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Midbrain dopaminergic (DAergic) regions including ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) are involved in diverse brain functions. Previous studies demonstrated that the VTA/SNc to nucleus accumbens (NAc) pathway is critical in reward and motivation. Moreover, DAergic innervations within the insular cortex (IC) are reported to play important roles in pain regulation. To investigate whether VTA/SNc sends collateral projections to NAc and IC, we injected retrograde tracer Fluoro-Gold (FG) into the NAc and Fluorescent retrograde tracer beads (RetroBeads) into the ipsilateral IC in rats. Then, to detect whether collateral projection neurons participate in neuropathic pain, parts of the rats received the spare nerve injury (SNI) surgery. The immunofluorescence staining results showed that FG, RetroBeads, and FG/RetroBeads double-labeled neurons were distributed in the VTA/SNc bilaterally with an ipsilateral predominance. The proportion of FG/RetroBeads double-labeled neurons to the total number of FG and RetroBeads-labeled neurons was 16.7% and 30.3%, respectively. About 90.3% of FG/RetroBeads double-labeled neurons showed DAergic neuron marker tyrosine hydroxylase (TH)-immunoreactive (IR), whereas, only 7.5% exhibited a subset of GABAergic inhibitory projection neuron marker parvalbumin (PV)-IR. One week after SNI, about 53.1% and 33.6% of FG- and RetroBeads-labeled neurons were FG/Fos- and RetroBeads/Fos-IR neurons, respectively. Finally, about 35.9% of the FG/RetroBeads double-labeled neurons showed Fos-IR. The present study indicates that parts of DAergic and PV-IR GABAergic neurons in the VTA/SNc send collateral projections to both NAc and IC, which are activated under SNI-induced neuropathic pain, and probably contribute to the regulation of nociception.

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Withdrawal from chronic opioid use often causes hypodopaminergic states and negative affect, which may drive relapse. Direct-pathway medium spiny neurons (dMSNs) in the striatal patch compartment contain µ-opioid receptors (MORs). It remains unclear how chronic opioid exposure and withdrawal impact these MOR-expressing dMSNs and their outputs. Here, we report that MOR activation acutely suppressed GABAergic striatopallidal transmission in habenula-projecting globus pallidus neurons. Notably, withdrawal from repeated morphine or fentanyl administration potentiated this GABAergic transmission. Furthermore, intravenous fentanyl self-administration enhanced GABAergic striatonigral transmission and reduced midbrain dopaminergic activity. Fentanyl-activated striatal neurons mediated contextual memory retrieval required for conditioned place preference tests. Importantly, chemogenetic inhibition of striatal MOR+ neurons rescued fentanyl withdrawal-induced physical symptoms and anxiety-like behaviors. These data suggest that chronic opioid use triggers GABAergic striatopallidal and striatonigral plasticity to induce a hypodopaminergic state, which may promote negative emotions and relapse.

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BACKGROUND: The mechanisms leading to a loss of dopaminergic (DA) neurons from the substantia nigra pars compacta (SNc) in Parkinson's disease (PD) have multifactorial origins. In this context, nutrition is currently investigated as a modifiable environmental factor for the prevention of PD. In particular, initial studies revealed the deleterious consequences of vitamin A signaling failure on dopamine-related motor behaviors. However, the potential of vitamin A supplementation itself to prevent neurodegeneration has not been established yet. OBJECTIVE: The hypothesis tested in this study is that preventive vitamin A supplementation can protect DA neurons in a rat model of PD. METHODS: The impact of a 5-week preventive supplementation with vitamin A (20 IU/g of diet) was measured on motor and neurobiological alterations induced by 6-hydroxydopamine (6-OHDA) unilateral injections in the striatum of rats. Rotarod, step test and cylinder tests were performed up to 3 weeks after the lesion. Post-mortem analyses (retinol and monoamines dosages, western blots, immunofluorescence) were performed to investigate neurobiological processes. RESULTS: Vitamin A supplementation improved voluntary movements in the cylinder test. In 6-OHDA lesioned rats, a marked decrease of dopamine levels in striatum homogenates was measured. Tyrosine hydroxylase labeling in the SNc and in the striatum was significantly decreased by 6-OHDA injection, without effect of vitamin A. By contrast, vitamin A supplementation increased striatal expression of D2 and RXR receptors in the striatum of 6-OHDA lesioned rats. CONCLUSIONS: Vitamin A supplementation partially alleviates motor alterations and improved striatal function, revealing a possible beneficial preventive approach for PD.

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The glutamatergic and GABAergic neurons in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) mediated diverse brain functions. However, their whole-brain neural connectivity has not been comprehensively mapped. Here we used the virus tracers to characterize the whole-brain inputs and outputs of glutamatergic and GABAergic neurons in VTA and SNc. We found that these neurons received similar inputs from upstream brain regions, but some quantitative differences were also observed. Neocortex and dorsal striatum provided a greater share of input to VTA glutamatergic neurons. Periaqueductal gray and lateral hypothalamic area preferentially innervated VTA GABAergic neurons. Specifically, superior colliculus provided the largest input to SNc glutamatergic neurons. Compared to input patterns, the output patterns of glutamatergic and GABAergic neurons in the VTA and SNc showed significant preference to different brain regions. Our results laid the anatomical foundation for understanding the functions of cell-type-specific neurons in VTA and SNc.

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OBJECTIVE: The loss of dopaminergic cells and excessive iron deposition in some deep brain nuclei are associated with the pathophysiology of PD, and different clinical subtypes may indicate different pathological processes. This study was designed to investigate the relationships between regional iron in the cardinal subcortical nuclei and different clinical subtypes. PATIENTS AND METHODS: Nine Arkinetic/Rigid-dominant Parkinson's disease (PDAR) patients, eight Tremor-dominant (PDTD)patients and 10 matched healthy controls were recruited for this study. The iron content in 8 cardinal subcortical nuclei was measured through SWI sequence scanning (3.0 T), and different patterns of iron deposition were analyzed not only between the PD patients and HC groups but also between the different clinical subtypes. RESULTS: Compared with the healthy controls, the iron content in the substantia nigra pars compacta(SNc), substantia nigra pars reticulata(SNr) from both the severe and milder side in PD groups were significantly increased (P < 0.01 and P < 0.02 for SNc; both P < 0.01 for SNr), and the iron content in the GP of both the severe and milder side of the PDAR patients was significantly increased compared with the PDTD patients (P < 0.01 and P = 0.02, respectively) CONCLUSION: SWI is a very good technique for the in vivo assessment of subcortical nucleus iron content, and abnormal deposition of iron in the SNc and SNr is an obvious characteristic in PD patients. Furthermore, our data indicates that PDAR patients have higher iron content in the GP than PDTD patients and HCs, indicating that abnormal iron deposition in GP is related to the phenotype of Akinetic/Rigid in PD patients.

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Parkinson's disease (PD) is a long-term neurodegenerative disorders that characterized by a progressive loss of dopaminergic neurons in substantia nigra pars compacta (SNc). Bone marrow stromal cells (BMSCs) are promising therapeutic agents for neurodegenerative disease due to their multipotent capacity. To promote the potential therapeutic effect of BMSCs on PD, we developed an injectable Gelatin-PANI hydrogels as a novel carrier for delivering BMSCs to the SNc region in mice with PD by stereotactic injection. Histology results showed that the BMSCs-loaded hydrogels lead to increased numbers of tyrosine hydroxylase positive (TH+) dopaminergic neurons and fibers in the SNc and striatum, and increased expression of brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF) in the SNc. Meanwhile, rotarod and open field evaluation demonstrated BMSCs-loaded hydrogels significantly improved the behavioral performance of PD mice. Importantly, BMSCs-loaded hydrogels imparted more sustained protective effects than BMSCs alone in PD mice. Overall, the current data indicate that the hydrogel serves as a promising carrier to deliver BMSCs to the SNc for the treatment of PD.

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BACKGROUND: Susceptibility MRI may capture Parkinson's disease-related pathology. This study delineated longitudinal changes in different substantia nigra regions. METHODS: Seventy-two PD patients and 62 controls were studied at both baseline and after 18 months with MRI. R2* and quantitative susceptibility mapping values from the substantia nigra pars compacta and substantia nigra pars reticulata were calculated. Mixed-effects models compared controls with PD or PD subgroups having different disease durations: early (<1 year), middle (<5 years, middle-stage PD), and late (>5 years, late-stage PD). Pearson's correlation assessed associations between imaging and clinical measures. RESULTS: At baseline, R2* and quantitative susceptibility mapping were higher in both the substantia nigra pars compacta and substantia nigra pars reticulata in all PD patients (group effect, P ≤ 0.003). Longitudinally, the substantia nigra pars compacta R2* showed a faster increase in PD compared with controls (time × group, P = 0.002), whereas quantitative susceptibility mapping did not (P = 0.668). The substantia nigra pars reticulata R2* and quantitative susceptibility mapping did not differ between PD and controls (time × group, P ≥ 0.084), although both decreased longitudinally (time effect, P ≤ 0.004). Baseline substantia nigra pars compacta R2* was higher in all PD subgroups (group, P ≤ 0.006), but showed a significantly faster increase only in later-stage PD (time × group, P < 0.0001) that correlated with changes in nonmotor symptoms (r = 0.746, P = 0.002). Baseline substantia nigra pars reticulata quantitative susceptibility mapping was higher in middle-stage PD and later-stage PD (group, P ≤ 0.002), but showed a longitudinal decrease (time × group, P = 0.004) only in later-stage PD that correlated with changes in motor signs (r = 0.837, P < 0.001). CONCLUSION: Susceptibility MRI revealed distinct patterns of PD progression in the substantia nigra pars compacta and substantia nigra pars reticulata. The different patterns are particularly clear in later-stage patients. These findings may resolve past controversies and have implications in the pathophysiological processes during PD progression. © 2018 International Parkinson and Movement Disorder Society.

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Parkinson's disease is one of the most common neurodegenerative diseases. Animal models have contributed a large part to our understanding and therapeutics developed for treatment of PD. There are several more exhaustive reviews of literature that provide the initiated insights into the specific models; however a novel synthesis of the basic advantages and disadvantages of different models is much needed. Here we compare both neurotoxin based and genetic models while suggesting some novel avenues in PD modeling. We also highlight the problems faced and promises of all the mammalian models with the hope of providing a framework for comparison of various systems.

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Voltage gated calcium channels (VGCC) are sensitive to oxidative stress, and their activation or inactivation can impact cell death. Although these channels have been extensively studied in expression systems, their role in the brain, particularly in the substantia nigra pars compacta (SNc), remain controversial. In this study, we assessed 6-hydroxydopamine (6-OHDA) induced transformation of firing pattern and functional changes of calcium channels in SNc dopaminergic neurons. Application of 6-OHDA (0.5-2mM) evoked a dose-dependent, desensitizing inward current and intracellular free calcium concentration ([Ca(2+)]i) rise. In voltage clamp, ω-conotoxin-sensitive Ca(2+) current modulation mediated by 6-OHDA reflected an altered sensitivity. Furthermore, we found that 6-OHDA modulated Ca(2+) currents through PKA pathway. These results provided evidence for the potential role of VGCCs and PKA involved in oxidative stress in degeneration of SNc neurons in Parkinson's disease (PD).

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