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Cell Oct 2016Understanding human embryonic ventral midbrain is of major interest for Parkinson's disease. However, the cell types, their gene expression dynamics, and their... (Comparative Study)
Comparative Study
Understanding human embryonic ventral midbrain is of major interest for Parkinson's disease. However, the cell types, their gene expression dynamics, and their relationship to commonly used rodent models remain to be defined. We performed single-cell RNA sequencing to examine ventral midbrain development in human and mouse. We found 25 molecularly defined human cell types, including five subtypes of radial glia-like cells and four progenitors. In the mouse, two mature fetal dopaminergic neuron subtypes diversified into five adult classes during postnatal development. Cell types and gene expression were generally conserved across species, but with clear differences in cell proliferation, developmental timing, and dopaminergic neuron development. Additionally, we developed a method to quantitatively assess the fidelity of dopaminergic neurons derived from human pluripotent stem cells, at a single-cell level. Thus, our study provides insight into the molecular programs controlling human midbrain development and provides a foundation for the development of cell replacement therapies.
Topics: Animals; Cell Line; Cellular Reprogramming Techniques; Dopaminergic Neurons; Humans; Machine Learning; Mesencephalon; Mice; Neural Stem Cells; Neurogenesis; Neuroglia; Pluripotent Stem Cells; Sequence Analysis, RNA; Single-Cell Analysis
PubMed: 27716510
DOI: 10.1016/j.cell.2016.09.027 -
FEBS Letters Dec 2015Midbrain dopaminergic neurons (MbDNs) modulate cognitive processes, regulate voluntary movement, and encode reward prediction errors and aversive stimuli. While the... (Review)
Review
Midbrain dopaminergic neurons (MbDNs) modulate cognitive processes, regulate voluntary movement, and encode reward prediction errors and aversive stimuli. While the degeneration of MbDNs underlies the motor defects in Parkinson's disease, imbalances in dopamine levels are associated with neuropsychiatric disorders such as depression, schizophrenia and substance abuse. In recent years, progress has been made in understanding how MbDNs, which constitute a relatively small neuronal population in the brain, can contribute to such diverse functions and dysfunctions. In particular, important insights have been gained regarding the distinct molecular, neurochemical and network properties of MbDNs. How this diversity of MbDNs is established during brain development is only starting to be unraveled. In this review, we summarize the current knowledge on the diversity in MbDN progenitors and differentiated MbDNs in the developing rodent brain. We discuss the signaling pathways, transcription factors and transmembrane receptors that contribute to setting up these diverse MbDN subpopulations. A better insight into the processes that establish diversity in MbDNs will ultimately improve the understanding of the architecture and function of the dopaminergic system in the adult brain.
Topics: Animals; Dopamine; Dopaminergic Neurons; Gene Expression Regulation, Developmental; Humans; Mesencephalon; Neural Stem Cells; Neurogenesis; Signal Transduction
PubMed: 26431946
DOI: 10.1016/j.febslet.2015.09.016 -
International Journal of Molecular... Jun 2020The mesodiencephalic dopaminergic (mdDA) group of neurons comprises molecularly distinct subgroups, of which the substantia nigra (SN) and ventral tegmental area (VTA)... (Review)
Review
The mesodiencephalic dopaminergic (mdDA) group of neurons comprises molecularly distinct subgroups, of which the substantia nigra (SN) and ventral tegmental area (VTA) are the best known, due to the selective degeneration of the SN during Parkinson's disease. However, although significant research has been conducted on the molecular build-up of these subsets, much is still unknown about how these subsets develop and which factors are involved in this process. In this review, we aim to describe the life of an mdDA neuron, from specification in the floor plate to differentiation into the different subsets. All mdDA neurons are born in the mesodiencephalic floor plate under the influence of both SHH-signaling, important for floor plate patterning, and WNT-signaling, involved in establishing the progenitor pool and the start of the specification of mdDA neurons. Furthermore, transcription factors, like Ngn2, Ascl1, Lmx1a, and En1, and epigenetic factors, like Ezh2, are important in the correct specification of dopamine (DA) progenitors. Later during development, mdDA neurons are further subdivided into different molecular subsets by, amongst others, Otx2, involved in the specification of subsets in the VTA, and En1, Pitx3, Lmx1a, and WNT-signaling, involved in the specification of subsets in the SN. Interestingly, factors involved in early specification in the floor plate can serve a dual function and can also be involved in subset specification. Besides the mdDA group of neurons, other systems in the embryo contain different subsets, like the immune system. Interestingly, many factors involved in the development of mdDA neurons are similarly involved in immune system development and vice versa. This indicates that similar mechanisms are used in the development of these systems, and that knowledge about the development of the immune system may hold clues for the factors involved in the development of mdDA neurons, which may be used in culture protocols for cell replacement therapies.
Topics: Animals; Cell Differentiation; Dopamine; Dopaminergic Neurons; Embryo, Mammalian; Gene Expression Regulation, Developmental; Humans; Mesencephalon; Substantia Nigra; Transcription Factors; Ventral Tegmental Area
PubMed: 32629812
DOI: 10.3390/ijms21134638 -
Oxidative Medicine and Cellular... 2020Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generated primarily from endogenous biochemical reactions in mitochondria, endoplasmic reticulum... (Review)
Review
Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generated primarily from endogenous biochemical reactions in mitochondria, endoplasmic reticulum (ER), and peroxisomes. Typically, ROS/RNS correlate with oxidative damage and cell death; however, free radicals are also crucial for normal cellular functions, including supporting neuronal homeostasis. ROS/RNS levels influence and are influenced by antioxidant systems, including the catabolic autophagy pathways. Autophagy is an intracellular lysosomal degradation process by which invasive, damaged, or redundant cytoplasmic components, including microorganisms and defunct organelles, are removed to maintain cellular homeostasis. This process is particularly important in neurons that are required to cope with prolonged and sustained operational stress. Consequently, autophagy is a primary line of protection against neurodegenerative diseases. Parkinson's is caused by the loss of midbrain dopaminergic neurons (mDANs), resulting in progressive disruption of the nigrostriatal pathway, leading to motor, behavioural, and cognitive impairments. Mitochondrial dysfunction, with associated increases in oxidative stress, and declining proteostasis control, are key contributors during mDAN demise in Parkinson's. In this review, we analyse the crosstalk between autophagy and redoxtasis, including the molecular mechanisms involved and the detrimental effect of an imbalance in the pathogenesis of Parkinson's.
Topics: Autophagy; Cell Death; Dopaminergic Neurons; Homeostasis; Humans; Mesencephalon; Oxidation-Reduction; Parkinson Disease; Reactive Nitrogen Species; Reactive Oxygen Species; Signal Transduction
PubMed: 33224433
DOI: 10.1155/2020/8865611 -
Nature Methods Dec 2023Ventral midbrain dopaminergic neurons project to the striatum as well as the cortex and are involved in movement control and reward-related cognition. In Parkinson's...
Ventral midbrain dopaminergic neurons project to the striatum as well as the cortex and are involved in movement control and reward-related cognition. In Parkinson's disease, nigrostriatal midbrain dopaminergic neurons degenerate and cause typical Parkinson's disease motor-related impairments, while the dysfunction of mesocorticolimbic midbrain dopaminergic neurons is implicated in addiction and neuropsychiatric disorders. Study of the development and selective neurodegeneration of the human dopaminergic system, however, has been limited due to the lack of an appropriate model and access to human material. Here, we have developed a human in vitro model that recapitulates key aspects of dopaminergic innervation of the striatum and cortex. These spatially arranged ventral midbrain-striatum-cortical organoids (MISCOs) can be used to study dopaminergic neuron maturation, innervation and function with implications for cell therapy and addiction research. We detail protocols for growing ventral midbrain, striatal and cortical organoids and describe how they fuse in a linear manner when placed in custom embedding molds. We report the formation of functional long-range dopaminergic connections to striatal and cortical tissues in MISCOs, and show that injected, ventral midbrain-patterned progenitors can mature and innervate the tissue. Using these assembloids, we examine dopaminergic circuit perturbations and show that chronic cocaine treatment causes long-lasting morphological, functional and transcriptional changes that persist upon drug withdrawal. Thus, our method opens new avenues to investigate human dopaminergic cell transplantation and circuitry reconstruction as well as the effect of drugs on the human dopaminergic system.
Topics: Humans; Parkinson Disease; Mesencephalon; Dopamine; Dopaminergic Neurons; Corpus Striatum
PubMed: 38052989
DOI: 10.1038/s41592-023-02080-x -
Targeted activation of midbrain neurons restores locomotor function in mouse models of parkinsonism.Nature Communications Jan 2022The pedunculopontine nucleus (PPN) is a locomotor command area containing glutamatergic neurons that control locomotor initiation and maintenance. These motor actions...
The pedunculopontine nucleus (PPN) is a locomotor command area containing glutamatergic neurons that control locomotor initiation and maintenance. These motor actions are deficient in Parkinson's disease (PD), where dopaminergic neurodegeneration alters basal ganglia activity. Being downstream of the basal ganglia, the PPN may be a suitable target for ameliorating parkinsonian motor symptoms. Here, we use in vivo cell-type specific PPN activation to restore motor function in two mouse models of parkinsonism made by acute pharmacological blockage of dopamine transmission. With a combination of chemo- and opto-genetics, we show that excitation of caudal glutamatergic PPN neurons can normalize the otherwise severe locomotor deficit in PD, whereas targeting the local GABAergic population only leads to recovery of slow locomotion. The motor rescue driven by glutamatergic PPN activation is independent of activity in nearby locomotor promoting glutamatergic Cuneiform neurons. Our observations point to caudal glutamatergic PPN neurons as a potential target for neuromodulatory restoration of locomotor function in PD.
Topics: Animals; Disease Models, Animal; Dopamine; Excitatory Amino Acid Agents; Female; Male; Mesencephalon; Mice; Mice, Inbred C57BL; Neurons; Parkinson Disease; Parkinsonian Disorders; Pedunculopontine Tegmental Nucleus
PubMed: 35082287
DOI: 10.1038/s41467-022-28075-4 -
Frontiers in Neural Circuits 2021Midbrain dopaminergic neurons located in the substantia nigra and the ventral tegmental area are the main source of dopamine in the brain. They send out projections to a... (Review)
Review
Midbrain dopaminergic neurons located in the substantia nigra and the ventral tegmental area are the main source of dopamine in the brain. They send out projections to a variety of forebrain structures, including dorsal striatum, nucleus accumbens, and prefrontal cortex (PFC), establishing the nigrostriatal, mesolimbic, and mesoprefrontal pathways, respectively. The dopaminergic input to the PFC is essential for the performance of higher cognitive functions such as working memory, attention, planning, and decision making. The gradual maturation of these cognitive skills during postnatal development correlates with the maturation of PFC local circuits, which undergo a lengthy functional remodeling process during the neonatal and adolescence stage. During this period, the mesoprefrontal dopaminergic innervation also matures: the fibers are rather sparse at prenatal stages and slowly increase in density during postnatal development to finally reach a stable pattern in early adulthood. Despite the prominent role of dopamine in the regulation of PFC function, relatively little is known about how the dopaminergic innervation is established in the PFC, whether and how it influences the maturation of local circuits and how exactly it facilitates cognitive functions in the PFC. In this review, we provide an overview of the development of the mesoprefrontal dopaminergic system in rodents and primates and discuss the role of altered dopaminergic signaling in neuropsychiatric and neurodevelopmental disorders.
Topics: Animals; Dopamine; Dopaminergic Neurons; Female; Mesencephalon; Pregnancy; Substantia Nigra; Ventral Tegmental Area
PubMed: 34712123
DOI: 10.3389/fncir.2021.746582 -
Journal of Oral Science 2017Neurons in the trigeminal mesencephalic nucleus (Vmes) receive deep sensation (proprioception) from jaw-closing muscle spindles and periodontal ligaments and project... (Review)
Review
Neurons in the trigeminal mesencephalic nucleus (Vmes) receive deep sensation (proprioception) from jaw-closing muscle spindles and periodontal ligaments and project primarily to the jaw-closing motoneuron pool (jaw-closing nucleus) of the trigeminal motor nucleus and to the supratrigeminal nucleus. Numerous articles have described the morphology and physiology of the central projections of Vmes afferents originating from the muscle spindles and periodontal ligaments. However, no report has provided a detailed description of projection and synaptic connectivity, especially of single afferents, and their functional implications. In this review, we reanalyze data obtained by single intra-axonal recording and labeling of functionally identified Vmes muscle spindle afferents and periodontal ligament afferents and by electron microscopic observation of their projection features and synaptic organization of boutons, to compare the data for the jaw-closing nucleus and supratrigeminal nucleus. Our analysis shows that each Vmes afferent type has characteristic projection pattern and synaptic feature that may be important in jaw-reflex control.
Topics: Animals; Jaw; Mesencephalon; Neurons; Reflex; Synapses; Trigeminal Nerve
PubMed: 28637975
DOI: 10.2334/josnusd.16-0845 -
Development (Cambridge, England) Mar 2013Mesodiencephalic dopaminergic (mdDA) neurons are located in the ventral mesodiencephalon and are involved in psychiatric disorders and severely affected in... (Review)
Review
Mesodiencephalic dopaminergic (mdDA) neurons are located in the ventral mesodiencephalon and are involved in psychiatric disorders and severely affected in neurodegenerative diseases such as Parkinson's disease. mdDA neuronal development has received much attention in the last 15 years and many transcription factors involved in mdDA specification have been discovered. More recently however, the impact of epigenetic regulation has come into focus, and it's emerging that the processes of histone modification and DNA methylation form the basis of genetic switches that operate during mdDA development. Here, we review the epigenetic control of mdDA development, maturation and maintenance. As we highlight, epigenetic mechanisms play a pivotal role in all of these processes and the knowledge gathered from studying epigenetics in these contexts may aid our understanding of mdDA-related pathologies.
Topics: Animals; Body Patterning; Cell Proliferation; Dopaminergic Neurons; Epigenesis, Genetic; Gene Expression Regulation, Developmental; Humans; Mesencephalon; Models, Biological; Neurogenesis
PubMed: 23444349
DOI: 10.1242/dev.089359 -
Genes, Brain, and Behavior Jan 2016The past two decades have seen an explosion in our understanding of the origin and development of the midbrain dopamine system. Much of this work has been focused on the... (Review)
Review
The past two decades have seen an explosion in our understanding of the origin and development of the midbrain dopamine system. Much of this work has been focused on the aspects of dopamine neuron development related to the onset of movement disorders such as Parkinson's disease, with the intent of hopefully delaying, preventing or fixing symptoms. While midbrain dopamine degeneration is a major focus for treatment and research, many other human disorders are impacted by abnormal dopamine, including drug addiction, autism and schizophrenia. Understanding dopamine neuron ontogeny and how dopamine connections and circuitry develops may provide us with key insights into potentially important avenues of research for other dopamine-related disorders. This review will provide a brief overview of the major molecular and genetic players throughout the development of midbrain dopamine neurons and what we know about the behavioral- and disease-related implications associated with perturbations to midbrain dopamine neuron development. We intend to combine the knowledge of two broad fields of neuroscience, both developmental and behavioral, with the intent on fostering greater discussion between branches of neuroscience in the service of addressing complex cognitive questions from a developmental perspective and identifying important gaps in our knowledge for future study.
Topics: Animals; Behavior; Dopamine; Humans; Mesencephalon; Mutation; Neurogenesis
PubMed: 26548362
DOI: 10.1111/gbb.12257