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Sample records for mouse substantia nigra

  1. Sequence analysis of 497 mouse brain ESTs expressed in the substantia nigra.

    PubMed

    Stewart, G J; Savioz, A; Davies, R W

    1997-01-15

    The use of subtracted, region-specific cDNA libraries combined with single-pass cDNA sequencing allows the discovery of novel genes and facilitates molecular description of the tissue or region involved. We report the sequence of 497 mouse expressed sequence tags (ESTs) from two subtracted libraries enriched for cDNAs expressed in the substantia nigra, a brain region with important roles in movement control and Parkinson disease. Of these, 238 ESTs give no database matches and therefore derive from novel genes. A further 115 ESTs show sequence similarity to ESTs from other organisms, which themselves do not yield any significant database matches to genes of known function. Fifty-six ESTs show sequence similarity to previously identified genes whose mouse homologues have not been reported. The total number of ESTs reported that are new for the mouse is 407, which, together with the 90 ESTs corresponding to known mouse genes or cDNAs, contributes to the molecular description of the substantia nigra. PMID:9027501

  2. Sequence analysis of 497 mouse brain ESTs expressed in the substantia nigra

    SciTech Connect

    Stewart, G.J.; Savioz, A.; Davies, R.W.

    1997-01-15

    The use of subtracted, region-specific cDNA libraries combined with single-pass cDNA sequencing allows the discovery of novel genes and facilitates molecular description of the tissue or region involved. We report the sequence of 497 mouse expressed sequence tags (ESTs) from two subtracted libraries enriched for cDNAs expressed in the substantia nigra, a brain region with important roles in movement control and Parkinson disease. Of these, 238 ESTs give no database matches and therefore derive from novel genes. A further 115 ESTs show sequence similarity to ESTs from other organisms, which themselves do not yield any significant database matches to genes of known function. Fifty-six ESTs show sequence similarity to previously identified genes whose mouse homologues have not been reported. The total number of ESTs reported that are new for the mouse is 407, which, together with the 90 ESTs corresponding to known mouse genes or cDNAs, contributes to the molecular description of the substantia nigra. 21 refs., 4 tabs.

  3. GABAergic Afferents activate both GABAA and GABAB receptors in mouse substantia nigra dopaminergic neurons in vivo

    PubMed Central

    Brazhnik, Elena; Shah, Fulva; Tepper, James M.

    2008-01-01

    Most in vivo electrophysiological studies of substantia nigra have employed rats. With the recent proliferation of the use of mice for in vitro neurophysiological studies due to the availability of various genetically modified strains to identify the roles of various channels and proteins in neuronal function, it is crucial to obtain data on in vivo responses in mice to verify that the in vitro results reflect functioning of systems comparable to those that have been well studied in rat. Inhibitory responses of rat nigral dopaminergic neurons by stimulation of afferents from striatum, globus pallidus or pars reticulata have been shown to be mediated predominantly or exclusively by GABAA receptors. This is puzzling given the substantial expression of GABAB receptors and the ubiquitous appearance of GABAB synaptic responses in rat dopaminergic neurons in vitro. In the present study we studied electrically evoked GABAergic inhibition in nigral dopaminergic neurons in C57BL/6J mice. Stimulation of the three major GABAergic inputs elicited stronger and longer lasting inhibitory responses than those seen in rats. The early inhibition was GABAA mediated, whereas the later component, absent in rats, was GABAB mediated and selectively enhanced by GABA uptake inhibition. Striatal-evoked inhibition exhibited a slower onset and a weaker initial component compared to inhibition from globus pallidus or substantia nigra pars reticulata. These results are discussed with respect to differences in the size and neuronal density of the rat and mouse brain, and the different sites of synaptic contact of the synapses from the three GABAergic afferents. PMID:18842898

  4. Dopaminergic Neurodegeneration in the Mouse Is Associated with Decrease of Viscoelasticity of Substantia Nigra Tissue

    PubMed Central

    Hain, Elisabeth G.; Klein, Charlotte; Munder, Tonia; Braun, Juergen; Riek, Kerstin; Mueller, Susanne; Sack, Ingolf; Steiner, Barbara

    2016-01-01

    The biomechanical properties of brain tissue are altered by histopathological changes due to neurodegenerative diseases like Parkinson's disease (PD). Such alterations can be measured by magnetic resonance elastography (MRE) as a non-invasive technique to determine viscoelastic parameters of the brain. Until now, the correlation between histopathological mechanisms and observed alterations in tissue viscoelasticity in neurodegenerative diseases is still not completely understood. Thus, the objective of this study was to evaluate (1) the validity of MRE to detect viscoelastic changes in small and specific brain regions: the substantia nigra (SN), midbrain and hippocampus in a mouse model of PD, and (2) if the induced dopaminergic neurodegeneration and inflammation in the SN is reflected by local changes in viscoelasticity. Therefore, MRE measurements of the SN, midbrain and hippocampus were performed in adult female mice before and at five time points after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin hydrochloride (MPTP) treatment specifically lesioning dopaminergic neurons in the SN. At each time point, additional mice were utilized for histological analysis of the SN. After treatment cessation, we observed opposed viscoelastic changes in the midbrain, hippocampus and SN with the midbrain showing a gradual rise and the hippocampus a distinct transient increase of viscous and elastic parameters, while viscosity and–to a lesser extent—elasticity in the SN decreased over time. The decrease in viscosity and elasticity in the SN was paralleled by a reduced number of neurons due to the MPTP-induced neurodegeneration. In conclusion, MRE is highly sensitive to detect local viscoelastic changes in specific and even small brain regions. Moreover, we confirmed that neuronal cells likely constitute the backbone of the adult brain mainly accounting for its viscoelasticity. Therefore, MRE could be established as a new potential instrument for clinical evaluation and

  5. Dopaminergic Neurodegeneration in the Mouse Is Associated with Decrease of Viscoelasticity of Substantia Nigra Tissue.

    PubMed

    Hain, Elisabeth G; Klein, Charlotte; Munder, Tonia; Braun, Juergen; Riek, Kerstin; Mueller, Susanne; Sack, Ingolf; Steiner, Barbara

    2016-01-01

    The biomechanical properties of brain tissue are altered by histopathological changes due to neurodegenerative diseases like Parkinson's disease (PD). Such alterations can be measured by magnetic resonance elastography (MRE) as a non-invasive technique to determine viscoelastic parameters of the brain. Until now, the correlation between histopathological mechanisms and observed alterations in tissue viscoelasticity in neurodegenerative diseases is still not completely understood. Thus, the objective of this study was to evaluate (1) the validity of MRE to detect viscoelastic changes in small and specific brain regions: the substantia nigra (SN), midbrain and hippocampus in a mouse model of PD, and (2) if the induced dopaminergic neurodegeneration and inflammation in the SN is reflected by local changes in viscoelasticity. Therefore, MRE measurements of the SN, midbrain and hippocampus were performed in adult female mice before and at five time points after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin hydrochloride (MPTP) treatment specifically lesioning dopaminergic neurons in the SN. At each time point, additional mice were utilized for histological analysis of the SN. After treatment cessation, we observed opposed viscoelastic changes in the midbrain, hippocampus and SN with the midbrain showing a gradual rise and the hippocampus a distinct transient increase of viscous and elastic parameters, while viscosity and-to a lesser extent-elasticity in the SN decreased over time. The decrease in viscosity and elasticity in the SN was paralleled by a reduced number of neurons due to the MPTP-induced neurodegeneration. In conclusion, MRE is highly sensitive to detect local viscoelastic changes in specific and even small brain regions. Moreover, we confirmed that neuronal cells likely constitute the backbone of the adult brain mainly accounting for its viscoelasticity. Therefore, MRE could be established as a new potential instrument for clinical evaluation and diagnostics

  6. Myricitrin Ameliorates 6-Hydroxydopamine-Induced Dopaminergic Neuronal Loss in the Substantia Nigra of Mouse Brain.

    PubMed

    Kim, Heung Deok; Jeong, Kyoung Hoon; Jung, Un Ju; Kim, Sang Ryong

    2016-04-01

    Parkinson's disease (PD) is a chronic and progressive movement disorder, resulting from the degeneration of the nigrostriatal dopaminergic (DA) pathway. The cause of DA neuronal loss in PD is still unclear; however, accumulating evidence suggests that treatment with certain flavonoids can induce neuroprotective properties, such as activation of mammalian target of rapamycin complex 1 (mTORC1) and anti-inflammatory activities in animal models of PD. The bioflavonoid myricitrin is well known for its anti-inflammatory and antioxidant properties. However, it is unclear whether systemic treatment with myricitrin can protect neurons against neurotoxin-induced DA degeneration in vivo via the preservation of tyrosine hydroxylase (TH) activity and the induction of mTORC1 activation. Our results found no significant neuroprotective effect of 30 mg/kg myricitrin on 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in the substantia nigra (SN) of mice. However, myricitrin treatment with 60 mg/kg protected DA neurons against 6-OHDA-induced neurotoxicity. Moreover, myricitrin treatment preserved TH enzyme activity and mTORC1 activation in nigral DA neurons in the SN of 6-OHDA-treated mice, and its treatment suppressed an increase in tumor necrosis factor-α expression in activated microglia. These results suggest that myricitrin may have neuroprotective properties linked to mTORC1 activation, preservation of TH enzyme activity, and anti-neuroinflammation for preventing DA neuronal degeneration in vivo. PMID:26991235

  7. Bursting Activity of Substantia Nigra pars Reticulata Neurons in Mouse Parkinsonism in Awake and Anesthetized States

    PubMed Central

    Lobb, CJ; Jaeger, D

    2015-01-01

    Electrophysiological changes in basal ganglia neurons are hypothesized to underlie motor dysfunction in Parkinson’s disease (PD). Previous results in head-restrained MPTP-treated non-human primates have suggested that increased bursting within the basal ganglia and related thalamic and cortical areas may be a hallmark of pathophysiological activity. In this study, we investigated whether there is increased bursting in substantia nigra pars reticulata (SNpr) output neurons in anesthetized and awake, head-restrained unilaterally lesioned 6-OHDA mice when compared to control mice. Confirming previous studies, we show that there are significant changes in the firing rate and pattern in SNpr neuron activity under urethane anesthesia. The regular firing pattern of control urethane-anesthetized SNpr neurons was not present in the 6-OHDA-lesioned group, as the latter neurons instead became phase locked with cortical slow wave activity (SWA). Next, we examined whether such robust electrophysiological changes between groups carried over to the awake state. SNpr neurons from both groups fired at much higher frequencies in the awake state than in the anesthetized state and surprisingly showed only modest changes between awake control and 6-OHDA groups. While there were no differences in firing rate between groups in the awake state, an increase in the coefficient of variation (CV) was observed in the 6-OHDA group. Contrary to the bursting hypothesis, this increased CV was not due to changes in bursting but was instead due to a mild increase in pausing. Together, these results suggest that differences in SNpr activity between control and 6-OHDA lesioned mice may be strongly influenced by changes in network activity during different arousal and behavioral states. PMID:25576395

  8. L-DOPA treatment in MPTP-mouse model of Parkinson's disease potentiates homocysteine accumulation in substantia nigra.

    PubMed

    Bhattacharjee, Nivedita; Mazumder, Muhammed Khairujjaman; Paul, Rajib; Choudhury, Amarendranath; Choudhury, Sabanum; Borah, Anupom

    2016-08-15

    One of the intermediates of methionine cycle, the homocysteine (Hcy), elevates in plasma of Parkinson's disease (PD) patients undergoing L-DOPA (3,4-dihydroxyphenylalanine) therapy and has been regarded as a risk factor of the disease. Several evidences pointed out that Hcy causes degeneration of dopaminergic neurons. In rodent, elevated level of Hcy in brain or infusion of the same directly into the substantia nigra (SN) potentiates dopaminergic neurodegeneration. However, the influence of L-DOPA therapy on the levels of Hcy in dopamine-rich regions of the brain (striatum and SN) of experimental models of PD is not known. The present study, for the first time, tested the hypothesis that L-DOPA treatment in experimental mouse model of PD potentiates Hcy accumulation in the dopamine-rich regions of the brain. We found a significant elevation of Hcy level in nigrostriatum in naïve as well as parkinsonian mice as a result of chronic L-DOPA treatment. Interestingly, L-DOPA treatment significantly elevates Hcy level in nigra but not in striatum of parkinsonian mice, when compared with L-DOPA naïve group. However, there is no significant decrease in the number of dopaminergic neurons in SN region in the parkinsonian mice given L-DOPA treatment. Thus, the present study demonstrates that L-DOPA treatment potentiates the level of Hcy in the SN without causing aggravated neurodegeneration in parkinsonian mice model. PMID:27283777

  9. Dopaminergic neuron loss and up-regulation of chaperone protein mRNA induced by targeted over-expression of alpha-synuclein in mouse substantia nigra.

    PubMed

    St Martin, Jessie L; Klucken, Jochen; Outeiro, Tiago F; Nguyen, Paul; Keller-McGandy, Christine; Cantuti-Castelvetri, Ippolita; Grammatopoulos, Tom N; Standaert, David G; Hyman, Bradley T; McLean, Pamela J

    2007-03-01

    Several transgenic mouse lines with altered alpha-synuclein expression have been developed that show a variety of Parkinson's disease-like symptoms without specific loss of dopaminergic neurons. Targeted over-expression of human alpha-synuclein using viral-vector mediated gene delivery into the substantia nigra of rats and non-human primates leads to dopaminergic cell loss and the formation of alpha-synuclein aggregates reminiscent of Lewy bodies. In the context of these recent findings, we used adeno-associated virus (AAV) to over-express wild type human alpha-synuclein in the substantia nigra of mice. We hypothesized that this over-expression would recapitulate pathological hallmarks of Parkinson's disease, creating a mouse model to further characterize the disease pathogenesis. Recombinant AAV expressing alpha-synuclein was stereotaxically injected into the substantia nigra of mice, leading to a 25% reduction of dopaminergic neurons after 24 weeks of transduction. Furthermore, examination of mRNA levels of stress-related proteins using laser capture microdissection and quantitative PCR revealed a positive correlation of Hsp27 expression with the extent of viral transduction at 4 weeks and a positive correlation of Hsp40, Hsp70 and caspase 9 with the extent of viral transduction at 24 weeks. Taken together, our findings suggest that targeted over-expression of alpha-synuclein can induce pathology at the gross anatomical and molecular level in the substantia nigra, providing a mouse model in which upstream changes in Parkinson's disease pathogenesis can be further elucidated. PMID:17241127

  10. rAAV2/7 vector-mediated overexpression of alpha-synuclein in mouse substantia nigra induces protein aggregation and progressive dose-dependent neurodegeneration

    PubMed Central

    2013-01-01

    Background Alpha-synuclein is a key protein implicated in the pathogenesis of Parkinson's disease (PD). It is the main component of the Lewy bodies, a cardinal neuropathological feature in the disease. In addition, whole locus multiplications and point mutations in the gene coding for alpha-synuclein lead to autosomal dominant monogenic PD. Over the past decade, research on PD has impelled the development of new animal models based on alpha-synuclein. In this context, transgenic mouse lines have failed to reproduce several hallmarks of PD, especially the strong and progressive dopaminergic neurodegeneration over time that occurs in the patients. In contrast, viral vector-based models in rats and non-human primates display prominent, although highly variable, nigral dopaminergic neuron loss. However, the few studies available on viral vector-mediated overexpression of alpha-synuclein in mice report a weak neurodegenerative process and no clear Lewy body-like pathology. To address this issue, we performed a comprehensive comparative study of alpha-synuclein overexpression by means of recombinant adeno-associated viral vectors serotype 2/7 (rAAV2/7) at different doses in adult mouse substantia nigra. Results We noted a significant and dose-dependent alpha-synucleinopathy over time upon nigral viral vector-mediated alpha-synuclein overexpression. We obtained a strong, progressive and dose-dependent loss of dopaminergic neurons in the substantia nigra, reaching a maximum of 82% after 8 weeks. This effect correlated with a reduction in tyrosine hydroxylase immunoreactivity in the striatum. Moreover, behavioural analysis revealed significant motor impairments from 12 weeks after injection on. In addition, we detected the presence of alpha-synuclein-positive aggregates in the remaining surviving neurons. When comparing wild-type to mutant A53T alpha-synuclein at the same vector dose, both induced a similar degree of cell death. These data were supported by a biochemical

  11. Differential distribution of hypoxia-inducible factor 1-beta (ARNT or ARNT2) in mouse substantia nigra and ventral tegmental area.

    PubMed

    Dela Cruz, J A D; Schmidt-Kastner, R; Stevens, J A A; Steinbusch, H W M; Rutten, B P F

    2014-11-01

    Hypoxia has been proposed as a mechanism underlying gene-environment interactions in the neurodevelopmental model of schizophrenia, and hypoxia-inducible factor 1 (HIF-1) could mediate the interactions. In the current study, we analyzed the HIF-1 beta subunit, as formed by aryl hydrocarbon receptor nuclear translocator (ARNT) or ARNT2, in the mouse substantia nigra (SN) and the ventral tegmental area (VTA). We performed immunohistochemical studies of ARNT and ARNT2 in the adult mouse brain, and colocalization analyses, with specific emphasis on dopaminergic cells, i.e. tyrosine hydroxylase (TH) immunoreactive cells. Bioinformatic analyses identified shared protein partners for ARNT and ARNT2. ARNT immunoreactivity showed widespread neuronal labeling without overt regional specificity. We observed co-localization of ARNT and TH in the SN compacta and VTA. Nuclei strongly labeled for ARNT2 were observed in the SN reticulata, while only weak immunoreactivity for ARNT2 was found in TH-immunoreactive neurons in SN compacta and VTA. Stereological analysis showed that ARNT was preferentially expressed in dopaminergic neurons in SN compacta and VTA. Nuclei strongly labeled for ARNT2 were present in neocortex and CA1 of hippocampus. Differential expression of ARNT and ARNT2 in dopaminergic neurons may relate to the vulnerability of distinct dopaminergic projections to hypoxia and to functional vulnerability in schizophrenia and other neuropsychiatric disorders. PMID:25017895

  12. Ginsenoside Rg1 attenuates motor impairment and neuroinflammation in the MPTP-probenecid-induced parkinsonism mouse model by targeting α-synuclein abnormalities in the substantia nigra.

    PubMed

    Heng, Yang; Zhang, Qiu-Shuang; Mu, Zheng; Hu, Jin-Feng; Yuan, Yu-He; Chen, Nai-Hong

    2016-01-22

    Parkinson's disease (PD) is pathologically characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the accumulation of aggregated α-synuclein in specific central nervous system (CNS) regions. Disease development is attributed to α-synuclein abnormalities, particularly aggregation and phosphorylation. The ginsenoside Rg1, an active component of ginseng, possesses neuroprotective and anti-inflammatory effects. The purpose of the present study was to evaluate these activities of Rg1 in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)/probenecid (MPTP/p)-induced PD mouse model for the first time and to elucidate the underlying mechanisms. Oral treatment with Rg1 significantly attenuated the high MPTP-induced mortality, behavior defects, loss of dopamine neurons and abnormal ultrastructure changes in the SNpc. Other assays indicated that the protective effect of Rg1 may be mediated by its anti-neuroinflammatory properties. Rg1 regulated MPTP-induced reactive astrocytes and microglia and decreased the release of cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in the SNpc. Rg1 also alleviated the unusual MPTP-induced increase in oligomeric, phosphorylated and disease-related α-synuclein in the SNpc. In conclusion, Rg1 protects dopaminergic neurons, most likely by reducing aberrant α-synuclein-mediated neuroinflammation, and holds promise for PD therapeutics. PMID:26723869

  13. Transplantation of mouse embryonic stem cell-derived neurons into the striatum, subthalamic nucleus and substantia nigra, and behavioral recovery in hemiparkinsonian rats.

    PubMed

    Inden, Masatoshi; Kim, Do-hoon; Qi, Meirigeng; Kitamura, Yoshihisa; Yanagisawa, Daijiro; Nishimura, Kaneyasu; Tsuchiya, Daiju; Takata, Kazuyuki; Hayashi, Kousuke; Taniguchi, Takashi; Yoshimoto, Kanji; Shimohama, Shun; Sumi, Shoichiro; Inoue, Kazutomo

    2005-10-28

    Usefulness of the in vitro and in vivo generation of neural precursors from embryonic stem (ES) cells has been widely discussed, but functional recovery in animal models of Parkinson's disease (PD) is not fully understood. The aim of this study was to investigate a transplantation strategy for PD by assessing whether double-transplants in the striatum (ST) and substantia nigra (SN), or ST and subthalamic nucleus (STN) induce functional recovery in 6-hydroxydopamine-lesioned rats. Methamphetamine-induced rotation was significantly reduced by transplantation of mouse ES cell-derived neurons into the ST, but not the STN or SN alone. Double-transplantation was also effective at recovering rotational behavior. Although immunoreactivity for tyrosine hydroxylase (TH) was almost completely lost in the ipsilateral striatum in hemiparkinsonian rats, TH immunoreactivity was detected in transplanted cells and sprouting fibers in the ST, STN and SN. These results suggest that both the involvement of ST as a place of transplantation and the number of ES cell-derived neurons are essential factors for efficacy on hemiparkinsonian behaviors. PMID:16023291

  14. Abnormal Expression of the GIRK2 Potassium Channel in Hippocampus, Frontal Cortex and Substantia Nigra of Ts65Dn Mouse: A Model of Down Syndrome

    PubMed Central

    Harashima, Chie; Jacobowitz, David M.; Witta, Jassir; Borke, Rosemary C.; Best, Tyler K.; Siarey, Richard J.; Galdzicki, Zygmunt

    2010-01-01

    Ts65Dn, a mouse model of Down syndrome (DS), demonstrates abnormal hippocampal synaptic plasticity and behavioral abnormalities related to spatial learning and memory. The molecular mechanisms leading to these impairments have not been identified. In this study, we focused on the G-protein-activated inwardly rectifying potassium channel 2 (GIRK2) gene that is highly expressed in the hippocampus region. We studied the expression pattern of GIRK subunits in Ts65Dn and found that GIRK2 was over-expressed in all analyzed Ts65Dn brain regions. Interestingly elevated levels of GIRK2 protein in the Ts65Dn hippocampus and frontal cortex correlated with elevated levels of GIRK1 protein. This suggests that heteromeric GIRK1-GIRK2 channels are over-expressed in Ts65Dn hippocampus and frontal cortex, which could impair excitatory input, modulate spike frequency and synaptic kinetics in the affected regions. All GIRK2 splicing isoforms examined were expressed at higher levels in the Ts65Dn in comparison to the diploid hippocampus. The pattern of GIRK2 expression in the Ts65Dn mouse brain revealed by in situ hybridization and immunohistochemistry was similar to that previously reported in the rodent brain. However, in the Ts65Dn mouse a strong immunofluorescent staining of GIRK2 was detected in the lacunosum molecular layer of the CA3 area of the hippocampus. In addition, tyrosine hydroxylase containing dopaminergic neurons that co-express GIRK2 were more numerous in the substantia nigra compacta and ventral tegmental area in the Ts65Dn compared to diploid controls. In summary, the regional localization and the increased brain levels coupled with known function of the GIRK channel may suggest an important contribution of GIRK2 containing channels to Ts65Dn and thus to DS neurophysiological phenotypes. PMID:16374808

  15. A cytoarchitectonic and chemoarchitectonic analysis of the dopamine cell groups in the substantia nigra, ventral tegmental area, and retrorubral field in the mouse.

    PubMed

    Fu, Yuhong; Yuan, Yuan; Halliday, Glenda; Rusznák, Zoltán; Watson, Charles; Paxinos, George

    2012-04-01

    The three main dopamine cell groups of the brain are located in the substantia nigra (A9), ventral tegmental area (A10), and retrorubral field (A8). Several subdivisions of these cell groups have been identified in rats and humans but have not been well described in mice, despite the increasing use of mice in neurodegenerative models designed to selectively damage A9 dopamine neurons. The aim of this study was to determine whether typical subdivisions of these dopamine cell groups are present in mice. The dopamine neuron groups were analysed in 15 adult C57BL/6J mice by anatomically localising tyrosine hydroxylase (TH), dopamine transporter protein (DAT), calbindin, and the G-protein-activated inward rectifier potassium channel 2 (GIRK2) proteins. Measurements of the labeling intensity, neuronal morphology, and the proportion of neurons double-labeled with TH, DAT, calbindin, or GIRK2 were used to differentiate subregions. Coronal maps were prepared and reconstructed in 3D. The A8 cell group had the largest dopamine neurons. Five subregions of A9 were identified: the reticular part with few dopamine neurons, the larger dorsal and smaller ventral dopamine tiers, and the medial and lateral parts of A9. The latter has groups containing some calbindin-immunoreactive dopamine neurons. The greatest diversity of dopamine cell types was identified in the seven subregions of A10. The main dopamine cell groups in the mouse brain are similar in terms of diversity to those observed in rats and humans. These findings are relevant to models using mice to analyse the selective vulnerability of different types of dopamine neurons. PMID:21935672

  16. Effect of total flavonoids from Scutellaria baicalensis on dopaminergic neurons in the substantia nigra

    PubMed Central

    Li, Xue-Li; Xu, Xiao-Fan; Bu, Qing-Xia; Jin, Wei-Rong; Sun, Qian-Ru; Feng, De-Peng; Zhang, Qing-Jv; Wang, Le-Xin

    2016-01-01

    The aim of the present study was to investigate the effect of Scutellaria baicalensis stem-leaf total flavonoid (SSTF) on the dopaminergic neurons in the substantia nigra in a mouse model of Parkinson's disease (PD). The mouse model was established by intravenous injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). SSTF (5 mg/kg) was administered to the mice before or after MPTP injection, and the effects of SSTF on the behavior of the mice and the dopaminergic neurons in the substantia nigra were assessed. In addition, the level of serum malondialdehyde (MDA) was measured. Following injection of MPTP, the number of dopaminergic neurons in the substantia nigra was decreased and the neurons appeared atrophic. In addition, the level of serum MDA in the MPTP mice increased. The mean behavioral scores and the number of dopaminergic neurons in the SSTF treatment groups were significantly higher than in the MPTP group (P<0.05), and the mean serum MDA levels were significantly lower (P<0.05). Thus, SSTF improves the behaviors and the numbers of dopaminergic neurons in the substantia nigra in MPTP-induced PD in mice. These beneficial effects appear to be associated with the reduction in serum MDA. PMID:27446544

  17. Immunohistochemical localization of TRPC6 in the rat substantia nigra.

    PubMed

    Giampà, Carmela; DeMarch, Zena; Patassini, Stefano; Bernardi, Giorgio; Fusco, Francesca R

    2007-09-13

    Transient receptor potential channels (TRPC) are plasma membrane, nonselective cationic channels and have been proposed as candidates involved in the regulation of cellular Ca2+ influx [D.E. Clapham, L.W. Runnels, C., Strubing, The TRP ion channel family, Nat. Rev. Neurosci. 2 (2001) 387-396; A. Martorana, C. Giampa, Z. DeMarch, M.T. Viscomi, S. Patassini, G. Sancesario, G. Bernardi, F.R. Fusco, Distribution of TRPC1 receptors in dendrites of rat substantia nigra: a confocal and electron microscopy study, Eur. J. Neurosci. 24 (2006) 732-738]. Studies on regional localization patterns of TRPCs are necessary to provide helpful guidelines for correlating current types with particular channels. In this study, we examined the distribution of one particular member of TRPC superfamily, namely, TRPC6, in the substantia nigra of normal rat brain. Single and double label immunohistochemistry were employed to perform both light and confocal microscopy observations. Our single label studies showed that, in the substantia nigra, TRPC6 labeled the perikarya with a diffuse and intense immunoreaction product distributed throughout cell cytoplasm whereas only a light immunostaining was observed in the cell nuclei. No labeling of axon or terminals was observed, although TRPC6 was evenly distributed in the neuropil. Our dual label studies showed a TRPC6 immunoreactivity pattern that was localized into the proximal dendrites and axon hillock of the large dopaminergic neurons identified by TH immunoreaction. Furthermore, our double label immunofluorescence study for TRPC6 and mGluR1 showed a complete co-localization of the two markers in the substantia nigra. Moreover, TRPC6 did not co-localize with synaptophysin. Thus, our study shows the postsynaptic localization of TRPC6 and its association with mGluR1 in the midbrain dopamine neurons. PMID:17723267

  18. Epstein-Barr virus encephalitis with substantia nigra involvement

    PubMed Central

    Çelik, Tamer; Çelik, Ümit; Tolunay, Orkun; Kömür, Mustafa; Başpınar, Hüseyin; Yılmaz, Cengiz; Mert, Gülen; Yıldızdaş, Dinçer

    2015-01-01

    Infectious mononucleosis due to Epstein–Barr virus (EBV) is a usually benign systemic viral illness common in children. Many studies described nervous system manifestations of infectious mononucleosis with a wide spectrum of neurologic deficits. Neurologic complications of EBV are seen in both acute and reactivate infection. Herein, we describe a patient diagnosed by acute EBV encephalitis with substantia nigra involvement and excellent clinical recovery. PMID:26962357

  19. Neuroprotective changes in degeneration-related gene expression in the substantia nigra following acupuncture in an MPTP mouse model of Parkinsonism: Microarray analysis.

    PubMed

    Yeo, Sujung; An, Keon Sang; Hong, Yeon-Mi; Choi, Yeong-Gon; Rosen, Bruce; Kim, Sung-Hoon; Lim, Sabina

    2015-03-01

    Parkinson's disease (PD) is a neurodegenerative disorder characterized by the death of dopamine-generating cells in the substantia nigra (SN). Acupuncture stimulation results in an enhanced survival of dopaminergic neurons in the SN in Parkinsonism animal models. The present study investigated changes in gene expression profiles measured using whole transcript array in the SN region related to the inhibitory effects of acupuncture in a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) Parkinsonism model. In this model, acupuncture stimulation at GB34 and LR3 attenuated the decrease in tyrosine hydroxylase in the SN region; stimulation at non-acupoints did not suppress this decrease. Gene array analysis revealed that 22 (10 annotated genes: Cdh1, Itih2, Mpzl2, Rdh9, Serping1, Slc6a13, Slc6a20a, Slc6a4, Tph2, and Ucma) probes that were up-regulated in MPTP animals relative to controls were exclusively down-regulated by acupuncture stimulation. In addition, 17 (two annotated genes: 4921530L21Rik and Gm13931) probes that were down-regulated in MPTP animals compared to controls were exclusively up-regulated by acupuncture stimulation. These findings indicate that the 39 probes (12 annotated genes) affected by MPTP and acupuncture may be responsible for the inhibitory effects of acupuncture on degeneration-related gene expression in the SN following damage induced by MPTP intoxication. PMID:25983633

  20. Ageing and Parkinson's disease: substantia nigra regional selectivity.

    PubMed

    Fearnley, J M; Lees, A J

    1991-10-01

    The micro-architecture of the substantia nigra was studied in control cases of varying age and patients with parkinsonism. A single 7 mu section stained with haematoxylin and eosin was examined at a specific level within the caudal nigra using strict criteria. The pars compacta was divided into a ventral and a dorsal tier, and each tier was further subdivided into 3 regions. In 36 control cases there was a linear fallout of pigmented neurons with advancing age in the pars compacta of the caudal substantia nigra at a rate of 4.7% per decade. Regionally, the lateral ventral tier was relatively spared (2.1% loss per decade) compared with the medial ventral tier (5.4%) and the dorsal tier (6.9%). In 20 Parkinson's disease (PD) cases of varying disease duration there was an exponential loss of pigmented neurons with a 45% loss in the first decade. Regionally, the pattern was opposite to ageing. Loss was greatest in the lateral ventral tier (average loss 91%) followed by the medial ventral tier (71%) and the dorsal tier (56%). The presymptomatic phase of PD from the onset of neuronal loss was estimated to be about 5 yrs. This phase is represented by incidental Lewy body cases: individuals who die without clinical signs of PD or dementia, but who are found to have Lewy bodies at post-mortem. In 7 cases cell loss was confined to the lateral ventral tier (average loss 52%) congruent with the lateral ventral selectivity of symptomatic PD. It was calculated that at the onset of symptoms there was a 68% cell loss in the lateral ventral tier and a 48% loss in the caudal nigra as a whole. The regional selectivity of PD is relatively specific. In 15 cases of striatonigral degeneration the distribution of cell loss was similar, but the loss in the dorsal tier was greater than PD by 21%. In 14 cases of Steele-Richardson-Olszewski syndrome (SRO) there was no predilection for the lateral ventral tier, but a tendency to involve the medial nigra and spare the lateral. These findings

  1. Microstimulation of the human substantia nigra alters reinforcement learning.

    PubMed

    Ramayya, Ashwin G; Misra, Amrit; Baltuch, Gordon H; Kahana, Michael J

    2014-05-14

    Animal studies have shown that substantia nigra (SN) dopaminergic (DA) neurons strengthen action-reward associations during reinforcement learning, but their role in human learning is not known. Here, we applied microstimulation in the SN of 11 patients undergoing deep brain stimulation surgery for the treatment of Parkinson's disease as they performed a two-alternative probability learning task in which rewards were contingent on stimuli, rather than actions. Subjects demonstrated decreased learning from reward trials that were accompanied by phasic SN microstimulation compared with reward trials without stimulation. Subjects who showed large decreases in learning also showed an increased bias toward repeating actions after stimulation trials; therefore, stimulation may have decreased learning by strengthening action-reward associations rather than stimulus-reward associations. Our findings build on previous studies implicating SN DA neurons in preferentially strengthening action-reward associations during reinforcement learning. PMID:24828643

  2. Illicit Stimulant Use Is Associated with Abnormal Substantia Nigra Morphology in Humans

    PubMed Central

    Todd, Gabrielle; Noyes, Carolyn; Flavel, Stanley C.; Della Vedova, Chris B.; Spyropoulos, Peter; Chatterton, Barry; Berg, Daniela; White, Jason M.

    2013-01-01

    Use of illicit stimulants such as methamphetamine, cocaine, and ecstasy is an increasing health problem. Chronic use can cause neurotoxicity in animals and humans but the long-term consequences are not well understood. The aim of the current study was to investigate the long-term effect of stimulant use on the morphology of the human substantia nigra. We hypothesised that history of illicit stimulant use is associated with an abnormally bright and enlarged substantia nigra (termed ‘hyperechogenicity’) when viewed with transcranial sonography. Substantia nigra morphology was assessed in abstinent stimulant users (n = 36; 31±9 yrs) and in two groups of control subjects: non-drug users (n = 29; 24±5 yrs) and cannabis users (n = 12; 25±7 yrs). Substantia nigra morphology was viewed with transcranial sonography and the area of echogenicity at the anatomical site of the substantia nigra was measured at its greatest extent. The area of substantia nigra echogenicity was significantly larger in the stimulant group (0.273±0.078 cm2) than in the control (0.201±0.054 cm2; P<0.001) and cannabis (0.202±0.045 cm2; P<0.007) groups. 53% of stimulant users exhibited echogenicity that exceeded the 90th percentile for the control group. The results of the current study suggest that individuals with a history of illicit stimulant use exhibit abnormal substantia nigra morphology. Substantia nigra hyperechogenicity is a strong risk factor for developing Parkinson's disease later in life and further research is required to determine if the observed abnormality in stimulant users is associated with a functional deficit of the nigro-striatal system. PMID:23418568

  3. Illicit stimulant use is associated with abnormal substantia nigra morphology in humans.

    PubMed

    Todd, Gabrielle; Noyes, Carolyn; Flavel, Stanley C; Della Vedova, Chris B; Spyropoulos, Peter; Chatterton, Barry; Berg, Daniela; White, Jason M

    2013-01-01

    Use of illicit stimulants such as methamphetamine, cocaine, and ecstasy is an increasing health problem. Chronic use can cause neurotoxicity in animals and humans but the long-term consequences are not well understood. The aim of the current study was to investigate the long-term effect of stimulant use on the morphology of the human substantia nigra. We hypothesised that history of illicit stimulant use is associated with an abnormally bright and enlarged substantia nigra (termed 'hyperechogenicity') when viewed with transcranial sonography. Substantia nigra morphology was assessed in abstinent stimulant users (n = 36; 31±9 yrs) and in two groups of control subjects: non-drug users (n = 29; 24±5 yrs) and cannabis users (n = 12; 25±7 yrs). Substantia nigra morphology was viewed with transcranial sonography and the area of echogenicity at the anatomical site of the substantia nigra was measured at its greatest extent. The area of substantia nigra echogenicity was significantly larger in the stimulant group (0.273±0.078 cm(2)) than in the control (0.201±0.054 cm(2); P<0.001) and cannabis (0.202±0.045 cm(2); P<0.007) groups. 53% of stimulant users exhibited echogenicity that exceeded the 90(th) percentile for the control group. The results of the current study suggest that individuals with a history of illicit stimulant use exhibit abnormal substantia nigra morphology. Substantia nigra hyperechogenicity is a strong risk factor for developing Parkinson's disease later in life and further research is required to determine if the observed abnormality in stimulant users is associated with a functional deficit of the nigro-striatal system. PMID:23418568

  4. Unitary synaptic connections among substantia nigra pars reticulata neurons.

    PubMed

    Higgs, Matthew H; Wilson, Charles J

    2016-06-01

    Neurons in substantia nigra pars reticulata (SNr) are synaptically coupled by local axon collaterals, providing a potential mechanism for local signal processing. Because SNr neurons fire spontaneously, these synapses are constantly active. To investigate their properties, we recorded spontaneous inhibitory postsynaptic currents (sIPSCs) from SNr neurons in brain slices, in which afferents from upstream nuclei are severed, and the cells fire rhythmically. The sIPSC trains contained a mixture of periodic and aperiodic events. Autocorrelation analysis of sIPSC trains showed that a majority of cells had one to four active unitary inputs. The properties of the unitary IPSCs (uIPSCs) were analyzed for cells with one unitary input, using a model of periodic presynaptic firing and stochastic synaptic transmission. The inferred presynaptic firing rates and coefficient of variation of interspike intervals (ISIs) corresponded well with direct measurements of spiking in SNr neurons. Methods were developed to estimate the success probability, amplitude distributions, and kinetics of the uIPSCs, while removing the contribution from aperiodic sIPSCs. The sIPSC amplitudes were not increased upon release from halorhodopsin silencing, suggesting that most synapses were not depressed at the spontaneous firing rate. Gramicidin perforated-patch recordings indicated that the average reversal potential of spontaneous inhibitory postsynaptic potentials was -64 mV. Because of the change in driving force across the ISI, the unitary inputs are predicted to have a larger postsynaptic impact when they arrive late in the ISI. Simulations of network activity suggest that this very sparse inhibitory coupling may act to desynchronize the activity of SNr neurons while having only a small effect on firing rate. PMID:26961101

  5. Mesencephalic origin of the rostral Substantia nigra pars reticulata.

    PubMed

    Madrigal, M Pilar; Moreno-Bravo, Juan A; Martínez-López, Jesús E; Martínez, Salvador; Puelles, Eduardo

    2016-04-01

    In embryonic development, the neurons that will constitute a heterogeneous nucleus may have distinct origins. The different components of these populations reach their final location by radial and tangential migrations. The Substantia nigra pars reticulata (SNR) presents a high level of neuronal heterogeneity. It is composed by GABAergic neurons located in the mes-diencephalic basal plate. These inhibitory neurons usually display tangential migrations and it has been already described that the caudal SNR is colonized tangentially from rhombomere 1. Our aim is to unveil the origin of the rostral SNR. We have localized a Nkx6.2 positive ventricular domain located in the alar midbrain. Nkx6.2 derivatives' fate map analysis showed mainly a rostral colonization of this GABAergic neuronal population. We confirmed the mesencephalic origin by the expression of Six3. Both transcription factors are sequentially expressed along the differentiation of these neurons. We demonstrated the origin of the rostral SNR; our data allowed us to postulate that this nucleus is composed by two neuronal populations distributed in opposite gradients with different origins, one from rhombomere 1, caudal to rostral, and the other from the midbrain, rostral to caudal. We can conclude that the SNR has multiple origins and follows complex mechanisms of specification and migration. Our results support vital information for the study of genetic modifications in these extremely complex processes that result in devastating behavioral alterations and predisposition to psychiatric diseases. Understanding the development, molecular identity and functional characteristics of these diverse neuronal populations might lead to better diagnosis and treatment of several forms of neurological and psychiatric disease. PMID:25579066

  6. Eyes as gateways for environmental light to the substantia nigra: relevance in Parkinson's disease.

    PubMed

    Romeo, Stefania; Di Camillo, Daniela; Splendiani, Alessandra; Capannolo, Marta; Rocchi, Cristina; Aloisi, Gabriella; Fasciani, Irene; Corsini, Giovanni U; Scarnati, Eugenio; Lozzi, Luca; Maggio, Roberto

    2014-01-01

    Recent data indicates that prolonged bright light exposure of rats induces production of neuromelanin and reduction of tyrosine hydroxylase positive neurons in the substantia nigra. This effect was the result of direct light reaching the substantia nigra and not due to alteration of circadian rhythms. Here, we measured the spectrum of light reaching the substantia nigra in rats and analysed the pathway that light may take to reach this deep brain structure in humans. Wavelength range and light intensity, emitted from a fluorescent tube, were measured, using a stereotaxically implanted optical fibre in the rat mesencephalon. The hypothetical path of environmental light from the eye to the substantia nigra in humans was investigated by computed tomography and magnetic resonance imaging. Light with wavelengths greater than 600 nm reached the rat substantia nigra, with a peak at 709 nm. Eyes appear to be the gateway for light to the mesencephalon since covering the eyes with aluminum foil reduced light intensity by half. Using computed tomography and magnetic resonance imaging of a human head, we identified the eye and the superior orbital fissure as possible gateways for environmental light to reach the mesencephalon. PMID:24578627

  7. Quantitative morphochemical characterization of the neurons in substantia nigra of rat brain and its volume reconstruction.

    PubMed

    Khudoerkov, R M; Voronkov, D N; Dikalova, Yu V

    2014-04-01

    Three cell compartments differing by size and proportion of neurons were identified by 3D reconstruction of the substantia nigra pars compacta of the rat brain based on immunohistochemical localization of tyrosine hydroxylase, a marker of dopamine neurons. Dopaminepositive neurons prevailed over dopamine-free neurons (1.45:1) in the most voluminous (75%) dorsal part, and in smaller lateral and ventral parts, inverse cell ratios were observed: 0.54:1 and 0.78:1, respectively. Morphometry characterized the substantia nigra pars compacta as a structure consisting not only of several parts, but of horizons and showed differences between the neurons both in several parts and in several layers within the part. The revealed morphochemical heterogeneity of the substantia nigra pars compacta provides better understanding of the selective damage to its structures in Parkinson's disease. PMID:24824717

  8. Genome-wide analysis of DNA methylation during antagonism of DMOG to MnCl2-induced cytotoxicity in the mouse substantia nigra

    PubMed Central

    Yang, Nannan; Wei, Yang; Wang, Tan; Guo, Jifeng; Sun, Qiying; Hu, Yacen; Yan, Xinxiang; Zhu, Xiongwei; Tang, Beisha; Xu, Qian

    2016-01-01

    Exposure to excessive manganese (Mn) causes manganism, a progressive neurodegenerative disorder similar to idiopathic Parkinson’s disease (IPD). The detailed mechanisms of Mn neurotoxicity in nerve cells, especially in dopaminergic neurons are not yet fully understood. Meanwhile, it is unknown whether there exists a potential antagonist or effective drug for treating neuron damage in manganism. In the present study, we report the discovery of an HIF prolyl-hydroxylase inhibitor, DMOG [N-(2-Methoxy-2-oxoacetyl) glycine methyl ester], that can partially inhibit manganese toxicity not only in the neuroblastoma cell line SH-SY5Y in vitro but also in a mouse model in vivo. A genome-wide methylation DNA analysis was performed using microarray hybridization. Intriguingly, DNA methylation in the promoter region of 226 genes was found to be regulated by MnCl2, while the methylation effects of MnCl2 could be restored with combinatorial DMOG treatment. Furthermore, we found that genes with converted promoter methylation during DMOG antagonism were associated across several categories of molecular function, including mitochondria integrity maintain, cell cycle and DNA damage response, and ion transportation. Collectively, our results serve as the basis of a mechanism analysis of neuron damage in manganism and may supply possible gene targets for clinical therapy. PMID:27380887

  9. Genome-wide analysis of DNA methylation during antagonism of DMOG to MnCl2-induced cytotoxicity in the mouse substantia nigra.

    PubMed

    Yang, Nannan; Wei, Yang; Wang, Tan; Guo, Jifeng; Sun, Qiying; Hu, Yacen; Yan, Xinxiang; Zhu, Xiongwei; Tang, Beisha; Xu, Qian

    2016-01-01

    Exposure to excessive manganese (Mn) causes manganism, a progressive neurodegenerative disorder similar to idiopathic Parkinson's disease (IPD). The detailed mechanisms of Mn neurotoxicity in nerve cells, especially in dopaminergic neurons are not yet fully understood. Meanwhile, it is unknown whether there exists a potential antagonist or effective drug for treating neuron damage in manganism. In the present study, we report the discovery of an HIF prolyl-hydroxylase inhibitor, DMOG [N-(2-Methoxy-2-oxoacetyl) glycine methyl ester], that can partially inhibit manganese toxicity not only in the neuroblastoma cell line SH-SY5Y in vitro but also in a mouse model in vivo. A genome-wide methylation DNA analysis was performed using microarray hybridization. Intriguingly, DNA methylation in the promoter region of 226 genes was found to be regulated by MnCl2, while the methylation effects of MnCl2 could be restored with combinatorial DMOG treatment. Furthermore, we found that genes with converted promoter methylation during DMOG antagonism were associated across several categories of molecular function, including mitochondria integrity maintain, cell cycle and DNA damage response, and ion transportation. Collectively, our results serve as the basis of a mechanism analysis of neuron damage in manganism and may supply possible gene targets for clinical therapy. PMID:27380887

  10. Pitx3 is required for development of substantia nigra dopaminergic neurons

    PubMed Central

    Nunes, Irene; Tovmasian, Lucy T.; Silva, Robert M.; Burke, Robert E.; Goff, Stephen P.

    2003-01-01

    Dopaminergic (DA) neurons of substantia nigra in the midbrain control voluntary movement, and their degeneration is the cause of Parkinson's disease. The complete set of genes required to specifically determine the development of midbrain DA subgroups is not known yet. We report here that mice lacking the bicoid-related homeoprotein Pitx3 fail to develop DA neurons of the substantia nigra. Other mesencephalic DA neurons of the ventral tegmental area and retrorubral field are unaltered in their dopamine expression and histological organization. These data suggest that Pitx3-dependent gene expression is specifically required for the differentiation of DA progenitors within the mesencephalic DA system. PMID:12655058

  11. Manganese exposure induces microglia activation and dystrophy in the substantia nigra of non-human primates

    PubMed Central

    Verina, Tatyana; Kiihl, Samara F; Schneider, Jay S; Guilarte, Tomás R

    2011-01-01

    Chronic manganese (Mn) exposure produces neurological deficits including a form of parkinsonism that is different from Parkinson's disease (PD). In chronic Mn exposure, dopamine neurons in the substantia nigra (SN) do not degenerate but they appear to be dysfunctional. Further, previous studies have suggested that the substantia nigra pars reticulata (SNr) is affected by Mn. In the present study, we investigated whether chronic Mn exposure induces microglia activation in the substantia nigra pars compacta (SNc) and SNr in Cynomolgus macaques. Animals were exposed to different weekly doses of Mn (3.3–5.0, 5.0-6.7, 8.3-10 mg Mn/kg body weight) and microglia were examined in the substantia nigra using LN3 immunohistochemistry. We observed that in control animals, LN3 labeled microglia were characterized by a resting phenotype. However, in Mn-treated animals, microglia increased in number and displayed reactive changes with increasing Mn exposure. This effect was more prominent in the SNr than in the SNc. In the SNr of animals administered the highest Mn dose, microglia activation was the most advanced and included dystrophic changes. Reactive microglia expressed increased iNOS, L-ferritin, and intracellular ferric iron which were particularly prominent in dystrophic compartments. Our observations indicate that moderate Mn exposure produces structural changes on microglia, which may have significant consequences on their function. PMID:21112353

  12. Ventral Tegmental Area and Substantia Nigra Neural Correlates of Spatial Learning

    ERIC Educational Resources Information Center

    Martig, Adria K.; Mizumori, Sheri J. Y.

    2011-01-01

    The ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) may provide modulatory signals that, respectively, influence hippocampal (HPC)- and striatal-dependent memory. Electrophysiological studies investigating neural correlates of learning and memory of dopamine (DA) neurons during classical conditioning tasks have found DA…

  13. Tonic Firing Rate Controls Dendritic Ca2+ Signaling and Synaptic Gain in Substantia Nigra Dopamine Neurons

    PubMed Central

    Hage, Travis A.

    2015-01-01

    Substantia nigra dopamine neurons fire tonically resulting in action potential backpropagation and dendritic Ca2+ influx. Using Ca2+ imaging in acute mouse brain slices, we find a surprisingly steep relationship between tonic firing rate and dendritic Ca2+. Increasing the tonic rate from 1 to 6 Hz generated Ca2+ signals up to fivefold greater than predicted by linear summation of single spike-evoked Ca2+-transients. This “Ca2+ supralinearity” was produced largely by depolarization of the interspike voltage leading to activation of subthreshold Ca2+ channels and was present throughout the proximal and distal dendrites. Two-photon glutamate uncaging experiments show somatic depolarization enhances NMDA receptor-mediated Ca2+ signals >400 μm distal to the soma, due to unusually tight electrotonic coupling of the soma to distal dendrites. Consequently, we find that fast tonic firing intensifies synaptically driven burst firing output in dopamine neurons. These results show that modulation of background firing rate precisely tunes dendritic Ca2+ signaling and provides a simple yet powerful mechanism to dynamically regulate the gain of synaptic input. PMID:25855191

  14. The leak channel NALCN controls tonic firing and glycolytic sensitivity of substantia nigra pars reticulata neurons

    PubMed Central

    Lutas, Andrew; Lahmann, Carolina; Soumillon, Magali; Yellen, Gary

    2016-01-01

    Certain neuron types fire spontaneously at high rates, an ability that is crucial for their function in brain circuits. The spontaneously active GABAergic neurons of the substantia nigra pars reticulata (SNr), a major output of the basal ganglia, provide tonic inhibition of downstream brain areas. A depolarizing 'leak' current supports this firing pattern, but its molecular basis remains poorly understood. To understand how SNr neurons maintain tonic activity, we used single-cell RNA sequencing to determine the transcriptome of individual mouse SNr neurons. We discovered that SNr neurons express the sodium leak channel, NALCN, and that SNr neurons lacking NALCN have impaired spontaneous firing. In addition, NALCN is involved in the modulation of excitability by changes in glycolysis and by activation of muscarinic acetylcholine receptors. Our findings suggest that disruption of NALCN could impair the basal ganglia circuit, which may underlie the severe motor deficits in humans carrying mutations in NALCN. DOI: http://dx.doi.org/10.7554/eLife.15271.001 PMID:27177420

  15. Effects of aging on glutamate neurotransmission in the substantia nigra of Gdnf heterozygous mice

    PubMed Central

    Farrand, Ariana Q; Gregory, Rebecca A; Scofield, Michael D; Helke, Kristi L; Boger, Heather A

    2015-01-01

    Glial cell line-derived neurotrophic factor (GDNF) helps protect dopaminergic neurons in the nigrostriatal tract. Although the cause of nigrostriatal degeneration is unknown, one theory is that excess glutamate from the subthalamic nucleus (STN) results in excitotoxic events in the substantia nigra (SN). Since dopaminergic degeneration is accompanied by a reduction in GDNF, we examined glutamate neurotransmission in the SN using a Gdnf heterozygous mouse model (Gdnf+/−) at 8 and 12 months of age. At 8 months, Gdnf+/− mice have greater glutamate release and higher basal glutamate levels, which precede the SN dopaminergic degeneration observed at 12 months of age. However, at 12 months, Gdnf+/− mice have lower basal levels of glutamate and less glutamate release than wildtype (WT) mice. Also at 8 months, Gdnf+/− mice have lower levels of GLT-1 and greater GFAP levels in the SN compared to WT mice, differences that increase with age. These data suggest that reduced levels of GDNF induce excess glutamate release and dysregulation of GLT-1, causing excitotoxicity in the SN that precedes dopaminergic degeneration. PMID:25577412

  16. Peripheral Inflammation is Associated with Altered Substantia Nigra Activity and Psychomotor Slowing in Humans

    PubMed Central

    Brydon, Lena; Harrison, Neil A.; Walker, Cicely; Steptoe, Andrew; Critchley, Hugo D.

    2008-01-01

    Background Systemic infections commonly cause sickness symptoms including psychomotor retardation. Inflammatory cytokines released during the innate immune response are implicated in the communication of peripheral inflammatory signals to the brain. Methods We used functional magnetic resonance brain imaging (fMRI) to investigate neural effects of peripheral inflammation following typhoid vaccination in 16 healthy men, using a double-blind, randomized, crossover-controlled design. Results Vaccination had no global effect on neurovascular coupling but markedly perturbed neural reactivity within substantia nigra during low-level visual stimulation. During a cognitive task, individuals in whom typhoid vaccination engendered higher levels of circulating interleukin-6 had significantly slower reaction time responses. Prolonged reaction times and larger interleukin-6 responses were associated with evoked neural activity within substantia nigra. Conclusions Our findings provide mechanistic insights into the interaction between inflammation and neurocognitive performance, specifically implicating circulating cytokines and midbrain dopaminergic nuclei in mediating the psychomotor consequences of systemic infection. PMID:18242584

  17. Postnatal changes in the distribution and morphology of rat substantia nigra dopaminergic neurons.

    PubMed

    Tepper, J M; Damlama, M; Trent, F

    1994-05-01

    Significant changes in the neurophysiology and neuropharmacology of nigral dopaminergic neurons take place in the first postnatal month. In order to correlate these changes with the postnatal development of dopaminergic neuron morphology and substantia nigra cytoarchitecture, brains from Sprague-Dawley rat pups of age postnatal days 1, 7, 14, 21 and 28 and adult rats were sectioned and processed for tyrosine hydroxylase immunocytochemistry. At postnatal day 1, pars compacta and pars reticulata were not clearly delineated; tyrosine hydroxylase positive neurons and a dense plexus of fibers were scattered throughout the substantia nigra. By day 7 the density of tyrosine hydroxylase positive neurons decreased markedly in ventral substantia nigra, and a dopaminergic pars compacta and a non-dopaminergic pars reticulata could be more clearly distinguished. By day 14 the substantia nigra appeared essentially as it does in the adult. Cell counts during development revealed that the number of tyrosine hydroxylase positive neurons/section in both pars compacta and pars reticulata decreased significantly from postnatal day 1 to postnatal day 14, while those in pars lateralis did not change. Tyrosine hydroxylase-positive somatic size increased modestly but significantly from postnatal day 1 to day 14 as did the diameter of the proximal and distal dendrites. However, even at day 1, the morphology of tyrosine hydroxylase positive neurons appeared essentially the same as in adults. Dendritic arborizations were well developed. The dendrites were non-varicose and modestly branched, with some of the longer ventrally directed dendrites passing through pars reticulata into the crus cerebri.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7915412

  18. MPDZ EXPRESSION IN THE CAUDOLATERAL SUBSTANTIA NIGRA PARS RETICULATA IS CRUCIALLY INVOLVED IN ALCOHOL WITHDRAWAL

    PubMed Central

    Kruse, L.C.; Walter, N.A.R.; Buck, K.J.

    2014-01-01

    Association studies implicate the multiple PDZ domain protein (MUPP1/MPDZ) gene in risk for alcoholism in humans and alcohol withdrawal in mice. Although manipulation of the Mpdz gene by homologous recombination and bacterial artificial chromosome transgenesis has suggested that its expression affects alcohol withdrawal risk, the potential confounding effects of linked genes and developmental compensation currently limit interpretation. Here, using RNA interference, we directly test the impact of Mpdz expression on alcohol withdrawal severity and provide brain regional mechanistic information. Lentiviral-mediated delivery of Mpdz short hairpin RNA (shRNA) to the caudolateral substantia nigra pars reticulata significantly reduces Mpdz expression and exacerbates alcohol withdrawal convulsions compared to control mice delivered a scrambled shRNA. Neither baseline nor pentylenetetrazol enhanced convulsions differed between Mpdz shRNA and control animals, indicating that Mpdz expression in the caudolateral substantia nigra pars reticulata does not generally affect seizure susceptibility. To our knowledge, these represent the first in vivo Mpdz RNA interference analyses, and provide the first direct evidence that Mpdz expression impacts behavior. Our results confirm that Mpdz is a quantitative trait gene for alcohol withdrawal and demonstrate that its expression in the caudolateral substantia nigra pars reticulata is crucially involved in risk for alcohol withdrawal. PMID:25109596

  19. Dopamine receptors in the substantia nigra are involved in the regulation of muscle tone.

    PubMed Central

    Double, K L; Crocker, A D

    1995-01-01

    The aim of the present study was to localize the dopamine receptors involved in the regulation of muscle tone. A strategy was used whereby the effects on muscle tone of injecting the irreversible dopamine receptor antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) in discrete brain regions were assessed. Increases in muscle tone were measured as changes in electromyographic activity of the gastrocnemius and tibialis muscles of conscious, unrestrained rats. No increases in muscle tone were found after injections of EEDQ into the anterior and posterior striatum, which produced marked reductions in dopamine receptor concentration. The effects of muscle tone of injecting EEDQ into the substantia nigra pars reticulata were also assessed. Large increases in muscle tone were observed associated with inactivation of either D1 or D2 dopamine receptors in the substantia nigra. The increased muscle tone was not reduced by subcutaneous administration of apomorphine, despite the presence of a normal population of striatal dopamine receptors. These findings provide evidence that dopamine receptors in the substantia nigra play an important role in the regulation of muscle tone. Further, they challenge the hypothesis that the muscle rigidity of Parkinson disease results primarily from loss of striatal dopamine receptor stimulation. Images Fig. 1 Fig. 3 PMID:7878037

  20. Ultra-High Field MRI Post Mortem Structural Connectivity of the Human Subthalamic Nucleus, Substantia Nigra, and Globus Pallidus

    PubMed Central

    Plantinga, Birgit R.; Roebroeck, Alard; Kemper, Valentin G.; Uludağ, Kâmil; Melse, Maartje; Mai, Jürgen; Kuijf, Mark L.; Herrler, Andreas; Jahanshahi, Ali; ter Haar Romeny, Bart M.; Temel, Yasin

    2016-01-01

    Introduction: The subthalamic nucleus, substantia nigra, and globus pallidus, three nuclei of the human basal ganglia, play an important role in motor, associative, and limbic processing. The network of the basal ganglia is generally characterized by a direct, indirect, and hyperdirect pathway. This study aims to investigate the mesoscopic nature of these connections between the subthalamic nucleus, substantia nigra, and globus pallidus and their surrounding structures. Methods: A human post mortem brain specimen including the substantia nigra, subthalamic nucleus, and globus pallidus was scanned on a 7 T MRI scanner. High resolution diffusion weighted images were used to reconstruct the fibers intersecting the substantia nigra, subthalamic nucleus, and globus pallidus. The course and density of these tracks was analyzed. Results: Most of the commonly established projections of the subthalamic nucleus, substantia nigra, and globus pallidus were successfully reconstructed. However, some of the reconstructed fiber tracks such as the connections of the substantia nigra pars compacta to the other included nuclei and the connections with the anterior commissure have not been shown previously. In addition, the quantitative tractography approach showed a typical degree of connectivity previously not documented. An example is the relatively larger projections of the subthalamic nucleus to the substantia nigra pars reticulata when compared to the projections to the globus pallidus internus. Discussion: This study shows that ultra-high field post mortem tractography allows for detailed 3D reconstruction of the projections of deep brain structures in humans. Although the results should be interpreted carefully, the newly identified connections contribute to our understanding of the basal ganglia. PMID:27378864

  1. Functional recovery of supersensitive dopamine receptors after intrastriatal grafts of fetal substantia nigra

    SciTech Connect

    Dawson, T.M.; Dawson, V.L.; Gage, F.H.; Fisher, L.J.; Hunt, M.A.; Wamsley, J.K. )

    1991-03-01

    Interruption of the ascending dopamine neurons of the nigrostriatal pathway, by 6-hydroxydopamine (6-OHDA) lesion in rats, produced a significant loss of the dopamine transport complexes labeled with the phencyclidine derivative (3H)BTCP. This loss of dopamine innervation in the striatum was present at least 12 to 14 months after lesioning and was functionally manifested by ipsilateral rotation of the animals in response to amphetamine. In these same animals, in comparison to controls, there was a significant increase in the number (Bmax) of (3H)SCH 23390-labeled D-1 receptors in the striatum (36.7%) and the substantia nigra (35.1%) and a 54.4% increase in the number (Bmax) of (3H)sulpiride-labeled striatal D-2 receptors without an apparent change in affinity (Kd). Ten to twelve months after the transplantation of homologous fetal substantia nigra into the denervated striatum, there was a significant decrease in amphetamine-induced turning behavior. In these animals, there was an ingrowth of dopamine nerve terminals in the striatum as demonstrated by a return of (3H)BTCP binding. Accompanying this reinnervation was the normalization of D-1 and D-2 receptors to control values in the striatum as well as the return of D-1 receptors to prelesion densities in the substantia nigra. In a subgroup of transplanted rats, amphetamine continued to induce ipsilateral turning. In these animals both D-1 and D-2 receptors remained supersensitive. These results support the hypothesis that the functional recovery of transplanted animals is due, in part, to reinnervation of the striatum. In addition, long-term alterations in receptor density may be related to the behavioral deficits that are associated with the 6-OHDA-lesioned rat.

  2. Cholinergic projections to the substantia nigra from the pedunculopontine and laterodorsal tegmental nuclei.

    PubMed

    Gould, E; Woolf, N J; Butcher, L L

    1989-01-01

    The cholinergic innervation of the compact and reticular parts of the substantia nigra in the rat was investigated by use of highly sensitive retrograde and anterograde tract-tracing methods in combination with choline acetyltransferase immunohistochemistry. The fluorescent tracers True Blue, propidium iodide, or fluorogold were infused preferentially into either nigral subnucleus. Cells positive for choline acetyltransferase and retrograde tracer were found in both the pedunculopontine and laterodorsal tegmental nuclei, although considerably more double-labeled somata were observed in the former than in the latter component of the pontomesencephalotegmental cholinergic complex. Approximately 2-3 times more cholinergic cells were labeled in the peduculopontine and laterodorsal tegmental nuclei when tracer injections were centered in the compact nigral subdivision than when infusions of about the same size were confined totally to the reticular part. Infusions of the anterogradely transported tracer Phaseolus vulgaris leucoagglutinin into the pontomesencephalotegmental cholinergic complex resulted in uptake and transport of that label to both nigral subnuclei, and some of the Phaseolus vulgaris leucoagglutinin-accumulating somata and proximal processes also demonstrated choline acetyltransferase-like immunoreactivity. The Phaseolus vulgaris agglutinin-labeled entities in the substantia nigra exhibited terminal-like profiles that were reminiscent of the pattern of nigral choline acetyltransferase-positive puncta demonstrated immunohistochemically by use of nickel ammonium sulfate enhancement of the final reaction product in the avidin-biotin procedure. These observations strongly support the contention that the pontomesencephalotegmental cholinergic complex is the major source of cholinergic projections to both the compact and reticular portions of the rat substantia nigra. PMID:2710334

  3. Microglial inflammation in the parkinsonian substantia nigra: relationship to alpha-synuclein deposition

    PubMed Central

    Croisier, Emilie; Moran, Linda B; Dexter, David T; Pearce, Ronald KB; Graeber, Manuel B

    2005-01-01

    Background The role of both microglial activation and alpha-synuclein deposition in Parkinson's disease remain unclear. We have tested the hypothesis that if microglia play a primary role in Parkinson's disease pathogenesis, the microglial "activated" phenotype should be associated with histopathological and/or clinical features of the disease. Methods We have examined microglial MHC class II expression, a widely used marker of microglial activation, the occurrence of CD68-positive phagocytes and alpha-synuclein immunoreactivity in post-mortem human substantia nigra affected by idiopathic Parkinson's disease (PD). Using semi-quantitative severity ratings, we have examined the relationship between microglial activation, alpha-synuclein deposition, classical neuropathological criteria for PD, subtype of the disease and clinical course. Results While we did not observe an association between microglial MHC class II expression and clinical parameters, we did find a correlation between disease duration and the macrophage marker CD68 which is expressed by phagocytic microglia. In addition, we observed a significant correlation between the degree of MHC class II expression and alpha-synuclein deposition in the substantia nigra in PD. Conclusion While microglia appeared to respond to alpha-synuclein deposition, MHC class II antigen expression by microglia in the substantia nigra cannot be used as an indicator of clinical PD severity or disease progression. In addition, a contributory or even causative role for microglia in the neuronal loss associated with PD as suggested by some authors seems unlikely. Our data further suggest that an assessment of microglial activation in the aged brain on the basis of immunohistochemistry for MHC class II antigens alone should be done with caution. PMID:15935098

  4. Environment- and activity-dependent dopamine neurotransmitter plasticity in the adult substantia nigra.

    PubMed

    Aumann, Tim D

    2016-04-01

    The ability of neurons to change the amount or type of neurotransmitter they use, or 'neurotransmitter plasticity', is an emerging new form of adult brain plasticity. For example, it has recently been shown that neurons in the adult rat hypothalamus up- or down-regulate dopamine (DA) neurotransmission in response to the amount of light the animal receives (photoperiod), and that this in turn affects anxiety- and depressive-like behaviors (Dulcis et al., 2013). In this Chapter I consolidate recent evidence from my laboratory suggesting neurons in the adult mouse substantia nigra pars compacta (SNc) also undergo DA neurotransmitter plasticity in response to persistent changes in their electrical activity, including that driven by the mouse's environment or behavior. Specifically, we have shown that the amounts of tyrosine hydroxylase (TH, the rate-limiting enzyme in DA synthesis) gene promoter activity, TH mRNA and TH protein in SNc neurons increases or decreases after ∼20h of altered electrical activity. Also, infusion of ion-channel agonists or antagonists into the midbrain for 2 weeks results in ∼10% (∼500 neurons) more or fewer TH immunoreactive (TH+) SNc neurons, with no change in the total number of SNc neurons (TH+ and TH-). Targeting ion-channels mediating cell-autonomous pacemaker activity in, or synaptic input and afferent pathways to, SNc neurons are equally effective in this regard. In addition, exposing mice to different environments (sex pairing or environment enrichment) for 1-2 weeks induces ∼10% more or fewer TH+ SNc (and ventral tegmental area or VTA) neurons and this is abolished by concurrent blockade of synaptic transmission in midbrain. Although further research is required to establish SNc (and VTA) DA neurotransmitter plasticity, and to determine whether it alters brain function and behavior, it is an exciting prospect because: (1) It may play important roles in movement, motor learning, reward, motivation, memory and cognition; and (2

  5. Increased Frequency of α-Synuclein in the Substantia Nigra in HIV Infection

    PubMed Central

    Khanlou, Negar; Moore, David J.; Chana, Gursharan; Cherner, Mariana; Lazzaretto, Deborah; Dawes, Sharron; Grant, Igor; Masliah, Eliezer; Everall, Ian P.

    2014-01-01

    The frequency of neurodegenerative markers among long surviving HIV infected individuals is unknown, therefore, the present study investigated the frequency of α-synuclein, β-amyloid and HIV-associated brain pathology in the brains of older HIV infected individuals. We examined the substantia nigra of 73 clinically well-characterized HIV infected individuals aged 50 to 76 years from the National NeuroAIDS Tissue Consortium. We also examined the frontal and temporal cortical regions of a subset of 36 individuals. The brain regions were examined for the presence of α-synuclein, β-amyloid and HIV-associated brain pathology. Neuritic α-synuclein expression was found in 16% (12/73) of the substantia nigra of the HIV+ cases and none of the older control cases (0/18). β-amyloid deposits were prevalent and found in nearly all of the HIV+ cases (35/36). Despite these increases of degenerative pathology, HIV-associated brain pathology was present in only 10% of cases. Among older HIV+ adults HIV-associated brain pathology does not appear elevated; however, the frequency of both α-synuclein and β-amyloid is higher than that found in older healthy persons. The increased prevalence of α-synuclein and β-amyloid in the brains of older HIV-infected individuals may predict an increased risk of developing neurodegenerative disease. PMID:19115126

  6. Verbascoside promotes the regeneration of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra

    PubMed Central

    Liang, Jian-qing; Wang, Li; He, Jian-cheng; Hua, Xian-dong

    2016-01-01

    Tyrosine hydroxylase is a key enzyme in dopamine biosynthesis. Change in tyrosine hydroxylase expression in the nigrostriatal system is closely related to the occurrence and development of Parkinson's disease. Verbascoside, an extract from Radix Rehmanniae Praeparata has been shown to be clinically effective in treating Parkinson's disease. However, the underlying mechanisms remain unclear. It is hypothesized that the effects of verbascoside on Parkinson's disease are related to tyrosine hydroxylase expression change in the nigrostriatal system. Rat models of Parkinson's disease were established and verbascoside (60 mg/kg) was administered intraperitoneally once a day. After 6 weeks of verbascoside treatment, rat rotational behavior was alleviated; tyrosine hydroxylase mRNA and protein expression and the number of tyrosine hydroxylase-immunoreactive neurons in the rat right substantia nigra were significantly higher than the Parkinson's model group. These findings suggest that the mechanism by which verbascoside treats Parkinson's disease is related to the regeneration of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra. PMID:26981096

  7. Navigation-supported diagnosis of the substantia nigra by matching midbrain sonography and MRI

    NASA Astrophysics Data System (ADS)

    Salah, Zein; Weise, David; Preim, Bernhard; Classen, Joseph; Rose, Georg

    2012-03-01

    Transcranial sonography (TCS) is a well-established neuroimaging technique that allows for visualizing several brainstem structures, including the substantia nigra, and helps for the diagnosis and differential diagnosis of various movement disorders, especially in Parkinsonian syndromes. However, proximate brainstem anatomy can hardly be recognized due to the limited image quality of B-scans. In this paper, a visualization system for the diagnosis of the substantia nigra is presented, which utilizes neuronavigated TCS to reconstruct tomographical slices from registered MRI datasets and visualizes them simultaneously with corresponding TCS planes in realtime. To generate MRI tomographical slices, the tracking data of the calibrated ultrasound probe are passed to an optimized slicing algorithm, which computes cross sections at arbitrary positions and orientations from the registered MRI dataset. The extracted MRI cross sections are finally fused with the region of interest from the ultrasound image. The system allows for the computation and visualization of slices at a near real-time rate. Primary tests of the system show an added value to the pure sonographic imaging. The system also allows for reconstructing volumetric (3D) ultrasonic data of the region of interest, and thus contributes to enhancing the diagnostic yield of midbrain sonography.

  8. No parkinsonism in SCA2 and SCA3 despite severe neurodegeneration of the dopaminergic substantia nigra.

    PubMed

    Schöls, Ludger; Reimold, Matthias; Seidel, Kay; Globas, Christoph; Brockmann, Kathrin; Hauser, Till Karsten; Auburger, Georg; Bürk, Katrin; den Dunnen, Wilfred; Reischl, Gerald; Korf, Horst-Werner; Brunt, Ewout R; Rüb, Udo

    2015-11-01

    See Klockgether (doi:10.1093/awv253) for a scientific commentary on this article.The spinocerebellar ataxias types 2 (SCA2) and 3 (SCA3) are autosomal dominantly inherited cerebellar ataxias which are caused by CAG trinucleotide repeat expansions in the coding regions of the disease-specific genes. Although previous post-mortem studies repeatedly revealed a consistent neurodegeneration of the dopaminergic substantia nigra in patients with SCA2 and with SCA3, parkinsonian motor features evolve only rarely. As the pathophysiological mechanism how SCA2 and SCA3 patients do not exhibit parkinsonism is still enigmatic, we performed a positron emission tomography and a post-mortem study of two independent cohorts of SCA2 and SCA3 patients with and without parkinsonian features. Positron emission tomography revealed a significant reduction of dopamine transporter levels in the striatum as well as largely unaffected postsynaptic striatal D2 receptors. In spite of this remarkable pathology in the motor mesostriatal pathway, only 4 of 19 SCA2 and SCA3 patients suffered from parkinsonism. The post-mortem investigation revealed, in addition to an extensive neuronal loss in the dopaminergic substantia nigra of all patients with spinocerebellar ataxia, a consistent affection of the thalamic ventral anterior and ventral lateral nuclei, the pallidum and the cholinergic pedunculopontine nucleus. With the exception of a single patient with SCA3 who suffered from parkinsonian motor features during his lifetime, the subthalamic nucleus underwent severe neuronal loss, which was clearly more severe in its motor territory than in its limbic or associative territories. Our observation that lesions of the motor territory of the subthalamic nucleus were consistently associated with the prevention of parkinsonism in our SCA2 and SCA3 patients matches the clinical experience that selective targeting of the motor territory of the subthalamic nucleus by focal lesions or deep brain stimulation

  9. Oxidative stress-dependent changes in immune responses and cell death in the substantia nigra after ozone exposure in rat.

    PubMed

    Rivas-Arancibia, Selva; Zimbrón, Luis Fernando Hernández; Rodríguez-Martínez, Erika; Maldonado, Perla D; Borgonio Pérez, Gabino; Sepúlveda-Parada, María

    2015-01-01

    Parkinson's disease has been associated with the selective loss of neurons in the substantia nigra pars compacta. Increasing evidence suggests that oxidative stress plays a major role. The resulting increase in reactive oxygen species triggers a sequence of events that leads to cell damage, activation of microglia cells and neuroinflammatory responses. Our objective was to study whether chronic exposure to low doses of ozone, which produces oxidative stress itself, induces progressive cell death in conjunction with glial alterations in the substantia nigra. Animals were exposed to an ozone-free air stream (control) or to low doses of ozone for 7, 15, 30, 60, or 90 days. Each group underwent (1) spectrophotometric analysis for protein oxidation; (2) western blot testing for microglia reactivity and nuclear factor kappa B expression levels; and (3) immunohistochemistry for cytochrome c, GFAP, Iba-1, NFkB, and COX-2. Our results indicate that ozone induces an increase in protein oxidation levels, changes in activated astrocytes and microglia, and cell death. NFkB and cytochrome c showed an increase until 30 days of exposure, while cyclooxygenase 2 in the substantia nigra increased from 7 days up to 90 days of repetitive ozone exposure. These results suggest that oxidative stress caused by ozone exposure induces changes in inflammatory responses and progressive cell death in the substantia nigra in rats, which could also be occurring in Parkinson's disease. PMID:25999851

  10. Oxidative stress-dependent changes in immune responses and cell death in the substantia nigra after ozone exposure in rat

    PubMed Central

    Rivas-Arancibia, Selva; Zimbrón, Luis Fernando Hernández; Rodríguez-Martínez, Erika; Maldonado, Perla D.; Borgonio Pérez, Gabino; Sepúlveda-Parada, María

    2015-01-01

    Parkinson's disease has been associated with the selective loss of neurons in the substantia nigra pars compacta. Increasing evidence suggests that oxidative stress plays a major role. The resulting increase in reactive oxygen species triggers a sequence of events that leads to cell damage, activation of microglia cells and neuroinflammatory responses. Our objective was to study whether chronic exposure to low doses of ozone, which produces oxidative stress itself, induces progressive cell death in conjunction with glial alterations in the substantia nigra. Animals were exposed to an ozone-free air stream (control) or to low doses of ozone for 7, 15, 30, 60, or 90 days. Each group underwent (1) spectrophotometric analysis for protein oxidation; (2) western blot testing for microglia reactivity and nuclear factor kappa B expression levels; and (3) immunohistochemistry for cytochrome c, GFAP, Iba-1, NFkB, and COX-2. Our results indicate that ozone induces an increase in protein oxidation levels, changes in activated astrocytes and microglia, and cell death. NFkB and cytochrome c showed an increase until 30 days of exposure, while cyclooxygenase 2 in the substantia nigra increased from 7 days up to 90 days of repetitive ozone exposure. These results suggest that oxidative stress caused by ozone exposure induces changes in inflammatory responses and progressive cell death in the substantia nigra in rats, which could also be occurring in Parkinson's disease. PMID:25999851

  11. Administration of MPTP acutely increases glucose utilization in the substantia nigra of primates.

    PubMed

    Palombo, E; Porrino, L J; Bankiewicz, K S; Crane, A M; Kopin, I J; Sokoloff, L

    1988-06-21

    The quantitative 2-[14C]deoxyglucose autoradiographic method was used to map the regional distribution of the acute effects of administration of the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), on local cerebral glucose utilization in rhesus monkeys. Metabolic activity was increased (+80%) in the substantia nigra pars compacta, which has been shown to be the main target site of MPTP toxicity. Metabolic activity was also increased in the nucleus paranigralis, nucleus parabrachialis pigmentosus, and ventral lamella of the inferior olive. In contrast, substantial decreases in glucose utilization were found diffusely distributed throughout many of the other structures examined, most prominently in portions of the cerebral cortex, thalamus, and cerebellum. PMID:3261197

  12. Substantia nigra reticulata neurons during sleep-waking states: relation with ponto-geniculo-occipital waves.

    PubMed

    Datta, S; Curró Dossi, R; Paré, D; Oakson, G; Steriade, M

    1991-12-01

    We have previously hypothesized that the spike bursts of brainstem peribrachial (PB) neurons, leading to ponto-geniculo-occipital (PGO) waves in thalamocortical systems, are triggered by phasic hyperpolarizations of sufficient magnitude or by excitatory inputs reaching a steadily hyperpolarized membrane. We have proposed that the source of these hyperpolarizing actions are substantia nigra pars reticulata (SNr) cells that project to, and exert inhibitory effects upon, PB neurons. Here we tested this hypothesis by recording antidromically identified SNr-PB cells in chronically implanted, naturally sleeping cats. A subpopulation of SNr-PB cells exhibited tonically increased firing preceding by 70-200 ms the thalamic PGO wave. These data support the hypothesis that an enhancement in SNr-cells' discharges may lead to hyperpolarization of PB neurons, with the consequence of spike bursts in one class of PGO-related PB-thalamic neurons. PMID:1814553

  13. Correlation of striatal dopamine transporter imaging with post mortem substantia nigra cell counts.

    PubMed

    Kraemmer, Julia; Kovacs, Gabor G; Perju-Dumbrava, Laura; Pirker, Susanne; Traub-Weidinger, Tatiana; Pirker, Walter

    2014-12-01

    Dopamine transporter imaging is widely used for the differential diagnosis of parkinsonism. Only limited data are available on the relationship between striatal dopamine transporter binding and dopaminergic cell loss in the substantia nigra (SN). We analyzed postmortem SN cell counts in patients who had previously undergone dopamine transporter single-photon emission computed tomography (SPECT). Pathological diagnoses included Parkinson's disease (n = 1), dementia with Lewy bodies (n = 2), multiple system atrophy (n = 1), corticobasal degeneration (n = 2), atypical parkinsonism with multiple pathological conditions (n = 1), Alzheimer's disease (n = 1), and Creutzfeldt-Jakob disease (n = 1). [(12) (3) I]β-CIT SPECT had been performed in all subjects using a standardized protocol on the same triple-head gamma camera. The density of neuromelanin-containing and tyrosine hydroxylase-positive substantia nigra neurons/mm(2) was evaluated in paraffin-embedded tissue sections by morphometric methods. Mean disease duration at the time of dopamine transporter imaging was 2.3 years, and the mean interval from imaging to death was 29.3 months (range, 4-68 months). Visual analysis of dopamine transporter images showed reduced striatal uptake in all seven patients with neurodegenerative parkinsonism, but not in Alzheimer's and Creutzfeldt-Jakob disease cases. Averaged [(right+left)/2] striatal uptake was highly correlated with averaged SN cell counts (rs  = 0.98, P < 0.0005 for neuromelanin- and rs  = 0.96, P < 0.0005 for tyrosine hydroxylase-positive cells). Similar strong correlations were found in separate analyses for the right and left sides. Striatal dopamine transporter binding highly correlated with postmortem SN cell counts, confirming the validity of dopamine transporter imaging as an excellent in vivo marker of nigrostriatal dopaminergic degeneration. PMID:25048738

  14. Striatal Infarction Elicits Secondary Extrafocal MRI Changes in Ipsilateral Substantia Nigra

    PubMed Central

    Winter, Benjamin; Brunecker, Peter; Fiebach, Jochen B.; Jungehulsing, Gerhard Jan

    2015-01-01

    Focal ischemia may induce pathological alterations in brain areas distant from the primary lesion. In animal models, exofocal neuron death in the ipsilateral midbrain has been described after occlusion of the middle cerebral artery (MCA). Using sequential magnetic resonance imaging (T2- and diffusion-weighted) at 3 Tesla, we investigated acute ischemic stroke patients on days 1, 2, 6, 8, and 10 after stroke onset. Sixteen consecutive patients who had suffered a stroke involving the caudate nucleus and/or putamen of either hemisphere were recruited into the study. Four additional patients with strokes sparing the caudate nucleus and putamen but encompassing at least one-third of the MCA territory served as controls. Ischemic lesions involving striatal structures resulted in hyperintense lesions in ipsilateral midbrain that emerged between days 6 and 10 after stroke and were not present on the initial scans. In contrast, none of the control stroke patients developed secondary midbrain lesions. Hyperintense lesions in the pyramidal tract or the brain stem caused by degeneration of the corticospinal tract could be clearly distinguished from these secondary midbrain gray matter lesions and were detectable from day 2 after ischemia. Co-registration of high-resolution images with a digitized anatomic atlas revealed localization of secondary lesions primarily in the substantia nigra pars compacta. Apparent diffusion coefficient (ADC) values in the secondary lesions showed a delayed sharp decline through day 10. Normalization of ADC values was observed at late measurements. Taken together, our study demonstrates that striatal infarction elicits delayed degenerative changes in ipsilateral substantia nigra pars compacta. PMID:26325192

  15. Enhanced training protects memory against amnesia produced by concurrent inactivation of amygdala and striatum, amygdala and substantia nigra, or striatum and substantia nigra

    PubMed Central

    Salado-Castillo, Rigoberto; Sánchez-Alavéz, Manuel; Quirarte, Gina L.; Martínez García, María Isabel; Prado-Alcalá, Roberto A.

    2011-01-01

    Memory is markedly impaired when normal activity of any of a number of cerebral structures is disturbed after a learning experience. A growing body of evidence indicates, however, that such interference with neuronal function becomes negligible when the learning experience is significantly enhanced. We now report on the effects of enhanced training on retention after temporary inactivation of cerebral nuclei known to be involved in memory, namely the substantia nigra (SN), striatum (STR), and amygdala (AMY). When training was conducted with a relatively low intensity of footshock (1.0 mA), post-training infusion of lidocaine into the SN, STR, or AMY produced a marked memory deficit. Increasing the aversive stimulation to 2.0 mA protected memory from the amnesic effect of intranigral lidocaine, but there was still a deficit after its infusion into the STR and AMY. Administration of lidocaine into each of these nuclei, in the groups that had been trained with 3.0 mA, was completely ineffective in producing alterations in memory consolidation. Simultaneous infusion of lidocaine into STR + SN, AMY + SN, or AMY + STR was also ineffective in altering memory formation when the highest footshock intensity was used for training. To our knowledge, this is the first demonstration that an enhanced learning experience guards against memory deficits after simultaneous temporary interruption of neural activity of brain nuclei heretofore thought to be necessary for memory formation. These findings support the proposition that brain structures involved in memory processing are functionally connected in series during memory consolidation and that, after an enhanced learning experience, these structures become functionally connected in parallel. PMID:22203796

  16. Metabolism Regulates the Spontaneous Firing of Substantia Nigra Pars Reticulata Neurons via KATP and Nonselective Cation Channels

    PubMed Central

    Lutas, Andrew; Birnbaumer, Lutz

    2014-01-01

    Neurons use glucose to fuel glycolysis and provide substrates for mitochondrial respiration, but neurons can also use alternative fuels that bypass glycolysis and feed directly into mitochondria. To determine whether neuronal pacemaking depends on active glucose metabolism, we switched the metabolic fuel from glucose to alternative fuels, lactate or β-hydroxybutyrate, while monitoring the spontaneous firing of GABAergic neurons in mouse substantia nigra pars reticulata (SNr) brain slices. We found that alternative fuels, in the absence of glucose, sustained SNr spontaneous firing at basal rates, but glycolysis may still be supported by glycogen in the absence of glucose. To prevent any glycogen-fueled glycolysis, we directly inhibited glycolysis using either 2-deoxyglucose or iodoacetic acid. Inhibiting glycolysis in the presence of alternative fuels lowered SNr firing to a slower sustained firing rate. Surprisingly, we found that the decrease in SNr firing was not mediated by ATP-sensitive potassium (KATP) channel activity, but if we lowered the perfusion flow rate or omitted the alternative fuel, KATP channels were activated and could silence SNr firing. The KATP-independent slowing of SNr firing that occurred with glycolytic inhibition in the presence of alternative fuels was consistent with a decrease in a nonselective cationic conductance. Although mitochondrial metabolism alone can prevent severe energy deprivation and KATP channel activation in SNr neurons, active glucose metabolism appears important for keeping open a class of ion channels that is crucial for the high spontaneous firing rate of SNr neurons. PMID:25471572

  17. Electroacupuncture-regulated neurotrophic factor mRNA expression in the substantia nigra of Parkinson's disease rats.

    PubMed

    Wang, Shuju; Fang, Jianqiao; Ma, Jun; Wang, Yanchun; Liang, Shaorong; Zhou, Dan; Sun, Guojie

    2013-02-25

    Acupuncture for the treatment of Parkinson's disease has a precise clinical outcome. This study investigated the effect of electroacupuncture at Fengfu (GV16) and Taichong (LR3) acupoints in rat models of Parkinson's disease induced by subcutaneous injection of rotenone into rat neck and back. Reverse transcription-PCR demonstrated that brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor mRNA expression was significantly increased in the substantia nigra of rat models of Parkinson's disease, and that abnormal behavior of rats was significantly improved following electroacupuncture treatment. These results indicated that electroacupuncture treatment upregulated brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor mRNA expression in the substantia nigra of rat models of Parkinson's disease. Thus, electroacupuncture may be useful in the treatment of Parkinson's disease. PMID:25206697

  18. Changes in Selenoprotein P in Substantia Nigra and Putamen in Parkinson’s Disease

    PubMed Central

    Bellinger, Frederick P.; Raman, Arjun V.; Rueli, Rachel H.; Bellinger, Miyoko T.; Dewing, Andrea S.; Seale, Lucia A.; Andres, Marilou A.; Uyehara-Lock, Jane H.; White, Lon R.; Ross, G. Webster; Berry, Marla J.

    2012-01-01

    Oxidative stress and oxidized dopamine contribute to the degeneration of the nigrostriatal pathway in Parkinson’s disease (PD). Selenoproteins are a family of proteins containing the element selenium in the form of the amino acid selenocysteine, and many of these proteins have antioxidant functions. We recently reported changes in expression of the selenoprotein, phospholipid hydroperoxide glutathione peroxidase GPX4 and its co-localization with neuromelanin in PD brain. To further understand the changes in GPX4 in PD, we examine here the expression of the selenium transport protein selenoprotein P (Sepp1) in postmortem Parkinson’s brain tissue. Sepp1 in midbrain was expressed in neurons of the substantia nigra (SN), and expression was concentrated within the centers of Lewy bodies, the pathological hallmark of PD. As with GPX4, Sepp1 expression was significantly reduced in SN from PD subjects compared with controls, but increased relative to cell density. In putamen, Sepp1 was found in cell bodies and in dopaminergic axons and terminals, although levels of Sepp1 were not altered in PD subjects compared to controls. Expression levels of Sepp1 and GPX4 correlated strongly in the putamen of control subjects but not in the putamen of PD subjects. These findings indicate a role for Sepp1 in the nigrostriatal pathway, and suggest that local release of Sepp1 in striatum may be important for signaling and/or synthesis of other selenoproteins such as GPX4. PMID:23268326

  19. The Neuromelanin-related T2* Contrast in Postmortem Human Substantia Nigra with 7T MRI

    PubMed Central

    Lee, Jae-Hyeok; Baek, Sun-Yong; Song, YoungKyu; Lim, Sujeong; Lee, Hansol; Nguyen, Minh Phuong; Kim, Eun-Joo; Huh, Gi Yeong; Chun, Se Young; Cho, HyungJoon

    2016-01-01

    High field magnetic resonance imaging (MRI)-based delineation of the substantia nigra (SN) and visualization of its inner cellular organization are promising methods for the evaluation of morphological changes associated with neurodegenerative diseases; however, corresponding MR contrasts must be matched and validated with quantitative histological information. Slices from two postmortem SN samples were imaged with a 7 Tesla (7T) MRI with T1 and T2* imaging protocols and then stained with Perl’s Prussian blue, Kluver-Barrera, tyrosine hydroxylase, and calbindin immunohistochemistry in a serial manner. The association between T2* values and quantitative histology was investigated with a co-registration method that accounts for histology slice preparation. The ventral T2* hypointense layers between the SNr and the crus cerebri extended anteriorly to the posterior part of the crus cerebri, which demonstrates the difficulty with an MRI-based delineation of the SN. We found that the paramagnetic hypointense areas within the dorsolateral SN corresponded to clusters of neuromelanin (NM). These NM-rich zones were distinct from the hypointense ventromedial regions with high iron pigments. Nigral T2* imaging at 7T can reflect the density of NM-containing neurons as the metal-bound NM macromolecules may decrease T2* values and cause hypointense signalling in T2* imaging at 7T. PMID:27596274

  20. Increased mitochondrial DNA deletions in substantia nigra dopamine neurons of the aged rat.

    PubMed

    Parkinson, Gemma M; Dayas, Christopher V; Smith, Doug W

    2014-01-01

    The dopaminergic neurons of the substantia nigra (SN), which constitute the origin of the nigrostriatal system, are vulnerable to age-related degenerative processes. For example, in humans there is a relatively small age-related loss of neurons but a marked decline of the dopaminergic phenotype associated with impaired voluntary motor control. However, the mechanisms responsible for the dysfunction and degeneration of SN dopamine neurons remain poorly understood. One potential contributor is mitochondrial dysfunction, resulting from an increased abundance of mitochondrial DNA (mtDNA) mutations such as deletions. Human studies have identified relatively high levels of mtDNA deletions in these cells in both aging and Parkinson's disease (>35%), with a higher abundance of deletions (>60%) in individual neurons with mitochondrial dysfunction. However, it is unknown whether similar mtDNA mutations occur in other species such as the rat. In the present study, we quantified mtDNA deletion abundance in laser microdissected SN dopaminergic neurons from young and old F344 rats. Our results indicate that mtDNA deletions accumulated with age, with approximately 20% more mtDNA deletions in SN dopaminergic neurons from old compared to young animals. Thus, while rat SN dopaminergic neurons do accumulate mtDNA deletions with aging, this does not reflect the deletion burden in humans, and other mechanisms may be operating to compensate for age-related mtDNA damage in the rat SN dopaminergic neurons. PMID:25612740

  1. Proteomic analysis of carbonylated proteins in the monkey substantia nigra after ischemia-reperfusion.

    PubMed

    Oikawa, Shinji; Kobayashi, Hatasu; Kitamura, Yuki; Zhu, Hong; Obata, Kumi; Minabe, Yoshio; Dazortsava, Maryia; Ohashi, Kyoko; Tada-Oikawa, Saeko; Takahashi, Hitoshi; Yata, Kenichiro; Murata, Mariko; Yamashima, Tetsumori

    2014-06-01

    In Parkinson's disease (PD), oxidative stresses cause cell death of dopaminergic neurons of the substantia nigra (SN), but its molecular mechanism still remains unclarified. Our previous study of proteomic analysis in the monkey CA1 hippocampus after ischemia-reperfusion revealed reactive oxygen species (ROS)-induced carbonyl modification of a molecular chaperone, heat shock 70-kDa protein 1 (Hsp70.1), especially in its key site, Arg469. Here, to clarify the mechanism of neurodegeneration in PD, the SN tissue of the same monkey experimental paradigm was studied for identifying and characterizing carbonylated proteins by the two-dimensional gel electrophoresis with immunochemical detection of protein carbonyls (2D Oxyblot). We found carbonyl modification not only of Hsp70.1 but also of mitochondrial aconitase, dihydropyrimidinase-related protein 2, T-complex protein 1 subunit alpha, dihydrolipoyl dehydrogenase, fructose-bisphosphate aldolase C, glutamate dehydrogenase 1, and aspartate aminotransferase. Intriguingly, in the SN also, the carbonylation site of Hsp70.1 was identified to be Arg469. Since Hsp70.1 is recently known to stabilize the lysosomal membrane, its oxidative injury conceivably plays an important role in the ROS-mediated neuronal cell death by inducing lysosomal destabilization. Implications of each carbonylated proteins for the dopaminergic neuronal death were discussed, in comparison with the CA1 neuronal death. PMID:24697733

  2. SUBSTANTIA NIGRA PARS RETICULATA IS CRUCIALLY INVOLVED IN BARBITURATE AND ETHANOL WITHDRAWAL IN MICE

    PubMed Central

    Chen, Gang; Kozell, Laura B.; Buck, Kari J.

    2011-01-01

    Sedative-hypnotic CNS depressant drugs are widely prescribed to treat a variety of disorders, and are abused for their sedative and euphoric effects. Physiological dependence and associated withdrawal episodes are thought to constitute a motivational force that sustains their use/abuse and may contribute to relapse in dependent individuals. Although no animal model duplicates depressant dependence, models for specific factors, like withdrawal, are useful for identifying potential neural determinants of liability in humans. Recent analyses implicate the caudolateral substantia nigra pars reticulata (clSNr) in withdrawal following acute and repeated ethanol exposures in mice, but did not assess its impact on withdrawal from other sedative-hypnotics or whether intrinsic neurons or fibers of passage are involved. Here, we demonstrate that bilateral chemical (ibotenic acid) lesions of the clSNr attenuate barbiturate (pentobarbital) and ethanol withdrawal. Chemical lesions did not affect convulsions in response to pentylenetetrazol, which blocks GABAA receptor-mediated transmission. Our results demonstrate that the clSNr nucleus itself rather than fibers of passage is crucial to its effects on barbiturate and ethanol withdrawal. These findings support suggest that clSNr could be one of the shared neural substrates mediating withdrawal from sedative-hypnotic drugs. PMID:20974184

  3. Electrophysiological evidence for functionally distinct neuronal populations in the human substantia nigra.

    PubMed

    Ramayya, Ashwin G; Zaghloul, Kareem A; Weidemann, Christoph T; Baltuch, Gordon H; Kahana, Michael J

    2014-01-01

    The human substantia nigra (SN) is thought to consist of two functionally distinct neuronal populations-dopaminergic (DA) neurons in the pars compacta subregion and GABA-ergic neurons in the pars reticulata subregion. However, a functional dissociation between these neuronal populations has not previously been demonstrated in the awake human. Here we obtained microelectrode recordings from the SN of patients undergoing deep brain stimulation (DBS) surgery for Parkinson's disease as they performed a two-alternative reinforcement learning task. Following positive feedback presentation, we found that putative DA and GABA neurons demonstrated distinct temporal dynamics. DA neurons demonstrated phasic increases in activity (250-500 ms post-feedback) whereas putative GABA neurons demonstrated more delayed and sustained increases in activity (500-1000 ms post-feedback). These results provide the first electrophysiological evidence for a functional dissociation between DA and GABA neurons in the human SN. We discuss possible functions for these neuronal responses based on previous findings in human and animal studies. PMID:25249957

  4. Impact of expected value on neural activity in rat substantia nigra pars reticulata

    PubMed Central

    Bryden, Daniel W.; Johnson, Emily E.; Diao, Xiayang; Roesch, Matthew R.

    2012-01-01

    SUMMARY The substantia nigra pars reticulata (SNr) is thought to serve as the output of the basal ganglia, whereby associative information from striatum influences behavior via disinhibition of downstream motor areas to motivate behavior. Unfortunately, few studies have examined activity in SNr in rats making decisions based on the value of predicted reward similar to those conducted in primates. To fill this void, we recorded from single neurons in SNr while rats performed a choice task in which different odor cues indicated what reward was available on the left or on the right. The value of reward associated with a left or rightward movement was manipulated by varying the size of and delay to reward in separate blocks of trials. Rats were faster or slower depending on whether the expected reward value was high or low, respectively. The number of neurons that increased firing during performance of the task outnumbered those that decreased firing. Both increases and decreases were modulated by expected value and response direction. Neurons that fired more or less strongly for larger reward tended to fire more or less strongly for immediate reward, reflecting their common motivational output. Finally, value selectivity was present prior to presentation of cues indicating the nature of the upcoming behavioral response for both increasing- and decreasing-type neurons, reflecting the internal bias or preparatory set of the rat. These results emphasize the importance of increasing-type neurons on behavioral output when animals are making decisions based on predicted reward value. PMID:21645133

  5. Non-linear developmental trajectory of electrical phenotype in rat substantia nigra pars compacta dopaminergic neurons

    PubMed Central

    Dufour, Martial A; Woodhouse, Adele; Amendola, Julien; Goaillard, Jean-Marc

    2014-01-01

    Neurons have complex electrophysiological properties, however, it is often difficult to determine which properties are the most relevant to neuronal function. By combining current-clamp measurements of electrophysiological properties with multi-variate analysis (hierarchical clustering, principal component analysis), we were able to characterize the postnatal development of substantia nigra dopaminergic neurons' electrical phenotype in an unbiased manner, such that subtle changes in phenotype could be analyzed. We show that the intrinsic electrical phenotype of these neurons follows a non-linear trajectory reaching maturity by postnatal day 14, with two developmental transitions occurring between postnatal days 3–5 and 9–11. This approach also predicted which parameters play a critical role in phenotypic variation, enabling us to determine (using pharmacology, dynamic-clamp) that changes in the leak, sodium and calcium-activated potassium currents are central to these two developmental transitions. This analysis enables an unbiased definition of neuronal type/phenotype that is applicable to a range of research questions. DOI: http://dx.doi.org/10.7554/eLife.04059.001 PMID:25329344

  6. The Neuromelanin-related T2* Contrast in Postmortem Human Substantia Nigra with 7T MRI.

    PubMed

    Lee, Jae-Hyeok; Baek, Sun-Yong; Song, YoungKyu; Lim, Sujeong; Lee, Hansol; Nguyen, Minh Phuong; Kim, Eun-Joo; Huh, Gi Yeong; Chun, Se Young; Cho, HyungJoon

    2016-01-01

    High field magnetic resonance imaging (MRI)-based delineation of the substantia nigra (SN) and visualization of its inner cellular organization are promising methods for the evaluation of morphological changes associated with neurodegenerative diseases; however, corresponding MR contrasts must be matched and validated with quantitative histological information. Slices from two postmortem SN samples were imaged with a 7 Tesla (7T) MRI with T1 and T2* imaging protocols and then stained with Perl's Prussian blue, Kluver-Barrera, tyrosine hydroxylase, and calbindin immunohistochemistry in a serial manner. The association between T2* values and quantitative histology was investigated with a co-registration method that accounts for histology slice preparation. The ventral T2* hypointense layers between the SNr and the crus cerebri extended anteriorly to the posterior part of the crus cerebri, which demonstrates the difficulty with an MRI-based delineation of the SN. We found that the paramagnetic hypointense areas within the dorsolateral SN corresponded to clusters of neuromelanin (NM). These NM-rich zones were distinct from the hypointense ventromedial regions with high iron pigments. Nigral T2* imaging at 7T can reflect the density of NM-containing neurons as the metal-bound NM macromolecules may decrease T2* values and cause hypointense signalling in T2* imaging at 7T. PMID:27596274

  7. Genomic convergence to identify candidate genes for Parkinson disease: SAGE analysis of the substantia nigra.

    PubMed

    Noureddine, Maher A; Li, Yi-Ju; van der Walt, Joelle M; Walters, Robert; Jewett, Rita M; Xu, Hong; Wang, Tianyuan; Walter, Jeffrey W; Scott, Burton L; Hulette, Christine; Schmechel, Don; Stenger, Judith E; Dietrich, Fred; Vance, Jeffery M; Hauser, Michael A

    2005-10-01

    Genomic convergence is a multistep approach that combines gene expression with genomic linkage to identify and prioritize susceptibility genes for complex disease. As a first step, we previously performed linkage analysis on 174 multiplex Parkinson's disease (PD) families, identifying five peaks for PD risk and two for genes affecting age at onset (AAO) in PD [Hauser et al., Hum Mol Genet 2003;12:671-677]. We report here the next step: serial analysis of gene expression [SAGE; Scott et al., JAMA 2001;286:2239-2242] to analyze substantia nigra tissue from three PD patients and two age-matched controls. We find 933 differentially expressed genes (P<0.05) between PD and controls, but of these, only 50 genes represented by unique SAGE tags map within our previously described PD linkage regions. Furthermore, genes encoded by mitochondrial DNA are expressed 1.5-fold higher in PD patients versus controls, without an increase in the corresponding nuclear-encoded mitochondrial components, suggesting an increase in mtDNA genomes in PD or a disjunction with nuclear expression. The next step in the genomic convergence process will be to screen these 50 high-quality candidate genes for association with PD risk susceptibility and genetic effects on AAO. PMID:15966006

  8. Whole genome expression profiling of the medial and lateral substantia nigra in Parkinson's disease.

    PubMed

    Moran, L B; Duke, D C; Deprez, M; Dexter, D T; Pearce, R K B; Graeber, M B

    2006-03-01

    We have used brain tissue from clinically well-documented and neuropathologically confirmed cases of sporadic Parkinson's disease to establish the transcriptomic expression profile of the medial and lateral substantia nigra. In addition, the superior frontal cortex was analyzed in a subset of the same cases. DNA oligonucleotide microarrays were employed, which provide whole human genome coverage. A total of 570 genes were found to be differentially regulated at a high level of significance. A large number of differentially regulated expressed sequence tags were also identified. Levels of mRNA sequences encoded by genes of key interest were validated by means of quantitative real-time polymerase chain reaction (PCR). Comparing three different normalization procedures, results based on the recently published GeneChip Robust Multi Array algorithm were found to be the most accurate predictor of real-time PCR results. Several new candidate genes which map to PARK loci are reported. In addition, the DNAJ family of chaperones is discussed in the context of Parkinson's disease pathogenesis. PMID:16344956

  9. Inhibitory synaptic transmission from the substantia nigra pars reticulata to the ventral medial thalamus in mice.

    PubMed

    Kase, Daisuke; Uta, Daisuke; Ishihara, Hiromi; Imoto, Keiji

    2015-08-01

    The cortico-basal ganglia-thalamic loop circuit is involved in variety of motor, association and limbic functions. The basal ganglia receive neural information from various areas of the cerebral cortex and transfer them back to the frontal and motor cortex via the ventral medial (VM), and the anterior-ventral lateral thalamic complex. The projection from the basal ganglia to the thalamus is GABAergic, and, therefore, the output from the basal ganglia cannot directly evoke excitation in the thalamic nuclei. The mechanism underlying the information transfer via the inhibitory projection remains unclear. To address this issue, we recorded electrophysiological properties of nigro-thalamic synapses from the VM neuron. We developed a nigro-thalamic slice preparation, in which the projection from the substantia nigra pars reticulata (SNr) to VM nucleus is stored, to enable the selective activation of the projection from the SNr. We characterized synaptic properties and membrane properties of the VM neuron, and developed a VM neuron model to simulate the impacts of SNr inputs on VM neuron activity. Neural simulation suggested that the inhibitory projection from SNr can control neural activity in two ways: a disinhibition from the spontaneous nigral inhibition and a β-band synchronization evoked by combination of excitation and inhibition of SNr activity. PMID:25887794

  10. Lesion of the substantia nigra pars compacta downregulates striatal glutamate receptor subunit mRNA expression.

    PubMed

    Fan, X D; Li, X M; Ashe, P C; Juorio, A V

    1999-12-11

    This is a study of the effect of the unilateral administration of dopamine (DA) in the pars compacta of the substantia nigra (SN) of the rat on striatal glutamate receptor subunit (GluR1, GluR2 and NMDAR1) gene expression determined by in situ hybridization. The location of the nigral lesion was determined by tyrosine hydroxylase (TH) immunohistochemistry and its extent by the striatal DA and 3,4-dihydroxyphenylacetic acid (DOPAC) concentrations. The DA-induced lesions produce significant bilateral reductions in the expression of GluR1 and NMDAR1 subunit mRNA in the medio-lateral striatum, whereas the expression of striatal GluR2 receptors was not changed. The reduction in GluR1 and NMDAR1 subunit mRNA may be the consequence of glutamatergic hyperactivity developed in the presence of a damaged nigro-striatal system and these may be associated with the genesis of some neurodegenerative diseases. PMID:10629751

  11. Interplay Between Cytosolic Dopamine, Calcium and α-Synuclein Causes Selective Death of Substantia Nigra Neurons

    PubMed Central

    Mosharov, Eugene V.; Larsen, Kristin E.; Kanter, Ellen; Phillips, Kester A.; Wilson, Krystal; Schmitz, Yvonne; Krantz, David E.; Kobayashi, Kazuto; Edwards, Robert H.; Sulzer, David

    2009-01-01

    Summary The basis for selective death of specific neuronal populations in neurodegenerative diseases remains unclear. Parkinson's disease (PD) is a synucleinopathy characterized by a preferential loss of dopaminergic neurons in the substantia nigra (SN), whereas neurons of the ventral tegmental area (VTA) are spared. Using intracellular patch electrochemistry to directly measure cytosolic dopamine (DAcyt) in cultured midbrain neurons, we confirm that elevated DAcyt and its metabolites are neurotoxic and that genetic and pharmacological interventions that decrease DAcyt provide neuroprotection. L-DOPA increased DAcyt in SN neurons to levels 2-3-fold higher than in VTA neurons, a response dependent on dihydropyridine-sensitive Ca2+ channels, resulting in greater susceptibility of SN neurons to L-DOPA-induced neurotoxicity. DAcyt was not altered by α-synuclein deletion, although dopaminergic neurons lacking α-synuclein were resistant to L-DOPA-induced cell death. Thus, an interaction between Ca2+, DAcyt and α-synuclein may underlie the susceptibility of SN neurons in PD, suggesting multiple therapeutic targets. PMID:19409267

  12. Substantia nigra pars reticulata modulates spontaneous and goal-directed behaviour of rat.

    PubMed

    Barth, T; Klingberg, F

    1988-01-01

    Spontaneous and active avoidance behaviour was compared pre- and postoperatively on 11 six month old male hooded rats of the Long-Evans strain. Seven of them with small bilateral symmetric lesions only in the ventromedial part of substantia nigra pars reticulata (SNR) were characterized by a strong decrease of exploratory parameters except rearings, without differences of ambulatory activity in the open field (OF) test. The SNR group showed a significant retention loss, increased reaction times and run durations in three variants of preoperatively consolidated Y-maze performance and weakened brightness discrimination. They were unable to relearn the tasks and to reduce errors to the preoperative level which was zero. Postoperative acquisition of a new active avoidance stereotype in the jump test box was impossible. They ignored the hanging rod in this box and did not find the escape possibility. Prevailing flexor tonus of trunk and forelegs after SNR lesions was no sufficient reason for these changes, because inborn and automated programs were far less concerned than learnt or operative programs and the accuracy of goal-directed behaviour. PMID:3390168

  13. Substantia nigra vulnerability after a single moderate diffuse brain injury in the rat

    PubMed Central

    van Bregt, Daniel R.; Thomas, Theresa Currier; Hinzman, Jason M.; Cao, Tuoxin; Liu, Mei; Bing, Guoying; Gerhardt, Greg A.; Pauly, James R.; Lifshitz, Jonathan

    2012-01-01

    Dementia and parkinsonism are late-onset symptoms associated with repetitive head injury, as documented in multiple contact-sport athletes. Clinical symptomatology is the likely phenotype of chronic degeneration and circuit disruption in the substantia nigra (SN). To investigate the initiating neuropathology, we hypothesize that a single diffuse brain injury is sufficient to initiate SN neuropathology including neuronal loss, vascular disruption and microglial activation, contributing to neurodegeneration and altered dopamine regulation. Adult, male Sprague-Dawley rats were subjected to sham or moderate midline fluid percussion brain injury. Stereological estimates indicated a significant 44% loss of the estimated total neuron number in the SN at 28-days post-injury, without atrophy of neuronal nuclear volumes, including 25% loss of tyrosine hydroxylase positive neurons by 28-days post-injury. Multi-focal vascular compromise occurred 1–2 days post-injury, with ensuing microglial activation (significant 40% increase at 4-days). Neurodegeneration (silver-stain technique) encompassed on average 21% of the SN by 7-days post-injury and increased to 29% by 28-days compared to sham (1%). Whole tissue SN, but not striatum, dopamine metabolism was altered at 28-days post-injury, without appreciable gene or protein changes in dopamine synthesis or regulation elements. Together, single moderate diffuse brain injury resulted in SN neurovascular pathology potentially associated with neuroinflammation or dopamine dysregulation. Compensatory mechanisms may preserve dopamine signaling acutely, but subsequent SN damage with aging or additional injury may expose clinical symptomatology of motor ataxias and dementia. PMID:22178300

  14. Convection-enhanced delivery of MANF--volume of distribution analysis in porcine putamen and substantia nigra.

    PubMed

    Barua, N U; Bienemann, A S; Woolley, M; Wyatt, M J; Johnson, D; Lewis, O; Irving, C; Pritchard, G; Gill, S

    2015-10-15

    Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a 20kDa human protein which has both neuroprotective and neurorestorative activity on dopaminergic neurons and therefore may have application for the treatment of Parkinson's Disease. The aims of this study were to determine the translational potential of convection-enhanced delivery (CED) of MANF for the treatment of PD by studying its distribution in porcine putamen and substantia nigra and to correlate histological distribution with co-infused gadolinium-DTPA using real-time magnetic resonance imaging. We describe the distribution of MANF in porcine putamen and substantia nigra using an implantable CED catheter system using co-infused gadolinium-DTPA to allow real-time MRI tracking of infusate distribution. The distribution of gadolinium-DTPA on MRI correlated well with immunohistochemical analysis of MANF distribution. Volumetric analysis of MANF IHC staining indicated a volume of infusion (Vi) to volume of distribution (Vd) ratio of 3 in putamen and 2 in substantia nigra. This study confirms the translational potential of CED of MANF as a novel treatment strategy in PD and also supports the co-infusion of gadolinium as a proxy measure of MANF distribution in future clinical studies. Further study is required to determine the optimum infusion regime, flow rate and frequency of infusions in human trials. PMID:26276514

  15. Aging Decreases L-Type Calcium Channel Currents and Pacemaker Firing Fidelity in Substantia Nigra Dopamine Neurons

    PubMed Central

    Branch, Sarah Y.; Sharma, Ramaswamy

    2014-01-01

    Substantia nigra dopamine neurons are involved in behavioral processes that include cognition, reward learning, and voluntary movement. Selective deterioration of these neurons is responsible for the motor deficits associated with Parkinson's disease (PD). Aging is the leading risk factor for PD, suggesting that adaptations occurring in dopamine neurons during normal aging may predispose individuals to the development of PD. Previous studies suggest that the unique set of ion conductances that drive spontaneous, rhythmic firing of action potentials could predispose substantia nigra dopamine neurons to selective neurodegeneration. Here we show, using patch-clamp electrophysiological recordings in brain slices, that substantia nigra dopamine neurons from mice 25–30 months of age (old) have comparable membrane capacitance and input resistance to neurons from mice 2–7 months of age (young). However, neurons from old mice exhibit slower firing rates, narrower spike widths, and more variable interspike intervals compared with neurons from young mice. Dopamine neurons from old mice also exhibit smaller L-type calcium channel currents, providing a plausible mechanism that likely contributes to the changes in impulse activity. Age-related decrements in the physiological function of dopamine neurons could contribute to the decrease in voluntary movement and other dopamine-mediated behaviors observed in aging populations. Furthermore, as pharmacological antagonism of L-type calcium channels has been proposed as a potential treatment for the early stages of PD, our results could point to a limited temporal window of opportunity for this therapeutic intervention. PMID:25009264

  16. Dopamine Pathology in Schizophrenia: Analysis of Total and Phosphorylated Tyrosine Hydroxylase in the Substantia Nigra

    PubMed Central

    Perez-Costas, Emma; Melendez-Ferro, Miguel; Rice, Matthew W.; Conley, Robert R.; Roberts, Rosalinda C.

    2012-01-01

    Introduction: Despite the importance of dopamine neurotransmission in schizophrenia, very few studies have addressed anomalies in the mesencephalic dopaminergic neurons of the substantia nigra/ventral tegmental area (SN/VTA). Tyrosine hydroxylase (TH) is the rate-limiting enzyme for the production of dopamine, and a possible contributor to the anomalies in the dopaminergic neurotransmission observed in schizophrenia. Objectives: In this study, we had three objectives: (1) Compare TH expression (mRNA and protein) in the SN/VTA of schizophrenia and control postmortem samples. (2) Assess the effect of antipsychotic medications on the expression of TH in the SN/VTA. (3) Examine possible regional differences in TH expression anomalies within the SN/VTA. Methods: To achieve these objectives three independent studies were conducted: (1) A pilot study to compare TH mRNA and TH protein levels in the SN/VTA of postmortem samples from schizophrenia and controls. (2) A chronic treatment study was performed in rodents to assess the effect of antipsychotic medications in TH protein levels in the SN/VTA. (3) A second postmortem study was performed to assess TH and phosphorylated TH protein levels in two types of samples: schizophrenia and control samples containing the entire rostro-caudal extent of the SN/VTA, and schizophrenia and control samples containing only mid-caudal regions of the SN/VTA. Results and Conclusion: Our studies showed impairment in the dopaminergic system in schizophrenia that could be mainly (or exclusively) located in the rostral region of the SN/VTA. Our studies also showed that TH protein levels were significantly abnormal in schizophrenia, while mRNA expression levels were not affected, indicating that TH pathology in this region may occur posttranscriptionally. Lastly, our antipsychotic animal treatment study showed that TH protein levels were not significantly affected by antipsychotic treatment, indicating that these anomalies are an intrinsic

  17. Activity-dependent regulation of NMDA receptors in substantia nigra dopaminergic neurones.

    PubMed

    Wild, Angela R; Jones, Susan; Gibb, Alasdair J

    2014-02-15

    N-Methyl-d-aspartate receptors (NMDARs) are Ca(2+)-permeable glutamate receptors that play a critical role in synaptic plasticity and promoting cell survival. However, overactive NMDARs can trigger cell death signalling pathways and have been implicated in substantia nigra pars compacta (SNc) pathology in Parkinson's disease. Calcium ion influx through NMDARs recruits Ca(2+)-dependent proteins that can regulate NMDAR activity. The surface density of NMDARs can also be regulated dynamically in response to receptor activity via Ca(2+)-independent mechanisms. We have investigated the activity-dependent regulation of NMDARs in SNc dopaminergic neurones. Repeated whole-cell agonist applications resulted in a decline in the amplitude of NMDAR currents (current run-down) that was use dependent and not readily reversible. Run-down was reduced by increasing intracellular Ca(2+) buffering or by reducing Ca(2+) influx but did not appear to be mediated by the same regulatory proteins that cause Ca(2+)-dependent run-down in hippocampal neurones. The NMDAR current run-down may be mediated in part by a Ca(2+)-independent mechanism, because intracellular dialysis with a dynamin-inhibitory peptide reduced run-down, suggesting a role for clathrin-mediated endocytosis in the regulation of the surface density of receptors. Synaptic NMDARs were also subject to current run-down during repeated low-frequency synaptic stimulation in a Ca(2+)-dependent but dynamin-independent manner. Thus, we report, for the first time, regulation of NMDARs in SNc dopaminergic neurones by changes in intracellular Ca(2+) at both synaptic and extrasynaptic sites and provide evidence for activity-dependent changes in receptor trafficking. These mechanisms may contribute to intracellular Ca(2+) homeostasis in dopaminergic neurones by limiting Ca(2+) influx through the NMDAR. PMID:24344168

  18. Autophagy Protects Against Aminochrome-Induced Cell Death in Substantia Nigra-Derived Cell Line

    PubMed Central

    Paris, Irmgard; Muñoz, Patricia; Huenchuguala, Sandro; Couve, Eduardo; Sanders, Laurie H.; Greenamyre, John Timothy; Caviedes, Pablo; Segura-Aguilar, Juan

    2011-01-01

    Aminochrome, the precursor of neuromelanin, has been proposed to be involved in the neurodegeneration neuromelanin-containing dopaminergic neurons in Parkinson’s disease. We aimed to study the mechanism of aminochrome-dependent cell death in a cell line derived from rat substantia nigra. We found that aminochrome (50μM), in the presence of NAD(P)H-quinone oxidoreductase, EC 1.6.99.2 (DT)-diaphorase inhibitor dicoumarol (DIC) (100μM), induces significant cell death (62 ± 3%; p < 0.01), increase in caspase-3 activation (p < 0.001), release of cytochrome C, disruption of mitochondrial membrane potential (p < 0.01), damage of mitochondrial DNA, damage of mitochondria determined with transmission electron microscopy, a dramatic morphological change characterized as cell shrinkage, and significant increase in number of autophagic vacuoles. To determine the role of autophagy on aminochrome-induced cell death, we incubated the cells in the presence of vinblastine and rapamycin. Interestingly, 10μM vinblastine induces a 5.9-fold (p < 0.001) and twofold (p < 0.01) significant increase in cell death when the cells were incubated with 30μM aminochrome in the absence and presence of DIC, respectively, whereas 10μM rapamycin preincubated 24 h before addition of 50μM aminochrome in the absence and the presence of 100μM DIC induces a significant decrease (p < 0.001) in cell death. In conclusion, autophagy seems to be an important protective mechanism against two different aminochrome-induced cell deaths that initially showed apoptotic features. The cell death induced by aminochrome when DT-diaphorase is inhibited requires activation of mitochondrial pathway, whereas the cell death induced by aminochrome alone requires inhibition of autophagy-dependent degrading of damaged organelles and recycling through lysosomes. PMID:21427056

  19. Effects of inflammation on hippocampus and substantia nigra responses to novelty in healthy human participants.

    PubMed

    Harrison, Neil A; Cercignani, Mara; Voon, Valerie; Critchley, Hugo D

    2015-03-01

    Humans are naturally inquisitive. This tendency is adaptive, aiding identification of potentially valuable novel outcomes. The dopaminergic substantia nigra (SN) is implicated in the drive to explore novel stimuli and situations. However, infection and inflammation inhibit the motivation to seek out novelty. This likely serves to limit exposure to uncertain, potentially detrimental outcomes when metabolic resources are limited. Nevertheless, the neural mechanisms through which inflammation constrains novelty seeking are poorly understood. We therefore scanned 16 healthy participants (6 male, mean 27.2±7.3 years), using fMRI, once following experimental inflammation (intramuscular (i.m.) typhoid vaccination) and once after placebo (i.m. saline), with the aim of characterizing effects of inflammation on neural processing of novel and familiar place, and face stimuli. We specifically tested the effects of inflammation on the hypothesized roles of SN and hippocampus in novelty processing. Typhoid vaccination evoked a nearly threefold increase in circulating pro-inflammatory cytokine (interleukin-6) levels 3 h after injection, indicating induction of mild systemic inflammation. Enhanced hippocampal responses to novel (compared with familiar) stimuli were observed following both vaccine and placebo, consistent with intact central novelty detection. However, the normal bilateral reactivity of SN to stimulus novelty was significantly attenuated following inflammation. Correspondingly, inflammation also markedly impaired novelty-related functional coupling between the SN and hippocampus. These data extend previous findings of SN sensitivity to mild inflammation associated with changes in psychomotor responding, and suggest that inflammation-induced blunting of SN responses to hippocampal novelty signals may represent a plausible mechanism through which inflammation impairs motivational responses to novelty. PMID:25154706

  20. Mapping dopaminergic deficiencies in the substantia nigra/ventral tegmental area in schizophrenia.

    PubMed

    Rice, Matthew W; Roberts, Rosalinda C; Melendez-Ferro, Miguel; Perez-Costas, Emma

    2016-01-01

    Previous work from our laboratory showed deficits in tyrosine hydroxylase protein expression within the substantia nigra/ventral tegmental area (SN/VTA) in schizophrenia. However, little is known about the nature and specific location of these deficits within the SN/VTA. The present study had two aims: (1) test if tyrosine hydroxylase deficits could be explained as the result of neuronal loss; (2) assess if deficits in tyrosine hydroxylase are sub-region specific within the SN/VTA, and thus, could affect specific dopaminergic pathways. To achieve these objectives: (1) we obtained estimates of the number of dopaminergic neurons, total number of neurons, and their ratio in matched SN/VTA schizophrenia and control samples; (2) we performed a qualitative assessment in SN/VTA schizophrenia and control matched samples that were processed simultaneously for tyrosine hydroxylase immunohistochemistry. We did not find any significant differences in the total number of neurons, dopaminergic neurons, or their ratio. Our qualitative study of TH expression showed a conspicuous decrease in labeling of neuronal processes and cell bodies within the SN/VTA, which was sub-region specific. Dorsal diencephalic dopaminergic populations of the SN/VTA presented the most conspicuous decrease in TH labeling. These data support the existence of pathway-specific dopaminergic deficits that would affect the dopamine input to the cortex without significant neuronal loss. Interestingly, these findings support earlier reports of decreases in tyrosine hydroxylase labeling in the target areas for this dopaminergic input in the prefrontal and entorhinal cortex. Finally, our findings support that tyrosine hydroxylase deficits could contribute to the hypodopaminergic state observed in cortical areas in schizophrenia. PMID:25269834

  1. AMP kinase regulates ligand-gated K-ATP channels in substantia nigra dopamine neurons.

    PubMed

    Shen, Ke-Zhong; Wu, Yan-Na; Munhall, Adam C; Johnson, Steven W

    2016-08-25

    AMP-activated protein kinase (AMPK) is a master enzyme that regulates ATP-sensitive K(+) (K-ATP) channels in pancreatic beta-cells and cardiac myocytes. We used patch pipettes to record currents and potentials to investigate effects of AMPK on K-ATP currents in substantia nigra compacta (SNC) dopamine neurons in slices of rat midbrain. When slices were superfused repeatedly with the K-ATP channel opener diazoxide, we were surprised to find that diazoxide currents gradually increased in magnitude, reaching 300% of the control value 60min after starting whole-cell recording. However, diazoxide current increased significantly more, to 472% of control, when recorded in the presence of the AMPK activator A769662. Moreover, superfusing the slice with the AMPK blocking agent dorsomorphin significantly reduced diazoxide current to 38% of control. Control experiments showed that outward currents evoked by the K-ATP channel opener NN-414 also increased over time, but not currents evoked by the GABAB agonist baclofen. Delaying the application of diazoxide after starting whole-cell recording correlated with augmentation of current. Loose-patch recording showed that diazoxide produced a 34% slowing of spontaneous firing rate that did not intensify with repeated applications of diazoxide. However, superfusion with A769662 significantly augmented the inhibitory effect of diazoxide on firing rate. We conclude that K-ATP channel function is augmented by AMPK, which is activated during the process of making whole-cell recordings. Our results suggest that AMPK and K-ATP interactions may play an important role in regulating dopamine neuronal excitability. PMID:27267246

  2. Effects of Inflammation on Hippocampus and Substantia Nigra Responses to Novelty in Healthy Human Participants

    PubMed Central

    Harrison, Neil A; Cercignani, Mara; Voon, Valerie; Critchley, Hugo D

    2015-01-01

    Humans are naturally inquisitive. This tendency is adaptive, aiding identification of potentially valuable novel outcomes. The dopaminergic substantia nigra (SN) is implicated in the drive to explore novel stimuli and situations. However, infection and inflammation inhibit the motivation to seek out novelty. This likely serves to limit exposure to uncertain, potentially detrimental outcomes when metabolic resources are limited. Nevertheless, the neural mechanisms through which inflammation constrains novelty seeking are poorly understood. We therefore scanned 16 healthy participants (6 male, mean 27.2±7.3 years), using fMRI, once following experimental inflammation (intramuscular (i.m.) typhoid vaccination) and once after placebo (i.m. saline), with the aim of characterizing effects of inflammation on neural processing of novel and familiar place, and face stimuli. We specifically tested the effects of inflammation on the hypothesized roles of SN and hippocampus in novelty processing. Typhoid vaccination evoked a nearly threefold increase in circulating pro-inflammatory cytokine (interleukin-6) levels 3 h after injection, indicating induction of mild systemic inflammation. Enhanced hippocampal responses to novel (compared with familiar) stimuli were observed following both vaccine and placebo, consistent with intact central novelty detection. However, the normal bilateral reactivity of SN to stimulus novelty was significantly attenuated following inflammation. Correspondingly, inflammation also markedly impaired novelty-related functional coupling between the SN and hippocampus. These data extend previous findings of SN sensitivity to mild inflammation associated with changes in psychomotor responding, and suggest that inflammation-induced blunting of SN responses to hippocampal novelty signals may represent a plausible mechanism through which inflammation impairs motivational responses to novelty. PMID:25154706

  3. Iron concentrations and distributions in the parkinsonian substantia nigra of aged and young primate models

    NASA Astrophysics Data System (ADS)

    Ren, M. Q.; Xie, J. P.; Wang, X. S.; Ong, W. Y.; Leong, S. K.; Watt, F.

    2001-07-01

    Parkinson's disease (PD) is a progressive neuronal degenerative brain disease of the elderly, and is caused by the selective degeneration of neurons in the substantia nigra (SN) region of the brain, resulting in a reduced production of the neurotransmitter dopamine. Iron has been linked to dopaminergic cell death in Parkinson's disease because of its potential to promote free radicals, leading to oxidative stress. The present study is aimed at using the techniques of nuclear microscopy to elucidate the iron concentrations and distributions in the SN of both young and old monkeys following unilateral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioning. A group of three old monkeys (older than 7 years) and a group of three young monkeys (younger than 7 years) were unilaterally MPTP-lesioned (right side) to induce parkinsonism and sacrificed after 35 days. The left side SN was used as a control. This time interval was chosen to correspond to an average 50% loss of dopamine producing cells in the lesioned right side SN. We have observed a significant difference in iron concentrations between the SNs of the young and old monkeys (increasing from an average of 233 to 1092 parts per million dry weight). When comparing the lesioned and non-lesioned SNs of the same animal, we found no significant difference in iron levels for each young monkey. However we have found a slight increase in iron (approximately 10%) between the lesioned SN and control SN for old monkeys. We have also observed that in the SN of younger primates, there is a weak anti-correlation in the SN iron levels with the neuron distribution. In the older monkeys, however, we have observed a proliferation of iron-rich granules, which appear to be more strongly anti-correlated with the distribution of neurons. The iron-cell anti-correlation occurs both in the control as well as the lesioned SN. Our results suggest that iron, particularly in the form of iron-rich deposits, accumulates in specific sites

  4. Sensory-motor processing in substantia nigra pars reticulata in conscious cats.

    PubMed Central

    Schwarz, M; Sontag, K H; Wand, P

    1984-01-01

    Extracellular recordings were made with chronically implanted micro-electrodes from 109 substantia nigra neurones in conscious cats. Ninety-six of 109 neurones met the criteria of presumed non-dopaminergic pars reticulata (s.n.r.) neurones. Background discharge, in animals in a state of relaxed wakefulness and in the absence of overt movements, was in the range of 11-37 impulses/s, mean 19.2 impulses/s. The discharges of fifty-two of ninety-six neurones tested were modified by innocuous mechanical skin stimulation. Neurones responded chiefly to stimuli delivered to the contralateral body side. Responses generally comprised net excitation and occurred with short latency (range 10-34 ms; mean 17.3 ms). Convergence from both forelimbs or the contralateral fore- and hind limbs was evident in a few cases. One-fourth (twenty-four out of ninety-six) of the s.n.r. neurones tested were sensitive to passive manipulation of limb joints in the quiet, conscious cat and responded exclusively to angular displacement of one contralateral joint. Responses were directional and phasic. None of the s.n.r. neurones tested responded to clicks and/or light flashes. However, stimuli moving across the contralateral visual field substantially modified the discharge rate of ten out of ninety-six s.n.r. neurones. Responses were directional and invariably associated with eye movements. Animals were also trained to walk on a treadmill and to perform certain self-generated limb movements. S.n.r. neurones with a receptive field on a limb regularly showed modulations in discharge during locomotion, phase-related to the step cycle, and also short-latency responses during disturbance of such movements. Ten out of ninety-six s.n.r. neurones discharged almost exclusively prior to and during self-generated movements of a single limb. Their most powerful modulations in firing rate occurred, whenever an animal tried to overcome an external impediment or to resist an imposed movement. These observations

  5. Oxidative stress, progressive damage in the substantia nigra and plasma dopamine oxidation, in rats chronically exposed to ozone.

    PubMed

    Santiago-López, D; Bautista-Martínez, J A; Reyes-Hernandez, C I; Aguilar-Martínez, M; Rivas-Arancibia, S

    2010-09-01

    The purpose of our work was to determine the effects of oxidative stress on the neurodegeneration process in the substantia nigra, and to evaluate dopamine-oxidation metabolites in the plasma using a cyclic voltammetry (CV) technique. We have also studied the correlation between the increases in oxidized dopamine-species levels with the severity of lipid-peroxidation in the plasma. Sixty-four male Wistar rats were divided into four experimental groups and received air (Group I, control) or ozone (0.25 ppm) daily by inhalation for 4h for 15 (Group II), 30 (Group III), and 60 (Group IV) days. The brains were processed for immunohistochemical location of dopamine and p53 in the substantia nigra. Plasma collected from these animals was assayed for oxidized dopamine products using CV and lipid-peroxidation levels were measured. Our results indicate that chronic exposure to low O(3) doses causes that the number of dopaminergic neurons decreased, and p53-immunoreactive cells increases until 30 days; which was a function of the time of exposure to ozone. Oxidative stress produces a significant increase in the levels of the dopamine quinones (DAQs) that correlated well (r=0.962) with lipid peroxides in the plasma during the study period. These results suggest that DAQ could be a reliable, peripheral oxidative indicator of nigral dopaminergic damage in the brain. PMID:20541596

  6. Hyperexcitable substantia nigra dopamine neurons in PINK1- and HtrA2/Omi-deficient mice.

    PubMed

    Bishop, Matthew W; Chakraborty, Subhojit; Matthews, Gillian A C; Dougalis, Antonios; Wood, Nicholas W; Festenstein, Richard; Ungless, Mark A

    2010-12-01

    The electrophysiological properties of substantia nigra pars compacta (SNC) dopamine neurons can influence their susceptibility to degeneration in toxin-based models of Parkinson's disease (PD), suggesting that excitotoxic and/or hypoactive mechanisms may be engaged during the early stages of the disease. It is unclear, however, whether the electrophysiological properties of SNC dopamine neurons are affected by genetic susceptibility to PD. Here we show that deletion of PD-associated genes, PINK1 or HtrA2/Omi, leads to a functional reduction in the activity of small-conductance Ca(2+)-activated potassium channels. This reduction causes SNC dopamine neurons to fire action potentials in an irregular pattern and enhances burst firing in brain slices and in vivo. In contrast, PINK1 deletion does not affect firing regularity in ventral tegmental area dopamine neurons or substantia nigra pars reticulata GABAergic neurons. These findings suggest that changes in SNC dopamine neuron excitability may play a role in their selective vulnerability in PD. PMID:20926611

  7. The vitamin D receptor in dopamine neurons; its presence in human substantia nigra and its ontogenesis in rat midbrain.

    PubMed

    Cui, X; Pelekanos, M; Liu, P-Y; Burne, T H J; McGrath, J J; Eyles, D W

    2013-04-16

    There is growing evidence that vitamin D is a neuroactive steroid capable of regulating multiple pathways important for both brain development and mature brain function. In particular, there is evidence from rodent models that prenatal vitamin D deficiency alters the development of dopaminergic pathways and this disruption is associated with altered behavior and neurochemistry in the adult brain. Although the presence of the vitamin D receptor (VDR) has been noted in the human substantia nigra, there is a lack of direct evidence showing that VDR is present in dopaminergic cells. Here we confirm that the VDR is present in the nucleus of tyrosine hydroxylase (TH)-positive neurons in both the human and rat substantia nigra, and it emerges early in development in the rat, between embryonic day 12 (E12) and E15. Consistent evidence based on immunohistochemistry, real-time PCR and western blot confirmed a pattern of increasing VDR expression in the rat midbrain until weaning. The nuclear expression of VDR in TH-positive neurons during critical periods of brain development suggests that alterations in early life vitamin D status may influence the orderly development of dopaminergic neurons. PMID:23352937

  8. Progressive Supranuclear Palsy: High-Field-Strength MR Microscopy in the Human Substantia Nigra and Globus Pallidus

    PubMed Central

    Foroutan, Parastou; Murray, Melissa E.; Fujioka, Shinsuke; Schweitzer, Katherine J.; Dickson, Dennis W.; Wszolek, Zbigniew K.

    2013-01-01

    Purpose: To characterize changes in the magnetic resonance (MR) relaxation properties of progressive supranuclear palsy (PSP) and tissue from neurologically normal brains by using high-resolution (21.1-T, 900-MHz) MR microscopy of postmortem human midbrain and basal ganglia. Materials and Methods: This HIPAA-compliant study was approved by the institutional review board at the Mayo Clinic and informed consent was obtained. Postmortem tissue from age-matched PSP (n = 6) and control (n = 3) brains was imaged by using three-dimensional fast low-angle shot MR imaging with isotropic resolution of 50 μm. Relaxation times and parametric relaxation maps were generated from spin-echo and gradient-recalled-echo sequences. MR findings were correlated with histologic features by evaluating the presence of iron by using Prussian blue and ferritin and microglia burden as determined by a custom-designed color deconvolution algorithm. T2 and T2*, signal intensities, percent pixels (that could not be fitted in a pixel-by-pixel regression analysis due to severe hypointensity), and histologic data (total iron, ferritin, and microglia burden) were statistically analyzed by using independent sample t tests (P < .05). Results: PSP specimens showed higher iron burden in the cerebral peduncles and substantia nigra than did controls. However, only the putamen was significantly different, and it correlated with a decrease of T2* compared with controls (−48%; P = .043). Similarly, substantia nigra showed a significant decrease of T2* signal in PSP compared with controls (−57%; P = .028). Compared with controls, cerebral peduncles showed increased T2 (38%; P = .026) and T2* (34%; P = .014), as well as higher T2 signal intensity (57%; P = .049). Ferritin immunoreactivity was the opposite from iron burden and was significantly lower compared with controls in the putamen (−74%; P = .025), red nucleus (−61%; P = .018), and entire basal ganglia section (−63%; P = .016). Conclusion: High

  9. Novel approaches for correction against the soft matrix effects in the quantitative elemental imaging of human substantia nigra tissue using synchrotron X-ray fluorescence

    NASA Astrophysics Data System (ADS)

    Surowka, A. D.; Wrobel, P.; Marzec, M. M.; Adamek, D.; Szczerbowska-Boruchowska, M.

    2016-09-01

    The inherent structural heterogeneity of biological specimens poses a number of problems for analytical techniques to assess for the elemental composition of a sample, and this is the case with quantitative X-ray fluorescence (XRF). Differences in density along with any possible variation in thickness upon frequently used freeze drying of thin samples could influence the results of the quantification and therefore underlie one of the most critical matrix effects in XRF, often referred to as the mass thickness effect. In our study, we analyzed substantia nigra tissue samples of various thicknesses mounted onto silicon nitride membranes. The aim was to show up the variation in the mass thickness of the different substantia nigra tissue compartments: the neuromelanine pigmented neurons and neuropil could influence the final quantitative results. In that respect, the main goal was to derive several semi- and fully-quantitative methods to correct for the mass thickness effects using either a membrane Si transmission signal or the intensity of incoherently scattered primary X-ray radiation. Also, the pioneer topographic studies on dried substantia nigra tissue specimens demonstrated the drying procedure is accompanied by an around 80% reduction in the samples' thickness. The correction scheme is presented together with the semi-theoretical procedure developed to compute for the mass thickness for substantia nigra tissue structures, and the correction scheme's robustness is also presented.

  10. Increased free-water in the substantia nigra of Parkinson’s disease: a single-site and multi-site study

    PubMed Central

    Ofori, E.; Pasternak, O.; Planetta, P.J.; Burciu, R.; Snyder, A.; Febo, M.; Golde, T.E.; Okun, M.S.; Vaillancourt, D.E.

    2014-01-01

    Measures from diffusion magnetic resonance imaging reflect changes in the substantia nigra of Parkinson’s disease. It is the case, however, that partial volume effects from free-water can bias diffusion measurements. The bi-tensor diffusion model was introduced to quantify the contribution of free-water and eliminates its bias on estimations of tissue microstructure. Here, we test the hypothesis that free-water is elevated in the substantia nigra for Parkinson’s disease compared with controls. This hypothesis was tested between large cohorts of Parkinson’s disease and control participants in a single-site study, and validated against a multi-site study using multiple scanners. The fractional volume of free-water was increased in the posterior region of the substantia nigra in Parkinson’s disease compared with controls in both the single-site and multi-site studies. We did not observe changes in either cohort for free-water corrected fractional anisotropy or free-water corrected mean diffusivity. Our findings provide new evidence that the free-water index reflects alteration of the substantia nigra in Parkinson’s disease, and this was evidenced across both single-site and multi-site cohorts. PMID:25467638

  11. In vivo release of dopamine from rat striatum, substantia nigra and prefrontal cortex: differential modulation by baclofen.

    PubMed Central

    Santiago, M.; Machado, A.; Cano, J.

    1993-01-01

    1. The effect of baclofen, a GABAB receptor agonist, on the release of dopamine from the striatum (ST), substantia nigra (SN) and prefrontal cortex (PFC) of the rat was examined by intracerebral microdialysis. 2. Perfusion of baclofen 50 microM did not affect the striatal release of dopamine. However, dopamine release was markedly reduced in the SN and PFC. 3. 3,4-Dihydroxyphenylacetic acid and homovanillic acid output increased in the ST and decreased in the SN and PFC when baclofen was perfused through the microdialysis probe. 5-Hydroxyindoleacetic acid levels were not affected in any experimental condition by baclofen perfusion. 4. The results suggest that GABAB receptors modulate the release of dopamine in the SN and PFC, but do not affect the striatal release of dopamine, which indicates that the role of GABA receptor activation is different in the dopaminergic terminals of the ST and PFC. PMID:7689406

  12. Anatomy, pigmentation, ventral and dorsal subpopulations of the substantia nigra, and differential cell death in Parkinson's disease.

    PubMed Central

    Gibb, W R; Lees, A J

    1991-01-01

    In six control subjects pars compacta nerve cells in the ventrolateral substantia nigra had a lower melanin content than nerve cells in the dorsomedial region. This coincides with a natural anatomical division into ventral and dorsal tiers, which represent functionally distinct populations. In six cases of Parkinson's disease (PD) the ventral tier showed very few surviving nerve cells compared with preservation of cells in the dorsal tier. In 13 subjects without PD, but with nigral Lewy bodies and cell loss, the degenerative process started in the ventral tier, and spread to the dorsal tier. This pattern of selective degeneration of nigrostriatal neurons is not seen in ageing or after acute administration of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). Images PMID:1865199

  13. Transplanted Neural Stem Cells: Playing a Neuroprotective Role by Ceruloplasmin in the Substantia Nigra of PD Model Rats?

    PubMed Central

    Xiao, Jia-Jia; Yin, Ming; Wang, Ze-Jian; Wang, Xiao-Ping

    2015-01-01

    Although mounting evidence suggests that ceruloplasmin (CP) deficiency and iron deposition are pivotal factors responsible for exacerbating demise of dopaminergic neurons in the substantia nigra (SN) of the Parkinsonism and neural stem cells (NSCs) are believed to be excellent candidates for compensating the lost dopaminergic neurons, there are few researches to explore the change of CP expression and of iron deposition in the pathological microenvironment of SN after NSCs transplantation and the ability of grafted NSCs to differentiate directionally into dopaminergic neurons under the changed homeostasis. With substantia nigral stereotaxic technique and NSCs transplantation, we found that tyrosine hydroxylase and CP expression decreased and iron deposition increased in the lesioned SN after 6-OHDA administration compared with control, while tyrosine hydroxylase and CP expression increased and iron deposition decreased after NSCs transplantation compared to 6-OHDA administration alone. Only a small number of embedding NSCs are able to differentiate into dopaminergic neurons. These results suggest that grafted NSCs have an influence on improving the content of CP expression, which may play a neuroprotective role by decreasing iron deposition and ameliorating damage of dopaminergic neurons and possibly underline the iron-related common mechanism of Parkinson's disease and Wilson's disease. PMID:26146528

  14. Comparison between the pharmacology of dopamine receptors mediating the inhibition of cell firing in rat brain slices through the substantia nigra pars compacta and ventral tegmental area.

    PubMed Central

    Bowery, B.; Rothwell, L. A.; Seabrook, G. R.

    1994-01-01

    1. Electrophysiological recordings were made from presumed dopaminergic neurons in the substantia nigra pars compacta and ventral tegmental area of rat brain slices. The ability of selective dopamine receptor agonists to hyperpolarize neurones and inhibit cell firing, as well as the ability of dopamine receptor antagonists to block responses to quinpirole were compared. 2. Six dopamine receptor agonists were examined for their ability to hyperpolarize neurones within the substantia nigra pars compacta. Of these, the most potent ligand tested was naxagolide with an EC50 value of 20 nM and estimated maximum of 10 mV. The rank order of agonist potency was naxagolide > quinpirole > apomorphine > dopamine. 3. Quinpirole was more potent at inhibiting cell firing in the substantia nigra pars compacta (pIC50 = 7.65 +/ 0.06, n = 35) than in the ventral tegmental area (pIC50 = 7.24 +/- 0.06, n = 32; P < 0.01, Student's t test). 7-Hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT), a putative D3 selective agonist, had a comparable potency to quinpirole in both the ventral tegmental area (pIC50 = 7.39 +/- 0.26, n = 4), and substantia nigra pars compacta (pIC50 = 7.71 +/- 0.20; n = 4). 4. The inhibition of cell firing by quinpirole was antagonized by haloperidol, S(-)-sulpiride, clozapine, and ritanserin. S(-)-sulpiride and haloperidol had the highest estimated affinities in the substantia nigra, with pA2 values of 8.97 (slope = 0.85) and 8.20 (slope = 2.09) respectively.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7921615

  15. Differential Regulation of Action Potential Shape and Burst-Frequency Firing by BK and Kv2 Channels in Substantia Nigra Dopaminergic Neurons

    PubMed Central

    Kimm, Tilia; Khaliq, Zayd M.

    2015-01-01

    Little is known about the voltage-dependent potassium currents underlying spike repolarization in midbrain dopaminergic neurons. Studying mouse substantia nigra pars compacta dopaminergic neurons both in brain slice and after acute dissociation, we found that BK calcium-activated potassium channels and Kv2 channels both make major contributions to the depolarization-activated potassium current. Inhibiting Kv2 or BK channels had very different effects on spike shape and evoked firing. Inhibiting Kv2 channels increased spike width and decreased the afterhyperpolarization, as expected for loss of an action potential-activated potassium conductance. BK inhibition also increased spike width but paradoxically increased the afterhyperpolarization. Kv2 channel inhibition steeply increased the slope of the frequency–current (f–I) relationship, whereas BK channel inhibition had little effect on the f–I slope or decreased it, sometimes resulting in slowed firing. Action potential clamp experiments showed that both BK and Kv2 current flow during spike repolarization but with very different kinetics, with Kv2 current activating later and deactivating more slowly. Further experiments revealed that inhibiting either BK or Kv2 alone leads to recruitment of additional current through the other channel type during the action potential as a consequence of changes in spike shape. Enhancement of slowly deactivating Kv2 current can account for the increased afterhyperpolarization produced by BK inhibition and likely underlies the very different effects on the f–I relationship. The cross-regulation of BK and Kv2 activation illustrates that the functional role of a channel cannot be defined in isolation but depends critically on the context of the other conductances in the cell. SIGNIFICANCE STATEMENT This work shows that BK calcium-activated potassium channels and Kv2 voltage-activated potassium channels both regulate action potentials in dopamine neurons of the substantia nigra

  16. Distinct Contributions of Ventromedial and Dorsolateral Subregions of the Human Substantia Nigra to Appetitive and Aversive Learning

    PubMed Central

    Larsen, Tobias; Collette, Sven; Tyszka, Julian M.; Seymour, Ben; O'Doherty, John P.

    2015-01-01

    The role of neurons in the substantia nigra (SN) and ventral tegmental area (VTA) of the midbrain in contributing to the elicitation of reward prediction errors during appetitive learning has been well established. Less is known about the differential contribution of these midbrain regions to appetitive versus aversive learning, especially in humans. Here we scanned human participants with high-resolution fMRI focused on the SN and VTA while they participated in a sequential Pavlovian conditioning paradigm involving an appetitive outcome (a pleasant juice), as well as an aversive outcome (an unpleasant bitter and salty flavor). We found a degree of regional specialization within the SN: Whereas a region of ventromedial SN correlated with a temporal difference reward prediction error during appetitive Pavlovian learning, a dorsolateral area correlated instead with an aversive expected value signal in response to the most distal cue, and to a reward prediction error in response to the most proximal cue to the aversive outcome. Furthermore, participants' affective reactions to both the appetitive and aversive conditioned stimuli more than 1 year after the fMRI experiment was conducted correlated with activation in the ventromedial and dorsolateral SN obtained during the experiment, respectively. These findings suggest that, whereas the human ventromedial SN contributes to long-term learning about rewards, the dorsolateral SN may be particularly important for long-term learning in aversive contexts. SIGNIFICANCE STATEMENT The role of the substantia nigra (SN) and ventral tegmental area (VTA) in appetitive learning is well established, but less is known about their contribution to aversive compared with appetitive learning, especially in humans. We used high-resolution fMRI to measure activity in the SN and VTA while participants underwent higher-order Pavlovian learning. We found a regional specialization within the SN: a ventromedial area was selectively engaged

  17. Enkephalin, dynorphin and substance P in postmortem substantia nigra from normals and schizophrenic patients

    SciTech Connect

    Iadarola, M.J.; Ofri, D.; Kleinman, J.E. National Institute of Mental Health, Washington, DC )

    1991-01-01

    Three peptide neuromodulators that are found in high concentration in the subtantia nigra: dynorphin A 1,8-met5-enkephalin-arg6-gly7-leu8 and substance P, were measured by specific radioimmunoassays in nigral tissue from normals and schizophrenics postmortem. Substance P and dynorphin were unchanged between the two groups. However, the proenkephalin-derived peptide was significantly elevated in the schizophrenic group. The immunoreactivity was identified as authentic met5-enkephalin-arg6-gly7-leu8 by high pressure liquid chromatography. The data suggest that a different set of regulatory controls exists for nigral enkephalin peptides as compared to dynorphin and substance P, and that the former system may be disordered in schizophrenia.

  18. Embryonic substantia nigra grafts in the mesencephalon send neurites to the host striatum in non-human primate after overexpression of GDNF

    PubMed Central

    Redmond, D.E.; Elsworth, J.D.; Roth, R.H.; Leranth, C.; Collier, T.J.; Blanchard, B.; Bjugstad, K.B.; Samulski, R.J.; Aebischer, P.; Sladek, J.R.

    2010-01-01

    In spite of partial success in treating Parkinson's disease 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 substantia nigra, and injections of AAV2/GDNF or EIAV/GDNF into the caudate. Three adult monkeys were co-grafted with fetal VM tissue near the substantia nigra 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 fluorogold (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 substantia nigra 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. PMID:19399891

  19. Morphological effects of cytidin-diphosphate-choline on rats with lesions of the substantia nigra: study using horse radish peroxidase method.

    PubMed

    Stanzani, S

    1981-09-15

    Morphological effects of Cytidin-diphosphate-Choline (CDP-choline) (Ni-cholin) on rat brain with Substantia nigra lesions were studied by using the horse radish peroxidase method (HRP). Three groups of animals were studied. Post-lesion axonal and cellular regeneration was detected only in the group of rats treated with CDP-choline q.d. i.m. for 15 days. PMID:7306424

  20. Sensory-motor performance after acute glutathione depletion by L-buthionine sulfoximine injection into substantia nigra pars compacta.

    PubMed

    Díaz-Hung, Mei-Li; Blanco, Lisette; Pavón, Nancy; León, Rilda; Estupiñan, Bárbara; Orta, Eduardo; Martínez, Klaudia; Fernández, Isabel

    2014-09-01

    Glutathione is the major antioxidant in the living cells. Its deficit has been linked to neurodegenerative disorders as Parkinson's disease but its role in the etiology of nigral degeneration and sensory-motor performance has been poorly explored. To evaluate the effect of glutathione depletion on nigro-striatal oxidative metabolism and sensory-motor performance in rats, l-buthionine sulfoximine (15 mM) or saline solution was injected into substantia nigra pars compacta (SNpc). Then, oxidative metabolism was studied 24h and 7 days later in SNpc and corpus striatum (CS). Tyrosine hydroxylase and GFAP immunohistochemistry assays were carried out at 7 days. In addition, animals were evaluated in open field, adhesive removal, staircase and traverse beam tests. Glutathione depletion induced compensatory response in catalase activity and glial response in the in SNpc and no oxidative damage was observed. However, a loss in dopaminergic cells was found. At the same time, animals with glutathione depletion have shown poor performance in behavioral tests except for staircase test. These results suggest that glutathione depletion can be related to sensory-motor dysfunction. PMID:24912031

  1. Inhibition of prothrombin kringle-2-induced inflammation by minocycline protects dopaminergic neurons in the substantia nigra in vivo.

    PubMed

    Nam, Jin Han; Leem, Eunju; Jeon, Min-Tae; Kim, Young-Je; Jung, Un Ju; Choi, Myung-Sook; Maeng, Sungho; Jin, Byung Kwan; Kim, Sang Ryong

    2014-05-01

    Prothrombin kringle-2 (pKr-2), a domain of prothrombin, can cause the degeneration of mesencephalic dopaminergic neurons through microglial activation. However, the chemical products that inhibit pKr-2-induced inflammatory activities in the brain are still not well known. The present study investigated whether minocycline, a semisynthetic tetracycline derivative, could inhibit pKr-2-induced microglial activation and prevent the loss of nigral dopaminergic (DA) neurons in vivo. To address this question, rats were administered a unilateral injection of pKr-2 in the substantia nigra in the presence or absence of minocycline. Our results show that pKr-2 induces the production of proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), and inducible nitric oxide synthase from the activated microglia. In parallel, 7 days after pKr-2 injection, tyrosine hydroxylase immunocytochemical analysis and western blot analysis showed a significant loss of nigral DA neurons. This neurotoxicity was antagonized by minocycline and the observed neuroprotective effects were associated with the ability of minocycline to suppress the expression of tumor necrosis factor-α, interleukin-1β, and nitric oxide synthase. These results suggest that minocycline may be promising as a potential therapeutic agent for the prevention of DA neuronal degeneration associated with pKr-2-induced microglial activation. PMID:24488033

  2. In vivo detection of iron and neuromelanin by transcranial sonography: a new approach for early detection of substantia nigra damage.

    PubMed

    Zecca, Luigi; Berg, Daniela; Arzberger, Thomas; Ruprecht, Petra; Rausch, Wolf D; Musicco, Massimo; Tampellini, Davide; Riederer, Peter; Gerlach, Manfred; Becker, Georg

    2005-10-01

    Early diagnosis of Parkinson's disease (PD) in nonsymptomatic patients is a key issue. An increased echogenicity of the substantia nigra (SN) was found previously in Parkinsonian patients and in a low percentage of healthy adults. These nonsymptomatic subjects also showed a reduced 18F-dopa uptake in striatum, suggesting a preclinical injury of the nigrostriatal system that could later proceed into PD. To investigate the ability of ultrasonography to detect markers of SN degeneration, such as iron deposition and neuromelanin depletion, we scanned postmortem brains from normal subjects at different ages by ultrasound and measured the echogenic area of the SN. The SN was then dissected and used for histological examinations and determination of iron, ferritin, and neuromelanin content. A significant positive correlation was found between the echogenic area of the SN and the concentration of iron, H- and L-ferritins. Multivariate analysis carried out considering the iron content showed a significant negative correlation between echogenicity and neuromelanin content of the SN. In PD, a typical loss of neuromelanin and increase of iron is observed in this brain area. The finding of a positive correlation between iron and ferritin levels and a negative correlation of neuromelanin content with the area of echogenicity at the SN could therefore provide an interesting basis for diagnosis and therapeutic follow-up studies in PD. PMID:15986424

  3. Age- and Sex-Related Characteristics of Tonic Gaba Currents in the Rat Substantia Nigra Pars Reticulata

    PubMed Central

    Hasson, H.; Bojar, M.; Moshé, S. L.; Galanopoulou, A. S.

    2015-01-01

    Previous studies have shown that the pharmacologic effects of GABAergic drugs and the postsynaptic phasic GABAAergic inhibitory responses in the anterior part of the rat substantia nigra pars reticulata (SNRA) are age- and sex-specific. Here, we investigate whether there are age- and sex-related differences in the expression of the δ GABAA receptor (GABAAR) subunit and GABAAR mediated tonic currents. We have used δ-specific immunochemistry and whole cell patch clamp to study GABAAR mediated tonic currents in the SNRA of male and female postnatal day (PN) PN5-9, PN11-16, and PN25-32 rats. We observed age-related decline, but no sex-specific changes, in bicuculline (BIM) sensitive GABAAR tonic current density, which correlated with the decline in δ subunit in the SNRA between PN15 and 30. Furthermore, we show that the GABAAR tonic currents can be modified by muscimol (GABAAR agonist; partial GABACR agonist), THIP (4,5,6,7-tetrahydroisoxazolo (5,4-c)pyridin-3-ol: α4β3δ GABAARs agonist and GABACR antagonist), and zolpidem (α1-subunit selective GABAAR agonist) in age-and sex-dependent manner specific for each drug. We propose that the emergence of the GABAAR-sensitive anticonvulsant effects of the rat SNRA during development may depend upon the developmental decline in tonic GABAergic inhibition of the activity of rat SNRA neurons, although other sex-specific factors are also involved. PMID:25645446

  4. Seizure-induced damage to substantia nigra and globus pallidus is accompanied by pronounced intra- and extracellular acidosis

    SciTech Connect

    Inamura, K.; Smith, M.L.; Hansen, A.J.; Siesjoe, B.K. )

    1989-12-01

    Status epilepticus of greater than 30-min duration in rats gives rise to a conspicuous lesion in the substantia nigra pars reticulata (SNPR) and globus pallidus (GP). The objective of the present study was to explore whether the lesion, which encompasses necrosis of both neurons and glial cells, is related to intra- and extracellular acidosis. Using the flurothyl model previously described to produce seizures, we assessed regional pH values with the autoradiographic 5,5-dimethyl(2-14C)oxazolidine-2,4-dione technique. Regional pH values were assessed in animals with continuous seizures for 20 and 60 min, as well as in those allowed to recover for 30 and 120 min after seizure periods of 20 or 60 min. In additional animals, changes in extracellular fluid pH (pHe) were measured with ion-selective microelectrodes, and extracellular fluid (ECF) volume was calculated from the diffusion profile for electrophoretically administered tetramethylammonium. In structures such as the neocortex and the hippocampus, which show intense metabolic activation during seizures, status epilepticus of 20- and 60-min duration was accompanied by a reduction of the composite tissue pH (pHt) of 0.2-0.3 unit. Recovery of pHt was observed upon termination of seizures. In SNPR and in GP, the acidosis was marked to excessive after 20 and 60 min of seizures (delta pHt approximately 0.6 after 60 min).

  5. Human substantia nigra neurons encode decision outcome and are modulated by categorization uncertainty in an auditory categorization task.

    PubMed

    McGovern, Robert A; Chan, Andrew K; Mikell, Charles B; Sheehy, John P; Ferrera, Vincent P; McKhann, Guy M

    2015-09-01

    The ability to categorize stimuli - predator or prey, friend or foe - is an essential feature of the decision-making process. Underlying that ability is the development of an internally generated category boundary to generate decision outcomes. While classic temporal difference reinforcement models assume midbrain dopaminergic neurons underlie the prediction error required to learn boundary location, these neurons also demonstrate a robust response to nonreward incentive stimuli. More recent models suggest that this may reflect a motivational aspect to performing a task which should be accounted for when modeling dopaminergic neuronal behavior. To clarify the role of substantia nigra dopamine neurons in uncertain perceptual decision making, we investigated their behavior using single neuron extracellular recordings in patients with Parkinson's disease undergoing deep brain stimulation. Subjects underwent a simple auditory categorical decision-making task in which they had to classify a tone as either low- or high-pitched relative to an explicit threshold tone and received feedback but no reward. We demonstrate that the activity of human SN dopaminergic neurons is predictive of perceptual categorical decision outcome and is modulated by uncertainty. Neuronal activity was highest during difficult (uncertain) decisions that resulted in correct responses and lowest during easy decisions that resulted in incorrect responses. This pattern of results is more consistent with a "motivational" role with regards to perceptual categorization and suggests that dopamine neurons are most active when critical information - as represented by uncertainty - is available for learning decision boundaries. PMID:26416969

  6. Protective Effects of Nicotine Against Aminochrome-Induced Toxicity in Substantia Nigra Derived Cells: Implications for Parkinson’s Disease

    PubMed Central

    Muñoz, Patricia; Huenchuguala, Sandro; Paris, Irmgard; Cuevas, Carlos; Villa, Monica; Caviedes, Pablo; Segura-Aguilar, Juan

    2013-01-01

    Parkinson’s disease is a debilitating progressive neurodegenerative disorder that results from the loss of or damage to dopaminergic cells containing neuromelanin in the substantia nigra (SN). The underlying neurodegenerative mechanism(s), however, remain elusive. Aminochrome, the precursor of neuromelanin is an endogenous substance capable of inducing selective neurotoxicity to dopaminergic neurons in SN. Nicotine, on the other hand, may offer protective effects against dopaminergic cell damage induced by various neurotoxins including MPTP and salsolinol. In this study, we sought to determine whether nicotine may also protect against aminochrome-induced toxicity in SN derived RCSN-3 cells. Exposure of RCSN-3 cells to a combination of aminochrome (50 μM) and dicoumarol (50 μM) for 48 h induced approximately 70 % cell death. Pretreatment with nicotine, dose-dependently blocked this toxicity. The effects of nicotine in turn were dose-dependently blocked by mecamylamine, a non-selective nicotinic receptor antagonist. These results suggest involvement of nicotinic receptors in protective effects of nicotine against aminochrome-induced toxicity and provide further evidence for possible therapeutic effects of nicotine or nicotinic agonists in Parkinson’s disease. PMID:22528249

  7. Diffusion Kurtosis Imaging of Substantia Nigra Is a Sensitive Method for Early Diagnosis and Disease Evaluation in Parkinson's Disease

    PubMed Central

    Zhang, Guohua; Zhang, Yuhu; Zhang, Chengguo; Wang, Yukai; Ma, Guixian; Nie, Kun; Xie, Haiqun; Liu, Jianping; Wang, Lijuan

    2015-01-01

    Background. To diagnose Parkinson disease (PD) in an early stage and accurately evaluate severity, it is important to develop a sensitive method for detecting structural changes in the substantia nigra (SN). Method. Seventy-two untreated patients with early PD and 72 healthy controls underwent diffusion tensor and diffusion kurtosis imaging. Regions of interest were drawn in the rostral, middle, and caudal SN by two blinded and independent raters. Mean kurtosis (MK) and fractional anisotropy in the SN were compared between the groups. Receiver operating characteristic (ROC) and Spearman correlation analyses were used to compare the diagnostic accuracy and correlate imaging findings with Hoehn-Yahr (H-Y) staging and part III of the Unified Parkinson's Disease Rating Scale (UPDRS-III). Result. MK in the SN was increased significantly in PD patients compared with healthy controls. The area under the ROC curve was 0.976 for MK in the SN (sensitivity, 0.944; specificity, 0.917). MK in the SN had a positive correlation with H-Y staging and UPDRS-III scores. Conclusion. Diffusion kurtosis imaging is a sensitive method for PD diagnosis and severity evaluation. MK in the SN is a potential biomarker for imaging studies of early PD that can be widely used in clinic. PMID:26770867

  8. Evidence for Immune Response, Axonal Dysfunction and Reduced Endocytosis in the Substantia Nigra in Early Stage Parkinson’s Disease

    PubMed Central

    Dijkstra, Anke A.; Ingrassia, Angela; de Menezes, Renee X.; van Kesteren, Ronald E.; Rozemuller, Annemieke J. M.; Heutink, Peter; van de Berg, Wilma D. J.

    2015-01-01

    Subjects with incidental Lewy body disease (iLBD) may represent the premotor stage of Parkinson’s disease (PD). To elucidate molecular mechanisms underlying neuronal dysfunction and alpha-synuclein pathology in the premotor phase of PD, we investigated the transcriptome of the substantia nigra (SN) of well-characterized iLBD, PD donors and age-matched controls with Braak alpha-synuclein stage ranging from 0–6. In Braak alpha-synuclein stages 1 and 2, we observed deregulation of pathways linked to axonal degeneration, immune response and endocytosis, including axonal guidance signaling, mTOR signaling, EIF2 signaling and clathrin-mediated endocytosis in the SN. In Braak stages 3 and 4, we observed deregulation of pathways involved in protein translation and cell survival, including mTOR and EIF2 signaling. In Braak stages 5 and 6, we observed deregulation of dopaminergic signaling, axonal guidance signaling and thrombin signaling. Throughout the progression of PD pathology, we observed a deregulation of mTOR, EIF2 and regulation of eIF4 and p70S6K signaling in the SN. Our results indicate that molecular mechanisms related to axonal dysfunction, endocytosis and immune response are an early event in PD pathology, whereas mTOR and EIF2 signaling are impaired throughout disease progression. These pathways may hold the key to altering the disease progression in PD. PMID:26087293

  9. Age- and sex-related characteristics of tonic GABA currents in the rat substantia nigra pars reticulata.

    PubMed

    Chudomel, O; Hasson, H; Bojar, M; Moshé, S L; Galanopoulou, A S

    2015-04-01

    Previous studies have shown that the pharmacologic effects of GABAergic drugs and the postsynaptic phasic GABAAergic inhibitory responses in the anterior part of the rat substantia nigra pars reticulata (SNRA) are age- and sex-specific. Here, we investigate whether there are age- and sex-related differences in the expression of the δ GABAA receptor (GABAAR) subunit and GABAAR mediated tonic currents. We have used δ-specific immunochemistry and whole cell patch clamp to study GABAAR mediated tonic currents in the SNRA of male and female postnatal day (PN) PN5-9, PN11-16, and PN25-32 rats. We observed age-related decline, but no sex-specific changes, in bicuculline (BIM) sensitive GABAAR tonic current density, which correlated with the decline in δ subunit in the SNRA between PN15 and 30. Furthermore, we show that the GABAAR tonic currents can be modified by muscimol (GABAAR agonist; partial GABACR agonist), THIP (4,5,6,7-tetrahydroisoxazolo (5,4-c)pyridin-3-ol: α4β3δ GABAARs agonist and GABACR antagonist), and zolpidem (α1-subunit selective GABAAR agonist) in age- and sex-dependent manner specific for each drug. We propose that the emergence of the GABAAR-sensitive anticonvulsant effects of the rat SNRA during development may depend upon the developmental decline in tonic GABAergic inhibition of the activity of rat SNRA neurons, although other sex-specific factors are also involved. PMID:25645446

  10. Effects of Zhichan powder on signal transduction and apoptosis-associated gene expression in the substantia nigra of Parkinson's disease rats.

    PubMed

    Chen, Jiajun; Ma, Jinshu; Qiu, Yafei; Yi, Shihong; Liu, Yongmao; Zhou, Qingwei; Zhang, Pengguo; Wan, Quan; Kuang, Ye

    2012-09-25

    Previous studies have shown that Zhichan powder elevated immunity and suppressed oxidation in mice. Rat models of Parkinson's disease were induced by stereotaxically injecting 6-hydroxydopamine into the substantia nigra. The rat models were intragastrically treated with Zhichan powder, which is composed of milkvetch root, ginseng, bunge swallowwort root, himalayan teasel root, Magnolia officinalis, Ligustrum lucidum Ait. and szechwan lovage rhizome. Immunohistochemistry and reverse transcription-PCR results demonstrated that mRNA and protein expression of tumor necrosis factor receptor 1, Fas, caspase-8, cytochrome C, Bax, caspase-3, and p53 significantly increased, but Bcl-2 expression significantly decreased in the substantia nigra of rats with Parkinson's disease. Following Zhichan powder administration, mRNA and protein expression of tumor necrosis factor receptor 1, Fas, caspase-8, cytochrome C, Bax, caspase-3, and p53 diminished, but Bcl-2 expression increased in the rat substantia nigra. These results indicate that Zhichan powder regulates signal transduction protein expression, inhibits apoptosis, and exerts therapeutic effects on Parkinson's disease. PMID:25558224

  11. Efferent projections of the retrorubral nucleus to the substantia nigra and ventral tegmental area in cats as shown by anterograde tracing.

    PubMed

    Arts, M P; Groenewegen, H J; Veening, J G; Cools, A R

    1996-01-01

    The aim of the present study was to determine whether the retrorubral nucleus projects to the dopaminergic nuclei in the ventral midbrain of the cat. For this purpose, injections of biotinylated dextran-amine or Phaseolus vulgaris-leucoagglutinin were placed into the retrorubral nucleus under stereotaxic guidance. The tracers were visualized by means of (immuno) histochemical procedures. In addition, tyrosine hydroxylase immunohistochemistry was used to evaluate the location of the injection sites and the distribution of the anterogradely labeled fibers. Both tracers reveal the same topography of labeled fibers in the ventral mesencephalon. Labeled fibers with varicosities were found ipsilaterally in the substantia nigra pars compacta, the substantia nigra pars lateralis, the ventral tegmental area and, contralaterally, in the substantia nigra pars compacta, the ventral tegmental area, and the retrorubral nucleus. A considerable number of labeled axons with varicosities were observed to be wrapped around the dendrites and perikarya of tyrosine hydroxylase-positive neurons in these areas. The present results are discussed in view of the possible role of the A8 dopaminergic cell group in the coordination of A9 nigrostriatal and A10 mesolimbic systems, as well as in the progressive pathology seen in patients suffering from Parkinson's disease. PMID:8736584

  12. Alteration of nuclear factor-kappaB pathway promote neuroinflammation depending on the functions of estrogen receptors in substantia nigra after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment.

    PubMed

    Mitra, Soham; Ghosh, Nabanita; Sinha, Priyobrata; Chakrabarti, Nilkanta; Bhattacharyya, Arindam

    2016-03-11

    The simultaneous role of neuroprotective estrogen and neurodegenerative inflammation during the progression of Parkinson's disease (PD) is still remaining elusive. The novel importance of the present study in MPTP mediated mouse model of Parkinson's disease (PD) is-to investigate the status of neuronal and glial cells in a time chase experiment; to explore which pathway of NF-kappaB exist to proceed the neuroinflammation; to investigate the status of estrogen and the activation pattern of nuclear or cytosolic estrogen receptors in either sexes of Swiss albino mice during MPTP mediated progressive neurodegeneration in the substantia nigra. After MPTP intoxication, the nigral molecular anatomy was changed differently in separate time interval during the progression of neurodegeneration with/without association of glial cells and functional (via its nuclear and cytosolic receptors) estrogen level. Both the canonical and/or non-canonical pathways of NF-kappaB exist in the substantia nigra of both the sexes after MPTP treatment that is why inspite of presence of estrogen, neuroinflammation progresses. The homodimeric or heterodimeric form of ER-beta binds with NF-kappaB molecules p65 and RelB differently, but the canonical or non-canonical pathways of NF-kappaB molecules could not be stopped or may be promoted. PMID:26827723

  13. Dopaminergic Presynaptic Modulation of Nigral Afferents: Its Role in the Generation of Recurrent Bursting in Substantia Nigra Pars Reticulata Neurons

    PubMed Central

    de Jesús Aceves, José; Rueda-Orozco, Pavel E.; Hernández, Ricardo; Plata, Víctor; Ibañez-Sandoval, Osvaldo; Galarraga, Elvira; Bargas, José

    2011-01-01

    Previous work has shown the functions associated with activation of dopamine presynaptic receptors in some substantia nigra pars reticulata (SNr) afferents: (i) striatonigral terminals (direct pathway) posses presynaptic dopamine D1-class receptors whose action is to enhance inhibitory postsynaptic currents (IPSCs) and GABA transmission. (ii) Subthalamonigral terminals posses D1- and D2-class receptors where D1-class receptor activation enhances and D2-class receptor activation decreases excitatory postsynaptic currents. Here we report that pallidonigral afferents posses D2-class receptors (D3 and D4 types) that decrease inhibitory synaptic transmission via presynaptic modulation. No action of D1-class agonists was found on pallidonigral synapses. In contrast, administration of D1-receptor antagonists greatly decreased striatonigral IPSCs in the same preparation, suggesting that tonic dopamine levels help in maintaining the function of the striatonigral (direct) pathway. When both D3 and D4 type receptors were blocked, pallidonigral IPSCs increased in amplitude while striatonigral connections had no significant change, suggesting that tonic dopamine levels are repressing a powerful inhibition conveyed by pallidonigral synapses (a branch of the indirect pathway). We then blocked both D1- and D2-class receptors to acutely decrease direct pathway (striatonigral) and enhance indirect pathways (subthalamonigral and pallidonigral) synaptic force. The result was that most SNr projection neurons entered a recurrent bursting firing mode similar to that observed during Parkinsonism in both patients and animal models. These results raise the question as to whether the lack of dopamine in basal ganglia output nuclei is enough to generate some pathological signs of Parkinsonism. PMID:21347219

  14. Chronic L-DOPA treatment attenuates behavioral and biochemical deficits induced by unilateral lactacystin administration into the rat substantia nigra.

    PubMed

    Konieczny, Jolanta; Czarnecka, Anna; Lenda, Tomasz; Kamińska, Kinga; Lorenc-Koci, Elżbieta

    2014-03-15

    The aim of the study was to determine whether the dopamine (DA) precursor l-DOPA attenuates parkinsonian-like symptoms produced by the ubiquitin-proteasome system inhibitor lactacystin. Wistar rats were injected unilaterally with lactacystin (2.5 μg/2 μl) or 6-OHDA (8 μg/2 μl) into the substantia nigra (SN) pars compacta. Four weeks after the lesion, the animals were treated chronically with l-DOPA (25 or 50 mg/kg) for two weeks. During l-DOPA treatment, the lactacystin-treated rats were tested for catalepsy and forelimb asymmetry. Rotational behavior was evaluated after apomorphine (0.25 mg/kg) and l-DOPA in both PD models. After completion of experiments, the animals were killed and the levels of DA and its metabolites in the striatum and SN were assayed. We found that acute l-DOPA administration effectively decreased catalepsy and increased the use of the compromised forelimb in the cylinder test. However, the lactacystin group did not respond to apomorphine or acute l-DOPA administration in the rotational test. Repeated l-DOPA treatment produced contralateral rotations in both PD models, but the number of rotations was much greater in the 6-OHDA-lesioned rats. Both toxins markedly (>90%) reduced the levels of DA and its metabolites in the striatum and SN, while l-DOPA diminished these decreases, especially in the SN. By demonstrating the efficacy of l-DOPA in several behavioral tests, our study confirms the usefulness of the lactacystin lesion as a model of PD. However, marked differences in the rotational response to apomorphine and l-DOPA suggest different mechanisms of neurodegeneration evoked by lactacystin and 6-OHDA. PMID:24361083

  15. Reduced Number of Pigmented Neurons in the Substantia Nigra of Dystonia Patients? Findings from Extensive Neuropathologic, Immunohistochemistry, and Quantitative Analyses

    PubMed Central

    Iacono, Diego; Geraci-Erck, Maria; Peng, Hui; Rabin, Marcie L.; Kurlan, Roger

    2015-01-01

    Background Dystonias (Dys) represent the third most common movement disorder after essential tremor (ET) and Parkinson's disease (PD). While some pathogenetic mechanisms and genetic causes of Dys have been identified, little is known about their neuropathologic features. Previous neuropathologic studies have reported generically defined neuronal loss in various cerebral regions of Dys brains, mostly in the basal ganglia (BG), and specifically in the substantia nigra (SN). Enlarged pigmented neurons in the SN of Dys patients with and without specific genetic mutations (e.g., GAG deletions in DYT1 dystonia) have also been described. Whether or not Dys brains are associated with decreased numbers or other morphometric changes of specific neuronal types is unknown and has never been addressed with quantitative methodologies. Methods Quantitative immunohistochemistry protocols were used to estimate neuronal counts and volumes of nigral pigmented neurons in 13 SN of Dys patients and 13 SN of age-matched control subjects (C). Results We observed a significant reduction (∼20%) of pigmented neurons in the SN of Dys compared to C (p<0.01). Neither significant volumetric changes nor evident neurodegenerative signs were observed in the remaining pool of nigral pigmented neurons in Dys brains. These novel quantitative findings were confirmed after exclusion of possible co-occurring SN pathologies including Lewy pathology, tau-neurofibrillary tangles, β-amyloid deposits, ubiquitin (ubiq), and phosphorylated-TAR DNA-binding protein 43 (pTDP43)-positive inclusions. Discussion A reduced number of nigral pigmented neurons in the absence of evident neurodegenerative signs in Dys brains could indicate previously unconsidered pathogenetic mechanisms of Dys such as neurodevelopmental defects in the SN. PMID:26069855

  16. The Longitudinal Transcriptomic Response of the Substantia Nigra to Intrastriatal 6-Hydroxydopamine Reveals Significant Upregulation of Regeneration-Associated Genes

    PubMed Central

    Cole-Strauss, Allyson; Grabinski, Tessa; Mattingly, Zachary R.; Winn, Mary E.; Steece-Collier, Kathy; Sortwell, Caryl E.; Manfredsson, Fredric P.; Lipton, Jack W.

    2015-01-01

    We hypothesized that the study of gene expression at 1, 2, 4, 6 and 16 weeks in the substantia nigra (SN) after intrastriatal 6-OHDA in the Sprague-Dawley rat (rattus norvegicus) would identify cellular responses during the degenerative process that could be axoprotective. Specifically, we hypothesized that genes expressed within the SN that followed a profile of being highly upregulated early after the lesion (during active axonal degeneration) and then progressively declined to baseline over 16 weeks as DA neurons died are indicative of potential protective responses to the striatal 6-OHDA insult. Utilizing a κ-means cluster analysis strategy, we demonstrated that one such cluster followed this hypothesized expression pattern over time, and that this cluster contained several interrelated transcripts that are classified as regeneration-associated genes (RAGs) including Atf3, Sprr1a, Ecel1, Gadd45a, Gpnmb, Sox11, Mmp19, Srgap1, Rab15,Lifr, Trib3, Tgfb1, and Sema3c. All exemplar transcripts tested from this cluster (Sprr1a, Ecel1, Gadd45a, Atf3 and Sox11) were validated by qPCR and a smaller subset (Sprr1a, Gadd45a and Sox11) were shown to be exclusively localized to SN DA neurons using a dual label approach with RNAScope in situ hybridization and immunohistochemistry. Upregulation of RAGs is typically associated with the response to axonal injury in the peripheral nerves and was not previously reported as part of the axodegenerative process for DA neurons of the SN. Interestingly, as part of this cluster, other transcripts were identified based on their expression pattern but without a RAG provenance in the literature. These "RAG-like" transcripts need further characterization to determine if they possess similar functions to or interact with known RAG transcripts. Ultimately, it is hoped that some of the newly identified axodegeneration-reactive transcripts could be exploited as axoprotective therapies in PD and other neurodegenerative diseases. PMID:25992874

  17. 6-Hydroxydopamine lesions of rat substantia nigra up-regulate dopamine-induced phosphorylation of the cAMP-response element-binding protein in striatal neurons.

    PubMed Central

    Cole, D G; Kobierski, L A; Konradi, C; Hyman, S E

    1994-01-01

    Destruction of the substantia nigra produces striatal D1 dopamine receptor supersensitivity without increasing receptor number or affinity, thus implicating postreceptor mechanisms. The nature of these mechanisms is unknown. Increased striatal c-fos expression ipsilateral to a unilateral lesion of the substantia nigra in rats treated with appropriate dopamine agonists provides a cellular marker of D1 receptor supersensitivity. D1 receptors are positively linked to adenylate cyclase and therefore to cAMP-dependent protein kinase. Because expression of the c-fos gene in response to cAMP- and Ca2+/calmodulin-regulated protein kinases depends on phosphorylation of cAMP-response element-binding protein (CREB) at Ser-133, we examined CREB phosphorylation after dopaminergic stimulation in cultured striatal neurons and in the striatum of rats after unilateral 6-hydroxydopamine ablation of the substantia nigra. Using an antiserum specific for CREB phosphorylated at Ser-133, we found that dopamine increases CREB phosphorylation in cultured striatal neurons. This effect was blocked by a D1 antagonist. L-Dopa produced marked CREB phosphorylation in striatal neurons in rats ipsilateral, but not contralateral, to a 6-hydroxydopamine lesion. This response was blocked by a D1 antagonist, but not a D2 antagonist, and was reproduced by a D1 agonist, but not a D2 agonist. These findings are consistent with the hypothesis that D1 receptor supersensitivity is associated with upregulated activity of cAMP-dependent or Ca2+/calmodulin-dependent protein kinases, or both, following dopamine denervation of striatal neurons. Images PMID:7937819

  18. Nuclear microscopic investigations into the elemental changes in the substantia nigra of unilaterally MPTP-lesioned Parkinsonian monkeys

    NASA Astrophysics Data System (ADS)

    Thong, P. S. P.; He, Y.; Lee, T.; Watt, F.

    1997-07-01

    Various transition metals, particularly iron, have been implicated in the aetiology of the neurodegenerative disease, Parkinson's disease, in which there is a characteristic loss of cells in the substantia nigra (SN) region of the brain. In this study, monkeys were unilaterally lesioned with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP) to obtain primate models of parkinsonism, with the non-lesioned side of the brain serving as controls. The monkeys were sacrificed at one day, one week, two weeks, one month and one year after lesioning to investigate the time dependent elemental changes in the parkinsonian SN. Sections of the brain encompassing both the lesioned and non-lesioned SNs were analysed using the National University of Singapore nuclear microscope. Adjacent sections were tyrosine hydroxylase (TH) immunohistochemically stained to provide complementary information on dopaminergic cell loss and to facilitate definition of the SN boundaries during data analysis. In one-day and one-week monkeys (representing early stages of the disease), there were no changes in elemental concentrations within experimental errors and the adjacent TH-stained sections did not show apparent cell loss in the SN. At two weeks, cell loss was seen in the lesioned SN compared to the control SN. Although there was no bulk increase in SN iron, localised accumulation of iron in granules containing up to 15% by weight iron was observed in the lesioned SN of one of the two-week monkeys. An average 15% increase in nigral iron, significant at the 90% confidence level ( p < 0.1), was seen in the one-month monkeys. TH-stained sections for the one-month monkeys showed cell loss in the lesioned SN. In one-year samples (representing the advanced stage of the disease) there was a significant ( p < 0.05) 56% increase in iron, 14% increase in phosphorous and a 20% decrease in copper. Here an almost complete loss of cells in the lesioned SN was apparent from the adjacent TH

  19. Intranasal insulin protects against substantia nigra dopaminergic neuronal loss and alleviates motor deficits induced by 6-OHDA in rats.

    PubMed

    Pang, Y; Lin, S; Wright, C; Shen, J; Carter, K; Bhatt, A; Fan, L-W

    2016-03-24

    Protection of substantia nigra (SN) dopaminergic (DA) neurons by neurotrophic factors (NTFs) is one of the promising strategies in Parkinson's disease (PD) therapy. A major clinical challenge for NTF-based therapy is that NTFs need to be delivered into the brain via invasive means, which often shows limited delivery efficiency. The nose to brain pathway is a non-invasive brain drug delivery approach developed in recent years. Of particular interest is the finding that intranasal insulin improves cognitive functions in Alzheimer's patients. In vitro, insulin has been shown to protect neurons against various insults. Therefore, the current study was designed to test whether intranasal insulin could afford neuroprotection in the 6-hydroxydopamine (6-OHDA)-based rat PD model. 6-OHDA was injected into the right side of striatum to induce a progressive DA neuronal lesion in the ipsilateral SN pars compact (SNc). Recombinant human insulin was applied intranasally to rats starting from 24h post lesion, once per day, for 2 weeks. A battery of motor behavioral tests was conducted on day 8 and 15. The number of DA neurons in the SNc was estimated by stereological counting. Our results showed that 6-OHDA injection led to significant motor deficits and 53% of DA neuron loss in the ipsilateral side of injection. Treatment with insulin significantly ameliorated 6-OHDA-induced motor impairments, as shown by improved locomotor activity, tapered/ledged beam-walking performance, vibrissa-elicited forelimb-placing, initial steps, as well as methamphetamine-induced rotational behavior. Consistent with behavioral improvements, insulin treatment provided a potent protection of DA neurons in the SNc against 6-OHDA neurotoxicity, as shown by a 74.8% increase in tyrosine hydroxylase (TH)-positive neurons compared to the vehicle group. Intranasal insulin treatment did not affect body weight and blood glucose levels. In conclusion, our study showed that intranasal insulin provided strong

  20. Functional glycine receptor maturation in the absence of glycinergic input in dopaminergic neurones of the rat substantia nigra

    PubMed Central

    Mangin, J M; Guyon, A; Eugène, D; Paupardin-Tritsch, D; Legendre, P

    2002-01-01

    The postnatal maturation pattern of glycine receptor channels (GlyRs) expressed by dopaminergic (DA) neurones of the rat substantia nigra pars compacta (SNc) was investigated using single-channel and whole-cell patch-clamp recordings in brain slices from rats aged 7–21 postnatal days (P). In neonatal rats (P7-P10), GlyRs exhibited a main conductance state of 100–110 pS with a mean open time of 16 ms. In juvenile rats (P19-P22), both the GlyR main conductance state (46-55 pS) and the mean open time (6.8 ms) were decreased. In neonatal rats, application of 30 μm picrotoxin, which is known to block homomeric GlyRs, strongly reduced glycine-evoked responses, while it was much less effective in juvenile rats. These results suggest that these GlyRs correspond functionally to α2 homomeric GlyRs in neonatal rats and α1/β heteromeric GlyRs in juvenile rats. A drastic but transient decrease in the glycine responsiveness of DA neurones occurred around P17 concomitant to the functional switch from the homomeric state to the heteromeric state. This age corresponds to a maturation phase for DA neurones. The application of 1 μm gabazine blocked spontaneous or evoked inhibitory synaptic current, while the addition of 1 μm strychnine had no effect, suggesting a lack of functional glycinergic synapses on DA neurones. Although it has been proposed that taurine is co-released with GABA at GABAergic synapses on DA neurones, in the present study the stimulation of GABAergic fibres failed to activate GlyRs. Blockade of taurine transporters and applications of high K+ and hyposmotic solutions were also unable to induce any strychnine-sensitive current. We conclude that functional maturation of GlyRs can occur in the absence of any detectable GlyR activation in DA neurones of the SNc. PMID:12154171

  1. Effect of exercise on hyperactivity, impulsivity and dopamine D2 receptor expression in the substantia nigra and striatum of spontaneous hypertensive rats

    PubMed Central

    Cho, Han Sam; Baek, Dae Jung; Baek, Seung Soo

    2014-01-01

    [Purpose] Attention-deficit/hyperactivity disorder (ADHD) is a heritable, chronic, neurobehavioral disorder that is characterized by hyperactivity, inattention, and impulsivity. It is commonly believed that the symptoms of ADHD are closely associated with hypo-function of the dopamine system. Dopamine D2 receptor activation decreases the excitability of dopamine neurons, as well as the release of dopamine. Physical exercise is known to improve structural and functional impairments in neuropsychiatric disorders. We investigated the therapeutic effect of exercise on ADHD. [Methods] Open field task and elevated-plus maze task were used in the evaluation of hyperactivity and impulsivity, respectively. Dopamine D2 receptor expression in the substantia nigra and striatum were evaluated by western blotting. [Results] The present results indicated that ADHD rats showed hyperactivity and impulsivity. Dopamine D2 receptor expression in the substantia nigra and striatum were increased in ADHD rats. Exercise alleviated hyperactivity and impulsivity in ADHD rats. Furthermore, dopamine D2 receptor expression in ADHD rats was also decreased by exercise. [Conclusion] We thus showed that exercise effectively alleviates ADHD-induced symptoms through enhancing dopamine D2 expression in the brain. PMID:25671205

  2. Cell type analysis of functional fetal dopamine cell suspension transplants in the striatum and substantia nigra of patients with Parkinson's disease.

    PubMed

    Mendez, Ivar; Sanchez-Pernaute, Rosario; Cooper, Oliver; Viñuela, Angel; Ferrari, Daniela; Björklund, Lars; Dagher, Alain; Isacson, Ole

    2005-07-01

    We report the first post-mortem analysis of two patients with Parkinson's disease who received fetal midbrain transplants as a cell suspension in the striatum, and in one case also in the substantia nigra. These patients had a favourable clinical evolution and positive 18F-fluorodopa PET scans and did not develop motor complications. The surviving transplanted dopamine neurons were positively identified with phenotypic markers of normal control human substantia nigra (n = 3), such as tyrosine hydroxylase, G-protein-coupled inward rectifying current potassium channel type 2 (Girk2) and calbindin. The grafts restored the cell type that provides specific dopaminergic innervation to the most affected striatal regions in the parkinsonian brain. Such transplants were able to densely reinnervate the host putamen with new dopamine fibres. The patients received only 6 months of standard immune suppression, yet by post-mortem analysis 3-4 years after surgery the transplants appeared only mildly immunogenic to the host brain, by analysis of microglial CD45 and CD68 markers. This study demonstrates that, using these methods, dopamine neuronal replacement cell therapy can be beneficial for patients with advanced disease, and that changing technical approaches could have a favourable impact on efficacy and adverse events following neural transplantation. PMID:15872020

  3. A cytoarchitectonic and TH-immunohistochemistry characterization of the dopamine cell groups in the substantia nigra, ventral tegmental area and retrorubral field in the rock cavy (Kerodon rupestris).

    PubMed

    Cavalcanti, José R L P; Soares, Joacil G; Oliveira, Francisco G; Guzen, Fausto P; Pontes, André L B; Sousa, Twyla B; Cavalcante, Jeferson S; Nascimento, Expedito S; Cavalcante, Judney C; Costa, Miriam S M O

    2014-01-01

    The 3-hydroxytyramine/dopamine is a monoamine of the catecholamine group and it is a precursor of the noradrenaline and adrenaline synthesis, in which the enzyme tyrosine hydroxylase acts as a rate-limiting enzyme. The dopaminergic nuclei retrorubral field (A8 group), substantia nigra pars compacta (A9 group) and ventral tegmental area (A10 group) are involved in three complex circuitries named mesostriatal, mesocortical and mesolimbic, which are directly related to various behavioral manifestations such as motor control, reward signaling in behavioral learning, motivation and pathological manifestations of Parkinson's disease and schizophrenia. The aim of this study was to describe the delimitation of A8, A9 and A10 groups and the morphology of their neurons in the brain of the rock cavy (Kerodon rupestris), a typical Brazilian Northeast rodent belonging to the suborder Hystricomorpha, family Caviidae. Coronal and sagittal sections of the rock cavy brains were submitted to Nissl staining and TH immunohistochemistry. The organization of these dopaminergic nuclei in the rock cavy brain is very similar to that found in other animals of the Rodentia order, except for the presence of the tail of the substantia nigra, which is found only in the species under study. The results revealed that, apart some morphological variations, A8, A9 and A10 groups are phylogenetically stable brain structures. PMID:24444614

  4. The role of alpha-synuclein in the development of the dopaminergic neurons in the substantia nigra and ventral tegmental area.

    PubMed

    Tarasova, T V; Lytkina, O A; Roman, A Yu; Bachurin, S O; Ustyugov, A A

    2016-01-01

    Alpha-synuclein is a presynaptic protein of vertebrates that belongs to the family of synucleins. Normal functions of synucleins remain unknown. Alpha-synuclein is one of the causative factors of the familial and idiopathic forms of Parkinson's disease (PD). The progressive loss of dopaminergic (DA) neurons is characteristic of PD and the most severe damage occurs in the substantia nigra (SN). This leads to an erraticism of the synthesis and synaptic secretion of the neurotransmitters, subsequently resulting in the loss of the connections between brain areas. This work shows that alpha-synuclein is directly involved in the formation of the mature DA neurons of the midbrain at different stages of the ontogenesis and these findings are consistent with data obtained in other studies. Thus, alpha-synuclein may have a varying modulating effect on the growth dynamics and the fate of populations of DA neurons. PMID:27021360

  5. Calcium-activated non-selective cation currents are involved in generation of tonic and bursting activity in dopamine neurons of the substantia nigra pars compacta.

    PubMed

    Mrejeru, Ana; Wei, Aguan; Ramirez, Jan Marino

    2011-05-15

    Nigral dopamine neurons are transiently activated by high frequency glutamatergic inputs relaying reward-predicting sensory information. The tonic firing pattern of dopamine cells responds to these inputs with a transient burst of spikes that requires NMDA receptors. Here, we show that NMDA receptor activation further excites the cell by recruiting a calcium-activated non-selective cation current (ICAN) capable of generating a plateau potential. Burst firing in vitro is eliminated after blockade of ICAN with flufenamic acid, 9-phenanthrol, or intracellular BAPTA. ICAN is likely to be mediated by a transient receptor potential (TRP) channel, and RT-PCR was used to confirm expression of TRPM2 and TRPM4mRNA in substantia nigra pars compacta.We propose that ICAN is selectively activated during burst firing to boost NMDA currents and allow plateau potentials. This boost mechanism may render DA cells vulnerable to excitotoxicity. PMID:21486760

  6. Molecular and functional differences in voltage-activated sodium currents between GABA projection neurons and dopamine neurons in the substantia nigra.

    PubMed

    Ding, Shengyuan; Wei, Wei; Zhou, Fu-Ming

    2011-12-01

    GABA projection neurons (GABA neurons) in the substantia nigra pars reticulata (SNr) and dopamine projection neurons (DA neurons) in substantia nigra pars compacta (SNc) have strikingly different firing properties. SNc DA neurons fire low-frequency, long-duration spikes, whereas SNr GABA neurons fire high-frequency, short-duration spikes. Since voltage-activated sodium (Na(V)) channels are critical to spike generation, the different firing properties raise the possibility that, compared with DA neurons, Na(V) channels in SNr GABA neurons have higher density, faster kinetics, and less cumulative inactivation. Our quantitative RT-PCR analysis on immunohistochemically identified nigral neurons indicated that mRNAs for pore-forming Na(V)1.1 and Na(V)1.6 subunits and regulatory Na(V)β1 and Na(v)β4 subunits are more abundant in SNr GABA neurons than SNc DA neurons. These α-subunits and β-subunits are key subunits for forming Na(V) channels conducting the transient Na(V) current (I(NaT)), persistent Na current (I(NaP)), and resurgent Na current (I(NaR)). Nucleated patch-clamp recordings showed that I(NaT) had a higher density, a steeper voltage-dependent activation, and a faster deactivation in SNr GABA neurons than in SNc DA neurons. I(NaT) also recovered more quickly from inactivation and had less cumulative inactivation in SNr GABA neurons than in SNc DA neurons. Furthermore, compared with nigral DA neurons, SNr GABA neurons had a larger I(NaR) and I(NaP). Blockade of I(NaP) induced a larger hyperpolarization in SNr GABA neurons than in SNc DA neurons. Taken together, these results indicate that Na(V) channels expressed in fast-spiking SNr GABA neurons and slow-spiking SNc DA neurons are tailored to support their different spiking capabilities. PMID:21880943

  7. LC/MS analysis of cardiolipins in substantia nigra and plasma of rotenone-treated rats: implication for mitochondrial dysfunction in Parkinson's disease

    PubMed Central

    Tyurina, Yulia Y.; Polimova, Anastasia M.; Maciel, Elisabete; Tyurin, Vladimir A.; Kapralova, Valentina I.; Winnica, Daniel E.; Vikulina, Anna S.; Domingues, Rosario M.; McCoy, Jennifer; Sanders, Laurie H.; Bayır, Hülya; Greenamyre, J. Timothy; Kagan, Valerian E.

    2015-01-01

    Exposure to rotenone in vivo results in selective degeneration of dopaminergic neurons and development of neuropathological features of Parkinson's disease. As rotenone acts as an inhibitor of mitochondrial respiratory complex I, we employed oxidative lipidomics to assess oxidative metabolism of a mitochondria-specific phospholipid, cardiolipin, in substantia nigra of exposed animals. We found a significant reduction of oxidizable PUFA-containing cardiolipin molecular species. We further revealed increased contents of mono-oxygenated cardiolipin species at late stages of the exposure. Notably, linoleic acid in sn-1 position was the major oxidation substrate yielding its mono-hydroxy- and epoxy-derivatives whereas more readily “oxidizable” fatty acid residues (arachidonic, docosahexaenoic acids) – remained non-oxidized. Elevated levels of PUFA cardiolipins were detected in plasma of rats exposed to rotenone. Characterization of oxidatively modified cardiolipin molecular species in substantia nirga and detection of PUFA-containing cardiolipin species in plasma may contribute to better understanding of the Parkinson's disease pathogenesis and lead to the development of new biomarkers of mitochondrial dysfunction associated with this disease. PMID:25740198

  8. Glucocorticoid receptor is involved in the neuroprotective effect of ginsenoside Rg1 against inflammation-induced dopaminergic neuronal degeneration in substantia nigra.

    PubMed

    Sun, Xian-Chang; Ren, Xiao-Fan; Chen, Lei; Gao, Xian-Qi; Xie, Jun-Xia; Chen, Wen-Fang

    2016-01-01

    Accumulating clinical and experimental evidence suggests that chronic neuroinflammation is associated with dopaminergic neuronal death in Parkinson's disease (PD). Ginsenoside Rg1, the most active components of ginseng, possesses a variety of biological effects on the central nervous system, cardiovascular system and immune system. The present study aimed to evaluate the protective effects of ginsenoside Rg1 on lipopolysaccharide (LPS)-induced microglia activation and dopaminergic neuronal degeneration in rat substantia nigra (SN) and its potential mechanisms. Treatment with Rg1 could ameliorate the apomorphine-induced rotational behavior in LPS-lesioned rats. GR antagonist RU486 partly abolished the protective effect of Rg1. Rg1 treatment significantly attenuated LPS-induced loss of tyrosin hydroxlase (TH) positive neurons in substantial nigra par compacta (SNpc) and decreased content of dopamine (DA) and its metabolites in striatum of the lesioned side. Meanwhile, Rg1 significantly inhibited LPS-induced microglial activation and production of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β) and nitric oxide (NO). These effects were abolished by co-treatment with RU486. In addition, Rg1 treatment significantly inhibited the LPS-induced phosphorylation of IκB, extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal protein kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) in the lesioned side of substantial nigra. These effect could be also partly blocked by RU486. Taken together, these data indicate that Rg1 has protective effects on mesencephalic dopaminergic neurons from LPS-induced microglia inflammation. GR signaling pathway might be involved in the anti-inflammatory effect of Rg1. PMID:26455404

  9. Impact of aging on heat shock protein expression in the substantia nigra and striatum of the female rat.

    PubMed

    Gleixner, A M; Pulugulla, S H; Pant, D B; Posimo, J M; Crum, T S; Leak, R K

    2014-07-01

    Many heat shock proteins are chaperones that help refold or degrade misfolded proteins and battle apoptosis. Because of their capacity to protect against protein misfolding, they may help keep diseases of aging at bay. A few reports have examined heat shock proteins (eg. Hsp25, Hsp60, Hsp70, and heat shock cognate 70 or Hsc70) as a function of age in the striatum and nigra. In the present study, we examined the impact of aging on Hsp25, heme oxygenase 1 (HO1 or Hsp32), Hsp40, Hsp60, Hsc70, Hsc/Hsp70 interacting protein (Hip), 78 kDa glucose-regulated protein (GRP78), Hsp90, and ubiquitinated proteins in the nigra and striatum of the female rat by infrared immunoblotting. Female animals are not typically examined in aging studies, adding further to the novelty of our study. Striatal HO1 and Hsp40 were both higher in middle-aged females than in the oldest group. Hsp60 levels were also highest in middle age in the nigra, but were highest in the oldest animals in the striatum. Striatal levels of Hsc70 and the co-chaperone Hip were lower in the oldest group relative to the youngest animals. In contrast, Hsp25 rose with advancing age in both regions. Hsp25 was also colocalized with tyrosine hydroxylase in nigral neurons. Ubiquitinated proteins exhibited a trend to rise in the oldest animals in both regions, and K48 linkage-specific ubiquitin rose significantly from 4-6 to 16-19 months in the striatum. Our study reveals a complex array of age-related changes in heat shock proteins. Furthermore, the age-related rises in some proteins, such as Hsp25, may reflect endogenous adaptations to cellular stress. PMID:24723229

  10. Elemental mapping of Neuromelanin organelles of human Substantia Nigra: correlative ultrastructural and chemical analysis by analytical transmission electron microscopy and nano-secondary ion mass spectrometry.

    PubMed

    Biesemeier, Antje; Eibl, Oliver; Eswara, Santhana; Audinot, Jean-Nicolas; Wirtz, Tom; Pezzoli, Gianni; Zucca, Fabio A; Zecca, Luigi; Schraermeyer, Ulrich

    2016-07-01

    Neuromelanin (NM) is a compound which highly accumulates mainly in catecholamine neurons of the substantia nigra (SN), and is contained in organelles (NM-containing organelles) with lipid bodies and proteins. These neurons selectively degenerate in Parkinson's disease and NM can play either a protective or toxic role. NM-containing organelles of SN were investigated by Analytical Electron Microscopy (AEM) and Nano-Secondary Ion Mass Spectrometry (NanoSIMS) within human tissue sections with respect to ultrastructure and elemental composition. Within the NM-containing organelle, the single NM granules and lipid bodies had sizes of about 200-600 nm. Energy-Dispersive X-ray microanalysis spectra of the NM granules and lipid bodies were acquired with 100 nm beam diameter in AEM, NanoSIMS yielded elemental maps with a lateral resolution of about 150 nm. AEM yielded the quantitative elemental composition of NM granules and bound metals, e.g., iron with a mole fraction of about 0.15 atomic percent. Chemical analyses by AEM and NanoSIMS were consistent at the subcellular level so that nanoSIMS measurements have been quantitated. In NM granules of SN from healthy subjects, a significant amount of S, Fe, and Cu was found. In lipid bodies an amount of P consistent with the presence of phospholipids was measured. The improved detection limits of nanoSIMS offer new possibilities for chemical mapping, high-sensitivity trace element detection, and reduced acquisition times. Variations between individual NM granules can now be investigated effectively and quantitatively by NanoSIMS mapping Cu and Fe. This should yield new insight into the changes in chemical composition of NM pigments during healthy aging and disease. Neuromelanin-containing organelles of dopamine neurons in normal human substantia nigra were investigated by analytical electron mircoscopy and secondary ion mass spectroscopy (NanoSIMS) yielding the ultrastructure and elemental composition. In neuromelanin

  11. In Vivo Electrochemical Evidence for Simultaneous 5-HT and Histamine Release in the Rat Substantia Nigra pars Reticulata Following Medial Forebrain Bundle Stimulation

    PubMed Central

    Hashemi, Parastoo; Dankoski, Elyse C.; Wood, Kevin M.; Ambrose, R. Ellen; Wightman, R. Mark

    2011-01-01

    Exploring the mechanisms of serotonin (5-hydoxytryptophan (5-HT)) in the brain requires an in vivo method that combines fast temporal resolution with chemical selectivity. Fast-scan cyclic voltammetry (FSCV) is a technique with sufficient temporal and chemical resolution for probing dynamic 5-HT neurotransmission events; however, traditionally it has not been possible to probe in vivo 5-HT mechanisms. Recently, we optimized FSCV for measuring 5-HT release and uptake in vivo in the substantia nigra pars reticulata (SNR) with electrical stimulation of the dorsal raphe nucleus (DRN) in the rat brain. Here, we address technical challenges associated with rat DRN surgery by electrically stimulating 5-HT projections in the medial forebrain bundle (MFB), a more accessible anatomical location. MFB stimulation elicits 5-HT in the SNR; furthermore, we find simultaneous release of an additional species. We use electrochemical and pharmacological methods and describe physiological, anatomical and independent chemical analyses to identify this species as histamine. We also show pharmacologically that increasing the lifetime of extracellular histamine significantly decreases 5-HT release, most likely due to increased activation of histamine H-3 receptors that inhibit 5-HT release. Despite this, under physiological conditions, we find by kinetic comparisons of DRN and MFB stimulations that the simultaneous release of histamine does not interfere with the quantitative 5-HT concentration profile. We therefore present a novel and robust electrical stimulation of the MFB that is technically less challenging than DRN stimulation to study 5-HT and histamine release in the SNR. PMID:21682723

  12. Dietary administration of diquat for 13 weeks does not result in a loss of dopaminergic neurons in the substantia nigra of C57BL/6J mice.

    PubMed

    Minnema, Daniel J; Travis, Kim Z; Breckenridge, Charles B; Sturgess, Nicholas C; Butt, Mark; Wolf, Jeffrey C; Zadory, Dan; Herberth, Mark T; Watson, Scott L; Cook, Andrew R; Botham, Philip A

    2016-03-01

    Male and female C57BL/6J mice were administered diquat dibromide (DQ∙Br2) in their diets at concentrations of 0 (control), 12.5 and 62.5 ppm for 13 weeks to assess the potential effects of DQ on the nigrostriatal dopaminergic system. Achieved dose levels at 62.5 ppm were 6.4 and 7.6 mg DQ (ion)/kg bw/day for males and females, respectively. A separate group of mice was administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) ip as a positive control. The comparative effects of DQ and MPTP on the substantia nigra pars compacta (SNpc) and/or striatum were assessed using neurochemical, neuropathological and stereological endpoints. Morphological and stereological assessments were performed by investigators who were "blinded" to dose group. DQ had no effect on striatal dopamine concentration or dopamine turnover. There was no evidence of neuronal degeneration, astrocytic or microglial activation, or a reduction in the number of tyrosine hydroxylase positive (TH(+)) neurons in the SNpc or neuronal processes in the striatum of DQ-treated mice. These results are consistent with the rapid clearance of DQ from the brain following a single dose of radiolabeled DQ. In contrast, MPTP-treated mice exhibited decreased striatal dopamine concentration, reduced numbers of TH(+) neurons in the SNpc, and neuropathological changes, including neuronal necrosis, as well as astrocytic and microglial activation in the striatum and SNpc. PMID:26683030

  13. Resting-State Functional Connectivity of the Locus Coeruleus in Humans: In Comparison with the Ventral Tegmental Area/Substantia Nigra Pars Compacta and the Effects of Age.

    PubMed

    Zhang, Sheng; Hu, Sien; Chao, Herta H; Li, Chiang-Shan R

    2016-08-01

    The locus coeruleus (LC) provides the primary noradrenergic inputs to the cerebral cortex. Despite numerous animal studies documenting the functions of the LC, research in humans is hampered by the small volume of this midbrain nucleus. Here, we took advantage of a probabilistic template, explored the cerebral functional connectivity of the LC with resting-state fMRI data of 250 healthy adults, and verified the findings by accounting for physiological noise in another data set. In addition, we contrasted connectivities of the LC and the ventral tegmental area/substantia nigra pars compacta. The results highlighted both shared and distinct connectivity of these 2 midbrain structures, as well as an opposite pattern of connectivity to bilateral amygdala, pulvinar, and right anterior insula. Additionally, LC connectivity to the fronto-parietal cortex and the cerebellum increases with age and connectivity to the visual cortex decreases with age. These findings may facilitate studies of the role of the LC in arousal, saliency responses and cognitive motor control and in the behavioral and cognitive manifestations during healthy and disordered aging. Although the first to demonstrate whole-brain LC connectivity, these findings need to be confirmed with high-resolution imaging. PMID:26223261

  14. Abnormal Echogenicity of the Substantia Nigra, Raphe Nuclei, and Third-Ventricle Width as Markers of Cognitive Impairment in Parkinsonian Disorders: A Cross-Sectional Study

    PubMed Central

    Bouwmans, Angela E. P.; Leentjens, Albert F. G.; Mess, Werner H.; Weber, Wim E. J.

    2016-01-01

    Background. Patients with Parkinson's disease (PD) have a high risk of cognitive problems. Objective. This study assesses whether abnormal echogenicity of the substantia nigra (SN) and raphe nuclei (RN) and the diameter of third ventricle are markers of cognitive impairment in patients with PD and other forms of parkinsonism. Methods. 126 outpatients with early signs of parkinsonism underwent transcranial sonography (TCS). The scales for the outcome of Parkinson's disease cognition (SCOPA-COG) were used as cognitive measure. Definite neurological diagnosis was established after two-year follow-up. Results. One-third of the patients with PD and half of those with APS had signs of cognitive impairment. The echogenicity of the SN was not related to cognitive impairment. The diameter of the third ventricle was significantly larger in PD patients with cognitive impairment compared to those without. In patients with APS we found a significantly higher frequency of hypoechogenic RN in patients with cognitive problems. Conclusions. Cognitive impairment is already present in a substantial proportion of patients with PD and APS at first referral. In patients with APS the frequency of hypoechogenic RN points to the direction of other pathophysiology with more emphasis on deficits in the serotonergic neurotransmitter system. The larger diameter of the third ventricle in PD patients with cognitive impairment may reflect Alzheimer like brain atrophy, as has been reported in earlier studies. PMID:26881179

  15. The absolute number of nerve cells in substantia nigra in normal subjects and in patients with Parkinson's disease estimated with an unbiased stereological method.

    PubMed Central

    Pakkenberg, B; Møller, A; Gundersen, H J; Mouritzen Dam, A; Pakkenberg, H

    1991-01-01

    Using an unbiased stereological technique, the total numbers of pigmented and non-pigmented neurons were estimated in the substantia nigra of seven patients with Parkinson's disease and seven control patients. Compared with the controls, in which the average total number of pigmented neurons was 550,000, the number of neurons was reduced by 66% in the patients. The average total number of non-pigmented neurons was 260,000 in controls and reduced by 24% in the patients. A significant correlation (r = 0.81) existed between the total numbers of pigmented and non-pigmented neurons in the controls, whereas a similar correlation (r = 0.72) in the patients fell just short of statistical significance. The stereological estimates made in this study are unbiased, in that they are independent of nerve cell size, section thickness and of dimensional changes in brain tissue induced by histological procedures. The stereological method is considerably more efficient than previous conventional methods. PMID:2010756

  16. Neuroprotection by Exendin-4 Is GLP-1 Receptor Specific but DA D3 Receptor Dependent, Causing Altered BrdU Incorporation in Subventricular Zone and Substantia Nigra.

    PubMed

    Harkavyi, A; Rampersaud, N; Whitton, P S

    2013-01-01

    Glucagon-like peptide-1 receptor (GLP-1R) activation by exendin-4 (EX-4) is effective in preclinical models of Parkinson's disease (PD) and appears to promote neurogenesis even in severely lesioned rats. In the present study, we determined the effects of EX-4 on cellular BrdU incorporation in the rat subventricular zone (SVZ) and substantia nigra (SN). We also determined the specificity of this effect with the GLP-1R antagonist EX-(9-39) as well as the potential role of dopamine (DA) D3 receptors. Rats were administered 6-OHDA and 1 week later given EX-4 alone, with EX-(9-39) or nafadotride (D3 antagonist) and BrdU. Seven days later, rats were challenged with apomorphine to evaluate circling. Extracellular DA was measured using striatal microdialysis and subsequently tissue DA measured. Tyrosine hydroxylase and BrdU were verified using immunohistochemistry. Apomorphine circling was reversed by EX-4 in lesioned rats, an effect reduced by EX-4, while both EX-(9-39) and NAF attenuated this. 6-OHDA decreased extracellular and tissue DA, both reversed by EX-4 but again attenuated by EX-(9-39) or NAF. Analysis of BrdU+ cells in the SVZ revealed increases in 6-OHDA-treated rats which were reversed by EX-4 and antagonised by either EX-(9-39) or NAF, while in the SN the opposite profile was seen. PMID:26316987

  17. Neuroprotection by Exendin-4 Is GLP-1 Receptor Specific but DA D3 Receptor Dependent, Causing Altered BrdU Incorporation in Subventricular Zone and Substantia Nigra

    PubMed Central

    Harkavyi, A.; Rampersaud, N.; Whitton, P. S.

    2013-01-01

    Glucagon-like peptide-1 receptor (GLP-1R) activation by exendin-4 (EX-4) is effective in preclinical models of Parkinson's disease (PD) and appears to promote neurogenesis even in severely lesioned rats. In the present study, we determined the effects of EX-4 on cellular BrdU incorporation in the rat subventricular zone (SVZ) and substantia nigra (SN). We also determined the specificity of this effect with the GLP-1R antagonist EX-(9-39) as well as the potential role of dopamine (DA) D3 receptors. Rats were administered 6-OHDA and 1 week later given EX-4 alone, with EX-(9-39) or nafadotride (D3 antagonist) and BrdU. Seven days later, rats were challenged with apomorphine to evaluate circling. Extracellular DA was measured using striatal microdialysis and subsequently tissue DA measured. Tyrosine hydroxylase and BrdU were verified using immunohistochemistry. Apomorphine circling was reversed by EX-4 in lesioned rats, an effect reduced by EX-4, while both EX-(9-39) and NAF attenuated this. 6-OHDA decreased extracellular and tissue DA, both reversed by EX-4 but again attenuated by EX-(9-39) or NAF. Analysis of BrdU+ cells in the SVZ revealed increases in 6-OHDA-treated rats which were reversed by EX-4 and antagonised by either EX-(9-39) or NAF, while in the SN the opposite profile was seen. PMID:26316987

  18. Meta-Analysis of Parkinson's Disease Transcriptome Data Using TRAM Software: Whole Substantia Nigra Tissue and Single Dopamine Neuron Differential Gene Expression.

    PubMed

    Mariani, Elisa; Frabetti, Flavia; Tarozzi, Andrea; Pelleri, Maria Chiara; Pizzetti, Fabrizio; Casadei, Raffaella

    2016-01-01

    The understanding of the genetic basis of the Parkinson's disease (PD) and the correlation between genotype and phenotype has revolutionized our knowledge about the pathogenetic mechanisms of neurodegeneration, opening up exciting new therapeutic and neuroprotective perspectives. Genomic knowledge of PD is still in its early stages and can provide a good start for studies of the molecular mechanisms that underlie the gene expression variations and the epigenetic mechanisms that may contribute to the complex and characteristic phenotype of PD. In this study we used the software TRAM (Transcriptome Mapper) to analyse publicly available microarray data of a total of 151 PD patients and 130 healthy controls substantia nigra (SN) samples, to identify chromosomal segments and gene loci differential expression. In particular, we separately analyzed PD patients and controls data from post-mortem snap-frozen SN whole tissue and from laser microdissected midbrain dopamine (DA) neurons, to better characterize the specific DA neuronal expression profile associated with the late-stage Parkinson's condition. The default "Map" mode analysis resulted in 10 significantly over/under-expressed segments, mapping on 8 different chromosomes for SN whole tissue and in 4 segments mapping on 4 different chromosomes for DA neurons. In conclusion, TRAM software allowed us to confirm the deregulation of some genomic regions and loci involved in key molecular pathways related to neurodegeneration, as well as to provide new insights about genes and non-coding RNA transcripts not yet associated with the disease. PMID:27611585

  19. A Comparison of Substantia Nigra T1 Hyperintensity in Parkinson's Disease Dementia, Alzheimer's Disease and Age-Matched Controls: Volumetric Analysis of Neuromelanin Imaging

    PubMed Central

    Park, Ju-Yeon; Yun, Won-Sung; Jeon, Ji Yeong; Moon, Yeon Sil; Kim, Heejin; Kwak, Ki-Chang; Lee, Jong-Min; Han, Seol-Heui

    2016-01-01

    Objective Neuromelanin loss of substantia nigra (SN) can be visualized as a T1 signal reduction on T1-weighted high-resolution imaging. We investigated whether volumetric analysis of T1 hyperintensity for SN could be used to differentiate between Parkinson's disease dementia (PDD), Alzheimer's disease (AD) and age-matched controls. Materials and Methods This retrospective study enrolled 10 patients with PDD, 18 patients with AD, and 13 age-matched healthy elderly controls. MR imaging was performed at 3 tesla. To measure the T1 hyperintense area of SN, we obtained an axial thin section high-resolution T1-weighted fast spin echo sequence. The volumes of interest for the T1 hyperintense SN were drawn onto heavily T1-weighted FSE sequences through midbrain level, using the MIPAV software. The measurement differences were tested using the Kruskal-Wallis test followed by a post hoc comparison. Results A comparison of the three groups showed significant differences in terms of volume of T1 hyperintensity (p < 0.001, Bonferroni corrected). The volume of T1 hyperintensity was significantly lower in PDD than in AD and normal controls (p < 0.005, Bonferroni corrected). However, the volume of T1 hyperintensity was not different between AD and normal controls (p = 0.136, Bonferroni corrected). Conclusion The volumetric measurement of the T1 hyperintensity of SN can be an imaging marker for evaluating neuromelanin loss in neurodegenerative diseases and a differential in PDD and AD cases. PMID:27587951

  20. Diagnostic Accuracy of Transcranial Sonography of the Substantia Nigra in Parkinson’s disease: A Systematic Review and Meta-analysis

    PubMed Central

    Li, Dun-Hui; He, Ya-Chao; Liu, Jun; Chen, Sheng-Di

    2016-01-01

    A large number of articles have reported substantia nigra hyperechogenicity in Parkinson’s disease (PD) and have assessed the diagnostic accuracy of transcranial sonography (TCS); however, the conclusions are discrepant. Consequently, this systematic review and meta-analysis aims to consolidate the available observational studies and provide a comprehensive evaluation of the clinical utility of TCS in PD. Totally, 31 studies containing 4,386 participants from 13 countries were included. A random effects model was utilized to pool the effect sizes. Meta-regression and sensitivity analysis were performed to explore potential heterogeneity. Overall diagnostic accuracy of TCS in differentiating PD from normal controls was quite high, with a pooled sensitivity of 0.83 (95% CI: 0.81–0.85) and a pooled specificity of 0.87 (95% CI: 0.85–0.88). The positive likelihood ratio, the negative likelihood ratio and diagnostic odds ratio were calculated 6.94 (95% CI: 5.09–9.48), 0.19 (95% CI: 0.16–0.23), and 42.89 (95% CI: 30.03–61.25) respectively. Our systematic review of the literature and meta-analysis suggest that TCS has high diagnostic accuracy in the diagnosis of PD when compared to healthy control. PMID:26878893

  1. Control of the subthalamic innervation of substantia nigra pars reticulata by D1 and D2 dopamine receptors.

    PubMed

    Ibañez-Sandoval, Osvaldo; Hernández, Adán; Florán, Benjamin; Galarraga, Elvira; Tapia, Dagoberto; Valdiosera, Rene; Erlij, David; Aceves, Jorge; Bargas, José

    2006-03-01

    The effects of activating dopaminergic D1 and D2 class receptors of the subthalamic projections that innervate the pars reticulata of the subtantia nigra (SNr) were explored in slices of the rat brain using the whole cell patch-clamp technique. Excitatory postsynaptic currents (EPSCs) that could be blocked by 6-cyano-7-nitroquinoxalene-2,3-dione and D-(-)-2-amino-5-phosphonopentanoic acid were evoked onto reticulata GABAergic projection neurons by local field stimulation inside the subthalamic nucleus in the presence of bicuculline. Bath application of (RS)-2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine hydrochloride (SKF-38393), a dopaminergic D1-class receptor agonist, increased evoked EPSCs by approximately 30% whereas the D2-class receptor agonist, trans-(-)-4aR-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo(3,4-g)quinoline (quinpirole), reduced EPSCs by approximately 25%. These apparently opposing actions were blocked by the specific D1- and D2-class receptor antagonists: R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetra-hydro-1H-3-benzazepinehydrochloride (SCH 23390) and S-(-)-5-amino-sulfonyl-N-[(1-ethyl-2-pyrrolidinyl)-methyl]-2-methoxybenzamide (sulpiride), respectively. Both effects were accompanied by changes in the paired-pulse ratio, indicative of a presynaptic site of action. The presynaptic location of dopamine receptors at the subthalamonigral projections was confirmed by mean-variance analysis. The effects of both SKF-38393 and quinpirole could be observed on terminals contacting the same postsynaptic neuron. Sulpiride and SCH 23390 enhanced and reduced the evoked EPSC, respectively, suggesting a constitutive receptor activation probably arising from endogenous dopamine. These data suggest that dopamine presynaptically modulates the subthalamic projection that targets GABAergic neurons of the SNr. Implications of this modulation for basal ganglia function are discussed. PMID:16306171

  2. Differential neuroprotective and anti-inflammatory effects of L-type voltage dependent calcium channel and ryanodine receptor antagonists in the substantia nigra and locus coeruleus.

    PubMed

    Hopp, Sarah C; Royer, Sarah E; D'Angelo, Heather M; Kaercher, Roxanne M; Fisher, David A; Wenk, Gary L

    2015-03-01

    Neuroinflammation and degeneration of catecholaminergic brainstem nuclei occur early in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Neuroinflammation increases levels of pro-inflammatory cytokines and reactive oxygen species which can alter neuronal calcium (Ca(+2)) homoeostasis via L-type voltage dependent calcium channels (L-VDCCs) and ryanodine receptors (RyRs). Alterations in Ca(+2) channel activity in the SN and LC can lead to disruption of normal pacemaking activity in these areas, contributing to behavioral deficits. Here, we utilized an in vivo model of chronic neuroinflammation: rats were infused intraventricularly with a continuous small dose (0.25 μg/h) of lipopolysaccharide (LPS) or artificial cerebrospinal fluid (aCSF) for 28 days. Rats were treated with either the L-VDCC antagonist nimodipine or the RyR antagonist dantrolene. LPS-infused rats had significant motor deficits in the accelerating rotarod task as well as abnormal behavioral agitation in the forced swim task and open field. Corresponding with these behavioral deficits, LPS-infused rats also had significant increases in microglia activation and loss of tyrosine hydroxylase (TH) immunoreactivity in the substantia nigra pars compacta (SNpc) and locus coeruleus (LC). Treatment with nimodipine or dantrolene normalized LPS-induced abnormalities in the rotarod and forced swim, restored the number of TH-immunoreactive cells in the LC, and significantly reduced microglia activation in the SNpc. Only nimodipine significantly reduced microglia activation in the LC, and neither drug increased TH immunoreactivity in the SNpc. These findings demonstrate that the Ca(+2) dysregulation in the LC and SN brainstem nuclei is differentially altered by chronic neuroinflammation. Overall, targeting Ca + 2 dysregulation may be an important target for ameliorating neurodegeneration in the SNpc and LC. PMID:25318607

  3. In vivo detection of iron and neuromelanin by transcranial sonography--a new approach for early detection of substantia nigra damage.

    PubMed

    Berg, D

    2006-06-01

    In more than 90% of patients with idiopathic Parkinson's disease (PD) hyperechogenicity of the substantia nigra (SN) can be found by transcranial sonography (TCS) as a typical, stable sign. Animal experiments provided first evidence that SN hyperechogenicity may be associated with increased tissue iron levels. Two consecutive studies revealed the same association in human brain. Postmortem brains of 60 subjects without clinical signs for Parkinson's disease during life time at different ages were scanned by ultrasound with planimetric measurement of the echogenic area of the SN. Afterwards the SN was dissected and used for histological examination and determination of iron content in all brains as well as ferritin and neuromelanin content in 40 brains. A significant positive correlation was found between the echogenic area of the SN and the concentration of iron, H- and L-ferritins. A multivariate analysis performed considering the iron content showed a significant negative correlation between echogenicity and neuromelanin content of the SN. Iron staining confirmed the biochemical findings. In PD a typical loss of neuromelanin and increase of iron is observed in this brain area. However, it is not clear yet, whether iron accumulation is a primary cause or a secondary phenomenon in the disease process. Screening of genes involved in brain iron metabolism showed a significant association of some sequence variations of the ceruloplasmin gene with PD. Others were associated with the ultrasound marker for increased iron levels in both PD patients and control subjects. As SN hyperechogenicity is typical for PD or subjects with a preclinical impairment of the nigrostriatal system, these findings indicate that TCS enables the detection of increased iron and decreased neuromelanin levels at the SN, even before the clinical manifestation of PD. PMID:16755382

  4. Gastric dysregulation induced by microinjection of 6-OHDA in the substantia nigra pars compacta of rats is determined by alterations in the brain-gut axis

    PubMed Central

    Toti, Luca

    2014-01-01

    Idiopathic Parkinson's disease (PD) is a late-onset, chronic, and progressive motor dysfunction attributable to loss of nigrostriatal dopamine neurons. Patients with PD experience significant gastrointestinal (GI) issues, including gastroparesis. We aimed to evaluate whether 6-hydroxy-dopamine (6-OHDA)-induced degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) induces gastric dysmotility via dysfunctions of the brain-gut axis. 6-OHDA microinjection into the SNpc induced a >90% decrease in tyrosine hydroxylase-immunoreactivity (IR) on the injection site. The [13C]-octanoic acid breath test showed a delayed gastric emptying 4 wk after the 6-OHDA treatment. In control rats, microinjection of the indirect sympathomimetic, tyramine, in the dorsal vagal complex (DVC) decreased gastric tone and motility; this inhibition was prevented by the fourth ventricular application of either a combination of α1- and α2- or a combination of D1 and D2 receptor antagonists. Conversely, in 6-OHDA-treated rats, whereas DVC microinjection of tyramine had reduced effects on gastric tone or motility, DVC microinjection of thyrotropin-releasing hormone induced a similar increase in motility as in control rats. In 6-OHDA-treated rats, there was a decreased expression of choline acetyl transferase (ChAT)-IR and neuronal nitric oxide synthase (NOS)-IR in DVC neurons but an increase in dopamine-β-hydroxylase-IR in the A2 area. Within the myenteric plexus of the esophagus, stomach, and duodenum, there were no changes in the total number of neurons; however, the percentage of NOS-IR neurons increased, whereas that of ChAT-IR decreased. Our data suggest that the delayed gastric emptying in a 6-OHDA rat model of PD may be caused by neurochemical and neurophysiological alterations in the brain-gut axis. PMID:25277799

  5. Metabotropic glutamate receptor 1 mediates the electrophysiological and toxic actions of the cycad derivative beta-N-Methylamino-L-alanine on substantia nigra pars compacta DAergic neurons.

    PubMed

    Cucchiaroni, Maria Letizia; Viscomi, Maria Teresa; Bernardi, Giorgio; Molinari, Marco; Guatteo, Ezia; Mercuri, Nicola B

    2010-04-14

    Amyotrophic lateral sclerosis-Parkinson dementia complex (ALS-PDC) is a neurodegenerative disease with ALS, parkinsonism, and Alzheimer's symptoms that is prevalent in the Guam population. beta-N-Methylamino alanine (BMAA) has been proposed as the toxic agent damaging several neuronal types in ALS-PDC, including substantia nigra pars compacta dopaminergic (SNpc DAergic) neurons. BMAA is a mixed glutamate receptor agonist, but the specific pathways activated in DAergic neurons are not yet known. We combined electrophysiology, microfluorometry, and confocal microscopy analysis to monitor membrane potential/current, cytosolic calcium concentration ([Ca(2+)](i)) changes, cytochrome-c (cyt-c) immunoreactivity, and reactive oxygen species (ROS) production induced by BMAA. Rapid toxin applications caused reversible membrane depolarization/inward current and increase of firing rate and [Ca(2+)](i) in DAergic neurons. The inward current (I(BMAA)) was mainly mediated by activation of metabotropic glutamate receptor 1 (mGluR1), coupled to transient receptor potential (TRP) channels, and to a lesser extent, AMPA receptors. Indeed, mGluR1 (CPCCOEt) and TRP channels (SKF 96365; Ruthenium Red) antagonists reduced I(BMAA), and a small component of I(BMAA) was reduced by the AMPA receptor antagonist CNQX. Calcium accumulation was mediated by mGluR1 but not by AMPA receptors. Application of a low concentration of NMDA potentiated the BMAA-mediated calcium increase. Prolonged exposure to BMAA caused significant modifications of membrane properties, calcium overload, cell shrinkage, massive cyt-c release into the cytosol and ROS production. In SNpc GABAergic neurons, BMAA activated only AMPA receptors. Our study identifies the mGluR1-activated mechanism induced by BMAA that may cause the neuronal degeneration and parkinsonian symptoms seen in ALS-PDC. Moreover, environmental exposure to BMAA might possibly also contribute to idiopathic PD. PMID:20392940

  6. Neuropathology and behavioral impairments in Wistar rats with a 6-OHDA lesion in the substantia nigra compacta and exposure to a static magnetic field.

    PubMed

    Bertolino, Guilherme; Dutra Souza, Hugo Celso; de Araujo, João Eduardo

    2013-12-01

    Studies have sought to assess various potential neuroprotective therapeutics in Parkinson's disease. The aim of this study was to evaluate the effects of static magnetic field stimulation 14 days after a 6-Hydroxydopamine (6-OHDA) substantia nigra compacta (SNc) lesion on motor behavior, as assessed by the rotarod (RR) test and brain tissue morphology. Forty male Wistar rats were used and were divided into five groups: control group, sham group (SG), lesion group (LG), lesion north pole group (LNPG) and lesion south pole group (LSPG). In groups with magnetic stimulation, a 3200-gauss magnet was fixed to the skull. After the experiments, the animals were anesthetized for brain perfusion. Coronal sections of the SNc were stained with Nissl. The RR test showed a decrease in the time spent on the apparatus in the LG compared with all groups. The LNPG and LSPG had significant increases in the time spent when compared to the LG. A morphometric analysis revealed a significant reduction in the number of neurons in the LG, LNPG and LSPG in relation to the SG. There were a higher number of neurons in the LNPG and LSPG than the LG, and a higher number of neurons in the LSPG than the LNPG. We observed that the LG, LNPG and LSPG showed a higher number of glial cells than the SG, and the LNPG and LSPG showed a lower number of glial cells than the LG. Our results demonstrate a potential therapeutic use of static magnetic fields for the preservation of motor behavior and brain morphology in the SNc after 14 days with 6-OHDA lesion. PMID:23631668

  7. Elemental micro-imaging and quantification of human substantia nigra using synchrotron radiation based x-ray fluorescence—in relation to Parkinson’s disease

    NASA Astrophysics Data System (ADS)

    Szczerbowska-Boruchowska, Magdalena; Krygowska-Wajs, Anna; Adamek, Dariusz

    2012-06-01

    Synchrotron radiation based x-ray fluorescence (SRXRF) was applied to the quantitative evaluation of elemental changes in substantia nigra pars compacta (SNc) in Parkinson’s disease (PD) in the framework of a study on the role of chemical elements in the pathophysiology of PD. The analysis was carried out for dopaminergic nerve cells and extraneuronal spaces. The mass fractions of P, S, Cl, K, Ca, Fe, Cu, Zn, Br and Rb were determined. The application of standard samples developed especially for the determination of elemental mass fractions in thin tissue sections using the SRXRF technique is presented. Two-dimensional maps of elemental distribution show that the location of nerve cells in SNc sections is precisely visualized by the high levels of most elements. It was found that statistically significant differences between control and PD neurons are observed for S (p = 0.04), Cl (p = 0.02), Ca (p = 0.08), Fe (p = 0.04) and Zn (p = 0.04). The mass fractions of P (p = 0.08), S (p = 0.07), Cl (p = 0.04), Zn (p = 0.08) and Rb (p = 0.08) in areas outside the nerve cell bodies differed significantly between PD and control groups. A clear cluster separation between the PD nerve cells and neurons representing the control group was noticed. It was found that Cl, Fe, Ca and Zn are the most significant elements in the general discrimination between PD nerve cells and the control. The comparison between the extraneuronal spaces showed that Cl, Fe and Cu differentiate the PD and control group the most. The evident contribution of chemical elements to the pathophysiology of PD was shown.

  8. Increased glutamate-stimulated release of dopamine in substantia nigra of a rat model for attention-deficit/hyperactivity disorder--lack of effect of methylphenidate.

    PubMed

    Warton, Fleur L; Howells, Fleur M; Russell, Vivienne A

    2009-12-01

    Attention-deficit/hyperactivity disorder (ADHD) is a behavioural disorder that has been associated with dysfunction of the dopaminergic system. Abnormal dopamine function could be the result of a primary defect in dopamine neurons (neuronal firing, dopamine transporter, synthesis, receptor function) or an indirect result of impaired glutamate and/or noradrenergic regulation of dopamine neurons. There is considerable evidence to suggest that dopamine release is impaired at mesolimbic and nigrostriatal dopaminergic terminals. However, it is not known whether dysregulation occurs at the level of the cell bodies in the ventral tegmental area of the midbrain (VTA) and substantia nigra (SN). An in vitro superfusion technique was used to measure dopamine release in a widely used model of ADHD, the spontaneously hypertensive rat (SHR), and its normotensive Wistar-Kyoto (WKY) control. At approximately 30 days of age, rats were analysed for behavioural differences in the open field in response to acute treatment with methylphenidate (0.5 to 2 mg/kg in condensed milk, oral self-administration). In addition, rats were treated chronically with methylphenidate (2 mg/kg, oral self-administration, twice daily for 14 days from postnatal day 21 to 34) before the VTA and the SN were analysed for glutamate-stimulated and depolarization-evoked release of dopamine in these areas. In support of its use as an animal model for ADHD, SHR were more active in the open field and displayed less anxiety-like behaviour than WKY. Neither strain showed any effect of treatment with methylphenidate. A significant difference was observed in glutamate-stimulated release of dopamine in the SN of SHR and WKY, with SHR releasing more dopamine, consistent with the hypothesis of altered glutamate regulation of dopamine neurons in SHR. PMID:19821016

  9. Age- and gender-related differences in GABAA receptor-mediated postsynaptic currents in GABAergic neurons of the substantia nigra reticulata in the rat.

    PubMed

    Chudomel, O; Herman, H; Nair, K; Moshé, S L; Galanopoulou, A S

    2009-09-29

    The responsiveness of the rat anterior substantia nigra pars reticulata (SNR) GABAergic neurons to GABA(A)ergic drugs changes with age and gender, altering its role in seizure control. To determine whether maturational and gender-specific differences in the properties of spontaneous GABA(A)Rs-mediated inhibitory postsynaptic currents (sIPSCs) underlie these events, we studied sIPSCs at baseline and after application of the alpha1 GABA(A)Rs subunit selective agonist zolpidem, at postnatal days (PN) 5-9, PN12-15, and PN28-32. Results were correlated with the alpha1 and alpha 3 GABA(A)Rs subunit immunoreactivity (-ir) at PN5, PN15, and PN30, using immunochemistry. The mean frequency, amplitude and charge transfer increased whereas the 10-90% rise time and decay time accelerated with age in both genders. The faster sIPSC kinetics in older rats were paralleled by increased alpha1-ir and decreased alpha 3-ir. At PN5-9, males had more robust sIPSCs (frequency, amplitude, charge carried per event and charge transfer) than females. At PN28-32, males exhibited higher amplitudes and faster kinetics than females. The zolpidem-induced increase of decay times, amplitude and charge transfer and alpha1-ir expression were the lowest in PN5-9 males but increased with age, in both genders. Our findings demonstrate that alterations in GABA(A)Rs subunit expression partially underlie age- and gender-specific sIPSC changes in SNR neurons. However, the observation of gender differences in sIPSC kinetics that cannot be attributed to changes in perisomatic alpha1 expression suggests the existence of additional gender-specific factors that control the sIPSC kinetics in rat SNR. PMID:19531372

  10. Gastric dysregulation induced by microinjection of 6-OHDA in the substantia nigra pars compacta of rats is determined by alterations in the brain-gut axis.

    PubMed

    Toti, Luca; Travagli, R Alberto

    2014-11-15

    Idiopathic Parkinson's disease (PD) is a late-onset, chronic, and progressive motor dysfunction attributable to loss of nigrostriatal dopamine neurons. Patients with PD experience significant gastrointestinal (GI) issues, including gastroparesis. We aimed to evaluate whether 6-hydroxy-dopamine (6-OHDA)-induced degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) induces gastric dysmotility via dysfunctions of the brain-gut axis. 6-OHDA microinjection into the SNpc induced a >90% decrease in tyrosine hydroxylase-immunoreactivity (IR) on the injection site. The [13C]-octanoic acid breath test showed a delayed gastric emptying 4 wk after the 6-OHDA treatment. In control rats, microinjection of the indirect sympathomimetic, tyramine, in the dorsal vagal complex (DVC) decreased gastric tone and motility; this inhibition was prevented by the fourth ventricular application of either a combination of α1- and α2- or a combination of D1 and D2 receptor antagonists. Conversely, in 6-OHDA-treated rats, whereas DVC microinjection of tyramine had reduced effects on gastric tone or motility, DVC microinjection of thyrotropin-releasing hormone induced a similar increase in motility as in control rats. In 6-OHDA-treated rats, there was a decreased expression of choline acetyl transferase (ChAT)-IR and neuronal nitric oxide synthase (NOS)-IR in DVC neurons but an increase in dopamine-β-hydroxylase-IR in the A2 area. Within the myenteric plexus of the esophagus, stomach, and duodenum, there were no changes in the total number of neurons; however, the percentage of NOS-IR neurons increased, whereas that of ChAT-IR decreased. Our data suggest that the delayed gastric emptying in a 6-OHDA rat model of PD may be caused by neurochemical and neurophysiological alterations in the brain-gut axis. PMID:25277799

  11. Mu opioid receptor knockdown in the substantia nigra/ventral tegmental area by synthetic small interfering RNA blocks the rewarding and locomotor effects of heroin

    PubMed Central

    Zhang, Yong; Landthaler, Markus; Schlussman, Stefan D.; Yuferov, Vadim; Ho, Ann; Tuschl, Thomas; Kreek, Mary Jeanne

    2014-01-01

    Mu opioid receptors (MOP-r) play an important role in the rewarding and locomotor stimulatory effects of heroin. The aim of the current study was to determine whether infusion of small interfering RNAs (siRNA) targeting MOP-r into the midbrain could knock down MOP-r mRNA and affect heroin-induced locomotor activity or heroin-induced conditioned place preference. Ten week old male C57BL/6J mice were surgically implanted bilaterally with guide cannulae directed between the substantia nigra and ventral tegmental area. After 4 days recovery, mice were infused bilaterally with siRNAs that target the MOP-r (2mM × 0.75 μl/side/day for 3 days) or control siRNA. Seven days after the last infusion, a procedure for conditioned place preference was begun with four heroin (3mg/kg i.p.) administration sessions alternating with four saline sessions. While heroin induced an increase in locomotor activity in all groups, siRNAs targeting specific regions of MOP-r significantly attenuated this effect. Of particular interest, mice infused with specific siRNAs targeting the MOP-r failed to develop and express conditioned place preference to heroin, or showed a significantly attenuated preference. These alterations in reward related behaviors are likely due to the reduction in MOP-r mRNA and protein, shown in separate studies by in situ hybridization and autoradiography using the same MOP-r- siRNA infusions. Taken together, these studies demonstrate the utility of siRNA in the neurobiological study of specific components of the reward system and should contribute to the study of other complex behaviors. PMID:18938225

  12. Endocannabinoid signaling mechanisms in the substantia nigra pars reticulata modulate GABAergic nigrotectal pathways in mice threatened by urutu-cruzeiro venomous pit viper.

    PubMed

    Almada, R C; Roncon, C M; Elias-Filho, D H; Coimbra, N C

    2015-09-10

    The substantia nigra pars reticulata (SNpr) is rich in γ-aminobutyric acid (GABA)-ergic neurons and connected to the mesencephalic tectum (MT) structures, such as the superior colliculus and dorsal periaqueductal gray matter. The SNpr presents a high density of cannabinoid receptors (CBRs), suggesting a possible regulatory role that is played by endocannabinoids (eCBs) in the ventral mesencephalon. The present study investigated the involvement of SNpr eCB mechanisms in nigrotectal pathways in the expression of defensive behavior associated with instinctive fear and panic reactions in mice that are confronted with the venomous Viperidae snake Bothrops alternatus. The localization of CB1 receptors (CB1RS) and synaptophysin glycoprotein in the SNpr was also evaluated. Administration of the GABAA receptor antagonist bicuculline in the MT increased defensive responses to the snake that are related to panic, such as freezing and non-oriented escape reactions, sometimes toward the snake itself. Mice that were pretreated with anandamide (5 or 50pmol) in the SNpr, followed by an injection of physiological saline or bicuculline in the MT, exhibited significant decreases in the expression of alertness, freezing, and escape responses. Immunofluorescence showed the presence of fibers that were rich in CB1RS and synaptophysin in the SNpr, indicating that these receptors appear to be located mainly in presynaptic terminals in the striatonigral pathway. These findings suggest that eCB mechanisms in the SNpr facilitate the activity of nigrotectal GABAergic pathways, modulating the activity of striatonigral links during the elaboration and organization of innate fear and panic-like responses in threatening situations. PMID:26141842

  13. The mesopontine rostromedial tegmental nucleus: a structure targeted by the lateral habenula that projects to the ventral tegmental area of Tsai and substantia nigra compacta

    PubMed Central

    Jhou, Thomas C.; Geisler, Stefanie; Marinelli, Michela; DeGarmo, Beth A.; Zahm, Daniel S.

    2011-01-01

    Prior studies revealed that aversive stimuli and psychostimulant drugs elicit Fos expression in neurons clustered above and behind the interpeduncular nucleus that project strongly to the ventral tegmental area (VTA) and substantia nigra (SN) compacta (C). Other reports suggest that these neurons modulate responding to aversive stimuli. We now designate the region containing them as the mesopontine rostromedial tegmental nucleus (RMTg) and report herein on its neuroanatomy. Dense mu opioid receptor and somatostatin immunoreactivity characterize the RMTg, as do neurons projecting to the VTA/SNC that are enriched in GAD 67 mRNA. Strong inputs to the RMTg arise in the lateral habenula (LHb) and, to a lesser extent, the SN. Other inputs come from the frontal cortex, ventral striatopallidum, extended amygdala, septum, preoptic region, lateral, paraventricular and posterior hypothalamus, zona incerta, periaqueductal gray, intermediate layers of the contralateral superior colliculus, dorsal raphe, mesencephalic, pontine and medullary reticular formation, and the following nuclei: parafascicular, supramammillary, mammillary, ventral lateral geniculate, deep mesencephalic, red, pedunculopontine and laterodorsal tegmental, cuneiform, parabrachial and deep cerebellar. The RMTg has meager outputs to the forebrain, mainly to the ventral pallidum, preoptic-lateral hypothalamic continuum and midline-intralaminar thalamus, but much heavier outputs to the brainstem, including, most prominently, the VTA/SNC, as noted above, and to medial tegmentum, pedunculopontine and laterodorsal tegmental nuclei, dorsal raphe and the locus ceruleus and subceruleus. The RMTg may integrate multiple forebrain and brainstem inputs in relation to a dominant LHb input. Its outputs to neuromodulatory projection systems likely converge with direct LHb projections to those structures. PMID:19235216

  14. Adolescent exposure to MDMA induces dopaminergic toxicity in substantia nigra and potentiates the amyloid plaque deposition in the striatum of APPswe/PS1dE9 mice.

    PubMed

    Abad, Sonia; Ramon, Carla; Pubill, David; Camarasa, Jorge; Camins, Antonio; Escubedo, Elena

    2016-09-01

    MDMA is one of the most used drugs by adolescents and its consumption has been associated with many psychobiological problems, among them psychomotor problems. Moreover, some authors described that early exposure to MDMA may render the dopaminergic neurons more vulnerable to the effects of future neurotoxic insults. Alzheimer disease (AD) is the main cause of dementia in the elderly and a percentage of the patients have predisposition to suffer nigrostriatal alterations, developing extrapyramidal signs. Nigrostriatal dysfunction in the brain of aged APPswe/PS1dE9 (APP/PS1), a mouse model of familiar AD (FAD), has also been described. The aim of the present study was to investigate the consequences of adolescent exposure to MDMA in APP/PS1 mice, on nigrostriatal function on early adulthood. We used a MDMA schedule simulating weekend binge abuse of this substance. Our MDMA schedule produced a genotype-independent decrease in dopaminergic neurons in the substantia nigra that remained at least 3months. Shortly after the injury, wild-type animals showed a decrease in the locomotor activity and apparent DA depletion in striatum, however in the APP/PS1 mice neither the locomotor activity nor the DA levels were modified, but a reduction in dopamine transporter (DAT) expression and a higher levels of oxidative stress were observed. We found that these disturbances are age-related characteristics that this APP/PS1 mice develops spontaneously much later. Therefore, MDMA administration seems to anticipate the striatal dopaminergic dysfunction in this FAD model. The most important outcome lies in a potentiation, by MDMA, of the amyloid beta deposition in the striatum. PMID:27344237

  15. Hypoxic-ischemic injury decreases anxiety-like behavior in rats when associated with loss of tyrosine-hydroxylase immunoreactive neurons of the substantia nigra

    PubMed Central

    Hei, Ming-Yan; Luo, Ya-Li; Zhang, Xiao-Chun; Liu, Hong; Gao, Ru; Wu, Jing-Jiang

    2011-01-01

    Neonatal Sprague-Dawley rats were randomly divided into normal control, mild hypoxia-ischemia (HI), and severe HI groups (N = 10 in each group at each time) on postnatal day 7 (P7) to study the effect of mild and severe HI on anxiety-like behavior and the expression of tyrosine hydroxylase (TH) in the substantia nigra (SN). The mild and severe HI groups were exposed to hypoxia (8% O2/92% N2) for 90 and 150 min, respectively. The elevated plus-maze (EPM) test was performed to assess anxiety-like behavior by measuring time spent in the open arms (OAT) and OAT%, and immunohistochemistry was used to determine the expression of TH in the SN at P14, P21, and P28. OAT and OAT% in the EPM were significantly increased in both the mild (1.88-, 1.99-, and 2.04-fold, and 1.94-, 1.51-, and 1.46-fold) and severe HI groups (1.69-, 1.68-, and 1.87-fold, and 1.83-, 1.43-, and 1.39-fold, respectively; P < 0.05). The percent of TH-positive cells occupying the SN area was significantly and similarly decreased in both the mild (17.7, 40.2, and 47.2%) and severe HI groups (16.3, 32.2, and 43.8%, respectively; P < 0.05). The decrease in the number of TH-positive cells in the SN and the level of protein expression were closely associated (Pearson correlation analysis: r = 0.991, P = 0.000 in the mild HI group and r = 0.974, P = 0.000 in the severe HI group) with the impaired anxiety-like behaviors. We conclude that neonatal HI results in decreased anxiety-like behavior during the juvenile period of Sprague-Dawley rats, which is associated with the decreased activity of TH in the SN. The impairment of anxiety and the expression of TH are not likely to be dependent on the severity of HI. PMID:22147192

  16. Altered Expression Patterns of Inflammation-Associated and Trophic Molecules in Substantia Nigra and Striatum Brain Samples from Parkinson's Disease, Incidental Lewy Body Disease and Normal Control Cases

    PubMed Central

    Walker, Douglas G.; Lue, Lih-Fen; Serrano, Geidy; Adler, Charles H.; Caviness, John N.; Sue, Lucia I.; Beach, Thomas G.

    2016-01-01

    Evidence of inflammation has been consistently associated with pathology in Parkinson's disease (PD)-affected brains, and has been suggested as a causative factor. Dopaminergic neurons in the substantia nigra (SN) pars compacta, whose loss results in the clinical symptoms associated with PD, are particularly susceptible to inflammatory damage and oxidative stress. Inflammation in the striatum, where SN dopaminergic neurons project, is also a feature of PD brains. It is not known whether inflammatory changes occur first in striatum or SN. Many animal models of PD have implicated certain inflammatory molecules with dopaminergic cell neuronal loss; however, there have been few studies to validate these findings by measuring the levels of these and other inflammatory factors in human PD brain samples. This study also included samples from incidental Lewy body disease (ILBD) cases, since ILBD is considered a non-symptomatic precursor to PD, with subjects having significant loss of tyrosine hydroxylase-producing neurons. We hypothesized that there may be a progressive change in key inflammatory factors in ILBD samples intermediate between neurologically normal and PD. To address this, we used a quantitative antibody-array platform (Raybiotech-Quantibody arrays) to measure the levels of 160 different inflammation-associated cytokines, chemokines, growth factors, and related molecules in extracts of SN and striatum from clinically and neuropathologically characterized PD, ILBD, and normal control cases. Patterns of changes in inflammation and related molecules were distinctly different between SN and striatum. Our results showed significantly different levels of interleukin (IL)-5, IL-15, monokine induced by gamma interferon, and IL-6 soluble receptor in SN between disease groups. A different panel of 13 proteins with significant changes in striatum, with IL-15 as the common feature, was identified. Although the ability to detect some proteins was limited by sensitivity

  17. Iron and cell death in Parkinson's disease: a nuclear microscopic study into iron-rich granules in the parkinsonian substantia nigra of primate models

    NASA Astrophysics Data System (ADS)

    Thong, P. S. P.; Watt, F.; Ponraj, D.; Leong, S. K.; He, Y.; Lee, T. K. Y.

    1999-10-01

    Parkinson's disease is a degenerative brain disease characterised by a loss of cells in the substantia nigra (SN) region of the brain and accompanying biochemical changes such as inhibition of mitochondrial function, increased iron concentrations and decreased glutathione levels in the parkinsonian SN. Though the aetiology of the disease is still unknown, the observed biochemical changes point to the involvement of oxidative stress. In particular, iron is suspected to play a role by promoting free radical production, leading to oxidative stress and cell death. The increase in iron in the parkinsonian SN has been confirmed by several research groups, both in human post-mortem brains and in brain tissue from parkinsonian animal models. However, the question remains as to whether the observed increase in iron is a cause or a consequence of the SN cell death process. Our previous study using unilaterally 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP)-lesioned monkeys in a time sequence experiment has shown that the increase in bulk iron concentrations follow rather than precede dopaminergic cell death. However, changes in the localised iron concentrations, which may play a more direct role in SN cell death, may not be reflected at the bulk level. Indeed, we have observed iron-rich granules in parkinsonian SNs. From this time sequence study into the iron content of iron-rich granules in the SNs of an untreated control and unilaterally MPTP-lesioned parkinsonian models, we present the following observations: (1) Iron-rich granules are found in both control and parkinsonian SNs and are variable in size and iron content in any one model. (2) These iron-rich granules may be associated with neuromelanin granules found in the SN and are known to accumulate transition metal ions such as iron. (3) The early onset of bulk SN cell loss (35%) was accompanied by a significant elevation of iron in granules found in the MPTP-injected SN compared to the contra-lateral SN. This

  18. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces lesions in the substantia nigra of the cat which are visible by nuclear magnetic resonance imaging (MRI)

    SciTech Connect

    Sharp, D.E.; Ali, I.I.; Hadjiconstantinou, M.; Keller, P.J.; Hunter, W.W.; Neff, N.H.

    1986-03-05

    Male cats aged 6-8 months were administered two doses of MPTP (10 mg/kg) ip in saline 48 hrs apart. The cats exhibited drooling, dilation of pupils, incontinence, heightened sensitivity to touch and light, hypo- and bradykinesia and ataxia. After the second injection marked rigidity was observed, especially in the hind limbs. The cats were anesthesized and imaged with a 1.5%T MR imager using a spin-echo sequence with TR 2500ms and Te 25ms. MRI showed an increase in signal intensity extending from the periaqueductal grey matter through the region of the substantia nigra. Further an acute decrease in the differentiation of white and grey matter was observed. This is commonly associated with generalized cerebral edema. Measurement of striatal biogenic amine contents showed 20-30% decreases in striatal dopamine, 77% decreases in DOPAC, and 73-80% decrease in HVA. The content of the serotonin metabolite 5-hydroxyindoleacetic acid was unchanged indicating that the toxic effects are specific to dopaminergic neurons. Pathological examinations of the brains showed no macro or microscopic changes. These findings could represent the first observation of the actual processes involved in the degeneration of dopaminergic neurons in Parkinsonism.

  19. Compensatory T-type Ca2+ channel activity alters D2-autoreceptor responses of Substantia nigra dopamine neurons from Cav1.3 L-type Ca2+ channel KO mice

    PubMed Central

    Poetschke, Christina; Dragicevic, Elena; Duda, Johanna; Benkert, Julia; Dougalis, Antonios; DeZio, Roberta; Snutch, Terrance P.; Striessnig, Joerg; Liss, Birgit

    2015-01-01

    The preferential degeneration of Substantia nigra dopamine midbrain neurons (SN DA) causes the motor-symptoms of Parkinson’s disease (PD). Voltage-gated L-type calcium channels (LTCCs), especially the Cav1.3-subtype, generate an activity-related oscillatory Ca2+ burden in SN DA neurons, contributing to their degeneration and PD. While LTCC-blockers are already in clinical trials as PD-therapy, age-dependent functional roles of Cav1.3 LTCCs in SN DA neurons remain unclear. Thus, we analysed juvenile and adult Cav1.3-deficient mice with electrophysiological and molecular techniques. To unmask compensatory effects, we compared Cav1.3 KO mice with pharmacological LTCC-inhibition. LTCC-function was not necessary for SN DA pacemaker-activity at either age, but rather contributed to their pacemaker-precision. Moreover, juvenile Cav1.3 KO but not WT mice displayed adult wildtype-like, sensitised inhibitory dopamine-D2-autoreceptor (D2-AR) responses that depended upon both, interaction of the neuronal calcium sensor NCS-1 with D2-ARs, and on voltage-gated T-type calcium channel (TTCC) activity. This functional KO-phenotype was accompanied by cell-specific up-regulation of NCS-1 and Cav3.1-TTCC mRNA. Furthermore, in wildtype we identified an age-dependent switch of TTCC-function from contributing to SN DA pacemaker-precision in juveniles to pacemaker-frequency in adults. This novel interplay of Cav1.3 L-type and Cav3.1 T-type channels, and their modulation of SN DA activity-pattern and D2-AR-sensitisation, provide new insights into flexible age- and calcium-dependent activity-control of SN DA neurons and its pharmacological modulation. PMID:26381090

  20. Chronic L-DOPA administration increases the firing rate but does not reverse enhanced slow frequency oscillatory activity and synchronization in substantia nigra pars reticulata neurons from 6-hydroxydopamine-lesioned rats.

    PubMed

    Aristieta, A; Ruiz-Ortega, J A; Miguelez, C; Morera-Herreras, T; Ugedo, L

    2016-05-01

    The pathophysiology of Parkinson's disease (PD) and of L-DOPA-induced dyskinesia (LID) is associated with dysfunctional neuronal activity in several nuclei of the basal ganglia. Moreover, high levels of oscillatory activity and synchronization have also been described in both intra- and inter-basal ganglia nuclei and the cerebral cortex. However, the relevance of these alterations in the motor symptomatology related to Parkinsonism and LID is not fully understood. Recently, we have shown that subthalamic neuronal activity correlates with axial abnormal movements and that a subthalamic nucleus (STN) lesion partially reduces LID severity as well as the expression of some striatal molecular modifications. The aim of the present study was to assess, through single-unit extracellular recording techniques under urethane anaesthesia, neuronal activity of the substantia nigra pars reticulata (SNr) and its relationship with LID and STN hyperactivity together with oscillatory and synchronization between these nuclei and the cerebral cortex in 6-OHDA-lesioned and dyskinetic rats. Twenty-four hours after the last injection of L-DOPA the firing rate and the inhibitory response to an acute challenge of L-DOPA of SNr neurons from dyskinetic animals were increased with respect to those found in intact and 6-OHDA-lesioned rats. Moreover, there was a significant correlation between the mean firing rate of SNr neurons and the severity of the abnormal movements (limb and orolingual subtypes). There was also a significant correlation between the firing activity of SNr and STN neurons recorded from dyskinetic rats. In addition, low frequency band oscillatory activity and synchronization both within the SNr or STN and with the cerebral cortex were enhanced in 6-OHDA-lesioned animals and not or slightly affected by chronic treatment with L-DOPA. Altogether, these results indicate that neuronal SNr firing activity is relevant in dyskinesia and may be driven by STN hyperactivity. Conversely

  1. Substantia nigra and Parkinson's disease (image)

    MedlinePlus

    ... is a slowly progressive disorder that affects movement, muscle control, and balance. Part of the disease process develops as cells are destroyed in certain parts of the brain stem, particularly the crescent-shaped cell mass known as ...

  2. Minimally invasive microendoscopy system for in vivo functional imaging of deep nuclei in the mouse brain

    PubMed Central

    Bocarsly, Miriam E.; Jiang, Wan-chen; Wang, Chen; Dudman, Joshua T.; Ji, Na; Aponte, Yeka

    2015-01-01

    The ability to image neurons anywhere in the mammalian brain is a major goal of optical microscopy. Here we describe a minimally invasive microendoscopy system for studying the morphology and function of neurons at depth. Utilizing a guide cannula with an ultrathin wall, we demonstrated in vivo two-photon fluorescence imaging of deeply buried nuclei such as the striatum (2.5 mm depth), substantia nigra (4.4 mm depth) and lateral hypothalamus (5.0 mm depth) in mouse brain. We reported, for the first time, the observation of neuronal activity with subcellular resolution in the lateral hypothalamus and substantia nigra of head-fixed awake mice. PMID:26601017

  3. Dissociation between the panicolytic effect of cannabidiol microinjected into the substantia nigra, pars reticulata, and fear-induced antinociception elicited by bicuculline administration in deep layers of the superior colliculus: The role of CB1-cannabinoid receptor in the ventral mesencephalon.

    PubMed

    da Silva, Juliana Almeida; Biagioni, Audrey Francisco; Almada, Rafael Carvalho; de Souza Crippa, José Alexandre; Cecílio Hallak, Jaime Eduardo; Zuardi, Antônio Waldo; Coimbra, Norberto Cysne

    2015-07-01

    Many studies suggest that the substantia nigra, pars reticulata (SNpr), a tegmental mesencephalic structure rich in γ-aminobutyric acid (GABA)- and cannabinoid receptor-containing neurons, is involved in the complex control of defensive responses through the neostriatum-nigral disinhibitory and nigro-tectal inhibitory GABAergic pathways during imminently dangerous situations. The aim of the present work was to investigate the role played by CB1-cannabinoid receptor of GABAergic pathways terminal boutons in the SNpr or of SNpr-endocannabinoid receptor-containing interneurons on the effect of intra-nigral microinjections of cannabidiol in the activity of nigro-tectal inhibitory pathways. GABAA receptor blockade in the deep layers of the superior colliculus (dlSC) elicited vigorous defensive behaviour. This explosive escape behaviour was followed by significant antinociception. Cannabidiol microinjection into the SNpr had a clear anti-aversive effect, decreasing the duration of defensive alertness, the frequency and duration of defensive immobility, and the frequency and duration of explosive escape behaviour, expressed by running and jumps, elicited by transitory GABAergic dysfunction in dlSC. However, the innate fear induced-antinociception was not significantly changed. The blockade of CB1 endocannabinoid receptor in the SNpr decreased the anti-aversive effect of canabidiol based on the frequency and duration of defensive immobility, the frequency of escape expressed by running, and both the frequency and duration of escape expressed by jumps. These findings suggest a CB1 mediated endocannabinoid signalling in cannabidiol modulation of panic-like defensive behaviour, but not of innate fear-induced antinociception evoked by GABAA receptor blockade with bicuculline microinjection into the superior colliculus, with a putative activity in nigro-collicular GABAergic pathways. PMID:25841876

  4. Multimodal MRI Evaluation of the MitoPark Mouse Model of Parkinson’s Disease

    PubMed Central

    Cong, Linlin; Muir, Eric R.; Chen, Cang; Qian, Yusheng; Liu, Jingwei; Biju, K. C.; Clark, Robert A.; Li, Senlin; Duong, Timothy Q.

    2016-01-01

    The MitoPark mouse, a relatively new genetic model of Parkinson’s disease (PD), has a dopaminergic neuron-specific knock-out that inactivates the mitochondrial transcription factor A (Tfam), a protein essential for mitochondrial DNA expression and maintenance. This study used multimodal MRI to characterize the neuroanatomical correlates of PD-related deficits in MitoPark mice, along with functional behavioral tests. Compared with age-matched wild-type animals, MitoPark mice at 30 weeks showed: i) reduced whole-brain volume and increased ventricular volume, indicative of brain atrophy, ii) reduced transverse relaxation time (T2*) of the substantia nigra and striatum, suggestive of abnormal iron accumulation, iii) reduced apparent diffusion coefficient in the substantia nigra, suggestive of neuronal loss, iv) reduced fractional anisotropy in the corpus callosum and substantia nigra, indicative of white-matter damages, v) cerebral blood flow was not significantly affected, and vi) reduced motor activity in open-field tests, reduced memory in novel object recognition tests, as well as decreased mobility in tail suspension tests, an indication of depression. In sum, MitoPark mice recapitulate changes in many MRI parameters reported in PD patients. Multimodal MRI may prove useful for evaluating neuroanatomical correlates of PD pathophysiology in MitoPark mice, and for longitudinally monitoring disease progression and therapeutic interventions for PD. PMID:27003179

  5. Electrophysiological properties of mouse dopamine neurons: in vivo and in vitro studies.

    PubMed

    Sanghera, M K; Trulson, M E; German, D C

    1984-07-01

    The present experiments were conducted to determine the electrophysiological and pharmacological properties of substantia nigra neurons in the mouse. These cells were studied using extracellular single unit recording and microiontophoretic techniques in both chloral hydrate anesthetized mice and in vitro mouse slices. In the in vivo preparation the substantia nigra zona compacta neurons had long duration action potentials (greater than 4 ms), fired from 1 to 7 impulses/s, and the cells discharged with either a decremental burst pattern or with a regular pattern. The dopamine agonists apomorphine and d-amphetamine, given systemically, decreased the firing rate of these neurons and the dopamine receptor blocker, haloperidol, reversed these effects. The zona compacta neurons were inhibited by the micro-iontophoretic application of dopamine and gamma-aminobutyric acid, and systemic haloperidol selectively attenuated the effects of dopamine. In vitro recordings from substantia nigra zona compacta and zona reticulata neurons were generally similar to those found in vivo, both in terms of the electrophysiological and pharmacological properties. However, the zona compacta cells fired faster in vitro than in vivo, and the firing pattern in vitro tended to be pacemaker-like, especially when recordings were made in an incubation medium which blocks synaptic transmission (e.g. low Ca2+/high Mg2+). Our data indicate that: (a) in vivo mouse zona compacta neurons exhibit the same electrophysiological and pharmacological properties as rat dopamine-containing neurons; (b) in vitro mouse dopaminergic neurons fire with pacemaker regularity when in a low Ca2+/high Mg2+ environment; and (c) in vitro studies offer an approach to examine the basic properties of dopaminergic neurons exclusive of feedback pathways and other afferent inputs. PMID:6472621

  6. Apoptotic-like changes in Lewy-body-associated disorders and normal aging in substantia nigral neurons.

    PubMed Central

    Tompkins, M. M.; Basgall, E. J.; Zamrini, E.; Hill, W. D.

    1997-01-01

    In Parkinson's disease and other Lewy-body-associated disorders, the substantia nigra pars compacta undergoes degeneration, but the mechanism of cell death has not been previously described. The substantia nigra of normal and Alzheimer's disease cases were compared with substantia nigra from patients with Lewy-body-associated disorders (Parkinson's disease, concomitant Alzheimer's/Parkinson's disease, and diffuse Lewy body disease) using in situ end labeling to detect fragmented DNA. In situ end-labeled neurons demonstrated changes resembling apoptosis: nuclear condensation, chromatin fragmentation, and formation of apoptotic-like bodies. Ultrastructural analysis confirmed nuclear condensation and formation of apoptotic-like bodies. Apoptotic-like changes were seen in the substantia nigra of both normal and diseased cases; concomitant Alzheimer's/Parkinson's disease and diffuse Lewy body disease cases had significantly higher amounts of apoptotic-like changes than normal controls or Alzheimer patients. The finding of neuronal death by apoptosis may have relevance for the development of new treatment strategies for Parkinson's disease and related disorders. Images Figure 1 Figure 2 Figure 5 PMID:9006329

  7. Quantitative gene expression profiling of mouse brain regions reveals differential transcripts conserved in human and affected in disease models.

    PubMed

    Brochier, Camille; Gaillard, Marie-Claude; Diguet, Elsa; Caudy, Nicolas; Dossat, Carole; Ségurens, Béatrice; Wincker, Patrick; Roze, Emmanuel; Caboche, Jocelyne; Hantraye, Philippe; Brouillet, Emmanuel; Elalouf, Jean-Marc; de Chaldée, Michel

    2008-04-22

    Using serial analysis of gene expression, we collected quantitative transcriptome data in 11 regions of the adult wild-type mouse brain: the orbital, prelimbic, cingulate, motor, somatosensory, and entorhinal cortices, the caudate-putamen, the nucleus accumbens, the thalamus, the substantia nigra, and the ventral tegmental area. With >1.2 million cDNA tags sequenced, this database is a powerful resource to explore brain functions and disorders. As an illustration, we performed interregional comparisons and found 315 differential transcripts. Most of them are poorly characterized and 20% lack functional annotation. For 78 differential transcripts, we provide independent expression level measurements in mouse brain regions by real-time quantitative RT-PCR. We also show examples where we used in situ hybridization to achieve infrastructural resolution. For 30 transcripts, we next demonstrated that regional enrichment is conserved in the human brain. We then quantified the expression levels of region-enriched transcripts in the R6/2 mouse model of Huntington disease and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson disease and observed significant alterations in the striatum, cerebral cortex, thalamus and substantia nigra of R6/2 mice and in the striatum of MPTP-treated mice. These results show that the gene expression data provided here for the mouse brain can be used to explore pathophysiological models and disclose transcripts differentially expressed in human brain regions. PMID:18252803

  8. Neuroprotective effects of a GIP analogue in the MPTP Parkinson's disease mouse model.

    PubMed

    Li, Yanwei; Liu, WeiZhen; Li, Lin; Hölscher, Christian

    2016-02-01

    Parkinson's disease (PD) is a chronic neurodegenerative disease, and there is no cure for it at present. Recent research has indicated a link between type 2 diabetes mellitus (T2DM) and PD, which suggested that a treatment to improve insulin resistance for T2DM may be useful for PD patients. Glucose-dependent insulinotropic polypeptide (GIP) belongs to the incretin hormone family, which can promote insulin release and improve insulin resistance. Several GIP analogues have been developed as potential treatments for T2DM. In the present study, a novel long-lasting GIP analogue, D-Ala2-GIP-glu-PAL, has been tested in an acute PD mouse model induced by four 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intraperitoneal injections. D-Ala2-GIP-glu-PAL treatment (25 nmol/kg ip.) for 7 days after MPTP treatment improved the locomotor and exploratory activity of mice, and improved bradykinesia and movement balance of mice. D-Ala2-GIP-glu-PAL treatment also restored tyrosine hydroxylase (TH) positive dopaminergic neuron numbers in the substantia nigra and TH levels in the striatum. D-Ala2-GIP-glu-PAL also reduced the chronic inflammation response as seen in astrocyte and microglia activation in the substantia nigra pars compacta (SNpc). D-Ala2-GIP-glu-PAL reversed the reduction of synapse numbers (synaptophysin levels), decreased the ratio of growth factor and apoptosis signaling molecules Bax/Bcl-2, and improved the decrease of p-CREB(S133) growth factor signaling in the substantia nigra. Therefore, D-Ala2-GIP-glu-PAL promotes cell survival of dopaminergic neuron in the SNpc by activating the cAMP/PKA/CREB growth factor second messenger pathway that also inhibits apoptosis. The present results demonstrate that D-Ala2-GIP-glu-PAL shows promise as a novel treatment of PD. PMID:26453962

  9. Attenuation of microglial RANTES by NEMO-binding domain peptide inhibits the infiltration of CD8(+) T cells in the nigra of hemiparkinsonian monkey.

    PubMed

    Roy, A; Mondal, S; Kordower, J H; Pahan, K

    2015-08-27

    Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). Despite intense investigations, little is known about its pathological mediators. Here, we report the marked upregulation of RANTES (regulated on activation, normal T cell expressed and secreted) and eotaxin, chemokines that are involved in T cell trafficking, in the serum of hemiparkinsonian monkeys. Interestingly, 1-methyl-4-phenylpyridinium (MPP(+)), a Parkinsonian toxin, increased the expression of RANTES and eotaxin in mouse microglial cells. The presence of NF-κB binding sites in promoters of RANTES and eotaxin and down-regulation of these genes by NEMO-binding domain (NBD) peptide, selective inhibitor of induced NF-κB activation, in MPP(+)-stimulated microglial cells suggest that the activation of NF-κB plays an important role in the upregulation of these two chemokines. Consistently, serum enzyme-linked immuno assay (ELISA) and nigral immunohistochemistry further confirmed that these chemokines were strongly upregulated in MPTP-induced hemiparkinsonian monkeys and that treatment with NBD peptides effectively inhibited the level of these chemokines. Furthermore, the microglial upregulation of RANTES in the nigra of hemiparkinsonian monkeys could be involved in the altered adaptive immune response in the brain as we observed greater infiltration of CD8(+) T cells around the perivascular niche and deep brain parenchyma of hemiparkinsonian monkeys as compared to control. The treatment of hemiparkinsonian monkeys with NBD peptides decreased the microglial expression of RANTES and attenuated the infiltration of CD8(+) T cells in nigra. These results indicate the possible involvement of chemokine-dependent adaptive immune response in Parkinsonism. PMID:25783477

  10. Neuroprotective effects of geniposide in the MPTP mouse model of Parkinson's disease.

    PubMed

    Chen, YiMei; Zhang, Yanfang; Li, Lin; Hölscher, Christian

    2015-12-01

    Parkinson's disease (PD) is a chronic neurodegenerative disease, and there is no cure for it at present. We tested the drug Geniposide, an active component of Gardenia jasminoides Ellis which is used in traditional Chinese medicine. Geniposide has shown neuroprotective and growth-factor like effects in several in vivo and in vitro studies. In the present study, Geniposide had been tested in an acute PD mouse model induced by four 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intraperitoneal injections. Geniposide treatment (100mg/kg ip.) for 8 days after MPTP treatment (30mg/kg ip.) improved the locomotor and exploratory activity of mice (open field), and improved bradykinesia and movement balance of mice (rotarod, swim test). Geniposide treatment also restored tyrosine hydroxylase (TH) positive dopaminergic neuron numbers in the substantia nigra pars compacta. Drug treatment also increased levels of growth factor signaling molecule Bax and reduced the apoptosis signaling molecule Bcl-2. Caspase 3 activation was also reduced in the substantia nigra. We conclude that Geniposide exerted its neuroprotective effect by enhancing growth factor signaling and the reduction of apoptosis. Geniposide is an ingredient in Chinese traditional medicine with few known side effects and shows potential as a drug treatment for Parkinson's disease. PMID:26409043

  11. The Central Amygdala Projection to the Substantia Nigra Reflects Prediction Error Information in Appetitive Conditioning

    ERIC Educational Resources Information Center

    Lee, Hongjoo J.; Gallagher, Michela; Holland, Peter C.

    2010-01-01

    The central amygdala nucleus (CeA) plays a critical role in cognitive processes beyond fear conditioning. For example, intact CeA function is essential for enhancing attention to conditioned stimuli (CSs). Furthermore, this enhanced attention depends on the CeA's connections to the nigrostriatal system. In the current study, we examined the role…

  12. Motor Asymmetry and Substantia Nigra Volume Are Related to Spatial Delayed Response Performance in Parkinson Disease

    ERIC Educational Resources Information Center

    Foster, Erin R.; Black, Kevin J.; Antenor-Dorsey, Jo Ann V.; Perlmutter, Joel S.; Hershey, Tamara

    2008-01-01

    Studies suggest motor deficit asymmetry may help predict the pattern of cognitive impairment in individuals with Parkinson disease (PD). We tested this hypothesis using a highly validated and sensitive spatial memory task, spatial delayed response (SDR), and clinical and neuroimaging measures of PD asymmetry. We predicted SDR performance would be…

  13. Electrical and Ca2+ signaling in dendritic spines of substantia nigra dopaminergic neurons

    PubMed Central

    Hage, Travis A; Sun, Yujie; Khaliq, Zayd M

    2016-01-01

    Little is known about the density and function of dendritic spines on midbrain dopamine neurons, or the relative contribution of spine and shaft synapses to excitability. Using Ca2+ imaging, glutamate uncaging, fluorescence recovery after photobleaching and transgenic mice expressing labeled PSD-95, we comparatively analyzed electrical and Ca2+ signaling in spines and shaft synapses of dopamine neurons. Dendritic spines were present on dopaminergic neurons at low densities in live and fixed tissue. Uncaging-evoked potential amplitudes correlated inversely with spine length but positively with the presence of PSD-95. Spine Ca2+ signals were less sensitive to hyperpolarization than shaft synapses, suggesting amplification of spine head voltages. Lastly, activating spines during pacemaking, we observed an unexpected enhancement of spine Ca2+ midway throughout the spike cycle, likely involving recruitment of NMDA receptors and voltage-gated conductances. These results demonstrate functionality of spines in dopamine neurons and reveal a novel modulation of spine Ca2+ signaling during pacemaking. DOI: http://dx.doi.org/10.7554/eLife.13905.001 PMID:27163179

  14. Functional Upregulation of Ca2+ -Activated K+ Channels in the Development of Substantia Nigra Dopamine Neurons

    PubMed Central

    Ramírez-Latorre, José A.

    2012-01-01

    Many connections in the basal ganglia are made around birth when animals are exposed to a host of new affective, cognitive, and sensori-motor stimuli. It is thought that dopamine modulates cortico-striatal synapses that result in the strengthening of those connections that lead to desired outcomes. We propose that there must be a time before which stimuli cannot be processed into functional connections, otherwise it would imply an effective link between stimulus, response, and reward in uterus. Consistent with these ideas, we present evidence that early in development dopamine neurons are electrically immature and do not produce high-frequency firing in response to salient stimuli. We ask first, what makes dopamine neurons immature? and second, what are the implications of this immaturity for the basal ganglia? As an answer to the first question, we find that at birth the outward current is small (3nS-V), insensitive to , TEA, BK, and SK blockers. Rapidly after birth, the outward current increases to 15nS-V and becomes sensitive to , TEA, BK, and SK blockers. We make a detailed analysis of the kinetics of the components of the outward currents and produce a model for BK and SK channels that we use to reproduce the outward current, and to infer the geometrical arrangement of BK and channels in clusters. In the first cluster, T-type and BK channels are coupled within distances of 20 nm (200 Å). The second cluster consists of L-type and BK channels that are spread over distances of at least 60 nm. As for the second question, we propose that early in development, the mechanism of action selection is in a “locked-in” state that would prevent dopamine neurons from reinforcing cortico-striatal synapses that do not have a functional experiential-based value. PMID:23284723

  15. Estrogen receptor-mediated effect of δ-tocotrienol prevents neurotoxicity and motor deficit in the MPTP mouse model of Parkinson's disease.

    PubMed

    Nakaso, Kazuhiro; Horikoshi, Yosuke; Takahashi, Toru; Hanaki, Takehiko; Nakasone, Masato; Kitagawa, Yoshinori; Koike, Taisuke; Matsura, Tatsuya

    2016-01-01

    Neuroprotection following signal transduction has been investigated recently as a strategy for Parkinson's disease (PD) therapy. While oxidative stress is important in the pathogenesis of PD, neuroprotection using antioxidants such as α-tocopherol have not been successful. δ-tocotrienol (δT3), a member of the vitamin E family, has received attention because of activities other than its antioxidative effects. In the present study, we examined the estrogen receptor-β (ERβ)-mediated neuroprotective effects of δT3 in a mouse model of PD. ERβ is expressed in neuronal cells, including dopaminergic neurons in the substantia nigra. Daily forced oral administration of δT3 inhibited the loss of dopaminergic neurons in the substantia nigra. In addition, the ER inhibitor tamoxifen canceled the neuroprotective effects of δT3. Moreover, δT3 administration improved the performance of the PD mice in the wheel running activity, while tamoxifen inhibited this improved performance. These results suggest that the oral administration of δT3 may be useful in the treatment of PD patients, and ERβ may be a candidate target for the neuroprotection activity of δT3. PMID:26523792

  16. A novel dual GLP-1 and GIP incretin receptor agonist is neuroprotective in a mouse model of Parkinson's disease by reducing chronic inflammation in the brain.

    PubMed

    Cao, Lijun; Li, Dongfang; Feng, Peng; Li, Lin; Xue, Guo-Fang; Li, Guanglai; Hölscher, Christian

    2016-04-13

    The incretins glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are growth factors. GLP-1 mimetics are on the market as treatments for type 2 diabetes. Both GLP-1 and GIP mimetics have shown neuroprotective properties in previous studies. In addition, the GLP-1 mimetic exendin-4 has shown protective effects in a clinical trial in Parkinson's disease (PD) patients. Novel GLP-1/GIP dual-agonist peptides have been developed to treat diabetes. Here, we report the neuroprotective effects of a novel dual agonist (DA-JC1) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. MPTP was injected once daily (20 mg/kg intraperitoneally) for 7 days and the dual agonist was coinjected once daily (50 nmol/kg intraperitoneally). We found that the drug reduced most of the MPTP-induced motor impairments in the rotarod, open-field locomotion, and muscle strength test. The number of tyrosine hydroxylase-positive neurons in the substantia nigra and striatum was reduced by MPTP and increased by DA-JC1. Synapse numbers (synaptophysin expression) were reduced in the substantia nigra and the striatum by MPTP and DA-JC1 reversed this effect. The activation of a chronic inflammation response by MPTP was considerably reduced by the dual agonist (DA) (astroglia and microglia activation). Therefore, dual agonists show promise as a novel treatment of PD. PMID:26918675

  17. Anatomical localization of leucine-rich repeat kinase 2 in mouse brain.

    PubMed

    Melrose, H; Lincoln, S; Tyndall, G; Dickson, D; Farrer, M

    2006-01-01

    Mutations in leucine-rich repeat kinase 2 (LRRK2) have recently been identified in autosomal dominant late-onset Parkinson's disease. Expression of LRRK2 has previously been reported in brain; however, no precise anatomical information is yet available. We have performed in situ hybridization and quantitative reverse transcription polymerase chain reaction to map LRRK2 mRNA expression in mouse brain. We find LRRK2 is highly expressed in the striatum, cortex and olfactory tubercle; however, little or no expression is found in the substantia nigra, where dopaminergic neurons preferentially degenerate in Parkinson's disease. These findings suggest that LRRK2 mRNA is expressed in dopamine-receptive areas rather than in the dopamine-synthesizing neurons. Consistent with a role LRRK2 in Parkinson's disease, dysfunction of leucine-rich repeat kinase 2 protein in dopamine-innervated areas may to lead to altered dopaminergic neurotransmission and degeneration of the nigro-striatal pathway. PMID:16504409

  18. Region-specific deficits in dopamine, but not norepinephrine, signaling in a novel A30P α-synuclein BAC transgenic mouse.

    PubMed

    Taylor, Tonya N; Potgieter, Dawid; Anwar, Sabina; Senior, Steven L; Janezic, Stephanie; Threlfell, Sarah; Ryan, Brent; Parkkinen, Laura; Deltheil, Thierry; Cioroch, Milena; Livieratos, Achilleas; Oliver, Peter L; Jennings, Katie A; Davies, Kay E; Ansorge, Olaf; Bannerman, David M; Cragg, Stephanie J; Wade-Martins, Richard

    2014-02-01

    Parkinson's disease (PD) is a neurodegenerative disorder classically characterized by the death of dopamine (DA) neurons in the substantia nigra pars compacta and by intracellular Lewy bodies composed largely of α-synuclein. Approximately 5-10% of PD patients have a familial form of Parkinsonism, including mutations in α-synuclein. To better understand the cell-type specific role of α-synuclein on DA neurotransmission, and the effects of the disease-associated A30P mutation, we generated and studied a novel transgenic model of PD. We expressed the A30P mutant form of human α-synuclein in a spatially-relevant manner from the 111kb SNCA genomic DNA locus on a bacterial artificial chromosome (BAC) insert on a mouse null (Snca-/-) background. The BAC transgenic mice expressed α-synuclein in tyrosine hydroxylase-positive neurons and expression of either A30P α-synuclein or wildtype α-synuclein restored the sensitivity of DA neurons to MPTP in resistant Snca-/- animals. A30P α-synuclein mice showed no Lewy body-like aggregation, and did not lose catecholamine neurons in substantia nigra or locus coeruleus. However, using cyclic voltammetry at carbon-fiber microelectrodes we identified a deficit in evoked DA release in the caudate putamen, but not in the nucleus accumbens, of SNCA-A30P Snca-/- mice but no changes to release of another catecholamine, norepinephrine (NE), in the NE-rich ventral bed nucleus of stria terminalis. SNCA-A30P Snca-/- mice had no overt behavioral impairments but exhibited a mild increase in wheel-running. In summary, this refined PD mouse model shows that A30P α-synuclein preferentially perturbs the dopaminergic system in the dorsal striatum, reflecting the region-specific change seen in PD. PMID:24121116

  19. Scanning electron microscopy of tinea nigra*

    PubMed Central

    Guarenti, Isabelle Maffei; de Almeida, Hiram Larangeira; Leitão, Aline Hatzenberger; Rocha, Nara Moreira; Silva, Ricardo Marques e

    2014-01-01

    Tinea nigra is a rare superficial mycosis caused by Hortaea werneckii. This infection presents as asymptomatic brown to black maculae mostly in palmo-plantar regions. We performed scanning electron microscopy of a superficial shaving of a tinea nigra lesion. The examination of the outer surface of the sample showed the epidermis with corneocytes and hyphae and elimination of fungal filaments. The inner surface of the sample showed important aggregation of hyphae among keratinocytes, which formed small fungal colonies. The ultrastructural findings correlated with those of dermoscopic examination - the small fungal aggregations may be the dark spicules seen on dermoscopy - and also allowed to document the mode of dissemination of tinea nigra, showing how hyphae are eliminated on the surface of the lesion. PMID:24770516

  20. Reciprocal regulation between sirtuin-1 and angiotensin-II in the substantia nigra: implications for aging and neurodegeneration

    PubMed Central

    Diaz-Ruiz, Carmen; Rodriguez-Perez, Ana I.; Beiroa, Daniel; Rodriguez-Pallares, Jannette; Labandeira-Garcia, Jose L.

    2015-01-01

    Local angiotensin II (AII) and sirtuin 1 (SIRT1) play a major role in the modulation of neuroinflammation, oxidative stress and aging-related dopaminergic vulnerability to damage. However, it is not known whether the modulation is related to reciprocal regulation between SIRT1 and AII. In the present study, a single intraventricular injection of AII increased nigral SIRT1 levels in young adult rats. Although AII activity is known to be increased in aged rats, levels of SIRT1 were significantly lower than in young controls. Treatment with the SIRT1-activating compound resveratrol increased nigral SIRT1 levels in aged rats. Levels of SIRT1 were significantly higher in aged wild type mice than in AII type-1 receptor (AT1) deficient mice. In cell culture studies, treatment with AII also induced a transitory increase in levels of SIRT1 in the MES 23.5 dopaminergic neuron and the N9 microglial cell lines. In aged rats, treatment with resveratrol induced a significant decrease in the expression of AT1 receptors and markers of NADPH-oxidase activation (p47phox). In aged transgenic mice over-expressing SIRT1, levels of AT1 and p47phox were lower than in aged wild type controls. In vitro, the inhibitory effects of resveratrol on AII/AT1/NADPH-oxidase activity were confirmed in primary mesencephalic cultures, the N9 microglial cell line, and the dopaminergic neuron cell line MES 23.5, and they were blocked by the SIRT1 specific inhibitor EX527. The present findings show that SIRT1 and the axis AII/AT1/NADPH-oxidase regulate each other. This is impaired in aged animals and may be mitigated with sirtuin-activating compounds. PMID:26384348

  1. Subthalamic nucleus high-frequency stimulation generates a concomitant synaptic excitation–inhibition in substantia nigra pars reticulata

    PubMed Central

    Bosch, Clémentine; Degos, Bertrand; Deniau, Jean-Michel; Venance, Laurent

    2011-01-01

    Abstract Deep brain stimulation is an efficient treatment for various neurological pathologies and a promising tool for neuropsychiatric disorders. This is particularly exemplified by high-frequency stimulation of the subthalamic nucleus (STN-HFS), which has emerged as an efficient symptomatic treatment for Parkinson's disease. How STN-HFS works is still not fully elucidated. With dual patch-clamp recordings in rat brain slices, we analysed the cellular responses of STN stimulation on SNr neurons by simultaneously recording synaptic currents and firing activity. We showed that STN-HFS caused an increase of the spontaneous spiking activity in half of SNr neurons while the remaining ones displayed a decrease. At the synaptic level, STN stimulation triggered inward current in 58% of whole-cell recorded neurons and outward current in the remaining ones. Using a pharmacological approach, we showed that STN-HFS-evoked responses were mediated in all neurons by a balance between AMPA/NMDA receptors and GABAA receptors, whose ratio promotes either a net excitation or a net inhibition. Interestingly, we observed a higher excitation occurrence in 6-hydroxydopamine (6-OHDA)-treated rats. In vivo injections of phaseolus revealed that GABAergic pallido-nigral fibres travel through the STN whereas striato-nigral fibres travel below it. Therefore, electrical stimulation of the STN does not only recruit glutamatergic axons from the STN, but also GABAergic passing fibres probably from the globus pallidus. For the first time, we showed that STN-HFS induces concomitant excitatory–inhibitory synaptic currents in SNr neurons by recruitment of efferences and passing fibres allowing a tight control on basal ganglia outflow. PMID:21690190

  2. Reconstruction of the nigrostriatal dopamine pathway in the adult mouse brain.

    PubMed

    Thompson, Lachlan H; Grealish, Shane; Kirik, Deniz; Björklund, Anders

    2009-08-01

    Transplants of fetal dopamine neurons can be used to restore dopamine neurotransmission in animal models of Parkinson's disease, as well as in patients with advanced Parkinson's disease. In these studies the cells are placed in the striatum rather than in the substantia nigra where they normally reside, which may limit their ability to achieve full restoration of motor function. Using a microtransplantation approach, which allows precise placement of small cell deposits directly into the host substantia nigra, and fetal donor cells that express green fluorescent protein under the control of the tyrosine hydroxylase promoter, we show that dopamine neuroblasts implanted into the substantia nigra of adult mice are capable of generating a new nigrostriatal pathway with an outgrowth pattern that matches the anatomy of the intrinsic system. This target-directed regrowth was closely aligned with the intrinsic striatonigral fibre projection and further enhanced by over-expression of glial cell line-derived neurotrophic factor in the striatal target. Results from testing of amphetamine-induced rotational behaviour suggest, moreover, that dopamine neurons implanted into the substantia nigra are also capable of integrating into the host circuitry at the functional level. PMID:19674082

  3. Tinea nigra: successful treatment with topical butenafine.

    PubMed

    Rossetto, André Luiz; Cruz, Rosana Cé Bella

    2012-01-01

    The authors report a case of Tinea nigra in an 8-year-old child, male, from Itajaí, SC, Brazil, with lesions of the macular hyperchromic type, unique, asymptomatic, localized in the right palmar area. The lesion was treated with the topical antifungal butenafine, with remission of symptoms and without recurrence at follow-up for two years. PMID:23197223

  4. Tinea nigra: successful treatment with topical butenafine*

    PubMed Central

    Rossetto, André Luiz; Cruz, Rosana Cé Bella

    2012-01-01

    The authors report a case of Tinea nigra in an 8-year-old child, male, from Itajaí, SC, Brazil, with lesions of the macular hyperchromic type, unique, asymptomatic, localized in the right palmar area. The lesion was treated with the topical antifungal butenafine, with remission of symptoms and without recurrence at follow-up for two years. PMID:23197223

  5. Lidocaine Inhibits HCN Currents in Rat Spinal Substantia Gelatinosa Neurons

    PubMed Central

    Hu, Tao; Liu, Nana; Lv, Minhua; Ma, Longxian; Peng, Huizhen; Peng, Sicong

    2016-01-01

    BACKGROUND: Lidocaine, which blocks voltage-gated sodium channels, is widely used in surgical anesthesia and pain management. Recently, it has been proposed that the hyperpolarization-activated cyclic nucleotide (HCN) channel is one of the other novel targets of lidocaine. Substantia gelatinosa in the spinal dorsal horn, which plays key roles in modulating nociceptive information from primary afferents, comprises heterogeneous interneurons that can be electrophysiologically categorized by firing pattern. Our previous study demonstrated that a substantial proportion of substantia gelatinosa neurons reveal the presence of HCN current (Ih); however, the roles of lidocaine and HCN channel expression in different types of substantia gelatinosa neurons remain unclear. METHODS: By using the whole-cell patch-clamp technique, we investigated the effect of lidocaine on Ih in rat substantia gelatinosa neurons of acute dissociated spinal cord slices. RESULTS: We found that lidocaine rapidly decreased the peak Ih amplitude with an IC50 of 80 μM. The inhibition rate on Ih was not significantly different with a second application of lidocaine in the same neuron. Tetrodotoxin, a sodium channel blocker, did not affect lidocaine’s effect on Ih. In addition, lidocaine shifted the half-activation potential of Ih from −109.7 to −114.9 mV and slowed activation. Moreover, the reversal potential of Ih was shifted by −7.5 mV by lidocaine. In the current clamp, lidocaine decreased the resting membrane potential, increased membrane resistance, delayed rebound depolarization latency, and reduced the rebound spike frequency. We further found that approximately 58% of substantia gelatinosa neurons examined expressed Ih, in which most of them were tonically firing. CONCLUSIONS: Our studies demonstrate that lidocaine strongly inhibits Ih in a reversible and concentration-dependent manner in substantia gelatinosa neurons, independent of tetrodotoxin-sensitive sodium channels. Thus, our

  6. Acupuncture promotes mTOR-independent autophagic clearance of aggregation-prone proteins in mouse brain

    PubMed Central

    Tian, Tian; Sun, Yanhong; Wu, Huangan; Pei, Jian; Zhang, Jing; Zhang, Yi; Wang, Lu; Li, Bin; Wang, Lihua; Shi, Jiye; Hu, Jun; Fan, Chunhai

    2016-01-01

    Acupuncture has historically been practiced to treat medical disorders by mechanically stimulating specific acupoints with fine needles. Despite its well-documented efficacy, its biological basis remains largely elusive. In this study, we found that mechanical stimulation at the acupoint of Yanglingquan (GB34) promoted the autophagic clearance of α-synuclein (α-syn), a well known aggregation-prone protein closely related to Parkinson’s disease (PD), in the substantia nigra par compacta (SNpc) of the brain in a PD mouse model. We found the protein clearance arose from the activation of the autophagy-lysosome pathway (ALP) in a mammalian target of rapamycin (mTOR)-independent approach. Further, we observed the recovery in the activity of dopaminergic neurons in SNpc, and improvement in the motor function at the behavior level of PD mice. Whereas acupuncture and rapamycin, a chemical mTOR inhibitor, show comparable α-syn clearance and therapeutic effects in the PD mouse model, the latter adopts a distinctly different, mTOR-dependent, autophagy induction process. Due to this fundamental difference, acupuncture may circumvent adverse effects of the rapamycin treatment. The newly discovered connection between acupuncture and autophagy not only provides a new route to understanding the molecular mechanism of acupuncture but also sheds new light on cost-effective and safe therapy of neurodegenerative diseases. PMID:26792101

  7. Validity of the MPTP-Treated Mouse as a Model for Parkinson's Disease.

    PubMed

    Klemann, Cornelius J H M; Martens, Gerard J M; Poelmans, Geert; Visser, Jasper E

    2016-04-01

    Parkinson's disease (PD) is characterized by dopaminergic (DA) neuron death in the substantia nigra (SN) and subsequent striatal adaptations. Mice treated with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrimidine (MPTP) are widely used as a model for PD. To assess the validity of the MPTP mouse model for PD pathogenesis, we here identify the biological processes that are dysregulated in both human PD and MPTP-treated mice. Gene enrichment analysis of published differentially expressed messenger RNAs (mRNAs) in the SN of PD patients and MPTP-treated mice revealed an enrichment of gene categories related to motor dysfunction and neurodegeneration. In the PD striatum, a similar enrichment was found, whereas in the striatum of MPTP mice, acute processes linked to epilepsy were selectively enriched shortly following MPTP treatment. More importantly, we integrated the proteins encoded by the differentially expressed mRNAs into molecular landscapes showing PD pathogenesis-implicated processes only in the SN, including vesicular trafficking, exocytosis, mitochondrial apoptosis, and DA neuron-specific transcription, but not in the striatum. We conclude that the current use of the MPTP mouse as a model for studying the molecular processes in PD pathogenesis is more valid for SN than striatal mechanisms in PD. This novel insight has important practical implications for future studies using this model to investigate PD pathogenesis and evaluate the efficacy of new treatments. PMID:25676140

  8. BCG Vaccine-Induced Neuroprotection in a Mouse Model of Parkinson's Disease

    PubMed Central

    Yong, Jing; Lacan, Goran; Dang, Hoa; Hsieh, Terry; Middleton, Blake; Wasserfall, Clive; Tian, Jide; Melega, William P.; Kaufman, Daniel L.

    2011-01-01

    There is a growing interest in using vaccination with CNS antigens to induce autoreactive T cell responses that home to damaged areas in the CNS and ameliorate neurodegenerative disease. Neuroprotective vaccine studies have focused on administering oligodendrocyte antigens or Copaxone® in complete Freund's adjuvant (CFA). Theoretical considerations, however, suggest that vaccination with a neuronal antigen may induce more robust neuroprotective immune responses. We assessed the neuroprotective potential of vaccines containing tyrosine hydroxylase (a neuronal protein involved in dopamine synthesis) or Copaxone® in CFA in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. Surprisingly, we observed that the main beneficial factor in these vaccines was the CFA. Since the major immunogenic component in CFA is Mycobacterium tuberculosis, which closely related to the bacille Calmette-Guérin (BCG) that is used in human vaccines, we tested BCG vaccination in the MPTP mouse model. We observed that BCG vaccination partially preserved markers of striatal dopamine system integrity and prevented an increase in activated microglia in the substantia nigra of MPTP-treated mice. These results support a new neuroprotective vaccine paradigm in which general (nonself-reactive) immune stimulation in the periphery can limit potentially deleterious microglial responses to a neuronal insult and exert a neurorestorative effect in the CNS. Accordingly, BCG vaccination may provide a new strategy to augment current treatments for a wide range of neuropathological conditions. PMID:21304945

  9. BCG vaccine-induced neuroprotection in a mouse model of Parkinson's disease.

    PubMed

    Yong, Jing; Lacan, Goran; Dang, Hoa; Hsieh, Terry; Middleton, Blake; Wasserfall, Clive; Tian, Jide; Melega, William P; Kaufman, Daniel L

    2011-01-01

    There is a growing interest in using vaccination with CNS antigens to induce autoreactive T cell responses that home to damaged areas in the CNS and ameliorate neurodegenerative disease. Neuroprotective vaccine studies have focused on administering oligodendrocyte antigens or Copaxone® in complete Freund's adjuvant (CFA). Theoretical considerations, however, suggest that vaccination with a neuronal antigen may induce more robust neuroprotective immune responses. We assessed the neuroprotective potential of vaccines containing tyrosine hydroxylase (a neuronal protein involved in dopamine synthesis) or Copaxone® in CFA in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. Surprisingly, we observed that the main beneficial factor in these vaccines was the CFA. Since the major immunogenic component in CFA is Mycobacterium tuberculosis, which closely related to the bacille Calmette-Guérin (BCG) that is used in human vaccines, we tested BCG vaccination in the MPTP mouse model. We observed that BCG vaccination partially preserved markers of striatal dopamine system integrity and prevented an increase in activated microglia in the substantia nigra of MPTP-treated mice. These results support a new neuroprotective vaccine paradigm in which general (nonself-reactive) immune stimulation in the periphery can limit potentially deleterious microglial responses to a neuronal insult and exert a neurorestorative effect in the CNS. Accordingly, BCG vaccination may provide a new strategy to augment current treatments for a wide range of neuropathological conditions. PMID:21304945

  10. Acupuncture promotes mTOR-independent autophagic clearance of aggregation-prone proteins in mouse brain.

    PubMed

    Tian, Tian; Sun, Yanhong; Wu, Huangan; Pei, Jian; Zhang, Jing; Zhang, Yi; Wang, Lu; Li, Bin; Wang, Lihua; Shi, Jiye; Hu, Jun; Fan, Chunhai

    2016-01-01

    Acupuncture has historically been practiced to treat medical disorders by mechanically stimulating specific acupoints with fine needles. Despite its well-documented efficacy, its biological basis remains largely elusive. In this study, we found that mechanical stimulation at the acupoint of Yanglingquan (GB34) promoted the autophagic clearance of α-synuclein (α-syn), a well known aggregation-prone protein closely related to Parkinson's disease (PD), in the substantia nigra par compacta (SNpc) of the brain in a PD mouse model. We found the protein clearance arose from the activation of the autophagy-lysosome pathway (ALP) in a mammalian target of rapamycin (mTOR)-independent approach. Further, we observed the recovery in the activity of dopaminergic neurons in SNpc, and improvement in the motor function at the behavior level of PD mice. Whereas acupuncture and rapamycin, a chemical mTOR inhibitor, show comparable α-syn clearance and therapeutic effects in the PD mouse model, the latter adopts a distinctly different, mTOR-dependent, autophagy induction process. Due to this fundamental difference, acupuncture may circumvent adverse effects of the rapamycin treatment. The newly discovered connection between acupuncture and autophagy not only provides a new route to understanding the molecular mechanism of acupuncture but also sheds new light on cost-effective and safe therapy of neurodegenerative diseases. PMID:26792101

  11. Ursolic acid attenuates oxidative stress in nigrostriatal tissue and improves neurobehavioral activity in MPTP-induced Parkinsonian mouse model.

    PubMed

    Rai, Sachchida Nand; Yadav, Satyndra Kumar; Singh, Divakar; Singh, Surya Pratap

    2016-01-01

    Parkinson's disease (PD) is characterized by a slow and progressive degeneration of dopaminergic neurons in substantia nigra pars compacta (SNpc) region of brain. Oxidative stress and inflammation plays important role in the neurodegeneration and development of PD. Ursolic Acid (UA: 3β-hydroxy-urs-12-en-28-oic acid) is a natural pentacyclic triterpenoid found in various medicinal plants. Its anti-inflammatory and antioxidant activity is a well-established fact. In this paper, the neuroprotective efficiency of UA in MPTP induced PD mouse model has been explored. For this purpose, we divided 30 mice into 5 different groups; first was control, second was MPTP-treated, third, fourth and fifth were different doses of UA viz., 5 mg/kg, 25 mg/kg, and 50 mg/kg body weight (wt) respectively, along with MPTP. After 21 days of treatment, different behavioral parameters and biochemical assays were conducted. Tyrosine hydroxylase (TH) immunostaining of SN dopaminergic neurons as well as HPLC quantification of dopamine and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanilic acid (HVA) were also performed. Our results proved that, UA improves behavioral deficits, restored altered dopamine level and protect dopaminergic neurons in the MPTP intoxicated mouse. Among three different doses, 25 mg/kg body wt was the most effective dose for the PD. This work reveals the potential of UA as a promising drug candidate for PD treatment. PMID:26686287

  12. Tinea nigra: report of two cases in infants.

    PubMed

    Pegas, José Roberto; Criado, Paulo Ricardo; Lucena, Suzana Kilian; de Oliveira, Marco Antônio

    2003-01-01

    Tinea nigra, a relatively uncommon mycosis caused by Phaeoannelomyces werneckii, is typically seen as an asymptomatic brown or black macule on the hands and feet. We present two cases of tinea nigra in children in São Paulo, Brazil, and alert readers to the potential for confusion with melanocytic lesions. PMID:12869152

  13. Acupuncture inhibits microglial activation and inflammatory events in the MPTP-induced mouse model.

    PubMed

    Kang, Jun Mo; Park, Hi Joon; Choi, Yeong Gon; Choe, Il Hwan; Park, Jae Hyun; Kim, Yong Sik; Lim, Sabina

    2007-02-01

    Using a mouse model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD), this study investigated on the neuroprotective effects of acupuncture by examining whether acupuncture contributed to inhibiting microglial activation and inflammatory events. C57BL/6 mice were treated with MPTP (30 mg/kg, i.p.) for 5 consecutive days. Acupuncture was then applied to acupoints Yanglingquan (GB34) and Taichong (LR3) starting 2 h after the first MPTP administration and then at 48 h intervals until the mice were sacrificed for analyses at 1, 3, and 7 days after the last MPTP injection. These experiments demonstrated that acupuncture inhibited the decreased of the tyrosine hydroxylase (TH) immunoreactivity (IR) and generated a neuroprotective effects in the striatum (ST) and the substantia nigra (SN) on days 1, 3, and 7 post-MPTP injections. Acupuncture attenuated the increase of macrophage antigen complex-1 (MAC-1), a marker of microglial activation, at 1 and 3 days and reduced the increases in cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression on days 1, 3, and 7. In MPTP group, striatal dopamine (DA) was measured by 46% at 7 days, whereas DA in the acupuncture group was 78%. On the basis of these results, we suggest that acupuncture could be used as a neuroprotective intervention for the purpose of inhibiting microglial activation and inflammatory events in PD. PMID:17173870

  14. Activin A Protects Midbrain Neurons in the 6-Hydroxydopamine Mouse Model of Parkinson’s Disease

    PubMed Central

    Li, Kong M.; Vissel, Bryce

    2015-01-01

    Parkinson’s disease (PD) is a chronic neurodegenerative disease characterized by a significant loss of dopaminergic neurons within the substantia nigra pars compacta (SNpc) and a subsequent loss of dopamine (DA) within the striatum. Despite advances in the development of pharmacological therapies that are effective at alleviating the symptoms of PD, the search for therapeutic treatments that halt or slow the underlying nigral degeneration remains a particular challenge. Activin A, a member of the transforming growth factor β superfamily, has been shown to play a role in the neuroprotection of midbrain neurons against 6-hydroxydopamine (6-OHDA) in vitro, suggesting that activin A may offer similar neuroprotective effects in in vivo models of PD. Using robust stereological methods, we found that intrastriatal injections of 6-OHDA results in a significant loss of both TH positive and NeuN positive populations in the SNpc at 1, 2, and 3 weeks post-lesioning in drug naïve mice. Exogenous application of activin A for 7 days, beginning the day prior to 6-OHDA administration, resulted in a significant survival of both dopaminergic and total neuron numbers in the SNpc against 6-OHDA-induced toxicity. However, we found no corresponding protection of striatal DA or dopamine transporter (DAT) expression levels in animals receiving activin A compared to vehicle controls. These results provide the first evidence that activin A exerts potent neuroprotection in a mouse model of PD, however this neuroprotection may be localized to the midbrain. PMID:25902062

  15. Developmental expression of orphan G protein-coupled receptor 50 in the mouse brain.

    PubMed

    Grünewald, Ellen; Tew, Kenneth D; Porteous, David J; Thomson, Pippa A

    2012-06-20

    Mental disorders have a complex etiology resulting from interactions between multiple genetic risk factors and stressful life events. Orphan G protein-coupled receptor 50 (GPR50) has been identified as a genetic risk factor for bipolar disorder and major depression in women, and there is additional genetic and functional evidence linking GPR50 to neurite outgrowth, lipid metabolism, and adaptive thermogenesis and torpor. However, in the absence of a ligand, a specific function has not been identified. Adult GPR50 expression has previously been reported in brain regions controlling the HPA axis, but its developmental expression is unknown. In this study, we performed extensive expression analysis of GPR50 and three protein interactors using rt-PCR and immunohistochemistry in the developing and adult mouse brain. Gpr50 is expressed at embryonic day 13 (E13), peaks at E18, and is predominantly expressed by neurons. Additionally we identified novel regions of Gpr50 expression, including brain stem nuclei involved in neurotransmitter signaling: the locus coeruleus, substantia nigra, and raphe nuclei, as well as nuclei involved in metabolic homeostasis. Gpr50 colocalizes with yeast-two-hybrid interactors Nogo-A, Abca2, and Cdh8 in the hypothalamus, amygdala, cortex, and selected brain stem nuclei at E18 and in the adult. With this study, we identify a link between GPR50 and neurotransmitter signaling and strengthen a likely role in stress response and energy homeostasis. PMID:22860215

  16. Parkinsonism and impaired axonal transport in a mouse model of frontotemporal dementia

    PubMed Central

    Ittner, Lars M.; Fath, Thomas; Ke, Yazi D.; Bi, Mian; van Eersel, Janet; Li, Kong M.; Gunning, Peter; Götz, Jürgen

    2008-01-01

    Frontotemporal dementia (FTD) is characterized by cognitive and behavioral changes and, in a significant subset of patients, Parkinsonism. Histopathologically, FTD frequently presents with tau-containing lesions, which in familial cases result from mutations in the MAPT gene encoding tau. Here we present a novel transgenic mouse strain (K3) that expresses human tau carrying the FTD mutation K369I. K3 mice develop a progressive histopathology that is reminiscent of that in human FTD with the K369I mutation. In addition, K3 mice show early-onset memory impairment and amyotrophy in the absence of overt neurodegeneration. Different from our previously generated tau transgenic strains, the K3 mice express the transgene in the substantia nigra (SN) and show an early-onset motor phenotype that reproduces Parkinsonism with tremor, bradykinesia, abnormal gait, and postural instability. Interestingly, motor performance of young, but not old, K3 mice improves upon L-dopa treatment, which bears similarities to Parkinsonism in FTD. The early-onset symptoms in the K3 mice are mechanistically related to selectively impaired anterograde axonal transport of distinct cargos, which precedes the loss of dopaminergic SN neurons that occurs in aged mice. The impaired axonal transport in SN neurons affects, among others, vesicles containing the dopamine-synthesizing enzyme tyrosine hydroxylase. Distinct modes of transport are also impaired in sciatic nerves, which may explain amyotrophy. Together, the K3 mice are a unique model of FTD-associated Parkinsonism, with pathomechanistic implications for the human pathologic process. PMID:18832465

  17. Rho kinase inhibition by fasudil in the striatal 6-hydroxydopamine lesion mouse model of Parkinson disease.

    PubMed

    Tatenhorst, Lars; Tönges, Lars; Saal, Kim-Ann; Koch, Jan C; Szegő, Éva M; Bähr, Mathias; Lingor, Paul

    2014-08-01

    Chronic degeneration of nigrostriatal projections, followed by nigral dopaminergic cell death, is a key feature of Parkinson disease (PD). This study examines the neuroprotective potential of the rho kinase inhibitor fasudil in the 6-hydroxydopamine (6-OHDA) mouse model of PD in vivo. C57Bl/6 mice were lesioned by striatal stereotactic injections with 4 μg of 6-OHDA and treated with fasudil 30 or 100 mg/kg body weight via drinking water. Motor behavior was tested biweekly; histologic and biochemical analyses were performed at 4 and 12 weeks after lesion. Motor behavior was severely impaired after 6-OHDA lesion and was not improved by fasudil treatment. Fasudil 100 mg/kg did not significantly increase the number of dopaminergic cells in the substantia nigra after 12 weeks versus lesion controls. Interestingly, however, high-performance liquid chromatography analysis of dopamine metabolites revealed that striatal levels of 3,4-dihydroxyphenylacetic acid were significantly increased after 12 weeks, suggesting a regenerative response. In contrast to recent findings in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin model, fasudil effects seem limited in this severe 6-OHDA model of PD. Nevertheless, high therapeutic concentrations of fasudil are suggestive of a proregenerative potential for dopaminergic neurons, making further evaluations of rho kinase inhibition as a proregenerative therapeutic strategy in PD promising. PMID:25003236

  18. Simvastatin inhibits the activation of p21ras and prevents the loss of dopaminergic neurons in a mouse model of Parkinson's disease

    PubMed Central

    Ghosh, Anamitra; Roy, Avik; Matras, Joanna; Brahmachari, Saurav; Gendelman, Howard E.; Pahan, Kalipada

    2010-01-01

    Parkinson's disease (PD) is second only to Alzheimer's disease as the most common devastating human neurodegenerative disorder. Despite intense investigation, no interdictive therapy is available for PD. We investigated whether simvastatin, an FDA-approved cholesterol-lowering drug, could protect against nigrostriatal degeneration following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication to model PD in mice. First, MPP+ induced the activation of p21ras and NF-κB in mouse microglial cells. Inhibition of MPP+-induced activation of NF-κB by Δp21ras, a dominant-negative mutant of p21ras, supported the involvement of p21ras in MPP+-induced microglial activation of NF-κB. Interestingly, simvastatin attenuated activation of both p21ras and NF-κB in MPP+-stimulated microglial cells. Consistently, we found a very rapid activation of p21ras in vivo in the substantia nigra pars compacta of MPTP-intoxicated mice. However, after oral administration, simvastatin entered into the nigra, reduced nigral activation of p21ras, attenuated nigral activation of NF-κB, inhibited nigral expression of proinflammatory molecules, and suppressed nigral activation of glial cells. These findings paralleled dopaminergic neuronal protection, normalized striatal neurotransmitters, and improved motor functions in MPTP-intoxicated mice. Similarly, pravastatin, another cholesterol-lowering drug, suppressed microglial inflammatory responses and protected dopaminergic neurons in MPTP-intoxicated mice; but at levels less than simvastatin. Furthermore, both the statins administered 2 days after initiation of the disease were still capable of inhibiting the demise of dopaminergic neurons and concomitant loss of neurotransmitters suggesting that statins are capable of slowing down the progression of neuronal loss in the MPTP mouse model. Therefore, we conclude that statins may be of therapeutic benefit for PD patients. PMID:19864567

  19. Palmar lichen planus mimicking tinea nigra.

    PubMed

    Madke, Bhushan; Doshi, Bhavana; Wankhede, Prasad; Nayak, Chitra

    2013-09-01

    Lichen planus (LP) is a chronic inflammatory skin disease characterized by polygonal, violaceous papules commonly involving flexural areas of the wrists, legs, and oral and genital mucous membranes. This report describes a patient who presented with asymptomatic black colored patches on both palms simulating Tinea nigra, a superficial fungal infection. She was previously diagnosed as allergic contact dermatitis and was being treated with potent topical steroid i.e. clobetasol propionate 0.05% and white soft paraffin. Dermatoscopy of the lesion showed brownish pigmentation along ridges of the dermatoglyphics. A biopsy from the lesional skin showed findings of lichen planus. Our case highlights the potential diagnostic confusion that can occur with unusual variants of palmoplantar lichen planus and importance of histopathology in diagnosis of such unusual lesions. PMID:24082209

  20. Comparative studies of the release of 1-methyl-4-phenyl-pyridinium species (MPP/sup +/) from rat and mouse brain synaptosomes

    SciTech Connect

    Abell, C.W.; Shen, R.S.; Gessner, W.; Brossi, A.

    1986-05-01

    The parkinsonian producing neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), selectively destroys nigrostriatal neurons in humans and primates and depletes striatal dopamine in mice but not in rats. MPTP is oxidized by monoamine oxidase B (MAO B) in glial cells and/or serotonergic neurons to form a 1-methyl-4-phenyl pyridinium species (MPP/sup +/), which accumulates in dopaminergic neurons in the substantia nigra and is thought to cause cell destruction. The authors compared the spontaneous release of MPP/sup +/ in striatal and hypothalamic synaptosomes prepared from male Sprague-Dawley rats and male C57BL mice. Synaptosomes were preloaded with (/sup 3/H)-MPP/sup +/ (final concentration of 0.8 ..mu..M, 265 ..mu..Ci/..mu..mol) in physiological Tris containing 0.02% ascorbic acid for 7.5 min at 37/sup 0/C. Hypothalamic, but not striatal, (/sup 3/H)-MPP/sup +/ release from rat and mouse brain was directly proportional to its initial loading concentration (0.008-0.8 ..mu..M). Striatal synaptosomes from rats and mice gave identical rates of spontaneous release of (/sup 3/H)- MPP/sup +/, but the rate of release of hypothalamus is 60% faster in rats than in mice. (/sup 3/H)-MPP/sup +/ release from rat and mouse striatum, but not hypothalamus, was stimulated by monoamines and MAO substrates and inhibitors, a finding that suggests a role for MAO in the intraneuronal transport of MPP/sup +/.

  1. Maternal vitamin D deficiency alters fetal brain development in the BALB/c mouse.

    PubMed

    Hawes, Jazmin E; Tesic, Dijana; Whitehouse, Andrew J; Zosky, Graeme R; Smith, Jeremy T; Wyrwoll, Caitlin S

    2015-06-01

    Prenatal exposure to vitamin D is thought to be critical for optimal fetal neurodevelopment, yet vitamin D deficiency is apparent in a growing proportion of pregnant women. The aim of this study was to determine whether a mouse model of vitamin D-deficiency alters fetal neurodevelopment. Female BALB/c mice were placed on either a vitamin D control (2,195 IU/kg) or deficient (0 IU/kg) diet for 5 weeks prior to and during pregnancy. Fetal brains were collected at embryonic day (E) 14.5 or E17.5 for morphological and gene expression analysis. Vitamin D deficiency during pregnancy reduced fetal crown-rump length and head size. Moreover, lateral ventricle volume was reduced in vitamin D-deficient foetuses. Expression of neurotrophin genes brain-derived neurotrophic factor (Bdnf) and transforming growth factor-β1 (Tgf-β1) was altered, with Bdnf reduced at E14.5 and increased at E17.5 following vitamin D deficiency. Brain expression of forkhead box protein P2 (Foxp2), a gene known to be important in human speech and language, was also altered. Importantly, Foxp2 immunoreactive cells in the developing cortex were reduced in vitamin D-deficient female foetuses. At E17.5, brain tyrosine hydroxylase (TH) gene expression was reduced in females, as was TH protein localization (to identify dopamine neurons) in the substantia nigra of vitamin D-deficient female foetuses. Overall, we show that prenatal vitamin D-deficiency leads to alterations in fetal mouse brain morphology and genes related to neuronal survival, speech and language development, and dopamine synthesis. Vitamin D appears to play an important role in mouse neurodevelopment. PMID:25753408

  2. Chemical defense against fouling in the solitary ascidian Phallusia nigra.

    PubMed

    Mayzel, Boaz; Haber, Markus; Ilan, Micha

    2014-12-01

    The solitary ascidian Phallusia nigra is rarely fouled by epibionts. Here, we tested the antifouling activity of its crude extracts in laboratory and field assays. P. nigra extracts inhibited the growth of all eight tested environmental bacteria and two of four laboratory bacteria. Extracts of the sympatric, but fouled solitary ascidian Herdmania momus inhibited only one test bacterium. Scanning electron microscopy confirmed that the tunic surface of P. nigra is largely bacteria-free. Both ascidian extracts significantly inhibited the larval metamorphosis of the bryozoan Bugula neritina at the tested concentration range of 0.05-2 mg ml(-1). Both crude extracts were toxic to larvae of the brine shrimp Artemia salina at natural volumetric whole-tissue concentrations, but only P. nigra showed activity at 2 mg ml(-1) and below (LC50 = 1.11 mg ml(-1)). P. nigra crude extracts also significantly reduced the settlement of barnacles, polychaetes, and algae in Mediterranean field assays and barnacle settlement in Red Sea trials. Comparisons between control experiments and pH values monitored in all experiments indicate that the observed effects were not due to acidity of the organic extracts. Our results show that P. nigra secondary metabolites have antifouling activities, which may act in synergy with previously proposed physiological antifouling mechanisms. PMID:25572211

  3. Escin attenuates behavioral impairments, oxidative stress and inflammation in a chronic MPTP/probenecid mouse model of Parkinson's disease.

    PubMed

    Selvakumar, Govindasamy Pushpavathi; Janakiraman, Udaiyappan; Essa, Musthafa Mohamed; Justin Thenmozhi, Arokiasamy; Manivasagam, Thamilarasan

    2014-10-17

    Parkinson's disease (PD) is a progressive neurodegenerative disorder that results mainly due to the death of dopaminergic neurons in the substantia nigra (SN), and subsequently has an effect on one's motor function and coordination. The current investigation explored the neuroprotective potential of escin, a natural triterpene-saponin on chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTP/p) induced mouse model of PD. Administration of MPTP led to the depleted striatal dopamine content, impaired patterns of behavior, enhanced oxidative stress and diminished expression of tyrosine hydroxylase (TH), dopamine transporter (DAT) and vesicular monoamine transporter-2 (VMAT-2). The expressions of interleukin-6 and -10, glial fibrillary acidic protein (GFAP), ionized calcium-binding adaptor protein-1 (IBA-1), tumor necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS) in SN were also enhanced. Oral treatment of escin significantly attenuated MPTP/p induced dopaminergic markers depletion, physiological abnormalities, oxidative stress and inhibit neuroinflammatory cytokine expressions in SN. The result of our study confirmed that escin mediated its protection against experimental PD through its antioxidant and anti-inflammatory properties. PMID:24657313

  4. JNK-mediated activation of ATF2 contributes to dopaminergic neurodegeneration in the MPTP mouse model of Parkinson's disease.

    PubMed

    Huang, Qiaoying; Du, Xiaoxiao; He, Xin; Yu, Qing; Hu, Kunhua; Breitwieser, Wolfgang; Shen, Qingyu; Ma, Shanshan; Li, Mingtao

    2016-03-01

    The c-Jun N-terminal kinase (JNK)/c-Jun pathway is a known critical regulator of dopaminergic neuronal death in Parkinson's disease (PD) and is considered a potential target for neuroprotective therapy. However, whether JNK is activated within dopaminergic neurons remains controversial, and whether JNK acts through downstream effectors other than c-Jun to promote dopaminergic neuronal death remains unclear. In this study, we confirm that JNK but not p38 is activated in dopaminergic neurons after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxication. Furthermore, within the dopaminergic neurons of the substantia nigra in MPTP-treated mice, JNK2/3 phosphorylates threonine 69 (Thr69) of Activating transcription factor-2 (ATF2), a transcription factor of the ATF/CREB family, whereas the phosphorylation of Thr71 is constitutive and remains unchanged. The increased phosphorylation of ATF2 on Thr69 by JNK in the MPTP mouse model suggests a functional relationship between the transcriptional activation of ATF2 and dopaminergic neuron death. By using dopaminergic neuron-specific conditional ATF2 mutant mice, we found that either partial or complete deletion of the ATF2 DNA-binding domain in dopaminergic neurons markedly alleviates the MPTP-induced dopaminergic neurodegeneration, indicating that the activation of ATF2 plays a detrimental role in neuropathogenesis in PD. Taken together, our findings demonstrate that JNK-mediated ATF2 activation contributes to dopaminergic neuronal death in an MPTP model of PD. PMID:26515688

  5. LPA signaling initiates schizophrenia-like brain and behavioral changes in a mouse model of prenatal brain hemorrhage

    PubMed Central

    Mirendil, H; Thomas, E A; De Loera, C; Okada, K; Inomata, Y; Chun, J

    2015-01-01

    Genetic, environmental and neurodevelopmental factors are thought to underlie the onset of neuropsychiatric disorders such as schizophrenia. How these risk factors collectively contribute to pathology is unclear. Here, we present a mouse model of prenatal intracerebral hemorrhage—an identified risk factor for schizophrenia—using a serum-exposure paradigm. This model exhibits behavioral, neurochemical and schizophrenia-related gene expression alterations in adult females. Behavioral alterations in amphetamine-induced locomotion, prepulse inhibition, thigmotaxis and social interaction—in addition to increases in tyrosine hydroxylase-positive dopaminergic cells in the substantia nigra and ventral tegmental area and decreases in parvalbumin-positive cells in the prefrontal cortex—were induced upon prenatal serum exposure. Lysophosphatidic acid (LPA), a lipid component of serum, was identified as a key molecular initiator of schizophrenia-like sequelae induced by serum. Prenatal exposure to LPA alone phenocopied many of the schizophrenia-like alterations seen in the serum model, whereas pretreatment with an antagonist against the LPA receptor subtype LPA1 prevented many of the behavioral and neurochemical alterations. In addition, both prenatal serum and LPA exposure altered the expression of many genes and pathways related to schizophrenia, including the expression of Grin2b, Slc17a7 and Grid1. These findings demonstrate that aberrant LPA receptor signaling associated with fetal brain hemorrhage may contribute to the development of some neuropsychiatric disorders. PMID:25849980

  6. Neuroprotective Effect of a DJ-1 Based Peptide in a Toxin Induced Mouse Model of Multiple System Atrophy

    PubMed Central

    Glat, Micaela Johanna; Ben-Zur, Tali; Barhum, Yael; Offen, Daniel

    2016-01-01

    Multiple System Atrophy (MSA) is a sporadic neurodegenerative disorder characterized by parkinsonism, cerebellar ataxia and dysautonomia, in various combinations. In MSA with parkinsonism (MSA-P), the degeneration is mainly restricted to the substantia nigra pars compacta and putamen. Studies have identified alterations in DJ-1 (PARK7), a key component of the anti-oxidative stress response, in Parkinson’s disease (PD) and MSA patients. Previously we have shown that a short DJ-1-based peptide named ND-13, protected cultured cells against neurotoxic insults and improved behavioral outcome in animal models of Parkinson’s disease (PD). In this study, we used the 3-Nitropropionic acid (3-NP)-induced mouse model of MSA and treated the animals with ND-13 in order to evaluate its therapeutic effects. Our results show that ND-13 protects cultured cells against oxidative stress generated by the mitochondrial inhibitor, 3-NP. Moreover, we show that ND-13 attenuates nigrostriatal degeneration and improves performance in motor-related behavioral tasks in 3-NP-treated mice. Our findings suggest a rationale for using ND-13 as a promising therapeutic approach for treatment of MSA. PMID:26901405

  7. Protective Effects of Valproic Acid on the Nigrostriatal Dopamine System in an MPTP Mouse Model of Parkinson’s Disease

    PubMed Central

    Kidd, Sarah K.; Schneider, Jay S.

    2011-01-01

    The use of animal models (including the 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) mouse model) to mimic dopaminergic (DAergic) cell loss and striatal DA depletion, as seen in Parkinson’s disease (PD), has implicated a multitude of factors that might be associated with DAergic cell death in PD including excitotoxicity, inflammation, and oxidative stress. All of these factors have been shown to be reduced by administration of histone deacetylase (HDAC) inhibitors (HDACis) resulting in some degree of neuroprotection in various models of neurodegenerative disease including in Huntington’s disease and amyotrophic lateral sclerosis. However, there is limited information of effects of HDACis in PD models. We have previously shown HDACis to be partially protective against 1-methyl-4-phenylpyridinium (MPP+) mediated cell loss in vitro. The present study was conducted to extend these findings to an in vivo PD model. The HDACi valproic acid (VPA) was co-administered with MPTP for 5 days to male FVBn mice and continued for an additional 2 weeks, throughout the period of active neurodegeneration associated with MPTP-mediated DAergic cell loss. VPA was able to partially prevent striatal dopamine depletion and almost completely protect against substantia nigra DAergic cell loss. These results suggest that VPA may be a potential disease modifying therapy for PD. PMID:21846494

  8. Neuroprotective effects of (Val8)GLP-1-Glu-PAL in the MPTP Parkinson's disease mouse model.

    PubMed

    Zhang, YanFang; Chen, YiMei; Li, Lin; Hölscher, Christian

    2015-10-15

    Glucagon-like peptide 1 (GLP-1) is a hormone and a growth factor. GLP-1 mimetics are currently on the market as treatments for type 2 diabetes. They also have shown neuroprotective properties in animal models of neurodegenerative disorders. In addition, the GLP-1 mimetic exendin-4 has shown protective effects in animal models of Parkinson's disease (PD), and a first clinical trial in PD patients showed promising results. (Val8)GLP-1-glu-PAL is a new GLP-1 analogue which has a longer biological half-life than exendin-4. We previously showed that (Val8)GLP-1-glu-PAL has neuroprotective properties. Here we tested the drug in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. MPTP was injected (30mg/kg i.p.) along with (Val8)GLP-1-glu-PAL (25nmol/kg i.p.) once-daily for 8 days. (Val8)GLP-1-glu-PAL showed good effects in preventing the MPTP-induced motor impairment (Rotarod, open field locomotion, swim test), reduction in tyrosine hydroxylase levels (dopamine synthesis) in the substantia nigra, a reduction of activated caspase 3 levels, of TUNEL positive cell numbers, of the pro-apoptotic signaling molecule BAX and an increase in the growth signaling molecule Bcl-2. The results demonstrate that (Val8)GLP-1-glu-PAL shows promise as a novel treatment of PD. PMID:26187689

  9. Biogeography of Phallusia nigra: is it really black and white?

    PubMed

    Vandepas, Lauren E; Oliveira, Livia M; Lee, Serina S C; Hirose, Euichi; Rocha, Rosana M; Swalla, Billie J

    2015-02-01

    Ascidians (Chordata, Tunicata) are an important group for the study of invasive species biology due to rapid generation times, potential for biofouling, and role as filter feeders in an ecosystem. Phallusia nigra is a putative cosmopolitan ascidian that has been described as introduced or invasive in a number of regions in the Indo-Pacific Ocean (India, Japan, and Hawaii) and in the Mediterranean. The taxonomic description of P. nigra includes a striking smooth, black tunic and large size. However, there are at least two similar Phallusia species-P. philippinensis and P. fumigata-which also have dark black tunics and can be difficult to discern from P. nigra. The distribution of P. nigra broadly overlaps with P. philippinensis in the Indo-Pacific and P. fumigata in the Mediterranean. A morphological comparison of P. nigra from Japan, the Caribbean coast of Panama, and Brazil found that Atlantic and Pacific samples were different species and led us to investigate the range of P. nigra using morphological and molecular analyses. We sequenced 18S rDNA and cytochrome oxidase B of individual ascidians from the Red Sea, Greece, Singapore, Japan, Caribbean Panama, Florida, and Brazil. Our results show that identification of the disparate darkly pigmented species has been difficult, and that several reports of P. nigra are likely either P. fumigata or P. philippinensis. Here we include detailed taxonomic descriptions of the distinguishing features of these three species and sequences for molecular barcoding in an effort to have ranges and potential invasions corrected in the ascidian literature. PMID:25745100

  10. Naringin treatment induces neuroprotective effects in a mouse model of Parkinson's disease in vivo, but not enough to restore the lesioned dopaminergic system.

    PubMed

    Kim, Heung Deok; Jeong, Kyoung Hoon; Jung, Un Ju; Kim, Sang Ryong

    2016-02-01

    We recently reported that treatment with naringin, a major flavonoid found in grapefruit and citrus fruits, attenuated neurodegeneration in a rat model of Parkinson's disease (PD) in vivo. In order to investigate whether its effects are universally applied to a different model of PD and whether its treatment induces restorative effects on the lesioned nigrostriatal dopaminergic (DA) projection, we observed the effects of pre-treatment or post-treatment with naringin in a mouse model of PD. For neuroprotective effects, 6-hydroxydopamine (6-OHDA) was unilaterally injected into the striatum of mouse brains for a neurotoxin model of PD in the presence or absence of naringin by daily intraperitoneal injection. Our results showed that naringin protected the nigrostriatal DA projection from 6-OHDA-induced neurotoxicity. Moreover, similar to the effects in rat brains, this treatment induced the activation of mammalian target of rapamycin complex 1 (mTORC1), which is well known as an important survival factor for DA neurons, and inhibited microglial activation in the substantia nigra (SN) of mouse brains treated with 6-OHDA. However, there was no significant change of DA phenotypes in the SN and striatum post-treated with naringin compared with 6-OHDA-lesioned mice, despite the treatment being continued for 12 weeks. These results suggest that post-treatment with naringin alone may not be enough to restore the nigrostriatal DA projection in a mouse model of PD. However, our results apparently suggest that naringin is a beneficial natural product to prevent DA degeneration, which is involved in PD. PMID:26878791

  11. Effect of GDNF on depressive-like behavior, spatial learning and key genes of the brain dopamine system in genetically predisposed to behavioral disorders mouse strains.

    PubMed

    Naumenko, Vladimir S; Kondaurova, Elena M; Bazovkina, Daria V; Tsybko, Anton S; Ilchibaeva, Tatyana V; Khotskin, Nikita V; Semenova, Alina A; Popova, Nina K

    2014-11-01

    The effect of glial cell line-derived neurotrophic factor (GDNF) on behavior and brain dopamine system in predisposed to depressive-like behavior ASC (Antidepressant Sensitive Cataleptics) mice in comparison with the parental "nondepressive" CBA mice was studied. In 7days after administration (800ng, i.c.v.) GDNF decreased escape latency time and the path traveled to reach hidden platform in Morris water maze in ASC mice. GDNF enhanced depressive-like behavioral traits in both "nondepressive" CBA and "depressive" ASC mice. In CBA mice, GDNF decreased functional response to agonists of D1 (chloro-APB hydrobromide) and D2 (sumanirole maleate) receptors in tail suspension test, reduced D2 receptor gene expression in the substantia nigra and increased monoamine oxydase A (MAO A) gene expression in the striatum. GDNF increased D1 and D2 receptor genes expression in the nucleus accumbens of ASC mice but failed to alter expression of catechol-O-methyltransferase, dopamine transporter, MAO B and tyrosine hydroxylase genes in both investigated mouse strains. Thus, GDNF produced long-term genotype-dependent effect on behavior and the brain dopamine system. GDNF pretreatment (1) reduced D1 and D2 receptors functional responses and D2 receptor gene expression in s. nigra of CBA mice; (2) increased D1 and D2 receptor genes expression in n. accumbens of ASC mice and (3) improved spatial learning in ASC mice. GDNF enhanced depressive-like behavior both in CBA and ASC mice. The data suggest that genetically defined variance in the cross-talk between GDNF and brain dopamine system contributes to the variability of GDNF-induced responses and might be responsible for controversial GDNF effects. PMID:25101543

  12. Neuronal NOS and cyclooxygenase-2 contribute to DNA damage in a mouse model of Parkinson disease.

    PubMed

    Hoang, Tuan; Choi, Dong-Kug; Nagai, Makiko; Wu, Du-Chu; Nagata, Tetsuya; Prou, Delphine; Wilson, Glenn L; Vila, Miquel; Jackson-Lewis, Vernice; Dawson, Valina L; Dawson, Ted M; Chesselet, Marie-Françoise; Przedborski, Serge

    2009-10-01

    DNA damage is a proposed pathogenic factor in neurodegenerative disorders such as Parkinson disease. To probe the underpinning mechanism of such neuronal perturbation, we sought to produce an experimental model of DNA damage. We thus first assessed DNA damage by in situ nick translation and emulsion autoradiography in the mouse brain after administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 4 x 20 mg/kg, ip, every 2 h), a neurotoxin known to produce a model of Parkinson disease. Here we show that DNA strand breaks occur in vivo in this mouse model of Parkinson disease with kinetics and a topography that parallel the degeneration of substantia nigra neurons, as assessed by FluoroJade labeling. Previously, nitric oxide synthase and cyclooxygenase-2 (Cox-2) were found to modulate MPTP-induced dopaminergic neuronal death. We thus assessed the contribution of these enzymes to DNA damage in mice lacking neuronal nitric oxide synthase (nNOS), inducible nitric oxide synthase (iNOS), or Cox-2. We found that the lack of Cox-2 and nNOS activities but not of iNOS activity attenuated MPTP-related DNA damage. We also found that not only nuclear, but also mitochondrial, DNA is a target for the MPTP insult. These results suggest that the loss of genomic integrity can be triggered by the concerted actions of nNOS and Cox-2 and provide further support to the view that DNA damage may contribute to the neurodegenerative process in Parkinson disease. PMID:19616617

  13. Extraction and antioxidant activity of flavonoids of Morus nigra

    PubMed Central

    Feng, Rui-Zhang; Wang, Qin; Tong, Wen-Zhi; Xiong, Juan; Wei, Qin; Zhou, Wan-Hai; Yin, Zhong-Qiong; Yin, Xiao-Ya; Wang, Li-Ying; Chen, Ya-Qin; Lai, Yong-Hong; Huang, Hong-Yan; Luo, Qiao-Li; Wang, Lu; Jia, Ren-Yong; Song, Xu; Zou, Yuan-Feng; Li, Li-Xia

    2015-01-01

    Morus nigra has a long history of medicinal use in Chinese medicine, but the study on it is limited, the flavonoids are one of the main biological active substances. In this study, the Morus nigra flavonoids were extracted by ultrasonic and antioxidant activities both in vitro and in vivo were measured. The results showed that hydroxyl radicals clearance rate and superoxide radical anion clearance rate in vitro increased with the concentration of the total flavonoids in the range of 0-1.05 mg/mL and the maximum clearance rate was 80.33% and 87.69%, respectively. After mice were treated with flavonoids, the content of malonaldehyde (MDA) in serum and liver decreased; the activities of superoxide dismutase (SOD) in serum and liver, catalase (CAT) in liver and glutathione peroxidase (GSH-PX) in blood and liver increased; Langhans cells increased in spleen. These results revealed that the Morus nigra flavonoids possessed strong antioxidant activity. PMID:26885210

  14. Ability to delay neuropathological events associated with astrocytic MAO-B increase in a Parkinsonian mouse model: implications for early intervention on disease progression.

    PubMed

    Siddiqui, Almas; Mallajosyula, Jyothi K; Rane, Anand; Andersen, Julie K

    2010-11-01

    We previously demonstrated that elevation of astrocytic monoamine oxidase B (MAO-B) levels in a doxycycline (dox)-inducible transgenic mouse model following 14 days of dox induction results in several neuropathologic features similar to those observed in the Parkinsonian midbrain (Mallajosyula et al., 2008). These include a specific, selective and progressive loss of dopaminergic neurons of the substantia nigra (SN), selective decreases in mitochondrial complex I (CI) activity and increased oxidative stress. Here, we report that the temporal sequence of events following MAO-B elevation initially involves increased oxidative stress followed by CI inhibition and finally neurodegeneration. Furthermore, dox removal (DR) at days 3 and 5 of MAO-B induction was sufficient to arrest further increases in oxidative stress as well as subsequent neurodegenerative events. In order to assess the contribution of MAO-B-induced oxidative stress to later events, we compared the impact of DR which reverses the MAO-B increase with treatment of animals with the lipophilic antioxidant compound EUK-189. EUK-189 was found to be as effective as DR in halting downstream CI inhibition and also significantly attenuated SN DA cell loss as a result of astrocytic MAO-B induction. This suggests that MAO-B-mediated ROS contributes to neuropathology associated with this model and that antioxidant treatment can arrest further progression of dopaminergic cell death. This has implications for early intervention therapies. PMID:20655384

  15. Optogenetic activation of nigral inhibitory inputs to motor thalamus in the mouse reveals classic inhibition with little potential for rebound activation.

    PubMed

    Edgerton, Jeremy R; Jaeger, Dieter

    2014-01-01

    The inhibitory output from the internal pallidum and substantia nigra to the thalamus forms an important link in the transmission of basal ganglia processing to cortex. Two hypotheses consider either inhibition of thalamic activity or thalamic excitation via post-inhibitory rebound burst firing as the functional mode of this link. We used optogenetics to characterize the synaptic properties of nigral input to motor thalamus in adult mouse brain slices, and to determine in what conditions the nigral inhibition of motor thalamus is transmitted via inhibition or rebound firing. Our results are more consistent with graded inhibition of spiking for conditions expected in normal awake animals, because inhibitory potentials from nigral input were generally not sufficient to elicit rebound spikes when the thalamic neurons were actively firing. However, with bursty or fast trains of nigral input low-threshold rebound spike bursts could be triggered for low levels of excitation. This may form the basis of pathological burst generation and transmission in parkinsonian conditions. PMID:24574972

  16. Intranasal PRGF-Endoret enhances neuronal survival and attenuates NF-κB-dependent inflammation process in a mouse model of Parkinson's disease.

    PubMed

    Anitua, Eduardo; Pascual, Consuelo; Pérez-Gonzalez, Rocio; Orive, Gorka; Carro, Eva

    2015-04-10

    Parkinson's disease is a common neurodegenerative disorder of unknown pathogenesis characterized by the loss of nigrostriatal dopaminergic neurons. Oxidative stress, microglial activation and inflammatory responses seem to contribute to the pathogenesis. Recent data showed that growth factors mediate neuroprotection in rodent models of Parkinson's disease, modulating pro-inflammatory processes. Based on our recent studies showing that plasma rich in growth factors (PRGF-Endoret) mediates neuroprotection as inflammatory moderator in Alzheimer's disease, in the present study we examined the effects of plasma rich in growth factors (PRGF-Endoret) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse as a translational therapeutic approach for Parkinson's disease. We found substantial neuroprotection by PRGF-Endoret in our model of Parkinson's disease, which resulted in diminished inflammatory responses and improved motor performance. Additionally, these effects were associated with robust reduction in nuclear transcription factor-κB (NF-κB) activation, and nitric oxide (NO), cyclooxygenase-2 (COX-2), and tumor necrosis factor-alpha (TNF-α) expression in the substantia nigra. We propose that PRGF-Endoret can prevent dopaminergic degeneration via an NF-κB-dependent signaling process. As the clinical safety profile of PRGF-Endoret is already established, these data suggest that PRGF-Endoret provides a novel neuroprotective strategy for Parkinson's disease. PMID:25702964

  17. Protection of dopamine neurons by vibration training and up-regulation of brain-derived neurotrophic factor in a MPTP mouse model of Parkinson's disease.

    PubMed

    Zhao, L; He, L X; Huang, S N; Gong, L J; Li, L; Lv, Y Y; Qian, Z M

    2014-01-01

    It is unknown whether the longer duration of vibration training (VT) has a beneficial effect on Parkinson's disease (PD). And also, the mechanisms underlying the reported sensorimotor-improvement in PD induced by short-duration of VT has not been determined. Here, we investigated the effects of longer duration (4 weeks) of low amplitude vibration (LAV) training on the numbers of dopaminergic neurons in the substantia nigra by immunostaining and the levels of dopamine (DA) and brain-derived neurotrophic factor (BDNF) in the striatum by HPLC and ELISA in the chronic MPTP lesion mouse. We demonstrated for the first time that the longer duration of VT could significantly increase the numbers of nigrostriatal DA neurons and the contents of striatal DA and BDNF in the MPTP mice. Our findings implied that longer duration of VT could protect dopaminergic neurons from the MPTP-induced damage probably by upregulating BDNF and also provided evidence for the beneficial effect of longer duration of VT on PD at the cellular and molecular level. PMID:24908088

  18. HIF1α is Necessary for Exercise-Induced Neuroprotection while HIF2α is Needed for Dopaminergic Neuron Survival in the Substantia Nigra pars compacta

    PubMed Central

    Smeyne, Michelle; Sladen, Paul; Jiao, Yun; Dragatsis, Ioannis; Smeyne, Richard Jay

    2015-01-01

    Exercise reduces the risk of developing a number of neurological disorders and increases the efficiency of cellular energy production. However, overly strenuous exercise produces oxidative stress. Proper oxygenation is crucial for the health of all tissues, and tight regulation of cellular oxygen is critical to balance O2 levels and redox homeostasis in the brain. Hypoxia Inducible Factor (HIF)1α and HIF2α are transcription factors regulated by cellular oxygen concentration that initiate gene regulation of vascular development, redox homeostasis, and cell cycle control. HIF1α and HIF2α contribute to important adaptive mechanisms that occur when oxygen and ROS homeostasis become unbalanced. It has been shown that preconditioning by exposure to a stressor prior to a hypoxic event reduces damage that would otherwise occur. Previously we reported that three months of exercise protects SNpc DA neurons from toxicity caused by Complex I inhibition. Here, we identify the cells in the SNpc that express HIF1α and HIF2α and show that running exercise produces hypoxia in SNpc DA neurons, and alters the expression of HIF1α and HIF2α. In mice carrying a conditional knockout of Hif1α in postnatal neurons we observe that exercise alone produces SNpc TH+ DA neuron loss. Loss of HIF1α also abolishes exercise-induced neuroprotection. In mice lacking Hif2α in postnatal neurons, the number of TH+ DA neurons in the adult SNpc is diminished, but three months of exercise rescues this loss. We conclude that HIF1α is necessary for exercise-induced neuroprotection and both HIF1α and HIF2α are necessary for the survival and function of adult SNpc DA neurons. PMID:25796140

  19. Lysosomal dysfunction in a mouse model of Sandhoff disease leads to accumulation of ganglioside-bound amyloid-β peptide.

    PubMed

    Keilani, Serene; Lun, Yi; Stevens, Anthony C; Williams, Hadis N; Sjoberg, Eric R; Khanna, Richie; Valenzano, Kenneth J; Checler, Frederic; Buxbaum, Joseph D; Yanagisawa, Katsuhiko; Lockhart, David J; Wustman, Brandon A; Gandy, Sam

    2012-04-11

    Alterations in the lipid composition of endosomal-lysosomal membranes may constitute an early event in Alzheimer's disease (AD) pathogenesis. In this study, we investigated the possibility that GM2 ganglioside accumulation in a mouse model of Sandhoff disease might be associated with the accumulation of intraneuronal and extracellular proteins commonly observed in AD. Our results show intraneuronal accumulation of amyloid-β peptide (Aβ)-like, α-synuclein-like, and phospho-tau-like immunoreactivity in the brains of β-hexosaminidase knock-out (HEXB KO) mice. Biochemical and immunohistochemical analyses confirmed that at least some of the intraneuronal Aβ-like immunoreactivity (iAβ-LIR) represents amyloid precursor protein C-terminal fragments (APP-CTFs) and/or Aβ. In addition, we observed increased levels of Aβ40 and Aβ42 peptides in the lipid-associated fraction of HEXB KO mouse brains, and intraneuronal accumulation of ganglioside-bound Aβ (GAβ) immunoreactivity in a brain region-specific manner. Furthermore, α-synuclein and APP-CTFs and/or Aβ were found to accumulate in different regions of the substantia nigra, indicating different mechanisms of accumulation or turnover pathways. Based on the localization of the accumulated iAβ-LIR to endosomes, lysosomes, and autophagosomes, we conclude that a significant accumulation of iAβ-LIR may be associated with the lysosomal-autophagic turnover of Aβ and fragments of APP-containing Aβ epitopes. Importantly, intraneuronal GAβ immunoreactivity, a proposed prefibrillar aggregate found in AD, was found to accumulate throughout the frontal cortices of postmortem human GM1 gangliosidosis, Sandhoff disease, and Tay-Sachs disease brains. Together, these results establish an association between the accumulation of gangliosides, autophagic vacuoles, and the intraneuronal accumulation of proteins associated with AD. PMID:22496568

  20. Neuronal NOS and cyclooxygenase-2 contribute to DNA damage in a mouse model of Parkinson’s disease

    PubMed Central

    Hoang, Tuan; Choi, Dong-Kug; Nagai, Makiko; Wu, Du-Chu; Nagata, Tetsuya; Prou, Delphine; Wilson, Glenn L.; Vila, Miquel; Jackson-Lewis, Vernice; Dawson, Valina L.; Dawson, Ted M.; Chesselet, Marie-Françoise; Przedborski, Serge

    2013-01-01

    DNA damage is a proposed pathogenic factor in neurodegenerative disorders such as Parkinson’s disease. To probe the underpinning mechanism of such neuronal perturbation, we sought to produce an experimental model of DNA damage. We thus first assessed by in situ nick translation and emulsion autoradiography in the mouse brain the effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 4 × 20mg/kg, i.p., every 2 hours), a neurotoxin known to produce a model of Parkinson’s disease, on DNA. Here we show that DNA strand breaks occur in vivo in this mouse model of Parkinson’s disease with kinetics and a topography that parallel the degeneration of substantia nigra neurons, as assessed by FluoroJade-labeling. Previously, nitric oxide synthase (NOS) and cyclooxygenase-2 (Cox-2) were found to modulate MPTP-induced dopaminergic neuronal death. We thus assessed the contribution of these enzymes to DNA damage in mice lacking either neuronal nitric oxide synthase (nNOS), inducible nitric oxide synthase (iNOS), or Cox-2. We found that the lack of Cox-2 and of nNOS, but not of iNOS activity, attenuate MPTP-related DNA damage. We also found that not only nuclear, but mitochondrial DNA as well is a target for the MPTP insult. These results suggest that the loss of genomic integrity can be triggered by the concerted actions of nNOS and Cox-2, and provide further support to the view that DNA damage may contribute to the neurodegenerative process in PD. PMID:19616617

  1. Expression of Tgfβ1 and Inflammatory Markers in the 6-hydroxydopamine Mouse Model of Parkinson’s Disease

    PubMed Central

    Haas, Stefan Jean-Pierre; Zhou, Xiaolai; Machado, Venissa; Wree, Andreas; Krieglstein, Kerstin; Spittau, Björn

    2016-01-01

    Parkinson’s disease (PD) is a neurodegenerative disorder that is characterized by loss of midbrain dopaminergic (mDA) neurons in the substantia nigra (SN). Microglia-mediated neuroinflammation has been described as a common hallmark of PD and is believed to further trigger the progression of neurodegenerative events. Injections of 6-hydroxydopamine (6-OHDA) are widely used to induce degeneration of mDA neurons in rodents as an attempt to mimic PD and to study neurodegeneration, neuroinflammation as well as potential therapeutic approaches. In the present study, we addressed microglia and astroglia reactivity in the SN and the caudatoputamen (CPu) after 6-OHDA injections into the medial forebrain bundle (MFB), and further analyzed the temporal and spatial expression patterns of pro-inflammatory and anti-inflammatory markers in this mouse model of PD. We provide evidence that activated microglia as well as neurons in the lesioned SN and CPu express Transforming growth factor β1 (Tgfβ1), which overlaps with the downregulation of pro-inflammatory markers Tnfα, and iNos, and upregulation of anti-inflammatory markers Ym1 and Arg1. Taken together, the data presented in this study suggest an important role for Tgfβ1 as a lesion-associated factor that might be involved in regulating microglia activation states in the 6-OHDA mouse model of PD in order to prevent degeneration of uninjured neurons by microglia-mediated release of neurotoxic factors such as Tnfα and nitric oxide (NO). PMID:26869879

  2. The novel adaptive rotating beam test unmasks sensorimotor impairments in a transgenic mouse model of Parkinson's disease.

    PubMed

    Gerstenberger, Julia; Bauer, Anne; Helmschrodt, Christin; Richter, Angelika; Richter, Franziska

    2016-05-01

    Development of disease modifying therapeutics for Parkinson's disease (PD), the second most common neurodegenerative disorder, relies on availability of animal models which recapitulate the disease hallmarks. Only few transgenic mouse models, which mimic overexpression of alpha-synuclein, show dopamine loss, behavioral impairments and protein aggregation. Mice overexpressing human wildtype alpha-synuclein under the Thy-1 promotor (Thy1-aSyn) replicate these features. However, female mice do not exhibit a phenotype. This was attributed to a potentially lower transgene expression located on the X chromosome. Here we support that female mice overexpress human wildtype alpha-synuclein only about 1.5 fold in the substantia nigra, compared to about 3 fold in male mice. Since female Thy1-aSyn mice were shown previously to exhibit differences in corticostriatal communication and synaptic plasticity similar to their male counterparts we hypothesized that female mice use compensatory mechanisms and strategies to not show overt motor deficits despite an underlying endophenotype. In order to unmask these deficits we translated recent findings in PD patients that sensory abnormalities can enhance motor dysfunction into a novel behavioral test, the adaptive rotating beam test. We found that under changing sensory input female Thy1-aSyn mice showed an overt phenotype. Our data supports that the integration of sensorimotor information is likely a major contributor to symptoms of movement disorders and that even low levels of overexpression of human wildtype alpha-synuclein has the potential to disrupt processing of these information. The here described adaptive rotating beam test represents a sensitive behavioral test to detect moderate sensorimotor alterations in mouse models. PMID:26880341

  3. Vesicular expression and release of ATP from dopaminergic neurons of the mouse retina and midbrain

    PubMed Central

    Ho, Tracy; Jobling, Andrew I.; Greferath, Ursula; Chuang, Trinette; Ramesh, Archana; Fletcher, Erica L.; Vessey, Kirstan A.

    2015-01-01

    Vesicular nucleotide transporter (VNUT) is required for active accumulation of adenosine tri-phosphate (ATP) into vesicles for purinergic neurotransmission, however, the cell types that express VNUT in the central nervous system remain unknown. This study characterized VNUT expression within the mammalian retina and brain and assessed a possible functional role in purinergic signaling. Two native isoforms of VNUT were detected in mouse retina and brain based on RNA transcript and protein analysis. Using immunohistochemistry, VNUT was found to co-localize with tyrosine hydroxylase (TH) positive, dopaminergic (DA) neurons of the substantia nigra and ventral tegmental area, however, VNUT expression in extranigral non-DA neurons was also observed. In the retina, VNUT labeling was found to co-localize solely with TH-positive DA-cells. In the outer retina, VNUT-positive interplexiform cell processes were in close contact with horizontal cells and cone photoreceptor terminals, which are known to express P2 purinergic-receptors. In order to assess function, dissociated retinal neurons were loaded with fluorescent ATP markers (Quinacrine or Mant-ATP) and the DA marker FFN102, co-labeled with a VNUT antibody and imaged in real time. Fluorescent ATP markers and FFN102 puncta were found to co-localize in VNUT positive neurons and upon stimulation with high potassium, ATP marker fluorescence at the cell membrane was reduced. This response was blocked in the presence of cadmium. These data suggest DA neurons co-release ATP via calcium dependent exocytosis and in the retina this may modulate the visual response by activating purine receptors on closely associated neurons. PMID:26500494

  4. Vesicular expression and release of ATP from dopaminergic neurons of the mouse retina and midbrain.

    PubMed

    Ho, Tracy; Jobling, Andrew I; Greferath, Ursula; Chuang, Trinette; Ramesh, Archana; Fletcher, Erica L; Vessey, Kirstan A

    2015-01-01

    Vesicular nucleotide transporter (VNUT) is required for active accumulation of adenosine tri-phosphate (ATP) into vesicles for purinergic neurotransmission, however, the cell types that express VNUT in the central nervous system remain unknown. This study characterized VNUT expression within the mammalian retina and brain and assessed a possible functional role in purinergic signaling. Two native isoforms of VNUT were detected in mouse retina and brain based on RNA transcript and protein analysis. Using immunohistochemistry, VNUT was found to co-localize with tyrosine hydroxylase (TH) positive, dopaminergic (DA) neurons of the substantia nigra and ventral tegmental area, however, VNUT expression in extranigral non-DA neurons was also observed. In the retina, VNUT labeling was found to co-localize solely with TH-positive DA-cells. In the outer retina, VNUT-positive interplexiform cell processes were in close contact with horizontal cells and cone photoreceptor terminals, which are known to express P2 purinergic-receptors. In order to assess function, dissociated retinal neurons were loaded with fluorescent ATP markers (Quinacrine or Mant-ATP) and the DA marker FFN102, co-labeled with a VNUT antibody and imaged in real time. Fluorescent ATP markers and FFN102 puncta were found to co-localize in VNUT positive neurons and upon stimulation with high potassium, ATP marker fluorescence at the cell membrane was reduced. This response was blocked in the presence of cadmium. These data suggest DA neurons co-release ATP via calcium dependent exocytosis and in the retina this may modulate the visual response by activating purine receptors on closely associated neurons. PMID:26500494

  5. Paraoxonase 2 (PON2) in the mouse central nervous system: a neuroprotective role?

    PubMed Central

    Giordano, Gennaro; Cole, Toby B.; Furlong, Clement E.; Costa, Lucio G.

    2011-01-01

    The aim of this study was to characterize the expression of paraoxonase 2 (PON2) in mouse brain and to assess its antioxidant properties. PON2 levels were highest in lung, intestine, heart and liver, and lower in brain; in all tissues, PON2 expression was higher in female than in male mice. PON2 knockout [PON2-/-] mice did not express any PON2, as expected. In brain, the highest levels of PON2 were found in the substantia nigra, the nucleus accumbens and the striatum, with lower levels in the cerebral cortex, hippocampus, cerebellum and brainstem. A similar regional distribution of PON2 activity (measured by dihydrocoumarin hydrolysis) was also found. PON3 was not detected in any brain area, while PON1 was expressed at very low levels, and did not show any regional difference. PON2 levels were higher in astrocytes than in neurons isolated from all brain regions, and were highest in cells from the striatum. PON2 activity and mRNA levels followed a similar pattern. Brain PON2 levels were highest around birth, and gradually declined. Subcellular distribution experiments indicated that PON2 is primarily expressed in microsomes and in mitochondria. The toxicity in neurons and astrocytes of agents known to cause oxidative stress (DMNQ and H2O2) was higher in cells from PON2-/- mice than in the same cells from wild-type mice, despite similar glutathione levels. These results indicate that PON2 is expressed in brain, and that higher levels are found in dopaminergic regions such as the striatum, suggesting that this enzyme may provide protection against oxidative stress-mediated neurotoxicity. PMID:21354197

  6. Neuroanatomical Visualization of the Impaired Striatal Connectivity in Huntington's Disease Mouse Model.

    PubMed

    Kim, Dohee; Jeon, Jeha; Cheong, Eunji; Kim, Dong Jin; Ryu, Hoon; Seo, Hyemyung; Kim, Yun Kyung

    2016-05-01

    Huntington's disease (HD) is a movement disorder characterized by the early selective degeneration of striatum. For motor control, the striatum receives excitatory inputs from multiple brain regions and projects the information to other basal ganglia nuclei. Despite the pathological importance of the striatal degeneration in HD, there are little anatomical data that show impaired striatal connectivity in HD. For the anatomical mapping of the striatum, we injected here a neurotracer DiD to the dorsal striatum of HD mouse model (YAC128). Compared with littermate controls, the number of the traced inputs to the striatum was reduced dramatically in YAC128 mice at 12 months of age suggesting massive destruction of the striatal connections. Basal ganglia inputs were significantly damaged in HD mice by showing 61 % decrease in substantia nigra pars compacta, 85% decrease in thalamic centromedian nucleus, and 55% decrease in thalamic parafascicular nucleus. Cortical inputs were also greatly decreased by 43% in motor cortex, 48% in somatosensory cortex, and 72% in visual cortex. Besides the known striatal connections, the neurotracer DiD also traced inputs from amygdala and the amygdala inputs were decreased by 68% in YAC128 mice. Considering the role of amygdala in emotion processing, the impairment in amygdalostriatal connectivity strongly suggests that emotional disturbances could occur in HD mice. Indeed, open-field tests further indicated that YAC128 mice exhibited changes in emotional behaviors related to symptoms of depression and anxiety. Although onset of HD is clinically determined on the basis of motor abnormality, emotional deficits are also common features of the disease. Therefore, our anatomical connectivity mapping of the striatum provides a new insight to interpret brain dysfunction in HD. PMID:25976370

  7. Paraoxonase 2 (PON2) in the mouse central nervous system: A neuroprotective role?

    SciTech Connect

    Giordano, Gennaro; Cole, Toby B.; Furlong, Clement E.; Costa, Lucio G.

    2011-11-15

    The aims of this study were to characterize the expression of paraoxonase 2 (PON2) in mouse brain and to assess its antioxidant properties. PON2 levels were highest in the lung, intestine, heart and liver, and lower in the brain; in all tissues, PON2 expression was higher in female than in male mice. PON2 knockout [PON2{sup -/-}] mice did not express any PON2, as expected. In the brain, the highest levels of PON2 were found in the substantia nigra, the nucleus accumbens and the striatum, with lower levels in the cerebral cortex, hippocampus, cerebellum and brainstem. A similar regional distribution of PON2 activity (measured by dihydrocoumarin hydrolysis) was also found. PON3 was not detected in any brain area, while PON1 was expressed at very low levels, and did not show any regional difference. PON2 levels were higher in astrocytes than in neurons isolated from all brain regions, and were highest in cells from the striatum. PON2 activity and mRNA levels followed a similar pattern. Brain PON2 levels were highest around birth, and gradually declined. Subcellular distribution experiments indicated that PON2 is primarily expressed in microsomes and in mitochondria. The toxicity in neurons and astrocytes of agents known to cause oxidative stress (DMNQ and H{sub 2}O{sub 2}) was higher in cells from PON2{sup -/-} mice than in the same cells from wild-type mice, despite similar glutathione levels. These results indicate that PON2 is expressed in the brain, and that higher levels are found in dopaminergic regions such as the striatum, suggesting that this enzyme may provide protection against oxidative stress-mediated neurotoxicity.

  8. Tinea nigra presenting speckled or "salt and pepper" pattern.

    PubMed

    Rossetto, André Luiz; Cruz, Rosana Cé Bella; Haddad, Vidal Junior

    2014-06-01

    A 7-year-old Caucasian female resident of the southern coast of Brazil presented dark spots on the left palm that converged to a unique macule with speckled pattern at about 1 month. The mycological exam and the fungi culture were typical of Hortaea werneckii, the agent of the superficial mycosis Tinea nigra. The patient received butenafine hydrochloride 1% for 30 days, resulting in a complete remission of the lesion. At a follow-up visit 12 months after treatment, there was no lesion recurrence. We describe a form of rare geographical Tinea nigra with a speckled pattern. The "salt and pepper" aspect should be taken into consideration when the mycosis was suspected. PMID:24898980

  9. Loss of collapsin response mediator protein 4 suppresses dopaminergic neuron death in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson's disease.

    PubMed

    Tonouchi, Aine; Nagai, Jun; Togashi, Kentaro; Goshima, Yoshio; Ohshima, Toshio

    2016-06-01

    Parkinson's disease (PD) is a progressive neurodegenerative disorder that is characterized by the selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNc). Several lines of evidence suggest that neurodegeneration in PD is accelerated by a vicious cycle in which apoptosis in dopaminergic neurons triggers the activation of microglia and harmful inflammatory processes that further amplify neuronal death. Recently, we demonstrated that the deletion of collapsin response mediator protein 4 (CRMP4) suppresses inflammatory responses and cell death in a mouse model of spinal cord injury, leading to improved functional recovery. We thus hypothesized that Crmp4-/- mice may have limited inflammatory responses and a decrease in the loss of SNc dopaminergic neurons in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model. We observed CRMP4 expression in neurons, astrocytes, and microglia/macrophages following the injection of 25 mg/kg MPTP. We compared the number of dopaminergic neurons and the inflammatory response in SNc between Crmp4+/+ and Crmp4-/- mice after MPTP injection. Limited loss of SNc dopaminergic neurons and decreased activations of microglia and astrocytes were observed in Crmp4-/- mice. These results suggest that CRMP4 is a novel therapeutic target in the treatment of PD patients. We demonstrated that genetic CRMP4 deletion delays a vicious cycle of inflammation and neurodegeneration in a Parkinson's disease mouse model. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) injection to wild-type mice induces collapsin response mediator protein 4 (CRMP4) up-regulation in neurons, astrocytes, and microglia. CRMP4-deficient mice show reduced inflammation and suppressed dopaminergic neuronal death after MPTP injection. These findings suggest that CRMP4 deletion may be a new therapeutic strategy against Parkinson's diseases. PMID:26991935

  10. Neuroprotective effects of piperine on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson's disease mouse model.

    PubMed

    Yang, Wei; Chen, Yu-Hua; Liu, Hao; Qu, Hong-Dang

    2015-11-01

    Parkinson's disease (PD) is second only to Alzheimer's disease as the most common and debilitating age-associated neurodegenerative disorder. Currently, no therapy has been shown to unequivocally retard or arrest the progression of the disease. The aim of the present study was to investigate the protective effect of piperine on the 1-methyl-4-phenyl-1,2,3,6‑tetrahydropyridine (MPTP)-induced Parkinson's mouse model. For MPTP treatment, the animals received repeated intraperitoneal injections (i.p.) of MPTP (30 mg/kg) solution for 7 days. Piperine (10 mg/kg) was administered orally for 15 days including 8 days of pretreatment. Motor behavior analysis was conducted with the rotarod test. The Morris water maze (MWM) was used to assess the cognitive learning ability of the mice. A histological examination was subsequently conducted. The results ddemonstrate that piperine treatment attenuated MPTP-induced deficits in motor coordination and cognitive functioning. Piperine also prevented MPTP-induced decreases in the number of tyrosine hydroxylase-positive cells in the substantia nigra. Additionally, piperine reduced the number of activated microglia, expression of cytokine IL-1β, and oxidative stress following MPTP treatment. An anti-apoptotic property of piperine was identified by maintaining the balance of Bcl-2/Bax. In conclusion, the results show that piperine exerts a protective effect on dopaminergic neurons via antioxidant, anti-apoptotic, and anti-inflammatory mechanisms in an MPTP-induced mouse model of PD. Thus, piperine is a potential therapeutic treatment for PD. PMID:26648012

  11. Diffusion Kurtosis Imaging Detects Microstructural Alterations in Brain of α-Synuclein Overexpressing Transgenic Mouse Model of Parkinson's Disease: A Pilot Study.

    PubMed

    Khairnar, Amit; Latta, Peter; Drazanova, Eva; Ruda-Kucerova, Jana; Szabó, Nikoletta; Arab, Anas; Hutter-Paier, Birgit; Havas, Daniel; Windisch, Manfred; Sulcova, Alexandra; Starcuk, Zenon; Rektorova, Irena

    2015-11-01

    Evidence suggests that accumulation and aggregation of α-synuclein contribute to the pathogenesis of Parkinson's disease (PD). The aim of this study was to evaluate whether diffusion kurtosis imaging (DKI) will provide a sensitive tool for differentiating between α-synuclein-overexpressing transgenic mouse model of PD (TNWT-61) and wild-type (WT) littermates. This experiment was designed as a proof-of-concept study and forms a part of a complex protocol and ongoing translational research. Nine-month-old TNWT-61 mice and age-matched WT littermates underwent behavioral tests to monitor motor impairment and MRI scanning using 9.4 Tesla system in vivo. Tract-based spatial statistics (TBSS) and the DKI protocol were used to compare the whole brain white matter of TNWT-61 and WT mice. In addition, region of interest (ROI) analysis was performed in gray matter regions such as substantia nigra, striatum, hippocampus, sensorimotor cortex, and thalamus known to show higher accumulation of α-synuclein. For the ROI analysis, both DKI (6 b-values) protocol and conventional (2 b-values) diffusion tensor imaging (cDTI) protocol were used. TNWT-61 mice showed significant impairment of motor coordination. With the DKI protocol, mean, axial, and radial kurtosis were found to be significantly elevated, whereas mean and radial diffusivity were decreased in the TNWT-61 group compared to that in the WT controls with both TBSS and ROI analysis. With the cDTI protocol, the ROI analysis showed decrease in all diffusivity parameters in TNWT-61 mice. The current study provides evidence that DKI by providing both kurtosis and diffusivity parameters gives unique information that is complementary to cDTI for in vivo detection of pathological changes that underlie PD-like symptomatology in TNWT-61 mouse model of PD. This result is a crucial step in search for a candidate diagnostic biomarker with translational potential and relevance for human studies. PMID:26153486

  12. A new humanized ataxin-3 knock-in mouse model combines the genetic features, pathogenesis of neurons and glia and late disease onset of SCA3/MJD.

    PubMed

    Switonski, Pawel M; Szlachcic, Wojciech J; Krzyzosiak, Wlodzimierz J; Figiel, Maciej

    2015-01-01

    Spinocerebellar ataxia type 3 (SCA3/MJD) is a neurodegenerative disease triggered by the expansion of CAG repeats in the ATXN3 gene. Here, we report the generation of the first humanized ataxin-3 knock-in mouse model (Ki91), which provides insights into the neuronal and glial pathology of SCA3/MJD. First, mutant ataxin-3 accumulated in cell nuclei across the Ki91 brain, showing diffused immunostaining and forming intranuclear inclusions. The humanized allele revealed expansion and contraction of CAG repeats in intergenerational transmissions. CAG mutation also exhibited age-dependent tissue-specific expansion, which was most prominent in the cerebellum, pons and testes of Ki91 animals. Moreover, Ki91 mice displayed neuroinflammatory processes, showing astrogliosis in the cerebellar white matter and the substantia nigra that paralleled the transcriptional deregulation of Serpina3n, a molecular sign of neurodegeneration and brain damage. Simultaneously, the cerebellar Purkinje cells in Ki91 mice showed neurodegeneration, a pronounced decrease in Calbindin D-28k immunoreactivity and a mild decrease in cell number, thereby modeling the degeneration of the cerebellum observed in SCA3. Moreover, these molecular and cellular neuropathologies were accompanied by late behavioral deficits in motor coordination observed in rotarod and static rod tests in heterozygous Ki91 animals. In summary, we created an ataxin-3 knock-in mouse model that combines the molecular and behavioral disease phenotypes with the genetic features of SCA3. This model will be very useful for studying the pathogenesis and responses to therapy of SCA3/MJD and other polyQ disorders. PMID:25301414

  13. Identification of Multiple QTLs Linked to Neuropathology in the Engrailed-1 Heterozygous Mouse Model of Parkinson's Disease.

    PubMed

    Kurowska, Zuzanna; Jewett, Michael; Brattås, Per Ludvik; Jimenez-Ferrer, Itzia; Kenéz, Xuyian; Björklund, Tomas; Nordström, Ulrika; Brundin, Patrik; Swanberg, Maria

    2016-01-01

    Motor symptoms in Parkinson's disease are attributed to degeneration of midbrain dopaminergic neurons (DNs). Heterozygosity for Engrailed-1 (En1), one of the key factors for programming and maintenance of DNs, results in a parkinsonian phenotype featuring progressive degeneration of DNs in substantia nigra pars compacta (SNpc), decreased striatal dopamine levels and swellings of nigro-striatal axons in the SwissOF1-En1+/- mouse strain. In contrast, C57Bl/6-En1+/- mice do not display this neurodegenerative phenotype, suggesting that susceptibility to En1 heterozygosity is genetically regulated. Our goal was to identify quantitative trait loci (QTLs) that regulate the susceptibility to PD-like neurodegenerative changes in response to loss of one En1 allele. We intercrossed SwissOF1-En1+/- and C57Bl/6 mice to obtain F2 mice with mixed genomes and analyzed number of DNs in SNpc and striatal axonal swellings in 120 F2-En1+/- 17 week-old male mice. Linkage analyses revealed 8 QTLs linked to number of DNs (p = 2.4e-09, variance explained = 74%), 7 QTLs linked to load of axonal swellings (p = 1.7e-12, variance explained = 80%) and 8 QTLs linked to size of axonal swellings (p = 7.0e-11, variance explained = 74%). These loci should be of prime interest for studies of susceptibility to Parkinson's disease-like damage in rodent disease models and considered in clinical association studies in PD. PMID:27550741

  14. Identification of Multiple QTLs Linked to Neuropathology in the Engrailed-1 Heterozygous Mouse Model of Parkinson’s Disease

    PubMed Central

    Kurowska, Zuzanna; Jewett, Michael; Brattås, Per Ludvik; Jimenez-Ferrer, Itzia; Kenéz, Xuyian; Björklund, Tomas; Nordström, Ulrika; Brundin, Patrik; Swanberg, Maria

    2016-01-01

    Motor symptoms in Parkinson’s disease are attributed to degeneration of midbrain dopaminergic neurons (DNs). Heterozygosity for Engrailed-1 (En1), one of the key factors for programming and maintenance of DNs, results in a parkinsonian phenotype featuring progressive degeneration of DNs in substantia nigra pars compacta (SNpc), decreased striatal dopamine levels and swellings of nigro-striatal axons in the SwissOF1-En1+/− mouse strain. In contrast, C57Bl/6-En1+/− mice do not display this neurodegenerative phenotype, suggesting that susceptibility to En1 heterozygosity is genetically regulated. Our goal was to identify quantitative trait loci (QTLs) that regulate the susceptibility to PD-like neurodegenerative changes in response to loss of one En1 allele. We intercrossed SwissOF1-En1+/− and C57Bl/6 mice to obtain F2 mice with mixed genomes and analyzed number of DNs in SNpc and striatal axonal swellings in 120 F2-En1+/− 17 week-old male mice. Linkage analyses revealed 8 QTLs linked to number of DNs (p = 2.4e-09, variance explained = 74%), 7 QTLs linked to load of axonal swellings (p = 1.7e-12, variance explained = 80%) and 8 QTLs linked to size of axonal swellings (p = 7.0e-11, variance explained = 74%). These loci should be of prime interest for studies of susceptibility to Parkinson’s disease-like damage in rodent disease models and considered in clinical association studies in PD. PMID:27550741

  15. Neutralization of RANTES and Eotaxin Prevents the Loss of Dopaminergic Neurons in a Mouse Model of Parkinson Disease.

    PubMed

    Chandra, Goutam; Rangasamy, Suresh B; Roy, Avik; Kordower, Jeffrey H; Pahan, Kalipada

    2016-07-15

    Parkinson disease (PD) is second only to Alzheimer disease as the most common human neurodegenerative disorder. Despite intense investigation, no interdictive therapy is available for PD. Recent studies indicate that both innate and adaptive immune processes are active in PD. Accordingly, we found a rapid increase in RANTES (regulated on activation normal T cell expressed and secreted) and eotaxin, chemokines that are involved in T cell trafficking, in vivo in the substantia nigra pars compacta and the serum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mice. RANTES and eotaxin were also up-regulated in the substantia nigra pars compacta of post-mortem PD brains as compared with age-matched controls. Therefore, we investigated whether neutralization of RANTES and eotaxin could protect against nigrostriatal degeneration in MPTP-intoxicated mice. Interestingly, after peripheral administration, functional blocking antibodies against RANTES and eotaxin reduced the infiltration of CD4(+) and CD8(+) T cells into the nigra, attenuated nigral expression of proinflammatory molecules, and suppressed nigral activation of glial cells. These findings paralleled dopaminergic neuronal protection, normalized striatal neurotransmitters, and improved motor functions in MPTP-intoxicated mice. Therefore, we conclude that attenuation of the chemokine-dependent adaptive immune response may be of therapeutic benefit for PD patients. PMID:27226559

  16. Responses of non-structural carbohydrates to shoot removal and soil moisture treatments in Salix nigra

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Above-ground disturbances are common in dynamic riparian environments, and Salix nigra is well-adapted with a vigorous resprouting response. Soil moisture stresses are also common, and S. nigra is flood tolerant and drought sensitive. Nonstructural carbohydrate (NSC) reserves provide energy for rege...

  17. Bacillus Calmette-Guerin vaccine-mediated neuroprotection is associated with regulatory T-cell induction in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease.

    PubMed

    Laćan, Goran; Dang, Hoa; Middleton, Blake; Horwitz, Marcus A; Tian, Jide; Melega, William P; Kaufman, Daniel L

    2013-10-01

    We previously showed that, in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD), vaccination with bacillus Calmette-Guerin (BCG) prior to MPTP exposure limited the loss of striatal dopamine (DA) and dopamine transporter (DAT) and prevented the activation of nigral microglia. Here, we conducted BCG dose studies and investigated the mechanisms underlying BCG vaccination's neuroprotective effects in this model. We found that a dose of 1 × 10(6) cfu BCG led to higher levels of striatal DA and DAT ligand binding (28% and 42%, respectively) in BCG-vaccinated vs. unvaccinated MPTP-treated mice, but without a significant increase in substantia nigra tyrosine hydroxylase-staining neurons. Previous studies showed that BCG can induce regulatory T cells (Tregs) and that Tregs are neuroprotective in models of neurodegenerative diseases. However, MPTP is lymphotoxic, so it was unclear whether Tregs were maintained after MPTP treatment and whether a relationship existed between Tregs and the preservation of striatal DA system integrity. We found that, 21 days post-MPTP treatment, Treg levels in mice that had received BCG prior to MPTP were threefold greater than those in MPTP-only-treated mice and elevated above those in saline-only-treated mice, suggesting that the persistent BCG infection continually promoted Treg responses. Notably, the magnitude of the Treg response correlated positively with both striatal DA levels and DAT ligand binding. Therefore, BCG vaccine-mediated neuroprotection is associated with Treg levels in this mouse model. Our results suggest that BCG-induced Tregs could provide a new adjunctive therapeutic approach to ameliorating pathology associated with PD and other neurodegenerative diseases. PMID:23907992

  18. DYRK1A promotes dopaminergic neuron survival in the developing brain and in a mouse model of Parkinson's disease

    PubMed Central

    Barallobre, M J; Perier, C; Bové, J; Laguna, A; Delabar, J M; Vila, M; Arbonés, M L

    2014-01-01

    In the brain, programmed cell death (PCD) serves to adjust the numbers of the different types of neurons during development, and its pathological reactivation in the adult leads to neurodegeneration. Dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A) is a pleiotropic kinase involved in neural proliferation and cell death, and its role during brain growth is evolutionarily conserved. Human DYRK1A lies in the Down syndrome critical region on chromosome 21, and heterozygous mutations in the gene cause microcephaly and neurological dysfunction. The mouse model for DYRK1A haploinsufficiency (the Dyrk1a+/− mouse) presents neuronal deficits in specific regions of the adult brain, including the substantia nigra (SN), although the mechanisms underlying these pathogenic effects remain unclear. Here we study the effect of DYRK1A copy number variation on dopaminergic cell homeostasis. We show that mesencephalic DA (mDA) neurons are generated in the embryo at normal rates in the Dyrk1a haploinsufficient model and in a model (the mBACtgDyrk1a mouse) that carries three copies of Dyrk1a. We also show that the number of mDA cells diminishes in postnatal Dyrk1a+/− mice and increases in mBACtgDyrk1a mice due to an abnormal activity of the mitochondrial caspase9 (Casp9)-dependent apoptotic pathway during the main wave of PCD that affects these neurons. In addition, we show that the cell death induced by 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP), a toxin that activates Casp9-dependent apoptosis in mDA neurons, is attenuated in adult mBACtgDyrk1a mice, leading to an increased survival of SN DA neurons 21 days after MPTP intoxication. Finally, we present data indicating that Dyrk1a phosphorylation of Casp9 at the Thr125 residue is the mechanism by which this kinase hinders both physiological and pathological PCD in mDA neurons. These data provide new insight into the mechanisms that control cell death in brain DA neurons and they show that

  19. Two new lignans and melanogenesis inhibitors from Schisandra nigra.

    PubMed

    Narukawa, Yuji; Komatsu, Chihiro; Yamauchi, Rina; Shibayama, Sakiko; Hachisuka, Mayuko; Kiuchi, Fumiyuki

    2016-07-01

    An acetone extract from the stems of Schisandra nigra MAX. (Schisandraceae) exhibited significant inhibition of 3-isobutyl-1-methylxanthine (IBMX)-stimulated melanogenesis in murine B16 melanoma F10 cells. Fractionation and purification of the extract led to the isolation of two new tetrahydrofuran-type lignans, (+)-5-methoxyzuonin A (2) and kadlongirin C (3), along with eight known compounds (1, 4-10). The structures of the new compounds were determined by spectroscopic analyses. Of the isolated compounds (1, 3 -10), (+)-zuonin A (1) showed remarkable inhibition of melanogenesis at concentrations without cytotoxicity in B16 melanoma F10 cells. (+)-Zuonin A (1) did not inhibit tyrosinase; however, Western blot analysis revealed that it decreased protein levels of tyrosinase and tyrosinase-related proteins (TRP)-1 and TRP-2 without changing phosphorylation level of cAMP response element-binding protein. PMID:27142263

  20. High density of benzodiazepine binding sites in the substantia innominata of the rat

    SciTech Connect

    Sarter, M.; Schneider, H.H.

    1988-07-01

    In order to study the neuronal basis of the pharmacological interactions between benzodiazepine receptor ligands and cortical cholinergic turnover, we examined the regional distribution of specific benzodiazepine binding sites using in vitro autoradiography. In the basal forebrain, the substantia innominata contained a high density of (/sup 3/H)lormetazepam (LMZ) binding sites (Bmax = 277 fmol/mg tissue; Kd = 0.55 nM). The label could be displaced by diazepam (IC50 = 100 nM), the benzodiazepine receptor antagonist beta-carboline ZK 93426 (45 nM) and the partial inverse agonist beta-carboline FG 7142 (540 nM). It is hypothesized that the amnesic effects of benzodiazepine receptor agonists are exerted through benzodiazepine receptors which are situated on cholinergic neurons in the substantia innominata and are involved in a tonic inhibition of cortical acetylcholine release. The benzodiazepine receptor antagonist ZK 93426 may exert its nootropic effects via benzodiazepine receptors in the substantia innominata and, consequently, by disinhibiting cortical acetylcholine release.

  1. Changes in Sensitivity of Reward and Motor Behavior to Dopaminergic, Glutamatergic, and Cholinergic Drugs in a Mouse Model of Fragile X Syndrome

    PubMed Central

    Fish, Eric W.; Krouse, Michael C.; Stringfield, Sierra J.; DiBerto, Jeffrey F.; Robinson, J. Elliott; Malanga, C. J.

    2013-01-01

    Fragile X syndrome (FXS) is a leading cause of intellectual disability. FXS is caused by loss of function of the FMR1 gene, and mice in which Fmr1 has been inactivated have been used extensively as a preclinical model for FXS. We investigated the behavioral pharmacology of drugs acting through dopaminergic, glutamatergic, and cholinergic systems in fragile X (Fmr1-/Y) mice with intracranial self-stimulation (ICSS) and locomotor activity measurements. We also measured brain expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine biosynthesis. Fmr1-/Y mice were more sensitive than wild type mice to the rewarding effects of cocaine, but less sensitive to its locomotor stimulating effects. Anhedonic but not motor depressant effects of the atypical neuroleptic, aripiprazole, were reduced in Fmr1-/Y mice. The mGluR5-selective antagonist, 6-methyl-2-(phenylethynyl)pyridine (MPEP), was more rewarding and the preferential M1 antagonist, trihexyphenidyl, was less rewarding in Fmr1-/Y than wild type mice. Motor stimulation by MPEP was unchanged, but stimulation by trihexyphenidyl was markedly increased, in Fmr1-/Y mice. Numbers of midbrain TH+ neurons in the ventral tegmental area were unchanged, but were lower in the substantia nigra of Fmr1-/Y mice, although no changes in TH levels were found in their forebrain targets. The data are discussed in the context of known changes in the synaptic physiology and pharmacology of limbic motor systems in the Fmr1-/Y mouse model. Preclinical findings suggest that drugs acting through multiple neurotransmitter systems may be necessary to fully address abnormal behaviors in individuals with FXS. PMID:24205018

  2. Specific Distribution of the Autophagic Protein GABARAPL1/GEC1 in the Developing and Adult Mouse Brain and Identification of Neuronal Populations Expressing GABARAPL1/GEC1

    PubMed Central

    Le Grand, Jaclyn Nicole; Bon, Karine; Fraichard, Annick; Zhang, Jianhua; Jouvenot, Michèle; Risold, Pierre-Yves; Boyer-Guittaut, Michaël; Delage-Mourroux, Régis

    2013-01-01

    Macroautophagy is a highly conserved cellular degradation process, regulated by autophagy-related (atg) factors, in which a double membrane autophagosome engulfs cytoplasmic components to target them for degradation. In yeast, the Atg8 protein is indispensable for autophagosome formation. In mammals, this is complicated by the presence of six Atg8 homologues grouped into the GABARAP and MAP1LC3 subfamilies. Although these proteins share a high similarity, their transcript expression, regulation and protein interactions differ, suggesting they may display individual properties and specific functions. GABARAPL1/GEC1 is a member of the GABARAP subfamily and its mRNA is the most highly expressed Atg8 homologue in the central nervous system. Consequently, we performed an in depth study of GABARAPL1 distribution in the developing and adult murine brain. Our results show that GABARAPL1 brain expression is visible as early as embryonic day 11 and progressively increases to a maximum level in the adult. Immunohistochemical staining was detected in both fibers and immature neurons in embryos but was restrained to neurons in adult tissue. By E17, intense punctate-like structures were visible and these accumulated in cortical primary neurons treated with the autophagosome/lysosome fusion inhibitor Bafilomycin A1 (Baf A1), suggesting that they represent autophagosomes. Finally, GABARAPL1 expression was particularly intense in motoneurons in the embryo and in neurons involved in somatomotor and neuroendocrine functions in the adult, particularly in the substantia nigra pars compacta, a region affected in Parkinson's disease. Our study of cerebral GABARAPL1 protein expression provides insight into its role in the development and homeostasis of the mouse brain. PMID:23690988

  3. The soluble isoform of CX3CL1 is necessary for neuroprotection in a mouse model of Parkinson’s disease

    PubMed Central

    Morganti, Josh M.; Nash, Kevin R.; Grimmig, Bethany A.; Ranjit, Sonali; Small, Brent; Bickford, Paula C.; Gemma, Carmelina

    2012-01-01

    The chemokine CX3CL1/fractalkine is expressed by neurons as a transmembrane-anchored protein, which can be cleaved to yield a soluble isoform. However, the roles for these two types of endogenous CX3CL1 in neurodegenerative pathophysiology remain elusive. As such, it has been difficult to delineate the function of the two isoforms of CX3CL1, as both are natively present in the brain. In this study we examined each isoform’s ability to regulate neuroinflammation in a mouse model of Parkinson’s disease initiated by the neurotoxin 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP). We were able to delineate the function of both CX3CL1 isoforms by using AAV mediated gene therapy to selectively express synthetic variants of CX3CL1 that remain either permanently soluble or membrane-bound. In the present study we injected each CX3CL1 variant or a GFP expressing vector directly into the substantia nigra of CX3CL1−/− mice. Our results show that only the soluble isoform of CX3CL1 is sufficient for neuroprotection after exposure to MPTP. Specifically, we show that the soluble CX3CL1 isoform reduces impairment of motor coordination, decreases dopaminergic neuron loss, and ameliorates microglia activation and pro-inflammatory cytokine release, resulting from MPTP exposure. Furthermore, we show that the membrane-bound isoform provides no neuroprotective capability to MPTP-induced pathologies, exhibiting similar motor coordination impairment, dopaminergic neuron loss, and inflammatory phenotypes as MPTP-treated CX3CL1−/− mice, which received the GFP expressing control vector. Our results reveal that the neuroprotective capacity of CX3CL1 resides solely upon the soluble isoform in an MPTP-induced model of Parkinson’s disease. PMID:23077045

  4. Neuroprotective and anti-inflammatory effects of the adenosine A(2A) receptor antagonist ST1535 in a MPTP mouse model of Parkinson's disease.

    PubMed

    Frau, Lucia; Borsini, Franco; Wardas, Jadwiga; Khairnar, Amit S; Schintu, Nicoletta; Morelli, Micaela

    2011-03-01

    Adenosine A(2A) receptor antagonists are one of the most attractive classes of drug for the treatment of Parkinson's disease (PD) as they are effective in counteracting motor dysfunctions and display neuroprotective and anti-inflammatory effects in animal models of PD. In this study, we evaluated the neuroprotective and anti-inflammatory properties of the adenosine A(2A) receptor antagonist ST1535 in a subchronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. C57BL/6J mice were repeatedly administered with vehicle, MPTP (20 mg/kg), or MPTP + ST1535 (2 mg/kg). Mice were sacrificed three days after the last administration of MPTP. Immunohistochemistry for tyrosine hydroxylase (TH) and cresyl violet staining were employed to evaluate dopaminergic neuron degeneration in the substantia nigra pars compacta (SNc) and caudate-putamen (CPu). CD11b and glial fibrillary acidic protein (GFAP) immunoreactivity were, respectively, evaluated as markers of microglial and astroglial response in the SNc and CPu. Stereological analysis for TH revealed a 32% loss of dopaminergic neurons in the SNc after repeated MPTP administration, which was completely prevented by ST1535 coadministration. Similarly, CPu decrease in TH (25%) was prevented by ST1535. MPTP treatment induced an intense gliosis in both the SNc and CPu. ST1535 totally prevented CD11b immunoreactivity in both analyzed areas, but only partially blocked GFAP increase in the SNc and CPu. A(2A) receptor antagonism is a new opportunity for improving symptomatic PD treatment. With its neuroprotective effect on dopaminergic neuron toxicity induced by MPTP and its antagonism on glial activation, ST1535 represents a new prospect for a disease-modifying drug. PMID:20665698

  5. Neuroprotective effects of lixisenatide and liraglutide in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease.

    PubMed

    Liu, W; Jalewa, J; Sharma, M; Li, G; Li, L; Hölscher, C

    2015-09-10

    Glucagon-like peptide 1 (GLP-1) is a growth factor. GLP-1 mimetics are on the market as treatments for type 2 diabetes and are well tolerated. These drugs have shown neuroprotective properties in animal models of neurodegenerative disorders. In addition, the GLP-1 mimetic exendin-4 has shown protective effects in animal models of Parkinson's disease (PD), and a clinical trial in PD patients showed promising first results. Liraglutide and lixisenatide are two newer GLP-1 mimetics which have a longer biological half-life than exendin-4. We previously showed that these drugs have neuroprotective properties in an animal model of Alzheimer's disease. Here we demonstrate the neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. MPTP was injected once-daily (20mg/kg i.p.) for 7 days, and drugs were injected once-daily for 14 days i.p. When comparing exendin-4 (10 nmol/kg), liraglutide (25 nmol/kg) and lixisenatide (10 nmol/kg), it was found that exendin-4 showed no protective effects at the dose chosen. Both liraglutide and lixisenatide showed effects in preventing the MPTP-induced motor impairment (Rotarod, open-field locomotion, catalepsy test), reduction in tyrosine hydroxylase (TH) levels (dopamine synthesis) in the substantia nigra and basal ganglia, a reduction of the pro-apoptotic signaling molecule BAX and an increase in the anti-apoptotic signaling molecule B-cell lymphoma-2. The results demonstrate that in this study, both liraglutide and lixisenatide are superior to exendin-4, and both drugs show promise as a novel treatment of PD. PMID:26141845

  6. Herbivores mediate different competitive and facilitative responses of native and invader populations of Brassica nigra.

    PubMed

    Oduor, Ayub M O; Strauss, Sharon Y; García, Yedra; Cascales, Modesto Berbel; Gómez, José M

    2013-10-01

    Differences in plant and herbivore community assemblages between exotic and native ranges may select for different levels of plant traits in invasive and native populations of plant species. Little is currently known of how herbivores may mediate competitive and facilitative interactions between invasive and native populations of plant species and their plant neighbors. Here, we conducted a common-garden field experiment to test whether invasive and native populations of Brassica nigra differ in phenotypic expressions of growth (biomass and plant height) and reproductive (seed yield) traits under different plant neighbor treatments and ambient vs. reduced level of insect herbivore damage on the B. nigra plants. We found significant interactive effects of plant neighbor treatments, level of insect herbivore damage on B. nigra plants, and invasive status of B. nigra on the phenotypic trait expressions. Plant neighbor treatments had minimal effects on phenotypic trait expressions by invasive populations of B. nigra under either level of insect herbivore damage. In contrast, for native populations of B. nigra, ambient level of insect herbivore damage resulted in plant neighbors facilitating expression of the traits above, while reduced damage resulted in plant neighbors competitively suppressing trait expression. Our results suggest that insect herbivores and plant neighbors interactively shape expression of plant traits in native and exotic ranges of invasive plants. Such interactions could potentially lead to different selection pressures on traits that determine antiherbivore defenses and plant-plant interactions. PMID:24358714

  7. Protective effects of 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside in the MPTP-induced mouse model of Parkinson's disease: Involvement of reactive oxygen species-mediated JNK, P38 and mitochondrial pathways.

    PubMed

    He, Hong; Wang, Songhai; Tian, Jiyu; Chen, Lei; Zhang, Wei; Zhao, Junjie; Tang, Haifeng; Zhang, Xiaojun; Chen, Jianzong

    2015-11-15

    Parkinson's disease (PD) is characterized by the selective death of dopaminergic neurons in the substantia nigra pars compacta. Oxidative stress-induced neuron loss is thought to play a crucial role in the pathogenesis of PD. Previous work from our group suggests that 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (TSG), an active component extracted from a traditional Chinese herb, Polygonum multiflorum thunb, can attenuate 1-methyl-4-phenyl pyridium-induced apoptosis in the neuronal cell line PC12, by inhibiting reactive oxygen species generation and modulating c-Jun N-terminal kinases (JNK) activation. Here, we investigated the protective effects of TSG against 1-methyl-4-phenyl-1,2,3,6-tetrahydropypridine (MPTP)-induced loss of tyrosine hydroxylase positive cells in mice and the underlying mechanisms. The results showed that MPTP-induced loss of tyrosine hydroxylase positive cells and reactive oxygen species generation were prevented by TSG in a dose-dependent manner. The reactive oxygen species scavenger N-acetylcysteine could also mitigate reactive oxygen species generation. Moreover, JNK and P38 were activated by MPTP, but extracellular signal-regulated protein kinases phosphorylation did not change after MPTP treatment. TSG at different doses blocked the activation of JNK and P38. The protective effect of TSG was also associated with downregulation of the bax/bcl-2 ratio, reversed the release of cytochrome c and smac, and inhibited the activation of caspase-3, -6, and -9 induced by MPTP. In conclusion, our studies demonstrated that the protective effects of TSG in the MPTP-induced mouse model of PD are involved, at least in part, in controlling reactive oxygen species-mediated JNK, P38, and mitochondrial pathways. PMID:26477638

  8. Signaling complex formation of phospholipase Cbeta4 with metabotropic glutamate receptor type 1alpha and 1,4,5-trisphosphate receptor at the perisynapse and endoplasmic reticulum in the mouse brain.

    PubMed

    Nakamura, Michiko; Sato, Kazunori; Fukaya, Masahiro; Araishi, Kenji; Aiba, Atsu; Kano, Masanobu; Watanabe, Masahiko

    2004-12-01

    Upon activation of cell surface receptors coupled to the Gq subclass of G proteins, phospholipase C (PLC) beta hydrolyses membrane phospholipid to yield a pair of second messengers, inositol 1,4,5-trisphosphate (IP3) and 1,2-diacylglycerol. PLCbeta4 has been characterized as the isoform enriched in cerebellar Purkinje cells (PCs) and the retina and involved in motor and visual functions. Here we examined cellular and subcellular distributions of PLCbeta4 in adult mouse brains. Immunohistochemistry showed that high levels of PLCbeta4 were detected in the somatodendritic domain of neuronal populations expressing the metabotropic glutamate receptor (mGluR) type 1alpha, including olfactory periglomerular cells, neurons in the bed nucleus anterior commissure, thalamus, substantia nigra, inferior olive, and unipolar brush cells and PCs in the cerebellum. Low to moderate levels were detected in many other mGluR1alpha-positive neurons and in a few mGluR1alpha-negative neurons. In PCs, immunogold electron microscopy localized PLCbeta4 to the perisynapse, at which mGluR1alpha is concentrated, and to the smooth endoplasmic reticulum in dendrites and spines, an intracellular Ca2+ store gated by IP3 receptors. In the cerebellum, immunoblot demonstrated its concentrated distribution in the post-synaptic density and microsomal fractions, where mGluR1alpha and type 1 IP3 receptor were also greatly enriched. Furthermore, PLCbeta4 formed coimmunoprecipitable complexes with mGluR1alpha, type 1 IP3 receptor and Homer 1. These results suggest that PLCbeta4 is preferentially localized in the perisynapse and smooth endoplasmic reticulum as a component of the physically linked phosphoinositide signaling complex. This close molecular relationship might provide PLCbeta4 with a high-fidelity effector function to mediate various neuronal responses under physiological and pathophysiological conditions. PMID:15579147

  9. Facial expression recognition in crested macaques (Macaca nigra).

    PubMed

    Micheletta, Jérôme; Whitehouse, Jamie; Parr, Lisa A; Waller, Bridget M

    2015-07-01

    Facial expressions are a main communication channel used by many different species of primate. Despite this, we know relatively little about how primates discriminate between different facial expressions, and most of what we do know comes from a restricted number of well-studied species. In this study, three crested macaques (Macaca nigra) took part in matching-to-sample tasks where they had to discriminate different facial expressions. In a first experiment, the macaques had to match a photograph of a facial expression to another exemplar of the same expression produced by a different individual, against examples of one of three other types of expressions and neutral faces. In a second experiment, they had to match a dynamic video recording of a facial expression to a still photograph of another exemplar of the same facial expression produced by another individual, also against one of four other expressions. The macaques performed above chance in both tasks, identifying expressions as belonging to the same category regardless of individual identity. Using matrix correlations and multidimensional scaling, we analysed the pattern of errors to see whether overall similarity between facial expressions and/or specific morphological features caused the macaques to confuse facial expressions. Overall similarity, measured with the macaque facial action coding system (maqFACS), did not correlate with performances. Instead, functional similarities between facial expressions could be responsible for the observed pattern of error. These results expand previous findings to a novel primate species and highlight the potential of using video stimuli to investigate the perception and categorisation of visual signals in primates. PMID:25821924

  10. Hormonal profiles of captive Galapagos tortoises (Chelonoidis nigra).

    PubMed

    Branson, Maile A; Atkinson, Shannon; Ramos, Meg Ferrell

    2016-05-01

    Monthly blood samples, daily mating observations from Galapagos tortoises (Chelonoidis nigra), and local rainfall and temperature were collected at the Honolulu Zoo as part of a fertility evaluation. Testosterone concentrations were measured for males (n = 6), two of which were seen copulating and were considered sexually active. Estrone sulfate and progesterone concentrations were measured for female tortoises (n = 9), two of which nested and only one had laid eggs. Testosterone profiles were similar for both sexually active and sexually inactive males, both of which were positively correlated with temperature but not rainfall. Peak testosterone concentrations (12.0 ± 1.4 ng/ml sexually active animals vs. 14.4 ± 2.4 ng/ml sexually inactive animals) occurred at the end of the nesting season, from April to July. Estrone sulfate concentrations were similar for nesting (n = 2) and non-nesting (n = 7) female tortoises, rising from non-detectable concentrations (September), and increasing to peak concentrations during the nesting season. Progesterone concentrations remained low and spiked (9.44 ng/ml) only for the female that nested and laid eggs. Testosterone was negatively correlated with mating behavior, and the male tortoises were likely capable of spermatogenesis even though only two of them engaged in mating behavior. The female tortoises were not senescent, as the estrone sulfate concentrations likely reflected waves of ovarian follicular activity. Endocrine parameters were not in synchrony with rainfall, and a disconnect between the timing of reproductive events and the environmental milieu may help to explain the poor fertility of these tortoises. Zoo Biol. 35:237-245, 2016. © 2016 Wiley Periodicals, Inc. PMID:26971322