Review

Authors: Ethan S Bromberg-Martin, Masayuki Matsumoto, Okihide Hikosaka...

Midbrain dopamine neurons are well known for their strong responses to rewards and their critical role in positive motivation. It has become increasingly clear, however, that dopamine neurons also transmit signals related to salient but nonrewarding experiences such as aversive and alerting events. Here we review recent advances in understanding the reward and nonreward functions of dopamine. Based on this data, we propose that dopamine neurons come in multiple types that are connected with distinct brain networks and have distinct roles in motivational control. Some dopamine neurons encode motivational value, supporting brain networks for seeking, evaluation, and value learning. Others encode motivational salience, supporting brain networks for orienting, cognition, and general motivation. Both types of dopamine neurons are augmented by an alerting signal involved in rapid detection of potentially important sensory cues. We hypothesize that these dopaminergic pathways for value, salience, and alerting cooperate to support adaptive behavior.

Topics: Animals; Arousal; Avoidance Learning; Dopamine; Humans; Mesencephalon; Motivation; Neural Pathways; Neurons; Reward

PubMed: 21144997
DOI: 10.1016/j.neuron.2010.11.022

Comparative Study

Authors: Gioele La Manno, Daniel Gyllborg, Simone Codeluppi...

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

Authors: Daniel Reumann, Christian Krauditsch, Maria Novatchkova...

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

Authors: Mateja Rybiczka-Tešulov, Oxana Garritsen, Morten T Venø...

Midbrain dopamine (mDA) neurons play an essential role in cognitive and motor behaviours and are linked to different brain disorders. However, the molecular mechanisms underlying their development, and in particular the role of non-coding RNAs (ncRNAs), remain incompletely understood. Here, we establish the transcriptomic landscape and alternative splicing patterns of circular RNAs (circRNAs) at key developmental timepoints in mouse mDA neurons in vivo using fluorescence-activated cell sorting followed by short- and long-read RNA sequencing. In situ hybridisation shows expression of several circRNAs during early mDA neuron development and post-transcriptional silencing unveils roles for different circRNAs in regulating mDA neuron morphology. Finally, in utero electroporation and time-lapse imaging implicate circRmst, a circRNA with widespread morphological effects, in the migration of developing mDA neurons in vivo. Together, these data for the first time suggest a functional role for circRNAs in developing mDA neurons and characterise poorly defined aspects of mDA neuron development.

Topics: Animals; RNA, Circular; Dopaminergic Neurons; Mesencephalon; Mice; Cell Movement; Gene Expression Regulation, Developmental; Neurogenesis; Female; Alternative Splicing; Mice, Inbred C57BL; Transcriptome

PubMed: 39117691
DOI: 10.1038/s41467-024-51041-1

Review

Authors: Suyan Li, Sampada Joshee, Anju Vasudevan...

Midbrain GABA neurons, endowed with multiple morphological, physiological and molecular characteristics as well as projection patterns are key players interacting with diverse regions of the brain and capable of modulating several aspects of behavior. The diversity of these GABA neuronal populations based on their location and function in the dorsal, medial or ventral midbrain has challenged efforts to rapidly uncover their developmental regulation. Here we review recent developments that are beginning to illuminate transcriptional control of GABA neurons in the embryonic midbrain (mesencephalon) and discuss its implications for understanding and treatment of neurological and psychiatric illnesses.

Topics: Animals; GABAergic Neurons; Gene Expression Regulation, Developmental; Humans; Mental Disorders; Mesencephalon; gamma-Aminobutyric Acid

PubMed: 25367618
DOI: 10.1515/bmc-2014-0023

Authors: Débora Masini, Ole Kiehn

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

Review

Authors: Gabriela O Bodea, Sandra Blaess

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

Review

Authors: G B Bissonette, M R Roesch

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

Authors: N B Marshall

Topics: Animals; Diencephalon; Electroencephalography; Fishes; Mesencephalon; Sleep

PubMed: 5085035
DOI: 10.1177/003591577206500235

Review

Authors: Sandra Blaess, Sabine Krabbe

Midbrain dopaminergic neurons are a relatively small group of neurons in the mammalian brain controlling a wide range of behaviors. In recent years, increasingly sophisticated tracing, imaging, transcriptomic, and machine learning approaches have provided substantial insights into the anatomical, molecular, and functional heterogeneity of dopaminergic neurons. Despite this wealth of new knowledge, it remains unclear whether and how the diverse features defining dopaminergic subclasses converge to delineate functional ensembles within the dopaminergic system. Here, we review recent studies investigating various aspects of dopaminergic heterogeneity and discuss how development, behavior, and disease influence subtype characteristics. We then outline what further approaches could be pursued to gain a more inclusive picture of dopaminergic diversity, which could be crucial to understanding the functional architecture of this system.

Topics: Animals; Mesencephalon; Brain; Dopaminergic Neurons; Mammals

PubMed: 37972537
DOI: 10.1016/j.conb.2023.102811