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Frontiers in Cell and Developmental... 2021The fasciculus retroflexus is an important fascicle that mediates reward-related behaviors and is associated with different psychiatric diseases. It is the main...
The fasciculus retroflexus is an important fascicle that mediates reward-related behaviors and is associated with different psychiatric diseases. It is the main habenular efference and constitutes a link between forebrain regions, the midbrain, and the rostral hindbrain. The proper functional organization of habenular circuitry requires complex molecular programs to control the wiring of the habenula during development. However, the mechanisms guiding the habenular axons toward their targets remain mostly unknown. Here, we demonstrate the role of the mesodiencephalic dopaminergic neurons (substantia nigra pars compacta and ventral tegmental area) as an intermediate target for the correct medial habenular axons navigation along the anteroposterior axis. These neuronal populations are distributed along the anteroposterior trajectory of these axons in the mesodiencephalic basal plate. Using and experiments, we determined that this navigation is the result of attraction generated by the mesodiencephalic dopaminergic neurons. This attraction is mediated by the receptor deleted in colorectal cancer (DCC), which is strongly expressed in the medial habenular axons. The increment in our knowledge on the fasciculus retroflexus trajectory guidance mechanisms opens the possibility of analyzing if its alteration in mental health patients could account for some of their symptoms.
PubMed: 34169076
DOI: 10.3389/fcell.2021.682067 -
European Journal of Pharmacology Jun 1988The effect of GABA agonists and antagonists on K+-stimulated [3H]GABA release was studied to assess how presynaptic GABA receptors modulate GABA release. The release was...
The effect of GABA agonists and antagonists on K+-stimulated [3H]GABA release was studied to assess how presynaptic GABA receptors modulate GABA release. The release was affected in a quite different manner in the pars compacta and in the pars reticulata. Muscimol markedly inhibited the release from the pars compacta but had no effect on the release from the pars reticulata. Baclofen inhibited the release from the pars reticulata without affecting the release from the pars compacta. Bicuculline itself facilitated the release from the pars compacta but inhibited the release from the pars reticulata. Picrotoxin facilitated the release from the pars compacta and had no effect in the pars reticulata. The results suggest that the release of GABA from GABAergic terminals in the substantia nigra of the rat brain is modulated by GABAA autoreceptors in the pars compacta and by GABAB receptors in the pars reticulata.
Topics: Animals; Baclofen; Bicuculline; Brain; In Vitro Techniques; Male; Muscimol; Potassium; Rats; Rats, Inbred Strains; Receptors, GABA-A; Substantia Nigra; gamma-Aminobutyric Acid
PubMed: 2843383
DOI: 10.1016/0014-2999(88)90008-8 -
Ultrastructural Pathology Jan 2022Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) with subsequent motor manifestations. This...
Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) with subsequent motor manifestations. This study aimed to assess the ameliorative effects of nicotine, in rotenone-induced PD rat model. Thirty adult male Albino Wistar rats were divided into three equal groups. Group I received an injection of normal saline. Group II received subcutaneous injection of rotenone at a dose of 1.5 mg/kg every other day. Group III received rotenone in the same previous dose and nicotine at a dose of 1.5 mg/kg daily. After 11 days of treatment, body weight (BW) and rat motor behavior were estimated. Specimens from the midbrain were processed for light and electron microscopy. The expression of tyrosine hydroxylase (TH), α-synuclein, and GFAP was examined. Serum levels of total antioxidant capacity (TAC) and malondialdehyde (MDA), and striatal levels of dopamine (DA) were analyzed. Group III revealed a significant improvement in BW and motor activity. Nicotine upregulated the expression of TH, downregulated the expression of α-synuclein and GFAP. The levels of MDA and TAC were improved but were still far from those of the control. Striatal DA levels increased. Nicotine activated the neurons and glial cells. The vascular endothelium, however, did not elicit improvement. Although nicotine ameliorated the loss of the dopaminergic neurons and motor deficit, it did not show improvement of vascular endothelium. It is still necessary to examine nicotin's ability to maintain the dopaminergic neurons in a good functioning state.
Topics: Animals; Dopaminergic Neurons; Male; Nicotine; Parkinson Disease; Pars Compacta; Rats; Rats, Sprague-Dawley; Substantia Nigra
PubMed: 35001795
DOI: 10.1080/01913123.2021.2015499 -
International Journal of Molecular... Aug 2023Methamphetamine (meth) is a neurotoxic psychostimulant that increases monoamine oxidase (MAO)-dependent mitochondrial oxidant stress in axonal but not somatic...
Repeated Methamphetamine Administration Results in Axon Loss Prior to Somatic Loss of Substantia Nigra Pars Compacta and Locus Coeruleus Neurons in Male but Not Female Mice.
Methamphetamine (meth) is a neurotoxic psychostimulant that increases monoamine oxidase (MAO)-dependent mitochondrial oxidant stress in axonal but not somatic compartments of substantia nigra pars compacta (SNc) and locus coeruleus (LC) neurons. Chronic meth administration results in the degeneration of SNc and LC neurons in male mice, and MAO inhibition is neuroprotective, suggesting that the deleterious effects of chronic meth begin in axons before advancing to the soma of SNc and LC neurons. To test this hypothesis, mice were administered meth (5 mg/kg) for 14, 21, or 28 days, and SNc and LC axonal lengths and numbers of neurons were quantified. In male mice, the SNc and LC axon lengths decreased with 14, 21, and 28 days of meth, whereas somatic loss was only observed after 28 days of meth; MAO inhibition (phenelzine; 20 mg/kg) prevented axonal and somatic loss of SNc and LC neurons. In contrast, chronic (28-day) meth had no effect on the axon length or numbers of SNc or LC neurons in female mice. The results demonstrate that repeated exposure to meth produces SNc and LC axonal deficits prior to somatic loss in male subjects, consistent with a dying-back pattern of degeneration, whereas female mice are resistant to chronic meth-induced degeneration.
Topics: Male; Animals; Mice; Methamphetamine; Pars Compacta; Locus Coeruleus; Neurons; Axons; Monoamine Oxidase
PubMed: 37685846
DOI: 10.3390/ijms241713039 -
Bio-protocol Aug 2021The Substantia Nigra pars compacta (SNc) is a midbrain dopaminergic nucleus that plays a key role in modulating motor and cognitive functions. It is crucially involved...
The Substantia Nigra pars compacta (SNc) is a midbrain dopaminergic nucleus that plays a key role in modulating motor and cognitive functions. It is crucially involved in several disorders, particularly Parkinson's disease, which is characterized by a progressive loss of SNc dopaminergic cells. Electrophysiological studies on SNc neurons are of paramount importance to understand the role of dopaminergic transmission in health and disease. Here, we provide an extensive protocol to prepare SNc-containing mouse brain slices and record the electrical activity of dopaminergic cells. We describe all the necessary steps, including mouse transcardiac perfusion, brain extraction, slice cutting, and patch-clamp recordings.
PubMed: 34458403
DOI: 10.21769/BioProtoc.4109 -
European Journal of Radiology Dec 2018To quantify dopaminergic neurodegeneration and iron overload in the substantia nigra pars compacta (SNpc) to evaluate Parkinson's disease (PD) using both quantitative...
PURPOSE
To quantify dopaminergic neurodegeneration and iron overload in the substantia nigra pars compacta (SNpc) to evaluate Parkinson's disease (PD) using both quantitative susceptibility mapping (QSM) and neuromelanin imaging.
MATERIALS AND METHODS
We studied 39 PD patients (PD group) and 25 healthy controls (HC group) who underwent brain MRI with QSM and neuromelanin imaging. QSM and neuromelanin values of the SNpc were obtained using a voxel-based automated region segmentation system. The signal-to-noise ratio (SNR) of the SNpc in the neuromelanin images was calculated based on the mean value for the background region. The neuromelanin value was defined as the neuromelanin volume with an SNR higher than that of the background. The significance of the intergroup differences, and according to the severity stages in the PD group was tested for each QSM and neuromelanin value. Receiver-operating characteristic (ROC) analysis for diagnosing PD was performed for QSM and neuromelanin values.
RESULTS
The QSM value was significantly higher in the PD group than in the HC group (P < 0.05). The neuromelanin value was significantly smaller in the PD group than in the HC group (P < 0.05). The areas under the ROC curve were 0.68 and 0.86 for QSM and neuromelanin values, respectively. Using QSM and neuromelanin imaging to classify the PD stage was difficult.
CONCLUSIONS
Quantifying the SNpc alterations with our region-based approach is useful for the diagnosis of PD.
Topics: Aged; Female; Humans; Iron Overload; Magnetic Resonance Imaging; Male; Parkinson Disease; Pars Compacta; Prospective Studies; ROC Curve; Signal-To-Noise Ratio
PubMed: 30527311
DOI: 10.1016/j.ejrad.2018.06.024 -
NeuroImage May 2020Visualizing gradual changes in neuromelanin distribution within the substantia nigra is an important metric used to monitor the progression of Parkinsonism. This study...
Visualizing gradual changes in neuromelanin distribution within the substantia nigra is an important metric used to monitor the progression of Parkinsonism. This study aimed to identify the origin of the mismatch region between magnetic resonance transverse relaxation times (T and T*) in the substantia nigra and investigate its feasibility and implications for in vivo detection of neuromelanin as a clinical biomarker. The relationships between neuromelanin distribution assessed by histological staining and the area of T and T* mismatch determined by high- and low-resolution magnetic resonance relaxometry at 7T were directly compared in two normal and one depigmented substantia nigra collected at postmortem. In vivo feasibility of assessing T and T* mismatch, clinically, was investigated using 3T magnetic resonance imaging. In the normal postmortem substantia nigra tissue, the T and T* mismatch region exhibiting a linear pattern was strongly colocalized with neuromelanin distribution along the dorsal substantia nigra pars compacta, but a negligible amount of dorsal mismatch was observed in the depigmented brain. The regions of T and T* mismatch from MRI, neuromelanin pigments from histology, and elevated iron signals from mass spectrometry were spatially overlapped for a normal postmortem brain. In preliminary in vivo studies, a similar, linear T and T* mismatch region was observed in the dorsal area of the substantia nigra in eight normal subjects; this mismatch was significantly obscured in eight Parkinson's disease patients. The length of the dorsal linear mismatch line based on the T*-T mask was significantly shorter in the Parkinson's disease patients compared to normal controls; this result was corroborated by reduced striatal uptake of [F] FP-CIT dopamine transporters assessed by positron emission tomography scans. In conclusion, the measurement of T and T* mismatch could serve as a complementary imaging biomarker to visualize the dorsal region of the substantia nigra pars compacta, which contains large amounts of neuromelanin.
Topics: Aged; Aged, 80 and over; Biomarkers; Diagnosis; Disease Progression; Feasibility Studies; Female; Humans; Magnetic Resonance Imaging; Melanins; Neuroimaging; Parkinson Disease; Pars Compacta
PubMed: 32058001
DOI: 10.1016/j.neuroimage.2020.116625 -
Scientific Reports Jan 2021Parkinson'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...
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.
Topics: Adenosine Triphosphate; Computational Biology; Computer Simulation; Dopamine; Humans; Hypoglycemia; Metabolic Networks and Pathways; Neurodegenerative Diseases; Parkinson Disease; Pars Compacta; Substantia Nigra
PubMed: 33462293
DOI: 10.1038/s41598-021-81185-9 -
Behavioural Brain Research Feb 2024Parkinson's disease (PD) is a neurodegenerative disease characterized by progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) and... (Review)
Review
Parkinson's disease (PD) is a neurodegenerative disease characterized by progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) and the presence of Lewy bodies (LBs) or Lewy neurites (LNs) which consist of α-synuclein (α-syn) and a complex mix of other biomolecules. Mitochondrial dysfunction is widely believed to play an essential role in the pathogenesis of PD and other related neurodegenerative diseases. But mitochondrial dysfunction is subject to complex genetic regulation. There is increasing evidence that PD-related genes directly or indirectly affect mitochondrial integrity. Therefore, targeted regulation of mitochondrial function has great clinical application prospects in the treatment of PD. However, lots of PD drugs targeting mitochondria have been developed but their clinical therapeutic effects are not ideal. This review aims to reveal the role of mitochondrial dysfunction in the pathogenesis of neurodegenerative diseases based on the mitochondrial structure and function, which may highlight potential interventions and therapeutic targets for the development of PD drugs to recover mitochondrial dysfunction in neurodegenerative diseases.
Topics: Humans; Parkinson Disease; Neurodegenerative Diseases; alpha-Synuclein; Pars Compacta; Mitochondria; Dopaminergic Neurons; Mitochondrial Diseases
PubMed: 38103871
DOI: 10.1016/j.bbr.2023.114811 -
Neuroscience Bulletin Mar 2023The accumulation of pathological α-synuclein (α-syn) in the central nervous system and the progressive loss of dopaminergic neurons in the substantia nigra pars... (Review)
Review
The accumulation of pathological α-synuclein (α-syn) in the central nervous system and the progressive loss of dopaminergic neurons in the substantia nigra pars compacta are the neuropathological features of Parkinson's disease (PD). Recently, the findings of prion-like transmission of α-syn pathology have expanded our understanding of the region-specific distribution of α-syn in PD patients. Accumulating evidence suggests that α-syn aggregates are released from neurons and endocytosed by glial cells, which contributes to the clearance of α-syn. However, the activation of glial cells by α-syn species produces pro-inflammatory factors that decrease the uptake of α-syn aggregates by glial cells and promote the transmission of α-syn between neurons, which promotes the spread of α-syn pathology. In this article, we provide an overview of current knowledge on the role of glia and α-syn pathology in PD pathogenesis, highlighting the relationships between glial responses and the spread of α-syn pathology.
Topics: Humans; Parkinson Disease; alpha-Synuclein; Dopaminergic Neurons; Pars Compacta
PubMed: 36229715
DOI: 10.1007/s12264-022-00957-z