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Degeneration of dopaminergic neurons in the substantia nigra and their striatal axon terminals causes cardinal motor symptoms of Parkinson's disease. In idiopathic cases, high levels of mitochondrial DNA alterations, leading to mitochondrial dysfunction, are a central feature of these vulnerable neurons. Here we present a mouse model expressing the K320E variant of the mitochondrial helicase Twinkle in dopaminergic neurons, leading to accelerated mitochondrial DNA mutations. These K320E-TwinkleDaN mice showed normal motor function at 20 months of age, although ∼70% of nigral dopaminergic neurons had perished. Remaining neurons still preserved ∼75% of axon terminals in the dorsal striatum and enabled normal dopamine release. Transcriptome analysis and viral tracing confirmed compensatory axonal sprouting of the surviving neurons. We conclude that a small population of substantia nigra dopaminergic neurons is able to adapt to the accumulation of mitochondrial DNA mutations and maintain motor control., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Parkinson's Disease is a progressive neurodegenerative disorder characterized by motor symptoms resulting from the loss of nigrostriatal dopaminergic neurons. Kisspeptins (KPs) are a family of neuropeptides that are encoded by the Kiss-1 gene, which exert their physiological effects through interaction with the GPR54 receptor. In the current investigation, we investigated the prospective protective effects of central KP-54 treatments on nigrostriatal dopaminergic neurons and consequent motor performance correlates in 6-hydroxydopamine (6-OHDA)-lesioned rats. Male adult Sprague Dawley rats underwent stereotaxic injection of 6-OHDA into the right medial forebrain bundle to induce hemiparkinsonism. Following surgery, rats received chronic central treatments of nasal or intracerebroventricular KP-54 (logarithmically increasing doses) for seven consecutive days. Motor performance was evaluated seven days post-surgery utilizing the open field test and catalepsy test. The levels of dopamine in the striatum were determined with mass spectrometry. Immunohistochemical analysis was conducted to assess the immunoreactivities of tyrosine hydroxylase (TH) and the GPR54 in the substantia nigra. The dose-response curve revealed a median effective dose value of ≈3 nmol/kg for both central injections. Due to its non-invasive and effective nature, nasal administration was utilized in the second phase of our study. Chronic administration of KP-54 (3nmol/kg, nasally) significantly protected 6-OHDA-induced motor deficits. Nasal KP-54 attenuated the loss of nigrostriatal dopaminergic neurons induced by 6-OHDA. Additionally, significant correlations were observed between motor performance and nigrostriatal dopamine levels. Immunohistochemical analysis demonstrated the localization of the GPR54 within TH-positive nigral cells. These findings suggest the potential efficacy of central KP-54 on motor impairments in hemiparkinsonism., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: Markers for treatment resistance in schizophrenia are needed to reduce delays in effective treatment. Nigrostriatal hyperdopaminergic function plays a critical role in the pathology of schizophrenia, yet antipsychotic nonresponders do not show increased dopamine function. Neuromelanin-sensitive MRI (NM-MRI), which indirectly measures dopamine function in the substantia nigra, has potential as a noninvasive marker for nonresponders. Increased NM-MRI signal has been shown in psychosis, but has not yet been assessed in nonresponders. In this study, the authors investigated whether nonresponders show lower NM-MRI signal than responders., Methods: NM-MRI scans were acquired in 79 patients with first-episode psychosis and 20 matched healthy control subjects. Treatment response was assessed at a 6-month follow-up. An a priori voxel-wise analysis within the substantia nigra tested the relation between NM-MRI signal and treatment response in patients., Results: Fifteen patients were classified as nonresponders and 47 patients as responders. Seventeen patients were excluded, primarily because of medication nonadherence or change in diagnosis. Voxel-wise analysis revealed 297 significant voxels in the ventral tier of the substantia nigra that were negatively associated with treatment response. Nonresponders and healthy control subjects had significantly lower NM-MRI signal than responders. Receiver operating characteristic curve analysis showed that NM-MRI signal separated nonresponders with areas under the curve between 0.62 and 0.85. In addition, NM-MRI signal in patients did not change over 6 months., Conclusions: These findings provide further evidence for dopaminergic differences between medication responders and nonresponders and support the potential of NM-MRI as a clinically applicable marker for treatment resistance in schizophrenia., Competing Interests: Drs. Wengler, Cassidy, and Horga are inventors on patents for analysis and use of NM-MRI, licensed to Terran Biosciences, but have received no royalties. Drs. Cassidy and Horga have an investigator-initiated sponsored research agreement and a licensing agreement with Terran Biosciences. The other authors report no financial relationships with commercial interests.

Parkinson's disease (PD) rodent models provide insight into the relationship between nigrostriatal dopamine (DA) signaling and locomotor function. Although toxin-based rat models produce frank nigrostriatal neuron loss and eventual motor decline characteristic of PD, the rapid nature of neuronal loss may not adequately translate premotor traits, such as cognitive decline. Unfortunately, rodent genetic PD models, like the Pink1 knockout (KO) rat, often fail to replicate the differential severity of striatal DA and tyrosine hydroxylase (TH) loss, and a bradykinetic phenotype, reminiscent of human PD. To elucidate this inconsistency, we evaluated aging as a progression factor in the timing of motor and non-motor cognitive impairments. Male PINK1 KO and age-matched wild type (WT) rats were evaluated in a longitudinal study from 3 to 16 months old in one cohort, and in a cross-sectional study of young adult (6-7 months) and aged (18-19 months) in another cohort. Young adult PINK1 KO rats exhibited hyperkinetic behavior associated with elevated DA and TH in the substantia nigra (SN), which decreased therein, but not striatum, in the aged KO rats. Additionally, norepinephrine levels decreased in aged KO rats in the prefrontal cortex (PFC), paired with a higher DA levels in young and aged KO. Although a younger age of onset characterizes familial forms of PD, our results underscore the critical need to consider age-related factors. Moreover, the results indicate that compensatory mechanisms may exist to preserve locomotor function, evidenced by increased DA in the SN early in the lifespan, in response to deficient PINK1 function, which declines with aging and the onset of motor decline., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Dopamine and serotonin are hypothesized to guide social behaviours. In humans, however, we have not yet been able to study neuromodulator dynamics as social interaction unfolds. Here, we obtained subsecond estimates of dopamine and serotonin from human substantia nigra pars reticulata during the ultimatum game. Participants, who were patients with Parkinson's disease undergoing awake brain surgery, had to accept or reject monetary offers of varying fairness from human and computer players. They rejected more offers in the human than the computer condition, an effect of social context associated with higher overall levels of dopamine but not serotonin. Regardless of the social context, relative changes in dopamine tracked trial-by-trial changes in offer value-akin to reward prediction errors-whereas serotonin tracked the current offer value. These results show that dopamine and serotonin fluctuations in one of the basal ganglia's main output structures reflect distinct social context and value signals., (© 2024. The Author(s).)

Evidence of direct reciprocal connections between the cerebellum and basal ganglia has challenged the long-held notion that these structures function independently. While anatomical studies have suggested the presence of cerebellar projections to the substantia nigra pars compacta (SNc), the nature and function of these connections (Cb-SNc) is unknown. Here we show, in mice, that Cb-SNc projections form monosynaptic glutamatergic synapses with dopaminergic and non-dopaminergic neurons in the SNc. Optogenetic activation of Cb-SNc axons in the SNc is associated with increased SNc activity, elevated striatal dopamine levels and increased locomotion. During behavior, Cb-SNc projections are bilaterally activated before ambulation and unilateral lever manipulation. Cb-SNc projections show prominent activation for water reward and higher activation for sweet water, suggesting that the pathway also encodes reward value. Thus, the cerebellum directly, rapidly and effectively modulates basal ganglia dopamine levels and conveys information related to movement initiation, vigor and reward processing., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

The auditory striatum, the tail portion of dorsal striatum in basal ganglia, is implicated in perceptual decision-making, transforming auditory stimuli to action outcomes. Despite its known connections to diverse neurological conditions, the dopaminergic modulation of sensory striatal neuronal activity and its behavioral influences remain unknown. We demonstrated that the optogenetic inhibition of dopaminergic projections from the substantia nigra pars compacta to the auditory striatum specifically impairs mouse choice performance but not movement in an auditory frequency discrimination task. In vivo dopamine and calcium imaging in freely behaving mice revealed that this dopaminergic projection modulates striatal tone representations, and tone-evoked striatal dopamine release inversely correlated with the evidence strength of tones. Optogenetic inhibition of D1-receptor expressing neurons and pharmacological inhibition of D1 receptors in the auditory striatum dampened choice performance accuracy. Our study uncovers a phasic mechanism within the nigrostriatal system that regulates auditory decisions by modulating ongoing auditory perception., (© 2022. The Author(s).)

G-protein-coupled D2 autoreceptors expressed on dopamine neurons (D2Rs) inhibit transmitter release and cell firing at axonal endings and somatodendritic compartments. Mechanistic details of somatodendritic dopamine release remain unresolved, partly due to insufficient information on the subcellular distribution of D2Rs. Previous studies localizing D2Rs have been hindered by a dearth of antibodies validated for specificity in D2R knockout animals and have been limited by the small sampling areas imaged by electron microscopy. This study utilized sub-diffraction fluorescence microscopy and electron microscopy to examine D2 receptors in a superecliptic pHlourin GFP (SEP) epitope-tagged D2 receptor knockin mouse. Incubating live slices with an anti-SEP antibody achieved the selective labeling of plasma membrane-associated receptors for immunofluorescent imaging over a large area of the substantia nigra pars compacta (SNc). SEP-D2Rs appeared as puncta-like structures along the surface of dendrites and soma of dopamine neurons visualized by antibodies to tyrosine hydroxylase (TH). TH-associated SEP-D2Rs displayed a cell surface density of 0.66 puncta/µm 2 , which corresponds to an average frequency of 1 punctum every 1.50 µm. Separate ultrastructural experiments using silver-enhanced immunogold revealed that membrane-bound particles represented 28% of total D2Rs in putative dopamine cells within the SNc. Structures immediately adjacent to dendritic membrane gold particles were unmyelinated axons or axon varicosities (40%), astrocytes (19%), other dendrites (7%), or profiles unidentified (34%) in single sections. Some apposed profiles also expressed D2Rs. Fluorescent and ultrastructural analyses also provided the first visualization of membrane D2Rs at the axon initial segment, a compartment critical for action potential generation. The punctate appearance of anti-SEP staining indicates there is a population of D2Rs organized in discrete signaling sites along the plasma membrane, and for the first time, a quantitative estimate of spatial frequency is provided., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Decades of research have revealed the remarkable complexity of the midbrain dopamine (DA) system, which comprises cells principally located in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). Neither homogenous nor serving a singular function, the midbrain DA system is instead composed of distinct cell populations that (1) receive different sets of inputs, (2) project to separate forebrain sites, and (3) are characterized by unique transcriptional and physiological signatures. To appreciate how these differences relate to circuit function, we first need to understand the anatomical connectivity of unique DA pathways and how this connectivity relates to DA-dependent motivated behavior. We and others have provided detailed maps of the input-output relationships of several subpopulations of midbrain DA cells and explored the roles of these different cell populations in directing behavioral output. In this study, we analyze VTA inputs and outputs as a high dimensional dataset (10 outputs, 22 inputs), deploying computational techniques well-suited to finding interpretable patterns in such data. In addition to reinforcing our previous conclusion that the connectivity in the VTA is dependent on spatial organization, our analysis also uncovered a set of inputs elevated onto each projection-defined VTA DA cell type. For example, VTA DA →NAcLat cells receive preferential innervation from inputs in the basal ganglia, while VTA DA →Amygdala cells preferentially receive inputs from populations sending a distributed input across the VTA, which happen to be regions associated with the brain's stress circuitry. In addition, VTA DA →NAcMed cells receive ventromedially biased inputs including from the preoptic area, ventral pallidum, and laterodorsal tegmentum, while VTA DA →mPFC cells are defined by dominant inputs from the habenula and dorsal raphe. We also go on to show that the biased input logic to the VTA DA cells can be recapitulated using projection architecture in the ventral midbrain, reinforcing our finding that most input differences identified using rabies-based (RABV) circuit mapping reflect projection archetypes within the VTA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Derdeyn, Hui, Macchia and Beier.)

Misfolding and aggregation of α-synuclein are specific features of Parkinson's disease and other neurodegenerative diseases defined as synucleinopathies. Parkinson's disease progression has been correlated with the formation and extracellular release of α-synuclein aggregates, as well as with their spread from neuron to neuron. Therapeutic interventions in the initial stages of Parkinson's disease require a clear understanding of the mechanisms by which α-synuclein disrupts the physiological synaptic and plastic activity of the basal ganglia. For this reason, we identified two early time points to clarify how the intrastriatal injection of α-synuclein-preformed fibrils in rodents via retrograde transmission induces time-dependent electrophysiological and behavioural alterations. We found that intrastriatal α-synuclein-preformed fibrils perturb the firing rate of dopaminergic neurons in the substantia nigra pars compacta, while the discharge of putative GABAergic cells of the substantia nigra pars reticulata is unchanged. The α-synuclein-induced dysregulation of nigrostriatal function also impairs, in a time-dependent manner, the two main forms of striatal synaptic plasticity, long-term potentiation and long-term depression. We also observed an increased glutamatergic transmission measured as an augmented frequency of spontaneous excitatory synaptic currents. These changes in neuronal function in the substantia nigra pars compacta and striatum were observed before overt neuronal death occurred. In an additional set of experiments, we were able to rescue α-synuclein-induced alterations of motor function, striatal synaptic plasticity and increased spontaneous excitatory synaptic currents by subchronic treatment with l-DOPA, a precursor of dopamine widely used in the therapy of Parkinson's disease, clearly demonstrating that a dysfunctional dopamine system plays a critical role in the early phases of the disease., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Saporin conjugated to oxytocin (OXY-SAP) destroys neurons expressing oxytocinergic receptors. When injected unilaterally in the substantia nigra of male rats, OXY-SAP causes a dose-dependent decrease up to 55 % in nigral Tyrosine Hydroxylase (TH)-immunoreactivity compared to control mock peptide BLANK-SAP- and PBS-treated rats or the contralateral substantia nigra. TH decrease was parallel to a dopamine content decrease in the ipsilateral striatum compared to BLANK-SAP- or PBS-treated rats or the contralateral striatum. OXY-SAP-treated rats showed a small but significant increase of locomotor activity 28 days after intranigral injection in the Open field test compared to BLANK-SAP- or PBS-treated rats, in line with an inhibitory role of nigral oxytocin on locomotor activity. OXY-SAP-, but not BLANK-SAP- or PBS-treated rats, also showed marked dose-dependent rotational turning ipsilateral to the injected substantia nigra when challenged with d-amphetamine, but not with apomorphine. Under isoflurane anesthesia OXY-SAP-treated rats showed levels of extracellular dopamine in the dialysate from the ipsilateral striatum only half those of BLANK-SAP- or PBS-treated rats or the contralateral striatum. When treated with d-amphetamine, OXY-SAP_60/120 rats showed increased extracellular dopamine levels in the dialysate from the ipsilateral striatum two third/one third only of those found in BLANK-SAP- or PBS-treated rats or the contralateral striatum, respectively. These results show that OXY-SAP destroys nigrostriatal dopaminergic neurons expressing oxytocin receptors leading to a reduced striatal dopamine function., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The main neuropathological feature of Parkinson's disease (PD) is degeneration of dopamine (DA) neurons in the substantia nigra (SN); PD prevalence is higher in men, suggesting a role of sex hormones in neuroprotection. This study sought the effects of sex hormones in the brain in a mouse model of PD and modulation of steroid metabolism/synthesis with the 5α-reductase inhibitor dutasteride shown to protect 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) male mice. Male and female mice were gonadectomized (GDX) or SHAM operated. They were treated with vehicle or dutasteride (5 mg/kg) for 10 days and administered a low dose of MPTP (5.5 mg/kg) or saline on the 5th day to model early PD; brains were collected thereafter. Striatal measures of the active metabolite 1-methyl-4-phenylpyridinium (MPP + ) contents showed no difference supporting an effect of the experimental conditions investigated. In SHAM MPTP male mice loss of striatal DA and metabolites, DA transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) specific binding in the striatum and SN was prevented by dutasteride treatment; these changes were inversely correlated with glial fibrillary acidic protein (GFAP, an astrogliosis marker) levels. In SHAM female mice MPTP treatment had little or no effect on striatal and SN DA markers and GFAP levels whereas GDX male and female mice showed a similar loss of striatal DA markers and increase of GFAP. No effect of dutasteride treatment was observed in GDX male and female mice. In conclusion, sex differences in mice MPTP toxicity and response to dutasteride were observed that were lost upon gonadectomy implicating neuroinflammation., (Copyright © 2021. Published by Elsevier Ltd.)

In Parkinson's disease, there is a progressive reduction in striatal dopaminergic function, and loss of neuromelanin-containing dopaminergic neurons and increased iron deposition in the substantia nigra. We tested the hypothesis of a relationship between impairment of the dopaminergic system and changes in the iron metabolism. Based on imaging data of patients with prodromal and early clinical Parkinson's disease, we assessed the spatiotemporal ordering of such changes and relationships in the sensorimotor, associative and limbic territories of the nigrostriatal system. Patients with Parkinson's disease (disease duration < 4 years) or idiopathic REM sleep behaviour disorder (a prodromal form of Parkinson's disease) and healthy controls underwent longitudinal examination (baseline and 2-year follow-up). Neuromelanin and iron sensitive MRI and dopamine transporter single-photon emission tomography were performed to assess nigrostriatal levels of neuromelanin, iron, and dopamine. For all three functional territories of the nigrostriatal system, in the clinically most and least affected hemispheres separately, the following was performed: cross-sectional and longitudinal intergroup difference analysis of striatal dopamine and iron, and nigral neuromelanin and iron; in Parkinson's disease patients, exponential fitting analysis to assess the duration of the prodromal phase and the temporal ordering of changes in dopamine, neuromelanin or iron relative to controls; and voxel-wise correlation analysis to investigate concomitant spatial changes in dopamine-iron, dopamine-neuromelanin and neuromelanin-iron in the substantia nigra pars compacta. The temporal ordering of dopaminergic changes followed the known spatial pattern of progression involving first the sensorimotor, then the associative and limbic striatal and nigral regions. Striatal dopaminergic denervation occurred first followed by abnormal iron metabolism and finally neuromelanin changes in the substantia nigra pars compacta, which followed the same spatial and temporal gradient observed in the striatum but shifted in time. In conclusion, dopaminergic striatal dysfunction and cell loss in the substantia nigra pars compacta are interrelated with increased nigral iron content., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Dopamine (DA) neurons in the ventral tier of the substantia nigra pars compacta (SNc) degenerate prominently in Parkinson's disease, while those in the dorsal tier are relatively spared. Defining the molecular, functional, and developmental characteristics of each SNc tier is crucial to understand their distinct susceptibility. We demonstrate that Sox6 expression distinguishes ventrally and dorsally biased DA neuron populations in the SNc. The Sox6 + population in the ventral SNc includes an Aldh1a1 + subset and is enriched in gene pathways that underpin vulnerability. Sox6 + neurons project to the dorsal striatum and show activity correlated with acceleration. Sox6 - neurons project to the medial, ventral, and caudal striatum and respond to rewards. Moreover, we show that this adult division is encoded early in development. Overall, our work demonstrates a dual origin of the SNc that results in DA neuron cohorts with distinct molecular profiles, projections, and functions., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Dopamine depletion and microstructural degradation underlie the neurodegenerative processes in Parkinson's disease (PD). To explore early alterations and underlying associations of dopamine and microstructure in PD patients utilizing the hybrid positron emission tomography (PET)-magnetic resonance imaging (MRI). Twenty-five PD patients in early stages and twenty-four matched healthy controls underwent hybrid 18 F-fluorodopa (DOPA) PET-diffusion tensor imaging (DTI) scanning. The striatal standardized uptake value ratio (SUVR), DTI maps (fractional anisotropy, FA; mean diffusivity, MD) in subcortical grey matter, and deterministic tractography of the nigrostriatal pathway were processed. Values in more affected (MA) side, less affected (LA) side and mean were analysed. Correlations and mediations among PET, DTI and clinical characteristics were further analysed. PD groups exhibited asymmetric pattern of dopaminergic dysfunction in putamen, impaired integrity in the microstructures (nigral FA, putaminal MD, and FA of nigrostriatal projection). On MA side, significant associations between DTI metrics (nigral FA, putaminal MD, and FA of nigrostriatal projection) and motor performance were significantly mediated by putaminal SUVR, respectively. Early asymmetric disruptions in putaminal dopamine concentrations and nigrostriatal pathway microstructure were detected using hybrid PET-MRI. The findings further implied that molecular degeneration mediates the modulation of microstructural disorganization on motor dysfunction in the early stages of PD., (© 2021. The Author(s).)

A molecular hallmark in Parkinson's disease (PD) pathogenesis are α-synuclein aggregates. Cerebral dopamine neurotrophic factor (CDNF) is an atypical growth factor that is mostly resident in the endoplasmic reticulum but exerts its effects both intracellularly and extracellularly. One of the beneficial effects of CDNF can be protecting neurons from the toxic effects of α-synuclein. Here, we investigated the effects of CDNF on α-synuclein aggregation in vitro and in vivo. We found that CDNF directly interacts with α-synuclein with a K D  = 23 ± 6 nM and reduces its auto-association. Using nuclear magnetic resonance (NMR) spectroscopy, we identified interaction sites on the CDNF protein. Remarkably, CDNF reduces the neuronal internalization of α-synuclein fibrils and induces the formation of insoluble phosphorylated α-synuclein inclusions. Intra-striatal CDNF administration alleviates motor deficits in rodents challenged with α-synuclein fibrils, though it did not reduce the number of phosphorylated α-synuclein inclusions in the substantia nigra. CDNF's beneficial effects on rodent behavior appear not to be related to the number of inclusions formed in the current context, and further study of its effects on the aggregation mechanism in vivo are needed. Nonetheless, the interaction of CDNF with α-synuclein, modifying its aggregation, spreading, and associated behavioral alterations, provides novel insights into the potential of CDNF as a therapeutic strategy in PD and other synucleinopathies., Competing Interests: Declaration of interests M.S. is the founder and shareholder of Herantis Pharma Plc. H.J.H. is an employee and a shareholder of Herantis Pharma Plc. A.D. is an employee of Orion Corporation., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

6-Hydroxydopamine (6-OHDA) is a widely used chemical to model Parkinson's disease (PD) in rats. Syringic acid (SA) is a polyphenolic compound which has antioxidant and anti-inflammatory properties. The present study aimed to evaluate the neuroprotective role of SA in a rat model of 6-OHDA-induced PD. Parkinson's disease was created by injection of 6-OHDA into the medial forebrain bundle via stereotaxic surgery. Syringic acid was administered daily by oral gavage, before or after surgery. All groups were tested for locomotor activity, rotarod performance and catatony. Dopamine levels in SN were determined by an optimized multiple reaction monitoring method using ultra-fast liquid chromatography coupled with tandem mass spectrometry (MS/MS). The immunoreactivities for tyrosine hydroxylase (TH) and inducible nitric oxide synthase (iNOS) were detected by immunohistochemistry in frozen substantia nigra (SN) sections. Nitrite/nitrate levels, iNOS protein, total oxidant (TOS) and total antioxidant (TAS) status were assayed in SN tissue by standard kits. Motor dysfunction, impaired nigral dopamine release, increased iNOS expression and elevated nitrite/nitrate levels induced by 6-OHDA were significantly restored by SA treatment. Syringic acid significantly improved the loss of nigral TH-positive cells, while increasing TAS capacity and reducing TOS capacity in SN of PD rats. These data conclude that SA is a potential therapeutic agent for the treatment of 6-OHDA-induced rat model of PD. Syringic acid reduced the progression of PD via its neuroprotective, antioxidant and anti-inflammatory effects.

Progressive loss of dopamine inputs in Parkinson's disease leads to imbalances in coordinated signaling of dopamine and acetylcholine (ACh) in the striatum, which is thought to contribute to parkinsonian motor symptoms. As reciprocal interactions between dopamine inputs and cholinergic interneurons (ChIs) control striatal dopamine and ACh transmission, we examined how partial dopamine depletion in an early-stage mouse model for Parkinson's disease alters nigral regulation of cholinergic activity. We found region-specific alterations in how remaining dopamine inputs regulate cholinergic excitability that differ between the dorsomedial (DMS) and dorsolateral (DLS) striatum. Specifically, we found that dopamine depletion downregulates metabotropic glutamate receptors (mGluR1) on DLS ChIs at synapses where dopamine inputs co-release glutamate, abolishing the ability of dopamine inputs to drive burst firing. This loss underlies parkinsonian motor impairments, as viral rescue of mGluR1 signaling in DLS ChIs was sufficient to restore circuit function and attenuate motor deficits in early-stage parkinsonian mice., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Phasic dopamine release from mid-brain dopaminergic neurons is thought to signal errors of reward prediction (RPE). If reward maximisation is to maintain homeostasis, then the value of primary rewards should be coupled to the homeostatic errors they remediate. This leads to the prediction that RPE signals should be configured as a function of homeostatic state and thus diminish with the attenuation of homeostatic error. To test this hypothesis, we collected a large volume of functional MRI data from five human volunteers on four separate days. After fasting for 12 hours, subjects consumed preloads that differed in glucose concentration. Participants then underwent a Pavlovian cue-conditioning paradigm in which the colour of a fixation-cross was stochastically associated with the delivery of water or glucose via a gustometer. This design afforded computation of RPE separately for better- and worse-than expected outcomes during ascending and descending trajectories of serum glucose fluctuations. In the parabrachial nuclei, regional activity coding positive RPEs scaled positively with serum glucose for both ascending and descending glucose levels. The ventral tegmental area and substantia nigra became more sensitive to negative RPEs when glucose levels were ascending. Together, the results suggest that RPE signals in key brainstem structures are modulated by homeostatic trajectories of naturally occurring glycaemic flux, revealing a tight interplay between homeostatic state and the neural encoding of primary reward in the human brain., Competing Interests: The authors declare no competing interests. H.R.S. has received honoraria as speaker from Genzyme, Denmark and as senior editor of Neuroimage from Elsevier Publishers, Amsterdam, The Netherlands. H.R.S. has received a research fund from Biogen-idec, Denmark. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Somatodendritic dopamine (DA) release from midbrain DA neurons activates D2 autoreceptors on these cells to regulate their activity. However, the source of autoregulatory DA remains controversial. Here, we test the hypothesis that D2 autoreceptors on a given DA neuron in the substantia nigra pars compacta (SNc) are activated primarily by DA released from that same cell, rather than from its neighbors. Voltage-clamp recording allows monitoring of evoked D2-receptor-mediated inhibitory currents (D2ICs) in SNc DA neurons as an index of DA release. Single-cell application of antibodies to Na + channels via the recording pipette decreases spontaneous activity of recorded neurons and attenuates evoked D2ICs; antibodies to SNAP-25, a soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein, also decrease D2IC amplitude. Evoked D2ICs are nearly abolished by the light chain of botulinum neurotoxin A, which cleaves SNAP-25, whereas synaptically activated GABA B -receptor-mediated currents are unaffected. Thus, somatodendritic DA release in the SNc autoinhibits the neuron that releases it., Competing Interests: Declaration of interests K.I. is the founder of and has financial interests in CytoDel, Inc., a biopharmaceutical company with license to NYU patents that protect the work related to BoNT/A constructs used in this report., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Degeneration of dopaminergic, nigrostriatal neurons is the hallmark of Parkinson disease (PD), and PET quantification of dopamine transporters is a widely accepted method for differential diagnosis between idiopathic PD and essential tremor. [18F]PR04.MZ is a new PET tracer with excellent imaging properties allowing for precise quantification of striatal and extrastriatal dopamine transporter. Here we describe our initial experience with [18F]PR04.MZ PET/CT in a larger cohort of healthy controls and PD patients as a proof-of-concept study for this tracer., Methods: Eighteen healthy subjects, 19 early PD patients (Hoehn-Yahr I-II), and 13 moderate-advanced PD patients (Hoehn-Yahr III-IV) underwent static PET/CT scans 60 to 90 minutes after injection of 5.16 ± 1.03 mCi (191 ± 38 MBq) [18F]PR04.MZ. Specific binding ratios (SBRs) were calculated for caudate nucleus, anterior putamen, posterior putamen, substantia nigra (SNpc), compared between different groups and correlated with clinical ratings., Results: [18F]PR04.MZ showed very high and specific uptake in the putamen, caudate, and substantia nigra pars compacta and very low nonspecific binding in other brain regions, and SBR values for the control group were 22.3 ± 4.1, 19.1 ± 3.5, and 5.4 ± 1.2, respectively. A reduction of SBR values was observed in all regions and in both initial and moderate PD, ranging from 35% to 89% (P < 0.001). The observed pattern of reduction was posterior putamen > anterior putamen > substantia nigra pars compacta > caudate, with contralateral posterior putamen being the most affected region. Rostrocaudal depletion gradient was evident in all PD patients and progression correlated with motor manifestations., Conclusions: [18F]PR04.MZ PET/CT is a highly sensitive imaging modality for the detection of dopaminergic deficit in nigrostriatal pathways in PD., Competing Interests: Conflicts of interest and sources of funding: This study was funded by national research grants from CORFO (13PIE-21682) and CONICYT (FONDECYT 11130534). None declared to all authors., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.)

Parkinson's disease (PD) is the second most prominent neurodegenerative disease around the world. Although it is known that PD is caused by the loss of dopaminergic cells in substantia nigra pars compacta (SNc), the decisive cause of this inexorable cell loss is not clearly elucidated. We hypothesize that "Energy deficiency at a sub-cellular/cellular/systems level can be a common underlying cause for SNc cell loss in PD." Here, we propose a comprehensive computational model of SNc cell, which helps us to understand the pathophysiology of neurodegeneration at the subcellular level in PD. The aim of the study is to see how deficits in the supply of energy substrates (glucose and oxygen) lead to a deficit in adenosine triphosphate (ATP). The study also aims to show that deficits in ATP are the common factor underlying the molecular-level pathological changes, including alpha-synuclein aggregation, reactive oxygen species formation, calcium elevation, and dopamine dysfunction. The model suggests that hypoglycemia plays a more crucial role in leading to ATP deficits than hypoxia. We believe that the proposed model provides an integrated modeling framework to understand the neurodegenerative processes underlying PD.

Background: Posture Instability (PI) is known to be a severe complication in Parkinson's Disease (PD), and its mechanism remains poorly understood. Our study aims to explore the changes of brain network in PI of PD, and further investigate the role of peripheral inflammation on activities of different brain regions in PD with PI., Methods: 167 individuals were recruited, including 36 PD cases with PI and 131 ones without PI. We carefully assessed the status of motor and cognitive function, measured serum inflammatory factors, and detected the dopaminergic pathways and the metabolism of different brain regions by Positron Emission Tomography (PET). Data analysis was conducted by variance, univariate analysis, chi-square analysis, logistic regression, and partial correlation., Results: No difference was found for age or onset age between the two groups (P>0.05). Female patients were susceptible to posture impairment and had a 2.14-fold risk for PI compared with male patients in PD (P<0.05). Patients with PI had more severe impairment of motor and cognitive function for a longer duration than those without PI (P<0.05). The mean uptake ratios of presynaptic vesicular monoamine transporter (VMAT2), which were detected in the caudate nucleus and putamen, were lower in PI group than those without PI (P<0.05). There were lower activities of the midbrain, caudate nucleus, and anterior medial temporal cortex in PI group than those in the non-PI group (P<0.05). Although serum concentrations of immunoglobulins (IgG, IgM, and IgA) and complements (C3, C4) were higher in the PI group than those in the non-PI group, only serum IgM concentration had a significant difference between the two groups (P<0.05). We further explored significant inverse correlations of IgG, IgM, IgA, and C4 with activities of some cerebral cortex in PI of PD (P<0.05)., Conclusion: Female patients were susceptible to posture instability and had a 2.14-fold risk for PI of PD. Patients with PI had more severe impairments of motor and cognitive function for a longer duration than those without PI. PI was associated with a dopamine drop of the nigrostriatal system and lower activities of the limbic cortex in PD. Peripheral inflammation may be involved in degeneration of the cerebral cortex in PD combined with PI., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Fragmentation of the Golgi ribbon is a common feature of Parkinson´s disease and other neurodegenerative diseases. This alteration could be the consequence of the anterograde and retrograde transport imbalance, α-synuclein aggregates, and/or cytoskeleton alterations. Most information on this process has been obtained from cellular and animal experimental models, and as such, there is little information available on human tissue. If the information on human tissue was available, it may help to understand the cytopathological mechanisms of this disease. In the present study, we analyzed the morphological characteristics of the Golgi complex of dopaminergic neurons in human samples of substantia nigra of control and Parkinson's disease patients. We measured the expression levels of putative molecules involved in Golgi fragmentation, including α-synuclein, tubulin, and Golgi-associated regulatory and structural proteins. We show that, as a consequence of the disease, the Golgi complex is fragmented into small stacks without vesiculation. We found that only a limited number of regulatory proteins are altered. Rab1, a small GTPase regulating endoplasmic reticulum-to-Golgi transport, is the most dramatically affected, being highly overexpressed in the surviving neurons. We found that the SNARE protein syntaxin 5 forms extracellular aggregates resembling the amyloid plaques characteristic of Alzheimer's disease. These findings may help to understand the cytopathology of Parkinson's disease.

α-Synuclein is expressed at high levels at presynaptic terminals, but defining its role in the regulation of neurotransmission under physiologically relevant conditions has proven elusive. We report that, in vivo, α-synuclein is responsible for the facilitation of dopamine release triggered by action potential bursts separated by short intervals (seconds) and a depression of release with longer intervals between bursts (minutes). These forms of presynaptic plasticity appear to be independent of the presence of β- and γ-synucleins or effects on presynaptic calcium and are consistent with a role for synucleins in the enhancement of synaptic vesicle fusion and turnover. These results indicate that the presynaptic effects of α-synuclein depend on specific patterns of neuronal activity., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)

Introduction: To investigate whether neurodegeneration underlying Parkinson's disease (PD) accounts for a substantial proportion of cases of minimal parkinsonism in the elderly., Methods: We recruited 48 consecutive subjects with minimal parkinsonism who visited the clinic with cognitive complaints. All subjects did not show findings compatible with PD on 18 F-FP-CIT PET scans, and had no evidence of other neurodegenerative disorders. Striatal dopamine transporter (DAT) availability was quantified, and mean diffusivity (MD) values in the pons were calculated to characterize structural damage using diffusion tensor imaging. Additionally, 35 patients with PD and 21 healthy controls were included as reference groups., Results: Individuals with minimal parkinsonism (mean age, 73.23 ± 7.03 years) exhibited mild decrease in DAT availability in the posterior putamen, which was at a level between that of healthy controls and patients with PD. DAT availability in the caudate and anterior putamen was also mildly decreased in the minimal parkinsonism group. Individuals with minimal parkinsonism also tended to have higher MD values in the pons compared to healthy controls., Conclusions: Our results suggest that a substantial proportion of minimal parkinsonism is associated with nigrostriatal dopamine depletion and pontine structural damage, which may be related to the disease process of prodromal PD., (Copyright © 2020. Published by Elsevier Ltd.)

The accumulation of aggregated α-synuclein (αSyn) is a hallmark of Parkinson's disease (PD). Current evidence indicates that small soluble αSyn oligomers (αSynOs) are the most toxic species among the forms of αSyn aggregates, and that size and topological structural properties are crucial factors for αSynOs-mediated toxicity, involving the interaction with either neurons or glial cells. We previously characterized a human αSynO (H-αSynO) with specific structural properties promoting toxicity against neuronal membranes. Here, we tested the neurotoxic potential of these H-αSynOs in vivo, in relation to the neuropathological and symptomatic features of PD. The H-αSynOs were unilaterally infused into the rat substantia nigra pars compacta (SNpc). Phosphorylated αSyn (p129-αSyn), reactive microglia, and cytokine levels were measured at progressive time points. Additionally, a phagocytosis assay in vitro was performed after microglia pre-exposure to αsynOs. Dopaminergic loss, motor, and cognitive performances were assessed. H-αSynOs triggered p129-αSyn deposition in SNpc neurons and microglia and spread to the striatum. Early and persistent neuroinflammatory responses were induced in the SNpc. In vitro, H-αSynOs inhibited the phagocytic function of microglia. H-αsynOs-infused rats displayed early mitochondrial loss and abnormalities in SNpc neurons, followed by a gradual nigrostriatal dopaminergic loss, associated with motor and cognitive impairment. The intracerebral inoculation of structurally characterized H-αSynOs provides a model of progressive PD neuropathology in rats, which will be helpful for testing neuroprotective therapies.

Objective: Recent evidence supports the use of neuromelanin-sensitive MRI (NM-MRI) as a novel tool to investigate dopamine function in the human brain. The authors investigated the NM-MRI signal in individuals with cocaine use disorder, compared with age- and sex-matched control subjects, based on previous imaging studies showing that this disorder is associated with blunted presynaptic striatal dopamine., Methods: NM-MRI and T 1 -weighted images were acquired from 20 participants with cocaine use disorder and 35 control subjects. Diagnostic group effects in NM-MRI signal were determined using a voxelwise analysis within the substantia nigra. A subset of 20 cocaine users and 17 control subjects also underwent functional MRI imaging using the monetary incentive delay task, in order to investigate whether NM-MRI signal was associated with alterations in reward processing., Results: Compared with control subjects, cocaine users showed significantly increased NM-MRI signal in ventrolateral regions of the substantia nigra (area under the receiver operating characteristic curve=0.83). Exploratory analyses did not find a significant correlation of NM-MRI signal to activation of the ventral striatum during anticipation of monetary reward., Conclusions: Given that previous imaging studies show decreased dopamine signaling in the striatum, the finding of increased NM-MRI signal in the substantia nigra provides additional insight into the pathophysiology of cocaine use disorder. One interpretation is that cocaine use disorder is associated with a redistribution of dopamine between cytosolic and vesicular pools, leading to increased accumulation of neuromelanin. The study findings thus suggest that NM-MRI can serve as a practical imaging tool for interrogating the dopamine system in addiction.

Substantia nigra (SNc) dopaminergic neurons respond to aversive stimuli with inhibitory pauses in firing followed by transient rebound activation. We tested integration of inhibitory synaptic inputs onto SNc neurons from genetically defined populations in dorsal striatum (striosome and matrix) and external globus pallidus (GPe; parvalbumin- and Lhx6-positive), and examined their contribution to pause-rebound firing. Activation of striosome projections, which target "dendron bouquets" in the pars reticulata (SNr), consistently quiets firing and relief from striosome inhibition triggers rebound activity. Striosomal inhibitory postsynaptic currents (IPSCs) display a prominent GABA-B receptor-mediated component that strengthens the impact of SNr dendrite synapses on somatic excitability and enables rebounding. By contrast, GPe projections activate GABA-A receptors on the soma and proximal dendrites but do not result in rebounding. Lastly, optical mapping shows that dorsal striatum selectively inhibits the ventral population of SNc neurons, which are intrinsically capable of rebounding. Therefore, we define a distinct striatonigral circuit for generating dopamine rebound., Competing Interests: Declaration of Interests The authors declare no competing interests., (Published by Elsevier Inc.)

Parkinson's disease (PD) is considered a synucleinopathy because of the intraneuronal accumulation of aggregated α-synuclein (αSyn). Recent evidence points to soluble αSyn-oligomers (αSynO) as the main cytotoxic species responsible for cell death. Given the pivotal role of αSyn in PD, αSyn-based models are crucial for the investigation of toxic mechanisms and the identification of new therapeutic targets in PD. By using a metabolomics approach, we evaluated the metabolic profile of brain and serum samples of rats infused unilaterally with preformed human αSynOs (HαSynOs), or vehicle, into the substantia nigra pars compacta (SNpc). Three months postinfusion, the striatum was dissected for striatal dopamine (DA) measurements via High Pressure Liquid Chromatography (HPLC) analysis and mesencephalon and serum samples were collected for the evaluation of metabolite content via gas chromatography mass spectrometry analysis. Multivariate, univariate and correlation statistics were applied. A 40% decrease of DA content was measured in the HαSynO-infused striatum as compared to the contralateral and the vehicle-infused striata. Decreased levels of dehydroascorbic acid, myo-inositol, and glycine, and increased levels of threonine, were found in the mesencephalon, while increased contents of fructose and mannose, and a decrease in glycine and urea, were found in the serum of HαSynO-infused rats. The significant correlation between DA and metabolite content indicated that metabolic variations reflected the nigrostriatal degeneration. Collectively, the metabolomic fingerprint of HαSynO-infused rats points to an increase of oxidative stress markers, in line with PD neuropathology, and provides hints for potential biomarkers of PD.

Studies indicate that mutant α-synuclein (mαSyn) is involved in the pathogenesis of Parkinson's disease (PD). The mαSyn expression leads to the loss of dopaminergic neurons in the substantia nigra (SN) and consequent motor dysfunctions. Additionally, studies found that PD was accompanied by extensive neuroinflammation of SN. However, it remains unclear as to whether microglia participate in the mαSyn pathology. This issue is addressed by using AAV-mα-Syn (A30P-A53T) to overexpress the human mαSyn in the SN in view of establishing the PD model. Subsequently, minocycline (Mino) was used to inhibit microglia activity, and an interleukin-1 receptor (IL-1R1) antagonist was used to hinder the IL-1R1 function. Finally, immunohistochemistry was used to analyze phosphorylated αSyn (Ser129) and TH-positive cells in the SN. Dopamine levels were analyzed by high performance liquid chromatography. mαSyn overexpression in the SN induced motor dysfunction, decreased striatal dopamine levels, and increased pathological αSyn 12 weeks after AAV injection. The data demonstrated that inhibiting microglial activation or hindering IL-1R1 reversed the persistent motor deficits, neurodegeneration of the nigrostriatal dopaminergic system, and development of Lewy body pathology caused by human mαSyn overexpression in the SN. Additionally, these findings indicate that neuroinflammation promotes the loss of neuronal cells.

The etiology and pathogenesis of Parkinson's disease (PD) are tightly linked to the gain-of-function of α-synuclein. However, gradual accumulation of α-synuclein aggregates in dopaminergic neurons of substantia nigra pars compacta (SNpc) leads to the depletion of the functional pool of soluble α-synuclein, and therefore, creates loss-of-function conditions, particularly in presynaptic terminals of these neurons. Studies of how this late-onset depletion of a protein involved in many important steps of neurotransmission contributes to PD progression and particularly, to worsening the nigrostriatal pathology at late stages of the disease are limited and obtained data, are controversial. Recently, we produced a mouse line for conditional knockout of the gene encoding α-synuclein, and here we used its tamoxifen-inducible pan-neuronal inactivation to study consequences of the adult-onset (from the age of 6 months) and late-onset (from the age of 12 months) α-synuclein depletion to the nigrostriatal system. No significant changes of animal balance/coordination, the number of dopaminergic neurons in the SNpc and the content of dopamine and its metabolites in the striatum were observed after adult-onset α-synuclein depletion, but in aging (18-month-old) late-onset depleted mice we found a significant reduction of major dopamine metabolites without changes to the content of dopamine itself. Our data suggest that this might be caused, at least partially, by reduced expression of aldehyde dehydrogenase ALDH1a1 and could lead to the accumulation of toxic intermediates of dopamine catabolism. By extrapolating our findings to a potential clinical situation, we suggest that therapeutic downregulation of α-synuclein expression in PD patients is a generally safe option as it should not cause adverse side effects on the functionality of their nigrostriatal system. However, if started in aged patients, this type of therapy might trigger slight functional changes of the nigrostriatal system with potentially unwanted additive effect to already existing pathology., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Dopamine (DA) modulates basal ganglia (BG) activity for initiation and execution of goal-directed movements and habits. While most studies are aimed to striatal function, the cellular and molecular mechanisms underlying dopaminergic regulation in other nuclei of the BG are not well understood. Therefore, we set to analyze the dopaminergic modulation occurring in subthalamo-nigral synapse, in both pars compacta (SNc) and pars reticulata (SNr) neurons, because these synapses are important for the integration of information previously processed in striatum and globus pallidus. In this study, electrophysiological and pharmacological evidence of dopaminergic modulation on glutamate release through calcium channels is presented. Using paired pulse ratio (PPR) measurements and selective blockers of these ionic channels, together with agonists and antagonists of DA D 2 -like receptors, we found that blockade of the Ca V 3 family occludes the presynaptic inhibition produced by the activation of DA receptors pharmacologically profiled as D 3 -type in the STh-SNc synapses. On the contrast, the blockade of Ca V 2 channels, but not Ca V 3, occlude with the effect of the D 3 agonist, PD 128907, in the STh-SNr synapse. The functional role of this differential distribution of calcium channels that modulate the release of glutamate in the SN implies a fine adjustment of firing for both classes of neurons. Dopaminergic neurons of the SNc establish a DA tone within the SN based on the excitatory/inhibitory inputs; such tone may contribute to processing information from subthalamic nucleus and could also be involved in pathological DA depletion that drives hyperexcitation of SNr neurons., (© 2020 Wiley Periodicals, Inc.)

Cortical pyramidal cells are generated locally, from pre-programmed progenitors, to form functionally distinct areas. By contrast, striatal projection neurons (SPNs) are generated remotely from a common source, undergo migration to form mosaics of striosomes and matrix, and become incorporated into functionally distinct sectors. Striatal circuits might thus have a unique logic of developmental organization, distinct from those of the neocortex. We explore this possibility in mice by mapping one set of SPNs, those in striosomes, with striatonigral projections to the dopamine-containing substantia nigra pars compacta (SNpc). Same-age SPNs exhibit topographic striatonigral projections, according to their resident sector. However, the different birth dates of resident SPNs within a given sector specify the destination of their axons within the SNpc. These findings highlight a logic intercalating birth date-dependent and birth date-independent factors in determining the trajectories of SPN axons and organizing specialized units of striatonigral circuitry that could influence behavioral expression and vulnerabilities to disease., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Parkinson's disease is characterized by loss of dopamine neurons in the substantia nigra 1 . Similar to other major neurodegenerative disorders, there are no disease-modifying treatments for Parkinson's disease. While most treatment strategies aim to prevent neuronal loss or protect vulnerable neuronal circuits, a potential alternative is to replace lost neurons to reconstruct disrupted circuits 2 . Here we report an efficient one-step conversion of isolated mouse and human astrocytes to functional neurons by depleting the RNA-binding protein PTB (also known as PTBP1). Applying this approach to the mouse brain, we demonstrate progressive conversion of astrocytes to new neurons that innervate into and repopulate endogenous neural circuits. Astrocytes from different brain regions are converted to different neuronal subtypes. Using a chemically induced model of Parkinson's disease in mouse, we show conversion of midbrain astrocytes to dopaminergic neurons, which provide axons to reconstruct the nigrostriatal circuit. Notably, re-innervation of striatum is accompanied by restoration of dopamine levels and rescue of motor deficits. A similar reversal of disease phenotype is also accomplished by converting astrocytes to neurons using antisense oligonucleotides to transiently suppress PTB. These findings identify a potentially powerful and clinically feasible approach to treating neurodegeneration by replacing lost neurons.

The nigrostriatal dopaminergic system (NDS) controls motor activity, and its impairment during type 2 diabetes (T2D) progression could increase Parkinson's disease risk in diabetics. If so, whether glycemia regulation prevents this impairment needs to be addressed. We investigated whether T2D impairs the NDS and whether dipeptidyl peptidase-4 inhibition (DPP-4i; a clinical strategy against T2D but also neuroprotective in animal models) prevents this effect, in middle-aged mice. Neither T2D (induced by 12 months of high-fat diet) nor aging (14 months) changed striatal dopamine content assessed by high-performance liquid chromatography. However, T2D reduced basal and amphetamine-stimulated striatal extracellular dopamine, assessed by microdialysis. Both the DPP-4i linagliptin and the sulfonylurea glimepiride (an antidiabetic comparator unrelated to DPP-4i) counteracted these effects. The functional T2D-induced effects did not correlate with NDS neuronal/glial alterations. However, aging itself affected striatal neurons/glia, and the glia effects were counteracted mainly by DPP-4i. These findings show NDS functional pathophysiology in T2D and suggest the preventive use of two unrelated anti-T2D drugs. Moreover, DPP-4i counteracted striatal age-related glial alterations suggesting striatal rejuvenation properties., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Experimental evidence shows that the phenylpyrazole pesticide fipronil exerts neurotoxic effects at central level in rodents, and in particular on nigrostriatal dopaminergic neurons, whose degeneration is well known to cause motor and non-motor deficits in animals and in humans. In order to characterize better the central neurotoxic effect of fipronil, we injected fipronil (15 and 25 μg) dissolved in dimethyl sulfoxide (DMSO) unilaterally into the substantia nigra of male rats. Male rats injected with DMSO unilaterally into the substantia nigra were used as controls. Control and fipronil-treated rats were then tested in different motor (i.e., open field arena, rotarod, tail flick) and non motor tests (novel object recognition, social interaction) 15 days after injection. A systemic challenge dose of the dopamine-agonist apomorphine was also used to study the presence of a rotational behavior. Sixteen days after fipronil or DMSO injection into the substantia nigra, rats were sacrificed, and either striatal dopamine content or substantia nigra tyrosine hydroxylase (TH) immunoreactivity were measured. The results confirm that the unilateral injection of fipronil into the substantia nigra caused the degeneration of nigrostriatal dopaminergic neurons, which leads to a decrease around 50 % in striatal dopamine content and substantia nigra TH imunoreactivity. This occurred together with changes in motor activity and coordination, and in nociception but not in recognition memory and in social interaction, as revealed by the results of the behavioral experiments performed in fipronil-treated rats compared to vehicle-treated rats 15 days after treatment, as found with other compounds that destroy nigrostriatal dopaminergic neurons., Competing Interests: Declaration of Competing Interest The authors have nothing to declare., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Dopaminergic neurons have the ability to release Dopamine from their axons as well as from their soma and dendrites. This somatodendritically-released Dopamine induces an autoinhibition of Dopaminergic neurons mediated by D2 autoreceptors, and the stimulation of neighbor GABAergic neurons mediated by D1 receptors (D1r). Here, our results suggest that the somatodendritic release of Dopamine in the substantia nigra (SN) may stimulate GABAergic neurons that project their axons into the hippocampus. Using semiquantitative multiplex RT-PCR we show that chronic blockade of the Dopaminergic neurotransmission with both AMPT and reserpine specifically decreases the expression levels of D1r, remarkably this may be the result of an antagonistic effect between AMPT and reserpine, as they induced the expression of a different set of genes when treated by separate. Furthermore, using anterograde and retrograde tracing techniques, we found that the GABAergic neurons that express D1r also project their axons in to the CA1 region of the hippocampus. Finally, we also found that the same treatment that decreases the expression levels of D1r in SN, also induces an impairment in the performance in an appetitive learning task that requires the coding of reward as well as navigational skills. Overall, our findings show the presence of a GABAergic interconnection between the SNr and the hippocampus mediated by D1r., Competing Interests: Declaration of competing interest We have no conflicts of interest to declare., (Copyright © 2019. Published by Elsevier Ltd.)

CB 2 receptors (CB 2 R) are expressed in midbrain neurons. To evidence the control of dopamine release in dorsal striatum by CB 2 R, we performed experiments of [ 3 H]-dopamine release in dorsal striatal slices. We found a paradoxical increase in K + -induced [ 3 H]-dopamine release by CB 2 R activation with GW 833972A and JWH 133 two selective agonist. To understand the mechanism involved, we tested for a role of the D 2 autoreceptor in this effect; because in pallidal structures, the inhibitory effect of CB 1 receptors (CB 1 R) on GABA release is switched to a stimulatory effect by D 2 receptors (D 2 R). We found that the blockade of D 2 autoreceptors with sulpiride prevented the stimulatory effect of CB 2 R activation; in fact, under this condition, CB 2 R decreased dopamine release, indicating the role of the D 2 autoreceptor in the paradoxical increase. We also found that the effect occurs in nigrostriatal terminals, since lesions with 6-OH dopamine in the middle forebrain bundle prevented CB 2 R effects on release. In addition, D 2 -CB 2 R interaction promoted cAMP accumulation, and the increase in [ 3 H]-dopamine release was prevented by PKA blockade. D 2 -CB 2 R coprecipitation and proximity ligation assay studies indicated a close interaction of receptors that could participate in the observed effects. Finally, intrastriatal injection of CB 2 R agonist induced contralateral turning in amphetamine-treated rats, which was prevented by sulpiride, indicating the role of the interaction in motor behavior. Thus, these data indicate that the D 2 autoreceptor switches, from inhibitory to stimulatory, the CB 2 R effects on dopamine release, involving the cAMP → PKA pathway in nigrostriatal terminals., (© 2019 Wiley Periodicals, Inc.)

The spreading hypothesis of neurodegeneration assumes an expansion of neural pathologies along existing neural pathways. Multimodal neuroimaging studies have demonstrated distinct topographic patterns of cerebral pathologies in neurodegeneration. For Parkinson's disease the hypothesis so far rests largely on histopathological evidence of α-synuclein spreading in a characteristic pattern and progressive nigrostriatal dopamine depletion. Functional consequences of nigrostriatal dysfunction on cortical activity remain to be elucidated. Our goal was to investigate multimodal imaging correlates of degenerative processes in Parkinson's disease by assessing dopamine depletion and its potential effect on striatocortical connectivity networks and cortical metabolism in relation to parkinsonian symptoms. We combined 18F-DOPA-PET, 18F-fluorodeoxyglucose (FDG)-PET and resting state functional MRI to multimodally characterize network alterations in Parkinson's disease. Forty-two patients with mild-to-moderate stage Parkinson's disease and 14 age-matched healthy control subjects underwent a multimodal imaging protocol and comprehensive clinical examination. A voxel-wise group comparison of 18F-DOPA uptake identified the exact location and extent of putaminal dopamine depletion in patients. Resulting clusters were defined as seeds for a seed-to-voxel functional connectivity analysis. 18F-FDG metabolism was compared between groups at a whole-brain level and uptake values were extracted from regions with reduced putaminal connectivity. To unravel associations between dopaminergic activity, striatocortical connectivity, glucose metabolism and symptom severity, correlations between normalized uptake values, seed-to-cluster β-values and clinical parameters were tested while controlling for age and dopaminergic medication. Aside from cortical hypometabolism, 18F-FDG-PET data for the first time revealed a hypometabolic midbrain cluster in patients with Parkinson's disease that comprised caudal parts of the bilateral substantia nigra pars compacta. Putaminal dopamine synthesis capacity was significantly reduced in the bilateral posterior putamen and correlated with ipsilateral nigral 18F-FDG uptake. Resting state functional MRI data indicated significantly reduced functional connectivity between the dopamine depleted putaminal seed and cortical areas primarily belonging to the sensorimotor network in patients with Parkinson's disease. In the inferior parietal cortex, hypoconnectivity in patients was significantly correlated with lower metabolism (left P = 0.021, right P = 0.018). Of note, unilateral network alterations quantified with different modalities corresponded with contralateral motor impairments. In conclusion, our results support the hypothesis that degeneration of nigrostriatal fibres functionally impairs distinct striatocortical connections, disturbing the efficient interplay between motor processing areas and impairing motor control in patients with Parkinson's disease. The present study is the first to reveal trimodal evidence for network-dependent degeneration in Parkinson's disease by outlining the impact of functional nigrostriatal pathway impairment on striatocortical functional connectivity networks and cortical metabolism., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Parkinson's disease (PD) is a common neurodegenerative disease that is characterized by pathological dopaminergic (DA) neuronal death and α-synuclein aggregation. Glutamate excitotoxicity is a well-established pathogenesis of PD that involves dysfunctional expression of glutamate transporters. Glutamate transporter-1 (GLT-1) is mainly responsible for clearance of glutamate at synapses, including DA synapses. However, the role of GLT-1 in the aberrant synaptic transmission in PD remains elusive. In the present study, we generated small-interfering RNAs (siRNAs) to knockdown GLT-1 expression in primary astrocytes, and we report that siRNA knockdown of astrocytic GLT-1 decreased postsynaptic density-95 (PSD-95) expression in neuron-astrocyte cocultures in vitro . Using adeno-associated viruses (AAVs) targeting GLT-1 short-hairpin RNA (shRNA) sequences with a glial fibrillary acidic protein (GFAP) promoter, we abolished astrocytic GLT-1 expression in the substantia nigra pars compacta (SNpc) of mice. We found that GLT-1 deficiency in the SNpc induced parkinsonian phenotypes in terms of progressive motor deficits and nigral DA neuronal death in mice. We also found that there were reactive astrocytes and microglia in the SNpc upon GLT-1 knockdown. Furthermore, we used RNA sequencing to determine altered gene expression patterns upon GLT-1 knockdown in the SNpc, which revealed that disrupted calcium signaling pathways may be responsible for GLT-1 deficiency-mediated DA neuronal death in the SNpc. Taken together, our findings provide evidence for a novel role of GLT-1 in parkinsonian phenotypes in mice, which may contribute to further elucidation of the mechanisms of PD pathogenesis.

Background: Motor symptoms of Parkinson's disease (PD) are caused by degeneration and progressive loss of nigrostriatal dopamine neurons. Currently, no cure for this disease is available. Existing drugs alleviate PD symptoms but fail to halt neurodegeneration. Glial cell line-derived neurotrophic factor (GDNF) is able to protect and repair dopamine neurons in vitro and in animal models of PD, but the clinical use of GDNF is complicated by its pharmacokinetic properties. The present study aimed to evaluate the neuronal effects of a blood-brain-barrier penetrating small molecule GDNF receptor Rearranged in Transfection agonist, BT13, in the dopamine system., Methods: We characterized the ability of BT13 to activate RET in immortalized cells, to support the survival of cultured dopamine neurons, to protect cultured dopamine neurons against neurotoxin-induced cell death, to activate intracellular signaling pathways both in vitro and in vivo, and to regulate dopamine release in the mouse striatum as well as BT13's distribution in the brain., Results: BT13 potently activates RET and downstream signaling cascades such as Extracellular Signal Regulated Kinase and AKT in immortalized cells. It supports the survival of cultured dopamine neurons from wild-type but not from RET-knockout mice. BT13 protects cultured dopamine neurons from 6-Hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridinium (MPP + )-induced cell death only if they express RET. In addition, BT13 is absorbed in the brain, activates intracellular signaling cascades in dopamine neurons both in vitro and in vivo, and also stimulates the release of dopamine in the mouse striatum., Conclusion: The GDNF receptor RET agonist BT13 demonstrates the potential for further development of novel disease-modifying treatments against PD. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)

Objective: Manic and depressive phases of bipolar disorder (BD) show opposite psychomotor symptoms. Neuronally, these may depend on altered relationships between sensorimotor network (SMN) and subcortical structures. The study aimed to investigate the functional relationships of SMN with substantia nigra (SN) and raphe nuclei (RN) via subcortical-cortical loops, and their alteration in bipolar mania and depression, as characterized by psychomotor excitation and inhibition., Method: In this resting-state functional magnetic resonance imaging (fMRI) study on healthy (n = 67) and BD patients (n = 100), (1) functional connectivity (FC) between thalamus and SMN was calculated and correlated with FC from SN or RN to basal ganglia (BG)/thalamus in healthy; (2) using an a-priori-driven approach, thalamus-SMN FC, SN-BG/thalamus FC, and RN-BG/thalamus FC were compared between healthy and BD, focusing on manic (n = 34) and inhibited depressed (n = 21) patients., Results: (1) In healthy, the thalamus-SMN FC showed a quadratic correlation with SN-BG/thalamus FC and a linear negative correlation with RN-BG/thalamus FC. Accordingly, the SN-related FC appears to enable the thalamus-SMN coupling, while the RN-related FC affects it favoring anti-correlation. (2) In BD, mania showed an increase in thalamus-SMN FC toward positive values (ie, thalamus-SMN abnormal coupling) paralleled by reduction of RN-BG/thalamus FC. By contrast, inhibited depression showed a decrease in thalamus-SMN FC toward around-zero values (ie, thalamus-SMN disconnection) paralleled by reduction of SN-BG/thalamus FC (and RN-BG/thalamus FC). The results were replicated in independent HC and BD datasets., Conclusions: These findings suggest an abnormal relationship of SMN with neurotransmitters-related areas via subcortical-cortical loops in mania and inhibited depression, finally resulting in psychomotor alterations., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Although several epidemiologic and animal studies have revealed correlations between obesity and neurodegenerative disorders, such as Parkinson disease (PD), the underlying pathological mechanisms of obesity-induced PD remain unclear. Our study aimed to assess the effect of diet-induced obesity on the brain dopaminergic pathway. For five months, starting from weaning, we gave C57BL/6 mice a high-fat diet (HFD) to generate an obese mouse model and investigate whether the diet reprogrammed the midbrain dopaminergic system. Tyrosine hydroxylase staining showed that the HFD resulted in fewer dopaminergic neurons in the substantia nigra (SN), but not the striatum. It also induced neuroinflammation, with increased astrogliosis in the SN and striatum. Dendritic spine density in the SN of HFD-exposed mice decreased, which suggested that prolonged HFD altered dopaminergic neuroplasticity. All three peroxisome proliferator-activated receptor (PPAR) subtype (PPAR-α, PPAR-β/δ, PPAR-γ) levels were significantly reduced in the SN and the ventral tegmental area of HFD mice when compared to those in controls. This study showed that a prolonged HFD induced neuroinflammation, suppressed PPAR levels, caused degeneration of midbrain dopaminergic neurons, and resulted in symptoms reminiscent of human PD. To our knowledge, this is the first study documenting the effects of an HFD on PPARs in dopaminergic neurons.

Parkinson's disease (PD) is neurodegenerative movement disorder characterized by degeneration of midbrain-type dopamine (mDA) neurons in the substantia nigra (SN). The RNA-binding protein Lin28 plays a role in neuronal stem cell development and neuronal differentiation. In this study, we reveal that Lin28 conditional knockout (cKO) mice show degeneration of mDA neurons in the SN, as well as PD-related behavioral deficits. We identify a loss-of-function variant of LIN28A (R192G substitution) in two early-onset PD patients. Using an isogenic human embryonic stem cell (hESC)/human induced pluripotent stem cell (hiPSC)-based disease model, we find that the Lin28 R192G variant leads to developmental defects and PD-related phenotypes in mDA neuronal cells that can be rescued by expression of wild-type Lin28A. Cell transplantation experiments in PD model rats show that correction of the LIN28A variant in the donor patient (pt)-hiPSCs leads to improved behavioral phenotypes. Our data link LIN28A to PD pathogenesis and suggest future personalized medicine targeting this variant in patients., (© 2019 The Authors.)

In Parkinson's disease, degeneration of substantia nigra dopaminergic neurons is accompanied by damage on other neuronal systems. A severe denervation is for example seen in the locus coerulean noradrenergic system. Little is known about the relation between noradrenergic and dopaminergic degeneration, and the effects of noradrenergic denervation on the function of the dopaminergic neurons of substantia nigra are not fully understood. In this study, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) was injected in rats, whereafter behavior, striatal KCl-evoked dopamine and glutamate releases, and immunohistochemistry were monitored at 3 days, 3 months, and 6 months. Quantification of dopamine-beta-hydroxylase-immunoreactive nerve fiber density in the cortex revealed a tendency towards nerve fiber regeneration at 6 months. To sustain a stable noradrenergic denervation throughout the experimental timeline, the animals in the 6-month time point received an additional DSP4 injection (2 months after the first injection). Behavioral examinations utilizing rotarod revealed that DSP4 reduced the time spent on the rotarod at 3 but not at 6 months. KCl-evoked dopamine release was significantly increased at 3 days and 3 months, while the concentrations were normalized at 6 months. DSP4 treatment prolonged both time for onset and reuptake of dopamine release over time. The dopamine degeneration was confirmed by unbiased stereology, demonstrating significant loss of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra. Furthermore, striatal glutamate release was decreased after DSP4. In regards of neuroinflammation, reactive microglia were found over the substantia nigra after DSP4 treatment. In conclusion, long-term noradrenergic denervation reduces the number of dopaminergic neurons in the substantia nigra and affects the functionality of the nigrostriatal system. Thus, locus coeruleus is important for maintenance of nigral dopaminergic neurons., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Dystonia is a disabling neurological syndrome characterized by abnormal movements and postures that result from intermittent or sustained involuntary muscle contractions; mutations of DYT1/TOR1A are the most common cause of childhood-onset, generalized, inherited dystonia. Patient and mouse model data strongly support dysregulation of the nigrostriatal dopamine neurotransmission circuit in the presence of the DYT1-causing mutation. To determine striatal medium spiny neuron (MSN) cell-autonomous and non-cell autonomous effects relevant to dopamine transmission, we created a transgenic mouse in which expression of mutant torsinA in forebrain is restricted to MSNs. We assayed electrically evoked and cocaine-enhanced dopamine release and locomotor activity, dopamine uptake, gene expression of dopamine-associated neuropeptides and receptors, and response to the muscarinic cholinergic antagonist, trihexyphenidyl. We found that over-expression of mutant torsinA in MSNs produces complex cell-autonomous and non-cell autonomous alterations in nigrostriatal dopaminergic and intrastriatal cholinergic function, similar to that found in pan-cellular DYT1 mouse models. These data introduce targets for future studies to identify which are causative and which are compensatory in DYT1 dystonia, and thereby aid in defining appropriate therapies., (Copyright © 2019. Published by Elsevier Ltd.)

D-cycloserine (DCS) and amantadine (AMA) act as partial NMDA receptor (R) agonist and antagonist, respectively. In the present study, we compared the effects of DCS and AMA on dopamine D 2/3 R binding in the brain of adult rats in relation to motor behavior. D 2/3 R binding was determined with small animal SPECT in baseline and after challenge with DCS (20 mg/kg) or AMA (40 mg/kg) with [ 123 I]IBZM as radioligand. Immediately post-challenge, motor/exploratory behavior was assessed for 30 min in an open field. The regional binding potentials (ratios of the specifically bound compartments to the cerebellar reference region) were computed in baseline and post-challenge. DCS increased D 2/3 R binding in nucleus accumbens, substantia nigra/ventral tegmental area, thalamus, frontal, motor and parietal cortex as well as anterodorsal and posterior hippocampus, whereas AMA decreased D 2/3 R binding in nucleus accumbens, caudateputamen and thalamus. After DCS, ambulation and head-shoulder motility were decreased, while sitting was increased compared to vehicle and AMA. Moreover, DCS increased rearing relative to AMA. The regional elevations of D 2/3 R binding after DCS reflect a reduction of available dopamine throughout the mesolimbocortical system. In contrast, the reductions of D 2/3 R binding after AMA indicate increased dopamine in nucleus accumbens, caudateputamen and thalamus. Findings imply that, after DCS, nigrostriatal and mesolimbic dopamine levels are directly related to motor/exploratory activity, whereas an inverse relationship may be inferred for AMA.

l-3,4-Dihydroxyphenylalanine (l-DOPA) has been believed to be an inert amino acid precursor of dopamine, and is the most effective therapeutic agent in Parkinson's disease (PD). We proposed l-DOPA as a neurotransmitter in the central nervous system. Recently, the ocular albinism 1 gene product, OA1/GPR143 (GPR143), was identified as a receptor for l-DOPA. In this study, we examined by generating anti-human GPR143 antibody, the localization of GPR143-immunoreactive signals in the brains from control and PD subjects. GPR143-immunoreactive signals were detected throughout the entire midbrain including substantia nigra pars compacta. In the PD brains, we found that GPR143-immunoreactive signals were detected in Lewy bodies and were colocalized with immunoreactive signals with anti-human Ser129 phosphorylated α-synuclein antibody. Although the significance of its occurrence in the inclusion bodies is unknown, our finding suggests possible implications of GPR143 in PD., (Copyright © 2019 Elsevier B.V. and Japan Neuroscience Society. All rights reserved.)