Neurochemistry and circuit organization of the lateral spiriform nucleus of birds: A uniquely nonmammalian direct pathway component of the basal ganglia.

We used diverse methods to characterize the role of avian lateral spiriform nucleus (SpL) in basal ganglia motor function. Connectivity analysis showed that SpL receives input from globus pallidus (GP), and the intrapeduncular nucleus (INP) located ventromedial to GP, whose neurons express numerous striatal markers. SpL-projecting GP neurons were large and aspiny, while SpL-projecting INP neurons were medium sized and spiny. Connectivity analysis further showed that SpL receives inputs from subthalamic nucleus (STN) and substantia nigra pars reticulata (SNr), and that the SNr also receives inputs from GP, INP, and STN. Neurochemical analysis showed that SpL neurons express ENK, GAD, and a variety of pallidal neuron markers, and receive GABAergic terminals, some of which also contain DARPP32, consistent with GP pallidal and INP striatal inputs. Connectivity and neurochemical analysis showed that the SpL input to tectum prominently ends on GABAA receptor-enriched tectobulbar neurons. Behavioral studies showed that lesions of SpL impair visuomotor behaviors involving tracking and pecking moving targets. Our results suggest that SpL modulates brainstem-projecting tectobulbar neurons in a manner comparable to the demonstrated influence of GP internus on motor thalamus and of SNr on tectobulbar neurons in mammals. Given published data in amphibians and reptiles, it seems likely the SpL circuit represents a major direct pathway-type circuit by which the basal ganglia exerts its motor influence in nonmammalian tetrapods. The present studies also show that avian striatum is divided into three spatially segregated territories with differing connectivity, a medial striato-nigral territory, a dorsolateral striato-GP territory, and the ventrolateral INP motor territory.

Arkypallidal neurons in basal ganglia circuits: Unveiling novel pallidostriatal loops?

Just over a decade ago, a novel GABAergic input originating from a subpopulation of external globus pallidus neurons known as Arkypallidal and projecting exclusively to the striatum was unveiled. At the single-cell level, these pallidostriatal Arkypallidal projections represent one of the largest extrinsic sources of GABA known to innervate the dorsal striatum. This discovery has sparked new questions regarding their role in striatal information processing, the circuit that recruit these neurons, and their influence on behaviour, especially in the context of action selection vs. inhibition. In this review, we will present the different anatomo-functional organization of Arkypallidal neurons as compared to classic Prototypic neurons, including their unique molecular properties and what is known about their specific input/output synaptic organization. We will further describe recent findings that demonstrate one mode of action of Arkypallidal neurons, which is to convey feedback inhibition to the striatum, and how this mechanism is differentially modulated by both striatal projection pathways. Lastly, we will delve into speculations on their mechanistic contribution to striatal action execution or inhibition.

External segment of the globus pallidus in health and disease: Its interactions with the striatum and subthalamic nucleus.

The external segment of the globus pallidus (GPe) has long been considered a homogeneous structure that receives inputs from the striatum and sends processed information to the subthalamic nucleus, composing a relay nucleus of the indirect pathway that contributes to movement suppression. Recent methodological revolution in rodents led to the identification of two distinct cell types in the GPe with different fiber connections. The GPe may be regarded as a dynamic, complex and influential center within the basal ganglia circuitry, rather than a simple relay nucleus. On the other hand, many studies have so far been performed in monkeys to clarify the functions of the basal ganglia in the healthy and diseased states, but have not paid much attention to such classification and functional differences of GPe neurons. In this minireview, we consider the knowledge on the rodent GPe and discuss its impact on the understanding of the basal ganglia circuitry in monkeys.

The transcription regulator Lmo3 is required for the development of medial ganglionic eminence derived neurons in the external globus pallidus.

The external globus pallidus (GPe) is an essential component of the basal ganglia, a group of subcortical nuclei that are involved in control of action. Changes in the firing of GPe neurons are associated with both passive and active body movements. Aberrant activity of GPe neurons has been linked to motor symptoms of a variety of movement disorders, such as Parkinson's Disease, Huntington's disease and dystonia. Recent studies have helped delineate functionally distinct subtypes of GABAergic GPe projection neurons. However, not much is known about specific molecular mechanisms underlying the development of GPe neuronal subtypes. We show that the transcriptional regulator Lmo3 is required for the development of medial ganglionic eminence derived Nkx2.1+ and PV+ GPe neurons, but not lateral ganglionic eminence derived FoxP2+ neurons. As a consequence of the reduction in PV+ neurons, Lmo3-null mice have a reduced GPe input to the subthalamic nucleus.

Increased expression of Nav1.6 of reactive astrocytes in the globus pallidus is closely associated with motor deficits in a model of Parkinson's disease.

Parkinson's disease (PD) is a common neurodegenerative disease in elderly people, which is characterized by motor disabilities in PD patients. Nav1.6 is the most abundant subtype of voltage-gated sodium channels (VGSCs) in the brain of adult mammals and rodents. Here we investigated the role of Nav1.6 in the external globus pallidus (GP) involved in the pathogenesis of motor deficits in unilateral 6-OHDA(6-hydroxydopamine)lesioned rats. The results show that Nav1.6 is dramatically increased in reactive astrocytes of the ipsilateral GP in the middle stage, but not different from the control rats in the later stage of the pathological process in 6-OHDA lesioned rats. Furthermore, the down-regulation of Nav1.6 expression in the ipsilateral GP can significantly improve motor deficits in 6-OHDA lesioned rats in the middle stage of the pathological process. The electrophysiological experiments show that the down-regulation of Nav1.6 expression in the ipsilateral GP significantly decreases the abnormal high synchronization between the ipsilateral M1 (the primary motor cortex) and GP in 6-OHDA lesioned rats. Ca2+ imaging reveals that the down-regulation of Nav1.6 expression reduces the intracellular concentration of Ca2+ ([Ca2+ ]i) in primary cultured astrocytes. These findings suggest that the increased Nav1.6 expression of reactive astrocytes in the GP play an important role in the pathogenesis of motor dysfunction in the middle stage in 6-OHDA lesioned rats, which may participate in astrocyte-neuron communication by regulating [Ca2+ ]i of astrocytes, thereby contributing to the formation of abnormal electrical signals of the basal ganglia (BG) in 6-OHDA lesioned rats.

The Role of Decorin in the Adhesion Process of Treponema Pallidum Subspecies Pallidum to Human Brain Microvascular Endothelial Cells.

Objective: This study aims to investigate the role of decorin in the adhesion process of Treponema pallidum subspecies pallidum (T. pallidum) to human brain microvascular endothelial cells. Methods: The study involved an in vitro experimental design. Western blot analysis was conducted to determine the protein expression level of decorin in the cells. The cells were divided into four groups: Tp group, inactivated Tp group, LPS group, and negative control group. The adhesion of T. pallidum to the cells was analyzed using darkfield microscopy counting and quantitative polymerase chain reaction (qPCR). The cells were divided into four groups based on different preprocessing treatments: control group, decorin group, DCN-siRNA group, and DCN-siRNA+decorin group. Changes in the F-actin of the cells were explored using confocal laser scanning microscopy. The cells were divided into the Tp group, Tp+decorin group, and control group. Results: Western blot analysis showed high expression of decorin in the Tp group and LPS group. Darkfield microscopy counting revealed a significantly higher number of T. pallidum adhered to a single cell in the decorin group compared to the control group. Conversely, the number of adhered T. pallidum was significantly lower in the DCN-siRNA group compared to the control group. qPCR results indicated a considerably higher T. pallidum load in the decorin group compared to the control group. In the Tp group, T. pallidum treatment induced the reorganization of F-actin, while the distribution of F-actin in the Tp+decorin group was comparable to that of the control group. Conclusions: Decorin enhances the adhesion of T. pallidum to human brain microvascular endothelial cells, suggesting that decorin may act as one of the receptors regulating the adhesion of T. pallidum to cells. Furthermore, T. pallidum treatment triggers the rearrangement of F-actin in cells, and decorin plays a protective role in this process.

Pallidal GABA B receptors: involvement in cortex beta dynamics and thalamic reticular nucleus activity.

The external globus pallidus (GP) firing rate synchronizes the basal ganglia-thalamus-cortex network controlling GABAergic output to different nuclei. In this context, two findings are significant: the activity and GABAergic transmission of the GP modulated by GABA B receptors and the presence of the GP-thalamic reticular nucleus (RTn) pathway, the functionality of which is unknown. The functional participation of GABA B receptors through this network in cortical dynamics is feasible because the RTn controls transmission between the thalamus and cortex. To analyze this hypothesis, we used single-unit recordings of RTn neurons and electroencephalograms of the motor cortex (MCx) before and after GP injection of the GABA B agonist baclofen and the antagonist saclofen in anesthetized rats. We found that GABA B agonists increase the spiking rate of the RTn and that this response decreases the spectral density of beta frequency bands in the MCx. Additionally, injections of GABA B antagonists decreased the firing activity of the RTn and reversed the effects in the power spectra of beta frequency bands in the MCx. Our results proved that the GP modulates cortical oscillation dynamics through the GP-RTn network via tonic modulation of RTn activity.

Insights into the Glutamatergic and GABAergic Connections in the Conductance-Based Model of Subthalamic Nucleus in Hyperdirect Pathway.

Introduction: This study aimed to analyze the spiking patterns of subthalamic nucleus and globus pallidus coupling in hyperdirect pathway in healthy primates and in Parkinson's disease using a conductance-based model. The effect of calcium membrane potential has also been investigated. Materials and Methods: System of coupled differential equation arising from the conductance-based model has been simulated using ODE45 in MATLAB 7.14 to analyze the spiking patterns. Results: Analysis of spiking patterns suggests that subthalamic nucleus with synaptic input from globus pallidus in hyperdirect pathways is capable of showing two types of spiking pattern - irregular and rhythmic. Characterization of spiking patterns in healthy and Parkinson condition has been done based on their frequency, trend, and spiking rate. Results indicate that rhythmic patterns does not account for Parkinson's disease. Further, calcium membrane potential is an important parameter to target for identifying the cause of this disease. Conclusion: This work demonstrates that subthalamic nucleus and globus pallidus coupling in hyperdirect pathway can account for Parkinson's symptoms. However, the entire process of excitations and inhibition caused by glutamate and GABA receptors is limited by the timing of depolarization of the model. There is improvement in the correlation between healthy and Parkinson's patterns by increase in calcium membrane potential, however, for a limited time.

Fucoidan derived from Sargassum pallidum alleviates metabolism disorders associated with improvement of cardiac injury and oxidative stress in diabetic mice.

Type 2 diabetes mellitus (T2DM) and its complications have become a serious global health epidemic. Cardiovascular complications have considered as a major cause of high mortality in diabetic patients. Fucoidans from brown algae have diverse medicinal activities, however, few studies reported pharmacological activity of Sargassum. pallidum fucoidan (Sp-Fuc). Therefore, the aim of this study was to investigate the effects of Sp-Fuc on diabetic symptoms and cardiac injury in spontaneous diabetic db/db mice. SP-Fuc at 200 mg/(kg/d) was administered intragastrically to db/db mice for 8 weeks, the effects on hyperlipidemia, hyperglycemia, insulin resistance, and cardiac damage, as well as oxidative stress, inflammation, Nrf2/ARE, and NF-κB signaling pathways, were investigated. Our data demonstrated that Sp-Fuc significantly (p < 0.05) decreased body weights, hyperlipidemia, and hyperglycemia in db/db mice, along with improved insulin sensitivity. Additionally, Sp-Fuc significantly (p < 0.05) alleviated cardiac dysfunction and pathological morphology of cardiac tissue. Sp-Fuc also significantly (p < 0.05) decreased lipid peroxidation, increased antioxidant function, as well as reduced cardiac inflammation, possibly through Nrf2/ARE and NF-κB signaling. Sp-Fuc can ameliorate the metabolism disorders of glucose and lipid in diabetic mice by activating Nrf2/ARE antioxidant signaling, simultaneously reducing cardiac redox imbalance and inflammatory damage. The present findings provide a perspective on the therapy strategy for T2DM and its complications.

Cell type-specific processing of non-motor signals in the external pallidum.

The external globus pallidus (GPe) regulates motor control. However, whether the GPe encodes non-motor information remains unclear. Two recent studies, by Johansson and Ketzef, and Katabi et al., provide in vivo evidence for GPe neuron processing of sensory stimulation and reward cues via a division of labor among its cell types.

Sensory processing in external globus pallidus neurons.

Sensory processing is crucial for execution of appropriate behavior. The external globus pallidus (GPe), a nucleus within the basal ganglia, is highly involved in the control of movement and could potentially integrate sensory-motor information. The GPe comprises prototypic and arkypallidal cells, which receive partially overlapping inputs. It is unclear, however, which inputs convey sensory information to them. Here, we used in vivo whole-cell recordings in the mouse GPe and optogenetic silencing to characterize the pathways that shape the response to whisker stimulation in prototypic and arkypallidal cells. Our results show that sensory integration in prototypic cells is controlled by the subthalamic nucleus and indirect pathway medium spiny neurons (MSNs), whereas in arkypallidal cells, it is primarily shaped by direct pathway MSNs. These results suggest that GPe subpopulations receive sensory information from largely different neural populations, reinforcing that the GPe consists of two parallel pathways, which differ anatomically and functionally.

Distinct mechanisms of CB1 and GABAB receptor presynaptic modulation of striatal indirect pathway projections to mouse globus pallidus.

Presynaptic modulation is a fundamental process regulating synaptic transmission. Striatal indirect pathway projections originate from A2A-expressing spiny projection neurons (iSPNs), targeting the globus pallidus external segment (GPe) and control the firing of the tonically active GPe neurons via GABA release. It is unclear if and how the presynaptic G-protein-coupled receptors (GPCRs), GABAB and CB1 receptors modulate iSPN-GPe projections. Here we used an optogenetic platform to study presynaptic Ca2+ and GABAergic transmission at iSPN projections, using a genetic strategy to express the calcium sensor GCaMP6f or the excitatory channelrhodopsin (hChR2) on iSPNs. We found that P/Q-type calcium channels are the primary voltage-gated Ca2+ channel (VGCC) subtype controlling presynaptic calcium and GABA release at iSPN-GPe projections. N-type and L-type VGCCs also contribute to GABA release at iSPN-GPe synapses. GABAB receptor activation resulted in a reversible inhibition of presynaptic Ca2+ transients (PreCaTs) and an inhibition of GABAergic transmission at iSPN-GPe synapses. CB1 receptor activation did not inhibit PreCaTs but inhibited GABAergic transmission at iSPN-GPe projections. CB1 effects on GABAergic transmission persisted in experiments where NaV and KV 1 were blocked, indicating a VGCC- and KV 1-independent presynaptic mechanism of action of CB1 receptors. Taken together, presynaptic modulation of iSPN-GPe projections by CB1 and GABAB receptors is mediated by distinct mechanisms. KEY POINTS: P/Q-type are the predominant voltage-gated Ca2+ channels controlling presynaptic Ca2+ and GABA release on the striatal indirect pathway projections. GABAB receptors modulate iSPN-GPe projections via a VGCC-dependent mechanism. CB1 receptors modulate iSPN-GPe projections via a VGCC-independent mechanism.

Angiotensin II increases the firing activity of pallidal neurons and participates in motor control in rats.

The globus pallidus has emerged as a crucial node in the basal ganglia motor control circuit under both healthy and parkinsonian states. Previous studies have shown that angiotensin II (Ang II) and angiotensin subtype 1 receptor (AT1R) are closely related to Parkinson's disease (PD). Recent morphological study revealed the expression of AT1R in the globus pallidus of mice. To investigate the functions of Ang II/AT1R on the globus pallidus neurons of both normal and parkinsonian rats, electrophysiological recordings and behavioral tests were performed in the present study. Electrophysiological recordings showed that exogenous and endogenous Ang II mainly excited the globus pallidus neurons through AT1R. Behavioral tests further demonstrated that unilateral microinjection of Ang II into the globus pallidus induced significantly contralateral-biased swing in elevated body swing test (EBST), and bilateral microinjection of Ang II into the globus pallidus alleviated catalepsy and akinesia caused by haloperidol. AT1R was involved in Ang II-induced behavioral effects. Immunostaining showed that AT1R was expressed in the globus pallidus of rats. On the basis of the present findings, we concluded that pallidal Ang II/AT1R alleviated parkinsonian motor deficits through activating globus pallidus neurons, which will provide a rationale for further investigations into the potential of Ang II in the treatment of motor disorders originating from the basal ganglia.

Histamine bidirectionally regulates the intrinsic excitability of parvalbumin-positive neurons in the lateral globus pallidus and promotes motor behaviour.

BACKGROUND AND PURPOSE: Parvalbumin (PV)-positive neurons are a type of neuron in the lateral globus pallidus (LGP) which plays an important role in motor control. The present study investigated the effect of histamine on LGPPV neurons and motor behaviour. EXPERIMENTAL APPROACH: Histamine levels in LGP as well as its histaminergic innervation were determined through brain stimulation, microdialysis, anterograde tracing and immunostaining. Mechanisms of histamine action were detected by immunostaining, single-cell qPCR, whole-cell patch-clamp recording, optogenetic stimulation and CRISPR/Cas9 gene-editing techniques. The effect of histamine on motor behaviour was detected by animal behavioural tests. KEY RESULTS: A direct histaminergic innervation in LGP from the tuberomammillary nucleus (TMN) and a histamine-induced increase in the intrinsic excitability of LGPPV neurons were determined by pharmacological blockade or by genetic knockout of the histamine H1 receptor (H1 R)-coupled TWIK-related potassium channel-1 (TREK-1) and the small-conductance calcium-activated potassium channel (SK3), as well as by activation or overexpression of the histamine H2 receptor (H2 R)-coupled hyperpolarization-activated cyclic nucleotide-gated channel (HCN2). Histamine negatively regulated the STN → LGPGlu transmission in LGPPV neurons via the histamine H3 receptor (H3 R), whereas blockage or knockout of H3 R increased the intrinsic excitability of LGPPV neurons. CONCLUSIONS AND IMPLICATIONS: Our results indicated that the endogenous histaminergic innervation in the LGP can bidirectionally promote motor control by increasing the intrinsic excitability of LGPPV neurons through postsynaptic H1 R and H2 R, albeit its action was negatively regulated by the presynaptic H3 R, thereby suggesting possible role of histamine in motor deficits manifested in Parkinson's disease (PD).

Mass spectrometry-based proteomics analysis of human globus pallidus from progressive supranuclear palsy patients discovers multiple disease pathways.

BACKGROUND: Progressive supranuclear palsy (PSP) is a neurodegenerative disorder clinically characterized by progressive postural instability, supranuclear gaze palsy, parkinsonism, and cognitive decline caused by degeneration in specific areas of the brain including globus pallidus (GP), substantia nigra, and subthalamic nucleus. However, the pathogenetic mechanism of PSP remains unclear to date.Unbiased global proteome analysis of patients' brain samples is an important step toward understanding PSP pathogenesis, as proteins serve as workhorses and building blocks of the cell. METHODS: In this study, we conducted unbiased mass spectrometry-based global proteome analysis of GP samples from 15 PSP patients, 15 Parkinson disease (PD) patients, and 15 healthy control (HC) individuals. To analyze 45 samples, we conducted 5 batches of 11-plex isobaric tandem mass tag (TMT)-based multiplexing experiments. The identified proteins were subjected to statistical analysis, such as a permutation-based statistical analysis in the significance analysis of microarray (SAM) method and bootstrap receiver operating characteristic curve (ROC)-based statistical analysis. Subsequently, we conducted bioinformatics analyses using gene set enrichment analysis, Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) protein-protein interaction (PPI) analysis, and weighted gene co-expression network analysis (WGCNA). RESULTS: We have identified 10,231 proteins with ∼1,000 differentially expressed proteins. The gene set enrichment analysis results showed that the PD pathway was the most highly enriched, followed by pathways for oxidative phosphorylation, Alzheimer disease, Huntington disease, and non-alcoholic fatty liver disease (NAFLD) when PSP was compared to HC or PD. Most of the proteins enriched in the gene set enrichment analysis were mitochondrial proteins such as cytochrome c oxidase, NADH dehydrogenase, acyl carrier protein, succinate dehydrogenase, ADP/ATP translocase, cytochrome b-c1 complex, and/or ATP synthase. Strikingly, all of the enriched mitochondrial proteins in the PD pathway were downregulated in PSP compared to both HC and PD. The subsequent STRING PPI analysis and the WGCNA further supported that the mitochondrial proteins were the most highly enriched in PSP. CONCLUSION: Our study showed that the mitochondrial respiratory electron transport chain complex was the key proteins that were dysregulated in GP of PSP, suggesting that the mitochondrial respiratory electron transport chain complex could potentially be involved in the pathogenesis of PSP. This is the first global proteome analysis of human GP from PSP patients, and this study paves the way to understanding the mechanistic pathogenesis of PSP.

Three-Dimensional Spatial Analyses of Cholinergic Neuronal Distributions Across The Mouse Septum, Nucleus Basalis, Globus Pallidus, Nucleus Accumbens, and Caudate-Putamen.

Neuronal networks are regulated by three-dimensional spatial and structural properties. Despite robust evidence of functional implications in the modulation of cognition, little is known about the three-dimensional internal organization of cholinergic networks in the forebrain. Cholinergic networks in the forebrain primarily occur in subcortical nuclei, specifically the septum, nucleus basalis, globus pallidus, nucleus accumbens, and the caudate-putamen. Therefore, the present investigation analyzed the three-dimensional spatial organization of 14,000 cholinergic neurons that expressed choline acetyltransferase (ChAT) in these subcortical nuclei of the mouse forebrain. Point process theory and graph signal processing techniques identified three topological principles of organization. First, cholinergic interneuronal distance is not uniform across brain regions. Specifically, in the septum, globus pallidus, nucleus accumbens, and the caudate-putamen, the cholinergic neurons were clustered compared with a uniform random distribution. In contrast, in the nucleus basalis, the cholinergic neurons had a spatial distribution of greater regularity than a uniform random distribution. Second, a quarter of the caudate-putamen is composed of axonal bundles, yet the spatial distribution of cholinergic neurons remained clustered when axonal bundles were accounted for. However, comparison with an inhomogeneous Poisson distribution showed that the nucleus basalis and caudate-putamen findings could be explained by density gradients in those structures. Third, the number of cholinergic neurons varies as a function of the volume of a specific brain region but cell body volume is constant across regions. The results of the present investigation provide topographic descriptions of cholinergic somata distribution and axonal conduits, and demonstrate spatial differences in cognitive control networks. The study provides a comprehensive digital database of the total population of ChAT-positive neurons in the reported structures, with the x,y,z coordinates of each neuron at micrometer resolution. This information is important for future digital cellular atlases and computational models of the forebrain cholinergic system enabling models based on actual spatial geometry.

A polysaccharide from Sargassum pallidum reduces obesity in high-fat diet-induced obese mice by modulating glycolipid metabolism.

Sargassum pallidum polysaccharide (SPP) has been shown to have antioxidant, hypoglycemic, and hypolipidemic effects. However, the anti-obesity mechanism of SPP in obese mice remains unclear. This study aimed to investigate the anti-obesity effect and mechanism of SPP in obese mice induced by a high-fat diet (HFD). The model and experimental groups were fed with a HFD, and the experimental groups were simultaneously orally treated with degraded SPP (D-SPP) with dosages of 50, 100, and 200 mg kg-1 for 8 weeks, respectively. The results showed that oral administration of D-SPP not only dramatically suppressed body weight gain and reduced the fasting blood glucose level, but also lowered the levels of serum and hepatic lipids in HFD-induced obese mice. Histopathological analysis showed that D-SPP significantly prevented liver fat accumulation and reduced white adipose hypertrophy and adipocyte size. Real-time quantitative polymerase chain reaction (RT-qPCR) analysis indicated that D-SPP intervention significantly down-regulated the relative expressions of adipogenesis genes. Specifically, the peroxisome proliferator-activated receptors-γ (PPAR-γ), sterol regulatory element-binding protein-1 (Srebp-1c), acetyl-CoA carboxylase-1(ACC1) and fatty acid synthase (FAS) in the liver of obese mice were decreased by 68, 53, 73, and 78%, respectively. These findings suggest that D-SPP might potentially be used as a promising dietary supplement for ameliorating obesity.

Effects of repeated manganese treatment on proton magnetic resonance spectra of the globus pallidus in rat brain.

Excessive manganese is neurotoxic, which means that it can affect the concentrations of metabolite in 1 H MRS. In addition, manganese is paramagnetic and it may influence the relaxation times of the metabolite. The aim of this study is to assess the sensitivity of the metabolite relaxation properties and concentrations to exogenous manganese deposition in the globus pallidus (GP) of rat brain after repeated manganese injection. Proton magnetic resonance spectroscopy (1 H MRS) experiments in vivo and ex vivo were carried out to evaluate the changes in the metabolite concentration and the major metabolite relaxation times, and histological experiments were also performed after repeated manganese administration. Only the T1 value for N-acetylaspartate (NAA) of the GP was significantly reduced after 1 day of manganese injection compared with that of the control group (p < 0.025). The T1 and T2 values for NAA and total creatine (tCr) (p < 0.025), along with the amounts of NAA, tCr, myo-inositol, choline, and glutamate (p < 0.0086) in the GP, were all significantly decreased after 5 days of manganese administration compared with that of the control group. The changes in the concentration and relaxation properties of NAA and tCr in the GP of rat brain indicated that manganese represented paramagnetism and neurotoxicity after repeated administration. Accurate knowledge of relaxation properties and concentrations of NAA and tCr in this study could help appropriate selection of sequence parameters to improve the ability to distinguish the brain regions affected in cases of manganese poisoning.

Manganese exposure causes movement deficit and changes in the protein profile of the external globus pallidus in Sprague Dawley rats.

Manganese (Mn) is required for normal brain development and function. Excess Mn may trigger a parkinsonian movement disorder but the underlying mechanisms are incompletely understood. We explored changes in the brain proteomic profile and movement behavior of adult Sprague Dawley (SD) rats systemically treated with or without 1.0 mg/mL MnCl2 for 3 months. Mn treatment significantly increased the concentration of protein-bound Mn in the external globus pallidus (GP), as demonstrated by inductively coupled plasma mass spectrometry. Behavioral study showed that Mn treatment induced movement deficits, especially of skilled movement. Proteome analysis by two-dimensional fluorescence difference gel electrophoresis coupled with mass spectrometry revealed 13 differentially expressed proteins in the GP of Mn-treated versus Mn-untreated SD rats. The differentially expressed proteins were mostly involved in glycolysis, metabolic pathways, and response to hypoxia. Selected pathway class analysis of differentially expressed GP proteins, which included phosphoglycerate mutase 1 (PGAM1), primarily identified enrichment in glycolytic process and innate immune response. In conclusion, perturbation of brain energy production and innate immune response, in which PGAM1 has key roles, may contribute to the movement disorder associated with Mn neurotoxicity.