SciCombinator

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Concept: Substantia nigra

173

Parkinson’s disease is a chronic progressive neurodegenerative disorder characterized by resting tremor, slowness of movements, rigidity, gait disturbance and postural instability. Most investigations on Parkinson’s disease focused on the basal ganglia, whereas the cerebellum has often been overlooked. However, increasing evidence suggests that the cerebellum may have certain roles in the pathophysiology of Parkinson’s disease. Anatomical studies identified reciprocal connections between the basal ganglia and cerebellum. There are Parkinson’s disease-related pathological changes in the cerebellum. Functional or morphological modulations in the cerebellum were detected related to akinesia/rigidity, tremor, gait disturbance, dyskinesia and some non-motor symptoms. It is likely that the major roles of the cerebellum in Parkinson’s disease include pathological and compensatory effects. Pathological changes in the cerebellum might be induced by dopaminergic degeneration, abnormal drives from the basal ganglia and dopaminergic treatment, and may account for some clinical symptoms in Parkinson’s disease. The compensatory effect may help maintain better motor and non-motor functions. The cerebellum is also a potential target for some parkinsonian symptoms. Our knowledge about the roles of the cerebellum in Parkinson’s disease remains limited, and further attention to the cerebellum is warranted.

Concepts: Neurology, Parkinson's disease, Deep brain stimulation, Basal ganglia, Substantia nigra, Dopamine, Haloperidol, Tremor

171

Neuroimaging studies using positron emission tomography suggest that reduced dopamine D(2) receptor availability in the neostriatum is associated with increased vulnerability to drug addiction in humans and experimental animals. The role of D(3) receptors (D(3)Rs) in the neurobiology of addiction remains unclear, however. Here we report that D(3)R KO (D(3)(-/-)) mice display enhanced cocaine self-administration and enhanced motivation for cocaine-taking and cocaine-seeking behavior. This increased vulnerability to cocaine is accompanied by decreased dopamine response to cocaine secondary to increased basal levels of extracellular dopamine in the nucleus accumbens, suggesting a compensatory response to decreased cocaine reward in D(3)(-/-) mice. In addition, D(3)(-/-) mice also display up-regulation of dopamine transporters in the striatum, suggesting a neuroadaptative attempt to normalize elevated basal extracellular dopamine. These findings suggest that D(3)R deletion increases vulnerability to cocaine, and that reduced D(3)R availability in the brain may constitute a risk factor for the development of cocaine addiction.

Concepts: Ventral tegmental area, Positron emission tomography, Substantia nigra, Drug addiction, Dopamine, Nucleus accumbens, Putamen, Cocaine

167

Beyond the cardinal motor symptoms, bradykinesia, rigidity, tremor and postural instability, defining the diagnosis of Parkinson’s disease, there is a big spectrum of non-motor features that patients may suffer from and that may reduce their quality of life. Non-motor symptoms are not only frequent but also often under-reported by patients and caregivers. As they are frequently under-recognized by clinicians, they remain consequently under-treated. This review wants to give a short overview of the importance of non-motor symptoms on patients' quality of life and helpful assessment tools that might facilitate recognition of non-motor features during clinical setting. Given the wide range of non-motor symptoms in Parkinson’s disease, we concentrate on common issues such as depression and sleep disorders like sleep-onset insomnia or sleep maintenance insomnia and restless legs syndrome. Thereby, we present some recent studies that have investigated the efficacy of dopaminergic drugs, especially dopamine agonists, revealing possible treatment strategies and thus improving disease management.

Concepts: Parkinson's disease, Substantia nigra, Dopamine, Haloperidol, Pramipexole, Ropinirole, Restless legs syndrome, Dopamine agonist

139

Parkinson’s disease (PD) is one of the most epidemic neurodegenerative diseases, and is characterized by movement disorders arising from loss of midbrain dopaminergic (DA) neurons. Recently, the relationship between PD and autophagy has received considerable attention, but information about the mechanisms involved is lacking. Here, we report that autophagy-related gene 5 (ATG5) is potentially important in protecting dopaminergic neurons in a 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model in zebrafish. Using analyses of zebarfish swimming behavior, in situ hybridizatiton, immunofluorescence and expressions of genes and proteins related to PD and autophagy, we found that ATG5 expression level was decreased and autophagy flux was blocked in this model. The ATG5 down-regulation led to the upgrade of PDassociated proteins, such as β-synuclein, Parkin, and PINK1, aggravation of MPTP-induced PDmimicking pathological locomotor behavior, DA neuron loss labelled by tyrosine hydroxylase (TH) or dopamine transporter (DAT), and blocked autophagy flux in the zebrafish model. ATG5 overexpression alleviated or reversed these PD pathological features, rescued DA neuron cells as indicated by elevated TH /DAT levels, and restored autophagy flux. The role of ATG5 in protecting DA neurons was confirmed by expression of the human atg5 gene in the zebrafish model. Our findings reveal that ATG5 has a role in neuroprotection, and upregulation of ATG5 may serve as a goal in the development of drugs for PD prevention and management.

Concepts: Neuron, Gene, Gene expression, Parkinson's disease, Substantia nigra, Neurotransmitter, Dopamine, Alpha-synuclein

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This study provides a demonstration in the rat of a clear genetic difference in the propensity for addiction-related behaviors following prolonged cocaine self-administration. It relies on the use of selectively bred high-responder (bHR) and low-responder (bLR) rat lines that differ in several characteristics associated with “temperament,” including novelty-induced locomotion and impulsivity. We show that bHR rats exhibit behaviors reminiscent of human addiction, including persistent cocaine-seeking and increased reinstatement of cocaine seeking. To uncover potential underlying mechanisms of this differential vulnerability, we focused on the core of the nucleus accumbens and examined expression and epigenetic regulation of two transcripts previously implicated in bHR/bLR differences: fibroblast growth factor (FGF2) and the dopamine D2 receptor (D2). Relative to bHRs, bLRs had lower FGF2 mRNA levels and increased association of a repressive mark on histones (H3K9me3) at the FGF2 promoter. These differences were apparent under basal conditions and persisted even following prolonged cocaine self-administration. In contrast, bHRs had lower D2 mRNA under basal conditions, with greater association of H3K9me3 at the D2 promoter and these differences were no longer apparent following prolonged cocaine self-administration. Correlational analyses indicate that the association of H3K9me3 at D2 may be a critical substrate underlying the propensity to relapse. These findings suggest that low D2 mRNA levels in the nucleus accumbens core, likely mediated via epigenetic modifications, may render individuals more susceptible to cocaine addiction. In contrast, low FGF2 levels, which appear immutable even following prolonged cocaine exposure, may serve as a protective factor.

Concepts: DNA, Ventral tegmental area, Gene expression, Basal ganglia, Substantia nigra, Dopamine, Nucleus accumbens, Cocaine

53

The purpose of this study was to assess the biological and clinical effects of n-acetyl-cysteine (NAC) in Parkinson’s disease (PD).

Concepts: Alzheimer's disease, Stem cell, Cell biology, Parkinson's disease, Substantia nigra, Neurotransmitter, Dopamine, Acetylcysteine

46

Parkinson’s Disease (PD) is the second most common neurodegenerative disease worldwide, affecting 1 % of the population over 65 years of age. Dopaminergic cell death in the substantia nigra and accumulation of Lewy bodies are the defining neuropathological hallmarks of the disease. Neuronal death and dysfunction have been reported in other central nervous system regions, including the retina. Symptoms of PD typically manifest only when more than 70 % of dopaminergic cells are lost, and the definitive diagnosis of PD can only be made histologically at post-mortem, with few biomarkers available.In this study, a rotenone-induced rodent model of PD was employed to investigate retinal manifestations in PD and their usefulness in assessing the efficacy of a novel therapeutic intervention with a liposomal formulation of the PPAR-γ (Peroxisome proliferator-activated receptor gamma) agonist rosiglitazone.Retinal assessment was performed using longitudinal in vivo imaging with DARC (detection of apoptosing retinal cells) and OCT (optical coherence tomography) technologies and revealed increased RGCs (Retinal Ganglion Cells) apoptosis and a transient swelling of the retinal layers at day 20 of the rotenone insult. Follow-up of this model demonstrated characteristic histological neurodegenerative changes in the substantia nigra and striatum by day 60, suggesting that retinal changes precede the “traditional” pathological manifestations of PD. The therapeutic effect of systemic administration of different formulations of rosiglitazone was then evaluated, both in the retina and the brain. Of all treatment regimen tested, sustained release administration of liposome-encapsulated rosiglitazone proved to be the most potent therapeutic strategy, as evidenced by its significant neuroprotective effect on retinal neurons at day 20, and on nigrostriatal neurons at day 60, provided convincing evidence for its potential as a treatment for PD.Our results demonstrate significant retinal changes occurring in this model of PD. We show that rosiglitazone can efficiently protect retinal neurons from the rotenone insult, and that systemic administration of liposome-encapsulated rosiglitazone has an enhanced neuroprotective effect on the retina and CNS (Central Nervous System). To our knowledge, this is the first in vivo evidence of RGCs loss and early retinal thickness alterations in a PD model. Together, these findings suggest that retinal changes may be a good surrogate biomarker for PD, which may be used to assess new treatments both experimentally and clinically.

Concepts: Nervous system, Neuron, Brain, Neurology, Basal ganglia, Substantia nigra, Retina, Dopamine

46

Placebos have been found to affect the patient’s brain in a number of conditions, such as pain and motor disorders. For example, in Parkinson’s disease, a placebo treatment induces a release of dopamine in the striatum and changes the activity of neurons in both thalamic and subthalamic nuclei. The present study shows that placebo administration for the first time induces neither clinical nor neuronal improvement in Parkinson patients who undergo the implantation of electrodes for deep brain stimulation. However, this lack of placebo responsiveness can be turned into substantial placebo responses following previous exposure to repeated administrations of the anti-Parkinson agent apomorphine. As the number of apomorphine administrations increased from 1 through 4, both the clinical response and the neuronal activity in the ventral anterior and anterior ventrolateral thalamus increased. In fact, after 4 apomorphine exposures, placebo administration induced clinical responses that were as large as those to apomorphine, along with long-lasting neuronal changes. These clinical placebo responses following 4 apomorphine administrations were again elicited after a re-exposure to a placebo 24 hr post-surgery, but not after 48 hr. These data indicate that learning plays a crucial role in placebo responsiveness and suggest that placebo nonresponders can be turned into responders, with important implications in the clinical setting. This article is protected by copyright. All rights reserved.

Concepts: Alzheimer's disease, Parkinson's disease, Deep brain stimulation, Basal ganglia, Substantia nigra, Placebo, Neurotransmitter, Dopamine

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This study examined the heritability of brain grey matter structures in a subsample of older adult twins (93 MZ and 68 DZ twin pairs; mean age 70 years) from the Older Australian Twins Study. The heritability estimates of subcortical regions ranged from 0.41 (amygdala) to 0.73 (hippocampus), and of cortical regions, from 0.55 (parietal lobe) to 0.78 (frontal lobe). Corresponding structures in the two hemispheres were influenced by the same genetic factors and high genetic correlations were observed between the two hemispheric regions. There were three genetically correlated clusters, comprising (i) the cortical lobes (frontal, temporal, parietal and occipital lobes); (ii) the basal ganglia (caudate, putamen and pallidum) with weak genetic correlations with cortical lobes, and (iii) the amygdala, hippocampus, thalamus and nucleus accumbens grouped together, which genetically correlated with both basal ganglia and cortical lobes, albeit relatively weakly. Our study demonstrates a complex but patterned and clustered genetic architecture of the human brain, with divergent genetic determinants of cortical and subcortical structures, in particular the basal ganglia.

Concepts: Central nervous system, Neuroanatomy, Brain, Cerebral cortex, Cerebrum, Basal ganglia, Substantia nigra, Frontal lobe

37

Clinical trials using cells derived from embryonic ventral mesencephalon have shown that transplanted dopaminergic neurons can survive and function in the long term, as demonstrated by in vivo brain imaging using (18)F-fluorodopa and (11)C-raclopride positron emission tomography. Here we report the postmortem analysis of a patient with Parkinson’s disease who 24 y earlier underwent unilateral transplantation of embryonic dopaminergic neurons in the putamen and subsequently exhibited major motor improvement and recovery of striatal dopaminergic function. Histopathological analysis showed that a dense, near-normal graft-derived dopaminergic reinnervation of the putamen can be maintained for a quarter of a century despite severe host brain pathology and with no evidence of immune response. In addition, ubiquitin- and α-synuclein-positive inclusions were seen, some with the appearance of typical Lewy bodies, in 11-12% of the grafted dopaminergic neurons, reflecting the spread of pathology from the host brain to the transplants. Because the clinical benefits induced by transplantation in this patient were gradually lost after 14 y posttransplantation, our findings provide the first reported evidence, to our knowledge, that even a viable dopaminergic graft giving rise to extensive striatal reinnervation may lose its efficacy if widespread degenerative changes develop in the host brain.

Concepts: Alzheimer's disease, Nervous system, Pathology, Positron emission tomography, Parkinson's disease, Substantia nigra, Dopamine, Lewy body