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Radiographics : a Review Publication of... 2019The anatomy of the brainstem is complex. It contains numerous cranial nerve nuclei and is traversed by multiple tracts between the brain and spinal cord. Improved MRI... (Review)
Review
The anatomy of the brainstem is complex. It contains numerous cranial nerve nuclei and is traversed by multiple tracts between the brain and spinal cord. Improved MRI resolution now allows the radiologist to identify a higher level of anatomic detail, but an understanding of functional anatomy is crucial for correct interpretation of disease. Brainstem syndromes are most commonly due to occlusion of the posterior circulation or mass effect from intrinsic space-occupying lesions. These syndromes can have subtle imaging findings that may be missed by a radiologist unfamiliar with the anatomy or typical manifesting features. This article presents the developmental anatomy of the brainstem and discusses associated pathologic syndromes. Congenital and acquired syndromes are described and correlated with anatomic locations at imaging, with diagrams to provide a reference to aid in radiologic interpretation. RSNA, 2019.
Topics: Brain Diseases; Brain Infarction; Craniofacial Abnormalities; Humans; Magnetic Resonance Imaging; Medulla Oblongata; Mesencephalon; Neuroimaging; Pons; Syndrome
PubMed: 31283463
DOI: 10.1148/rg.2019180126 -
Nature Reviews. Neuroscience May 2020The past decade has witnessed exponentially growing interest in the lateral habenula (LHb) owing to new discoveries relating to its critical role in regulating... (Review)
Review
The past decade has witnessed exponentially growing interest in the lateral habenula (LHb) owing to new discoveries relating to its critical role in regulating negatively motivated behaviour and its implication in major depression. The LHb, sometimes referred to as the brain's 'antireward centre', receives inputs from diverse limbic forebrain and basal ganglia structures, and targets essentially all midbrain neuromodulatory systems, including the noradrenergic, serotonergic and dopaminergic systems. Its unique anatomical position enables the LHb to act as a hub that integrates value-based, sensory and experience-dependent information to regulate various motivational, cognitive and motor processes. Dysfunction of the LHb may contribute to the pathophysiology of several psychiatric disorders, especially major depression. Recently, exciting progress has been made in identifying the molecular and cellular mechanisms in the LHb that underlie negative emotional state in animal models of drug withdrawal and major depression. A future challenge is to translate these advances into effective clinical treatments.
Topics: Animals; Basal Ganglia; Habenula; Health; Humans; Limbic System; Mental Disorders; Mesencephalon; Neural Pathways
PubMed: 32269316
DOI: 10.1038/s41583-020-0292-4 -
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 -
Cell Stem Cell Apr 2023The cell lineages across developmental stages remain to be elucidated. Here, we developed single-cell split barcoding (SISBAR) that allows clonal tracking of single-cell...
The cell lineages across developmental stages remain to be elucidated. Here, we developed single-cell split barcoding (SISBAR) that allows clonal tracking of single-cell transcriptomes across stages in an in vitro model of human ventral midbrain-hindbrain differentiation. We developed "potential-spective" and "origin-spective" analyses to investigate the cross-stage lineage relationships and mapped a multi-level clonal lineage landscape depicting the whole differentiation process. We uncovered many previously uncharacterized converging and diverging trajectories. Furthermore, we demonstrate that a transcriptome-defined cell type can arise from distinct lineages that leave molecular imprints on their progenies, and the multilineage fates of a progenitor cell-type represent the collective results of distinct rather than similar clonal fates of individual progenitors, each with distinct molecular signatures. Specifically, we uncovered a ventral midbrain progenitor cluster as the common clonal origin of midbrain dopaminergic (mDA) neurons, midbrain glutamatergic neurons, and vascular and leptomeningeal cells and identified a surface marker that can improve graft outcomes.
Topics: Humans; Cell Differentiation; Mesencephalon; Stem Cells; Neurons; Cell Lineage
PubMed: 36933556
DOI: 10.1016/j.stem.2023.02.007 -
Neuron Jan 2019Ventral tegmental area (VTA) dopamine (DA) neurons play a central role in mediating motivated behaviors, but the circuitry through which they signal positive and...
Ventral tegmental area (VTA) dopamine (DA) neurons play a central role in mediating motivated behaviors, but the circuitry through which they signal positive and negative motivational stimuli is incompletely understood. Using in vivo fiber photometry, we simultaneously recorded activity in DA terminals in different nucleus accumbens (NAc) subnuclei during an aversive and reward conditioning task. We find that DA terminals in the ventral NAc medial shell (vNAcMed) are excited by unexpected aversive outcomes and to cues that predict them, whereas DA terminals in other NAc subregions are persistently depressed. Excitation to reward-predictive cues dominated in the NAc lateral shell and was largely absent in the vNAcMed. Moreover, we demonstrate that glutamatergic (VGLUT2-expressing) neurons in the lateral hypothalamus represent a key afferent input for providing information about aversive outcomes to vNAcMed-projecting DA neurons. Collectively, we reveal the distinct functional contributions of separate mesolimbic DA subsystems and their afferent pathways underlying motivated behaviors. VIDEO ABSTRACT.
Topics: Animals; Avoidance Learning; Dopaminergic Neurons; Limbic System; Male; Mesencephalon; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nerve Net; Organ Culture Techniques; Photometry; Ventral Tegmental Area; Vesicular Glutamate Transport Protein 2
PubMed: 30503173
DOI: 10.1016/j.neuron.2018.11.005 -
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 -
Neurobiology of Learning and Memory Dec 2020Novelty triggers an increase in orienting behavior that is critical to evaluate the potential salience of unknown events. As novelty becomes familiar upon repeated... (Review)
Review
Novelty triggers an increase in orienting behavior that is critical to evaluate the potential salience of unknown events. As novelty becomes familiar upon repeated encounters, this increase in response rapidly habituates as a form of behavioral adaptation underlying goal-directed behaviors. Many neurodevelopmental, psychiatric and neurodegenerative disorders are associated with abnormal responses to novelty and/or familiarity, although the neuronal circuits and cellular/molecular mechanisms underlying these natural behaviors in the healthy brain are largely unknown, as is the maladaptive processes that occur to induce impairment of novelty signaling in diseased brains. In rodents, the development of cutting-edge tools that allow for measurements of real time activity dynamics in selectively identified neuronal ensembles by gene expression signatures is beginning to provide advances in understanding the neural bases of the novelty response. Accumulating evidence indicate that midbrain circuits, the majority of which linked to dopamine transmission, promote exploratory assessments and guide approach/avoidance behaviors to different types of novelty via specific projection sites. The present review article focuses on midbrain circuit analysis relevant to novelty processing and habituation with familiarity.
Topics: Animals; Dopaminergic Neurons; Exploratory Behavior; Habituation, Psychophysiologic; Humans; Mesencephalon; Mice; Nerve Net; Raphe Nuclei; Rats; Recognition, Psychology
PubMed: 33053429
DOI: 10.1016/j.nlm.2020.107323 -
Nature Aug 2022Food and water are rewarding in part because they satisfy our internal needs. Dopaminergic neurons in the ventral tegmental area (VTA) are activated by gustatory...
Food and water are rewarding in part because they satisfy our internal needs. Dopaminergic neurons in the ventral tegmental area (VTA) are activated by gustatory rewards, but how animals learn to associate these oral cues with the delayed physiological effects of ingestion is unknown. Here we show that individual dopaminergic neurons in the VTA respond to detection of nutrients or water at specific stages of ingestion. A major subset of dopaminergic neurons tracks changes in systemic hydration that occur tens of minutes after thirsty mice drink water, whereas different dopaminergic neurons respond to nutrients in the gastrointestinal tract. We show that information about fluid balance is transmitted to the VTA by a hypothalamic pathway and then re-routed to downstream circuits that track the oral, gastrointestinal and post-absorptive stages of ingestion. To investigate the function of these signals, we used a paradigm in which a fluid's oral and post-absorptive effects can be independently manipulated and temporally separated. We show that mice rapidly learn to prefer one fluid over another based solely on its rehydrating ability and that this post-ingestive learning is prevented if dopaminergic neurons in the VTA are selectively silenced after consumption. These findings reveal that the midbrain dopamine system contains subsystems that track different modalities and stages of ingestion, on timescales from seconds to tens of minutes, and that this information is used to drive learning about the consequences of ingestion.
Topics: Animals; Cues; Digestion; Dopamine; Dopaminergic Neurons; Eating; Gastrointestinal Tract; Hypothalamus; Mesencephalon; Mice; Neural Pathways; Nutrients; Organism Hydration Status; Reward; Time Factors; Ventral Tegmental Area; Water; Water-Electrolyte Balance
PubMed: 35831501
DOI: 10.1038/s41586-022-04954-0 -
Science (New York, N.Y.) Sep 2017Channelrhodopsins are light-gated ion channels that, via regulation of flagellar function, enable single-celled motile algae to seek ambient light conditions suitable... (Review)
Review
Channelrhodopsins are light-gated ion channels that, via regulation of flagellar function, enable single-celled motile algae to seek ambient light conditions suitable for photosynthesis and survival. These plant behavioral responses were initially investigated more than 150 years ago. Recently, major principles of function for light-gated ion channels have been elucidated by creating channelrhodopsins with kinetics that are accelerated or slowed over orders of magnitude, by discovering and designing channelrhodopsins with altered spectral properties, by solving the high-resolution channelrhodopsin crystal structure, and by structural model-guided redesign of channelrhodopsins for altered ion selectivity. Each of these discoveries not only revealed basic principles governing the operation of light-gated ion channels, but also enabled the creation of new proteins for illuminating, via optogenetics, the fundamentals of brain function.
Topics: Animals; Channelrhodopsins; Chlamydomonas reinhardtii; Crystallography; Dopaminergic Neurons; Light; Mesencephalon; Opsins; Optogenetics; Rats
PubMed: 28912215
DOI: 10.1126/science.aan5544 -
Bulletin of Experimental Biology and... Apr 2019An original concept of a two-stage mechanism of positive reinforcement is proposed. The first stage, "virtual" reinforcement, is formed in parallel with the action... (Review)
Review
An original concept of a two-stage mechanism of positive reinforcement is proposed. The first stage, "virtual" reinforcement, is formed in parallel with the action result acceptor when the result is still not achieved. At this stage, the importance of the planned result and the probability of its achievement are assessed. The greater are these indices, the stronger is "virtual" reinforcement. Hypothetically, the "virtual" reinforcement is mediated by dopamine release from nerve terminals in the mesencephalon. The "real" reinforcement (the second stage) occurs after achievement of the result. Probably, an important role in the mechanisms of the "real" reinforcement is given to endogenous opioids, cannabinoids, and GABA. Based on the advanced hypothesis on interaction between the central and peripheral subdivisions of the corresponding neurochemical systems, the review focuses on possibility of pharmacological intervention into the mechanisms of positive reinforcement by modifying activity of the peripheral opioid and dopamine receptors with the ligands that cannot cross blood-brain barrier.
Topics: Analgesics, Opioid; Animals; Cannabinoids; Feedback, Physiological; Humans; Mesencephalon; Neurons; Personal Satisfaction; Receptors, Dopamine; Receptors, Opioid; Reinforcement, Psychology; gamma-Aminobutyric Acid
PubMed: 31020579
DOI: 10.1007/s10517-019-04423-1