level of N-terminal fragments of mutant huntingtin and associated apoptosis, and increased PGC-1, expression. Interpretation Collectively, ASC transplantation slowed striatal degeneration and behavioral deterioration of HD models, possibly via secreted factors. Ann Neurol 2009;66:671,681 [source] Insulin like growth factor-1 and insulin like growth factor binding proteins in the cerebrospinal fluid and serum from patients with Alzheimer's diseaseBIOFACTORS, Issue 2 2008Zivar Salehi Insulin like growth factor-1 (IGF-1) is ubiquitously expressed growth factor that has profound effects on the growth and differentiation of many cell types and tissues, including cells of the central nervous system (CNS). IGF-1 is produced by a wide variety of cells and is found in many biological fluids including cerebrospinal fluid (CSF). IGF-1 plays important role during CNS development and repair. IGF-1 has broad range neuroprotective effects and is a therapeutic candidate for Huntington's disease (HD). IGF-1 protects striatal neurons from the toxicity of mutated Huntington in vitro and improves neuronal survival in vivo in a phenotypic model of HD. Alzheimer's disease (AD) is an age-dependent dementia characterized by progressive loss of cognitive functions and by characteristic pathological changes in the brain: the formation of aggregates extracellularly by ß-amyloid (AB) peptide and intracellularly by tau proteins. Since cerebrospinal fluid (CSF) is in contact with the extracellular space of the brain, biochemical brain modifications could be reflected in the CSF. IGFs in circulation and other physiological fluids are associated with a group of high-affinity binding proteins insulin like growth factor binding proteins (IGFBPs) that specifically bind and modulate their bioactivity at the cellular level. The aim of this study was to determine the level of CSF and serum IGF-1 and IGFBPs concentrations in the patients with AD. CSF was obtained by lumbar puncture. The presence of IGF-1 and IGFBPs in the CSF and serum samples was confirmed by Western blot using anti-IGF-1 and IGFBPs antibodies. Using enzyme linked immunosorbent assay (ELISA), it was shown that the concentration of CSF and serum IGF-1 and IGFBPs in the patients with AD is higher than in normal control. The data from this study indicate that IGF-1 is a constant component of human CSF. It is also concluded that high levels of CSF IGF-1 may be partly related to AD pathophysiology. [source] A1 Adenosine Receptors Accumulate in Neurodegenerative Structures in Alzheimer's Disease and Mediate Both Amyloid Precursor Protein Processing and Tau Phosphorylation and TranslocationBRAIN PATHOLOGY, Issue 4 2003Ester Angulo Immunostaining of adenosine receptors in the hippocampus and cerebral cortex from necropsies of Alzheimer's disease (AD) patients shows that there is a change in the pattern of expression and a redistribution of receptors in these brain areas when compared with samples from controls. Adenosine A1 receptor (A1R) immunoreactivity was found in degenerating neurons with neurofibrillary tangles and in dystrophic neurites of senile plaques. A high degree of colocalization for A1R and pA4 amyloid in senile plaques and for A1R and tau in neurons with tau deposition, but without tangles, was seen. Additionally, adenosine A2A receptors, located mainly in striatal neurons in controls, appeared in glial cells in the hippocampus and cerebral cortex of patients. On comparing similar samples from controls and patients, no significant change was evident for metabotropic glutamate receptors. In the human neuroblastoma SH-SY5Y cell line, agonists for A1R led to a dose-dependent increase in the production of soluble forms of amyloid precursor protein in a process mediated by PKC. A1R agonist induced p21 Ras activation and ERK1/2 phosphorylation. Furthermore, activation of A1R led to and ERK-dependent increase of tau phosphorylation and translocation towards the cytoskeleton. These results indicate that adenosine receptors are potential targets for AD. [source] | |||||||||||||