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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 -
Journal of Computer Assisted Tomography 2016We aim to review the magnetic resonance imaging appearance of malformations of midbrain and hindbrain. These can be classified as predominantly cerebellar malformations,... (Review)
Review
We aim to review the magnetic resonance imaging appearance of malformations of midbrain and hindbrain. These can be classified as predominantly cerebellar malformations, combined cerebellar and brain stem malformations, and predominantly brain stem malformations. The diagnostic criteria for the majority of these morphological malformations are based on neuroimaging findings. The predominantly cerebellar malformations include predominantly vermian hypoplasia seen in Dandy-Walker malformation and rhombencephalosynapsis, global cerebellar hypoplasia reported in lissencephaly and microlissencephaly, and unilateral cerebellar hypoplasia seen in PHACES, vanishing cerebellum, and cerebellar cleft. Cerebellar dysplasias are seen in Chudley-McCullough syndrome, associated with LAMA1 mutations and GPR56 mutations; Lhermitte-Duclos disease; and focal cerebellar dysplasias. Cerebellar hyperplasias are seen in megalencephaly-related syndromes and hemimegalencephaly with ipsilateral cerebellomegaly. Cerebellar and brain stem malformations include tubulinopathies, Joubert syndrome, cobblestone malformations, pontocerebellar hypoplasias, and congenital disorders of glycosylation type Ia. Predominantly brain stem malformations include congenital innervation dysgenesis syndrome, pontine tegmental cap dysplasia, diencephalic-mesencephalic junction dysplasia, disconnection syndrome, and pontine clefts.
Topics: Humans; Magnetic Resonance Imaging; Mesencephalon; Neuroimaging; Rhombencephalon
PubMed: 26599961
DOI: 10.1097/RCT.0000000000000340 -
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 -
Neuroradiology Feb 2015Neuroimaging techniques including structural magnetic resonance imaging (MRI) and functional positron emission tomography (PET) are useful in categorizing various... (Review)
Review
PURPOSE
Neuroimaging techniques including structural magnetic resonance imaging (MRI) and functional positron emission tomography (PET) are useful in categorizing various midbrain-hindbrain (MHB) malformations, both in allowing diagnosis and in helping to understand the developmental processes that were disturbed. Brain imaging phenotypes of numerous malformations are characteristic features that help in guiding the genetic testing in case of direct neuroimaging-genotype correlation or, at least, to differentiate among MHB malformations entities. The present review aims to provide the reader with an update of the use of neuroimaging applications in the fine analysis of MHB malformations, using a comprehensive, recently proposed developmental and genetic classification.
METHODS
We have performed an extensive systematic review of the literature, from the embryology main steps of MHB development through the malformations entities, with regard to their molecular and genetic basis, conventional MRI features, and other neuroimaging characteristics.
RESULTS
We discuss disorders in which imaging features are distinctive and how these features reflect the structural and functional impairment of the brain.
CONCLUSION
Recognition of specific MRI phenotypes, including advanced imaging features, is useful to recognize the MHB malformation entities, to suggest genetic investigations, and, eventually, to monitor the disease outcome after supportive therapies.
Topics: Humans; Magnetic Resonance Imaging; Mesencephalon; Nervous System Malformations; Neuroimaging; Rhombencephalon
PubMed: 25339235
DOI: 10.1007/s00234-014-1431-2 -
The European Journal of Neuroscience Aug 2019Nicotine and alcohol addiction are leading causes of preventable death worldwide and continue to constitute a huge socio-economic burden. Both nicotine and alcohol... (Review)
Review
Nicotine and alcohol addiction are leading causes of preventable death worldwide and continue to constitute a huge socio-economic burden. Both nicotine and alcohol perturb the brain's mesocorticolimbic system. Dopamine (DA) neurons projecting from the ventral tegmental area (VTA) to multiple downstream structures, including the nucleus accumbens, prefrontal cortex, and amygdala, are highly involved in the maintenance of healthy brain function. VTA DA neurons play a crucial role in associative learning and reinforcement. Nicotine and alcohol usurp these functions, promoting reinforcement of drug taking behaviors. In this review, we will first describe how nicotine and alcohol individually affect VTA DA neurons by examining how drug exposure alters the heterogeneous VTA microcircuit and network-wide projections. We will also examine how coadministration or previous exposure to nicotine or alcohol may augment the reinforcing effects of the other. Additionally, this review briefly summarizes the role of VTA DA neurons in nicotine, alcohol, and their synergistic effects in reinforcement and also addresses the remaining questions related to the circuit-function specificity of the dopaminergic system in mediating nicotine/alcohol reinforcement and comorbidity.
Topics: Alcohol Drinking; Animals; Dopaminergic Neurons; Ethanol; Humans; Mesencephalon; Nerve Net; Nicotine; Reinforcement, Psychology
PubMed: 30251377
DOI: 10.1111/ejn.14160 -
Cell May 2019The perioculomotor (pIII) region of the midbrain was postulated as a sleep-regulating center in the 1890s but largely neglected in subsequent studies. Using...
The perioculomotor (pIII) region of the midbrain was postulated as a sleep-regulating center in the 1890s but largely neglected in subsequent studies. Using activity-dependent labeling and gene expression profiling, we identified pIII neurons that promote non-rapid eye movement (NREM) sleep. Optrode recording showed that pIII glutamatergic neurons expressing calcitonin gene-related peptide alpha (CALCA) are NREM-sleep active; optogenetic and chemogenetic activation/inactivation showed that they strongly promote NREM sleep. Within the pIII region, CALCA neurons form reciprocal connections with another population of glutamatergic neurons that express the peptide cholecystokinin (CCK). Activation of CCK neurons also promoted NREM sleep. Both CALCA and CCK neurons project rostrally to the preoptic hypothalamus, whereas CALCA neurons also project caudally to the posterior ventromedial medulla. Activation of each projection increased NREM sleep. Together, these findings point to the pIII region as an excitatory sleep center where different subsets of glutamatergic neurons promote NREM sleep through both local reciprocal connections and long-range projections.
Topics: Animals; Cholecystokinin; Hypothalamus; Mesencephalon; Mice; Mice, Transgenic; Neurons; Optogenetics; Sleep Stages
PubMed: 31031008
DOI: 10.1016/j.cell.2019.03.041 -
Neuron Jul 2017Oxytocin and dopamine possess significant overlap in the modulation of life-essential behaviors. Here, Xiao et al. (2017) show that the activity of dopamine neurons of... (Review)
Review
Oxytocin and dopamine possess significant overlap in the modulation of life-essential behaviors. Here, Xiao et al. (2017) show that the activity of dopamine neurons of the ventral tegmental area and the substantia nigra is finely tuned by axonal release of oxytocin.
Topics: Animals; Dopamine; Humans; Mesencephalon; Neurons; Oxytocin; Substantia Nigra; Ventral Tegmental Area
PubMed: 28728017
DOI: 10.1016/j.neuron.2017.07.002 -
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 -
Proceedings of the National Academy of... Jul 2022Intraneuronal inclusions of misfolded α-synuclein (α-syn) and prion-like spread of the pathologic α-syn contribute to progressive neuronal death in Parkinson's...
Intraneuronal inclusions of misfolded α-synuclein (α-syn) and prion-like spread of the pathologic α-syn contribute to progressive neuronal death in Parkinson's disease (PD). Despite the pathologic significance, no efficient therapeutic intervention targeting α-synucleinopathy has been developed. In this study, we provide evidence that astrocytes, especially those cultured from the ventral midbrain (VM), show therapeutic potential to alleviate α-syn pathology in multiple in vitro and in vivo α-synucleinopathic models. Regulation of neuronal α-syn proteostasis underlies the therapeutic function of astrocytes. Specifically, VM-derived astrocytes inhibited neuronal α-syn aggregation and transmission in a paracrine manner by correcting not only intraneuronal oxidative and mitochondrial stresses but also extracellular inflammatory environments, in which α-syn proteins are prone to pathologic misfolding. The astrocyte-derived paracrine factors also promoted disassembly of extracellular α-syn aggregates. In addition to the aggregated form of α-syn, VM astrocytes reduced total α-syn protein loads both by actively scavenging extracellular α-syn fibrils and by a paracrine stimulation of neuronal autophagic clearance of α-syn. Transplantation of VM astrocytes into the midbrain of PD model mice alleviated α-syn pathology and protected the midbrain dopamine neurons from neurodegeneration. We further showed that cografting of VM astrocytes could be exploited in stem cell-based therapy for PD, in which host-to-graft transmission of α-syn pathology remains a critical concern for long-term cell therapeutic effects.
Topics: Animals; Astrocytes; Brain Tissue Transplantation; Disease Models, Animal; Dopaminergic Neurons; Mesencephalon; Mice; Parkinson Disease; Proteostasis; alpha-Synuclein
PubMed: 35858361
DOI: 10.1073/pnas.2110746119 -
Viral vector strategies for investigating midbrain dopamine circuits underlying motivated behaviors.Pharmacology, Biochemistry, and Behavior Nov 2018Midbrain dopamine (DA) neurons have received significant attention in brain research because of their central role in reward processing and their dysfunction in... (Review)
Review
Midbrain dopamine (DA) neurons have received significant attention in brain research because of their central role in reward processing and their dysfunction in neuropsychiatric disorders such as Parkinson's disease, drug addiction, depression and schizophrenia. Until recently, it has been thought that DA neurons form a homogeneous population whose primary function is the computation of reward prediction errors. However, through the implementation of viral vector strategies, an unexpected complexity and diversity has been revealed at the anatomical, molecular and functional level. In this review, we discuss recent viral vector approaches that have been leveraged to dissect how different circuits involving distinct DA neuron subpopulations may contribute to the role of DA in reward- and aversion-related behaviors. We focus on studies that have used cell type- and projection-specific optogenetic manipulations, discuss the strengths and limitations of each approach, and critically examine emergent organizational principles that have led to a reclassification of midbrain DA neurons.
Topics: Animals; Brain Mapping; Dopaminergic Neurons; Genetic Vectors; Humans; Magnetic Resonance Imaging; Mesencephalon; Motivation; Optogenetics; Rabies virus; Reward; Synapses; Ventral Tegmental Area; Viruses
PubMed: 28257849
DOI: 10.1016/j.pbb.2017.02.006