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International Journal of Molecular... May 2023Disease modeling in non-human subjects is an essential part of any clinical research. To gain proper understanding of the etiology and pathophysiology of any disease,... (Review)
Review
Disease modeling in non-human subjects is an essential part of any clinical research. To gain proper understanding of the etiology and pathophysiology of any disease, experimental models are required to replicate the disease process. Due to the huge diversity in pathophysiology and prognosis in different diseases, animal modeling is customized and specific accordingly. As in other neurodegenerative diseases, Parkinson's disease is a progressive disorder coupled with varying forms of physical and mental disabilities. The pathological hallmarks of Parkinson's disease are associated with the accumulation of misfolded protein called α-synuclein as Lewy body, and degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) area affecting the patient's motor activity. Extensive research has already been conducted regarding animal modeling of Parkinson's diseases. These include animal systems with induction of Parkinson's, either pharmacologically or via genetic manipulation. In this review, we will be summarizing and discussing some of the commonly employed Parkinson's disease animal model systems and their applications and limitations.
Topics: Animals; Parkinson Disease; alpha-Synuclein; Pars Compacta; Lewy Bodies; Disease Models, Animal; Dopaminergic Neurons; Substantia Nigra
PubMed: 37240432
DOI: 10.3390/ijms24109088 -
Experimental Neurology Nov 2020GABAergic neurons in the rostromedial tegmental nucleus (RMTg) receive major input from the lateral habenula (LHb), which conveys negative reward and motivation related...
GABAergic neurons in the rostromedial tegmental nucleus (RMTg) receive major input from the lateral habenula (LHb), which conveys negative reward and motivation related information, and project intensively to midbrain dopamine neurons, including those in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). The RMTg-VTA circuit has been shown to be linked to the affective behavior, but the role of the RMTg-SNc circuit in aversion and depression has not been well understood. This study demonstrated that exciting or inhibiting Vgat neurons was sufficient to increase or decrease immobility time in the forced swim test (FST), respectively. Furthermore, exciting the Vgat pathway caused aversive behavior. Ninety percent of the SNc putative dopamine neurons were inhibited in extracellular recordings. Furthermore, inhibiting the Vgat pathway reversed behavioral despair in chronic restraint stress (CRS) depression model mice. Manipulations of the pathway did not affect the hedonic value of the reward in the sucrose-preference test (SPT) or general motor function. In conclusion, these results indicate that the Vgat pathway regulates aversive and despair behavior, which suggests that the RMTg may mediate the role of LHb in negative behaviors through regulating the activity of SNc neurons.
Topics: Anhedonia; Animals; Avoidance Learning; Depression; Dopaminergic Neurons; Female; Male; Mice; Motor Activity; Neurons; Pars Compacta; Restraint, Physical; Reward; Signal Transduction; Stress, Psychological; Swimming; Ventral Tegmental Area; Vesicular Inhibitory Amino Acid Transport Proteins
PubMed: 32791155
DOI: 10.1016/j.expneurol.2020.113433 -
Medizinische Monatsschrift Fur... Jul 2016Pharmacotherapy in Parkinson’s disease is complex and requires expertise in all health-care professions. Besides idiopathic Parkinson’s disease (IPD) secondary... (Review)
Review
Pharmacotherapy in Parkinson’s disease is complex and requires expertise in all health-care professions. Besides idiopathic Parkinson’s disease (IPD) secondary parkinsonism, monogenetic Parkinson’s disease and atypical syndromes need to be differentiated. The prevalence in the European population is estimated to be approximately 1 %. Lifestyle and age are closely linked to IPD. Neurodegeneration with formation of Lewy-bodies and increased oxidative stress in the pars compacta of the substantia nigra are closely linked to IPD. Lewy-bodies show misfolded α-Synuclein. The balance of glutamate, GABA and dopamine is essential for motor complications. Bradykinesia/akinesia, rigidity, rest tremor and postural instability are typical symptoms along with dissymmetry, shuffling gait and camptocormia, micrographia, aphasia, hypophonia, dysphagia, and hypomimia. Early symptoms are akathisia/restlessness, insomnia, somnolence, hyposmia and neck pain. With further progression of IPD, neurons of the ventral tegmental area are affected and lead to non-motor symptoms, which hence are directly related to the underlying disease. Gastric dysmotility, depression, urinary incontinence, excessive sweating, hallucinations, spasticity, muscle pain and Parkinson’s disease dementia are part of IPD.
Topics: Antiparkinson Agents; Humans; Neurologic Examination; Parkinson Disease; Pars Compacta; Risk Factors; Substantia Nigra; Ventral Tegmental Area
PubMed: 29953178
DOI: No ID Found -
Neuroscience Bulletin Jul 2022
Topics: Corpus Striatum; Dopaminergic Neurons; Humans; Mesencephalon; Parkinson Disease; Pars Compacta; Substantia Nigra
PubMed: 35195854
DOI: 10.1007/s12264-022-00829-6 -
International Journal of Molecular... Mar 2021Parkinson's disease is one of the most common neurodegenerative disorders worldwide, characterized by a progressive loss of dopaminergic neurons mainly localized in the... (Review)
Review
Parkinson's disease is one of the most common neurodegenerative disorders worldwide, characterized by a progressive loss of dopaminergic neurons mainly localized in the . In recent years, the detailed analyses of both genetic and idiopathic forms of the disease have led to a better understanding of the molecular and cellular pathways involved in PD, pointing to the centrality of mitochondrial dysfunctions in the pathogenic process. Failure of mitochondrial quality control is now considered a hallmark of the disease. The peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1) family acts as a master regulator of mitochondrial biogenesis. Therefore, keeping PGC-1 level in a proper range is fundamental to guarantee functional neurons. Here we review the major findings that tightly bond PD and PGC-1s, raising important points that might lead to future investigations.
Topics: Animals; DNA, Mitochondrial; DNA-Binding Proteins; Dopaminergic Neurons; Genome-Wide Association Study; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Mice; Mitochondria; Neurodegenerative Diseases; Neurons; Organelle Biogenesis; Oxidative Stress; Parkinson Disease; Pars Compacta; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Phosphorylation; Protein Deglycase DJ-1; Protein Kinases; Transcription Factors; Ubiquitin-Protein Ligases; Vesicular Transport Proteins; alpha-Synuclein
PubMed: 33800548
DOI: 10.3390/ijms22073487 -
Brain Research Oct 1994Intracellular recordings were performed in vitro from both pars compacta and pars reticulata neurones of the substantia nigra, and their postsynaptic responses to...
Intracellular recordings were performed in vitro from both pars compacta and pars reticulata neurones of the substantia nigra, and their postsynaptic responses to electrical stimulation within the nucleus were analysed. Intracellular staining by biocytin was used to reveal the morphology and location of the recorded neurone and its position and distance to the stimulating electrode. Inhibitory postsynaptic potentials in pars compacta neurones were evoked exclusively from a specific region of stimulation within the pars reticulata; this field could be mapped out as a cone-shaped region surrounding the apical dendrite of the cell and perpendicular to the plane of the pars compacta. Furthermore, hemitransection, prior to the experiments which eliminated the most likely source of extrinsic inhibition (the GABAergic striatonigral pathway) affected neither the generation of inhibitory postsynaptic potentials nor its topographic pattern during pars reticulata stimulation. In contrast to the response of dopaminergic pars compacta neurones, pars reticulata neurones responded to stimulation over wide areas of substantia nigra, without any clear site-specific selectivity. It is concluded that within the substantia nigra, dopaminergic neurones are arranged in functional modules such that most inhibition is derived from a highly local circuit with the collaterals of adjacent pars reticulata cells. This module is intrinsic to the substantia nigra and may represent the basic functional unit of the nucleus.
Topics: Action Potentials; Animals; Electric Stimulation; Evoked Potentials; Female; Guinea Pigs; Immunohistochemistry; In Vitro Techniques; Male; Neurons; Substantia Nigra; Synapses; Synaptic Transmission; Time Factors; Tyrosine 3-Monooxygenase
PubMed: 7820690
DOI: 10.1016/0006-8993(94)91292-0 -
Behavioural Brain Research Apr 2019The basal ganglia circuitry plays a crucial role in the sequential organization of behavior. Here we studied the behavioral structure of the animals after 21 days of...
The basal ganglia circuitry plays a crucial role in the sequential organization of behavior. Here we studied the behavioral structure of the animals after 21 days of 6-OHDA-induced lesion of the dopaminergic nigrostriatal system. Frequencies and durations of individual components of the behavioral repertoire were calculated; moreover, whether a temporal organization of the activity was present, it was investigated by using T-pattern analysis, a multivariate approach able to detect the real-time sequential organization of behavior. Six sham-depleted and six rats with unilateral 6-OHDA-lesion of the Substantia Nigra pars compacta were used. As to quantitative evaluations, the comparison between lesioned and unlesioned rats revealed significant differences only for the mean occurrences of Walking, Immobile Sniffing and Stretched Sniffing, reduced in lesioned subjects. All the remaining components of the behavior did not show significant changes. On the other hand, results from T-pattern analysis showed a reduction of the number of different T-patterns, of their mean length and of their occurrences in 6-OHDA-lesioned rats. Overall, these results suggest that the main deficit in 6-OHDA-lesioned subjects, rather than in the production of individual behavioral components, lies in deficiencies of their sequential organization.
Topics: Animals; Behavior, Animal; Dopamine; Male; Oxidopamine; Parkinson Disease; Pars Compacta; Rats, Sprague-Dawley; Substantia Nigra; Subthalamic Nucleus
PubMed: 30630014
DOI: 10.1016/j.bbr.2019.01.004 -
The European Journal of Neuroscience Apr 2021Loss of nigrostriatal dopamine (DA) in Parkinson's disease results in over-activation/bursting of the subthalamic nucleus (STN). The STN projects to the substantia nigra...
Differential ultrastructural alterations in the Vglut2 glutamatergic input to the substantia nigra pars compacta/pars reticulata following nigrostriatal dopamine loss in a progressive mouse model of Parkinson's disease.
Loss of nigrostriatal dopamine (DA) in Parkinson's disease results in over-activation/bursting of the subthalamic nucleus (STN). The STN projects to the substantia nigra (SN) pars compacta (SNpc) and pars reticulata (SNpr). The vesicular glutamate transporter 2 (Vglut2) is localized within at least STN terminals synapsing within the SN, but it is not known if there are differential changes in the Vglut2+ input to the SNpc versus SNpr following DA loss. The goal/rationale of this current study was to determine whether there were differential changes in the density/levels of glutamate immuno-gold labeling within Vglut2+ nerve terminals synapsing in the SNpc/SNpr and in the proportion of Vglut2+ terminals contacting tyrosine hydroxylase (TH) positively(+) or negatively(-) labeled dendrites following DA loss. Within the SNpc, there was a significant increase (51.3%) in the density of nerve terminal glutamate immuno-gold labeling within Vglut2+ terminals synapsing on TH(-) dendrites following MPTP versus the vehicle (VEH) group. There was a significant decrease (16%) in the percentage of Vglut2+ terminals contacting TH(+) labeled dendrites in the MPTP- versus VEH-treated group within the SNpc. Within the SNpr, there was a significant decrease in the density of glutamate immuno-gold labeling in Vglut2+ terminals contacting TH(+) (71.5%) and TH(-) (55.5%) labeled dendrites, suggesting an increase in glutamate release. There was no change in the percentage of Vglut2+ terminals contacting TH(+) or TH(-) dendrites in the SNpr. We conclude that there is a differential effect following DA loss on the glutamate input from Vglut2+ terminals synapsing within the SNpr versus SNpc.
Topics: Animals; Dopamine; Mice; Parkinson Disease; Pars Compacta; Pars Reticulata; Substantia Nigra
PubMed: 32619030
DOI: 10.1111/ejn.14894 -
Neuropharmacology Nov 2022The dopaminergic neurons in the substantia nigra pars compacta are characterized by autonomous pacemaking activity. The spontaneous firing activity of nigral...
The dopaminergic neurons in the substantia nigra pars compacta are characterized by autonomous pacemaking activity. The spontaneous firing activity of nigral dopaminergic neurons plays an important role in physiological function and is essential for their survival. Importantly, the spontaneous firing activity may also be involved in the preferential vulnerability of the nigral dopaminergic neurons in Parkinson's disease (PD). The neuropeptide apelin was reported to exert neuroprotective effects in neurodegenerative diseases, including PD. And it was noticed that apelin modulates neuronal activity in some brain regions. The present study investigated the electrophysiological and behavioral effects of apelin in the substantia nigra. Double-labeling immunofluorescence showed that apelin was present in nigral dopaminergic neurons and that these neurons expressed apelin receptor APJ. Further single unit in vivo electrophysiological recordings revealed that endogenous apelin tonically increased the firing rate of nigral dopaminergic neurons in both normal and parkinsonian animals. Exogenous apelin-13 exerted excitatory effects on the majority of nigral dopaminergic neurons, yet reduced excitability in a subset of neurons. In addition, nigral application of apelin-13 increased motor activity in normal rats and blocking endogenous apelin reduced motor activity. Considering the involvement of the spontaneous firing activity of nigral dopaminergic neurons in the development of PD and the possibility that apelin acts in an autocrine manner on apelin receptors expressed by nigral dopaminergic neurons, the modulation of the spontaneous firing activity of nigral dopaminergic neurons by apelin may serve as a neuroprotective factor in PD.
Topics: Animals; Apelin; Apelin Receptors; Dopamine; Dopaminergic Neurons; Neuropeptides; Neuroprotective Agents; Parkinson Disease; Pars Compacta; Rats; Substantia Nigra
PubMed: 36041497
DOI: 10.1016/j.neuropharm.2022.109235 -
Aging Jun 2022The ventral tegmental area (VTA), substantia nigra pars compacta (SNpc) and nucleus accumbens (NAc) are involved in the regulation of appetite and motivational...
The effects of ninjin'yoeito on the electrophysiological properties of dopamine neurons in the ventral tegmental area/substantia nigra pars compacta and medium spiny neurons in the nucleus accumbens.
The ventral tegmental area (VTA), substantia nigra pars compacta (SNpc) and nucleus accumbens (NAc) are involved in the regulation of appetite and motivational behaviors. A traditional Japanese (Kampo) medicine, ninjin'yoeito (NYT), has been reported to improve decreased motivation and anorexia in patients with Alzheimer's disease and apathy-like model mice. Thus, NYT may affect the activities of neurons in the VTA, SNpc and NAc. However, little is known about the underlying mechanisms of NYT. Here, we investigated the effects of NYT on the electrophysiological properties of dopaminergic neurons in the VTA and SNpc, as well as on those of medium spiny neurons (MSNs) in the NAc (core and shell subregions), by applying the patch-clamp technique in the brain slices. NYT reduced the resting membrane potential of VTA and SNpc dopaminergic neurons. In contrast, NYT increased the firing frequency of NAc MSNs accompanied by shortened first spike latency and interspike interval. Furthermore, NYT attenuated the inward rectification and sustained outward currents. In conclusion, NYT may directly influence the excitability of dopaminergic neurons in the VTA and SNpc, as well as MSNs in the NAc (core and shell). NYT may modulate dopamine signals in appetite and motivational behaviors.
Topics: Animals; Dopaminergic Neurons; Drugs, Chinese Herbal; Humans; Mice; Nucleus Accumbens; Pars Compacta; Ventral Tegmental Area
PubMed: 35660668
DOI: 10.18632/aging.204109