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Frontiers in Neural Circuits 2022The mesencephalic locomotor region (MLR) was discovered several decades ago in the cat. It was functionally defined based on the ability of low threshold electrical... (Review)
Review
The mesencephalic locomotor region (MLR) was discovered several decades ago in the cat. It was functionally defined based on the ability of low threshold electrical stimuli within a region comprising the cuneiform and pedunculopontine nucleus to evoke locomotion. Since then, similar regions have been found in diverse vertebrate species, including the lamprey, skate, rodent, pig, monkey, and human. The MLR, while often viewed under the lens of locomotion, is involved in diverse processes involving the autonomic nervous system, respiratory system, and the state-dependent activation of motor systems. This review will discuss the pedunculopontine nucleus and cuneiform nucleus that comprises the MLR and examine their respective connectomes from both an anatomical and functional angle. From a functional perspective, the MLR primes the cardiovascular and respiratory systems before the locomotor activity occurs. Inputs from a variety of higher structures, and direct outputs to the monoaminergic nuclei, allow the MLR to be able to respond appropriately to state-dependent locomotion. These state-dependent effects are roughly divided into escape and exploratory behavior, and the MLR also can reinforce the selection of these locomotor behaviors through projections to adjacent structures such as the periaqueductal gray or to limbic and cortical regions. Findings from the rat, mouse, pig, and cat will be discussed to highlight similarities and differences among diverse species.
Topics: Animals; Electric Stimulation; Exploratory Behavior; Lampreys; Locomotion; Mesencephalon; Mice; Rats; Swine
PubMed: 35615623
DOI: 10.3389/fncir.2022.884785 -
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 -
Neuropharmacology Sep 2017Dopamine (DA) is a major catecholamine neurotransmitter in the mammalian brain that controls neural circuits involved in the cognitive, emotional, and motor aspects of... (Review)
Review
Dopamine (DA) is a major catecholamine neurotransmitter in the mammalian brain that controls neural circuits involved in the cognitive, emotional, and motor aspects of goal-directed behavior. Accordingly, perturbations in DA neurotransmission play a central role in several neuropsychiatric disorders. Somewhat surprisingly given its prominent role in numerous behaviors, DA is released by a relatively small number of densely packed neurons originating in the midbrain. The dopaminergic midbrain innervates numerous brain regions where extracellular DA release and receptor binding promote short- and long-term changes in postsynaptic neuron function. Striatal forebrain nuclei receive the greatest proportion of DA projections and are a predominant hub at which DA influences behavior. A number of excitatory, inhibitory, and modulatory inputs orchestrate DA neurotransmission by controlling DA cell body firing patterns, terminal release, and effects on postsynaptic sites in the striatum. The endocannabinoid (eCB) system serves as an important filter of afferent input that acts locally at midbrain and terminal regions to shape how incoming information is conveyed onto DA neurons and to output targets. In this review, we aim to highlight existing knowledge regarding how eCB signaling controls DA neuron function through modifications in synaptic strength at midbrain and striatal sites, and to raise outstanding questions on this topic. This article is part of the Special Issue entitled "A New Dawn in Cannabinoid Neurobiology".
Topics: Animals; Corpus Striatum; Dopaminergic Neurons; Endocannabinoids; Humans; Mesencephalon; Synaptic Transmission
PubMed: 28450060
DOI: 10.1016/j.neuropharm.2017.04.033 -
Nature Neuroscience Oct 2023The mesencephalic locomotor region (MLR) is a brain stem area whose stimulation triggers graded forward locomotion. How MLR neurons recruit downstream vsx2 (V2a)...
The mesencephalic locomotor region (MLR) is a brain stem area whose stimulation triggers graded forward locomotion. How MLR neurons recruit downstream vsx2 (V2a) reticulospinal neurons (RSNs) is poorly understood. Here, to overcome this challenge, we uncovered the locus of MLR in transparent larval zebrafish and show that the MLR locus is distinct from the nucleus of the medial longitudinal fasciculus. MLR stimulations reliably elicit forward locomotion of controlled duration and frequency. MLR neurons recruit V2a RSNs via projections onto somata in pontine and retropontine areas, and onto dendrites in the medulla. High-speed volumetric imaging of neuronal activity reveals that strongly MLR-coupled RSNs are active for steering or forward swimming, whereas weakly MLR-coupled medullary RSNs encode the duration and frequency of the forward component. Our study demonstrates how MLR neurons recruit specific V2a RSNs to control the kinematics of forward locomotion and suggests conservation of the motor functions of V2a RSNs across vertebrates.
Topics: Animals; Zebrafish; Larva; Mesencephalon; Locomotion; Neurons; Spinal Cord; Electric Stimulation
PubMed: 37667039
DOI: 10.1038/s41593-023-01418-0 -
Neurologia Medico-chirurgica 2016In Parkinson's disease (PD), dopamine neurons in the substantia nigra are degenerated and lost. Cell therapy for PD replaces the lost dopamine neurons by transplanting... (Review)
Review
In Parkinson's disease (PD), dopamine neurons in the substantia nigra are degenerated and lost. Cell therapy for PD replaces the lost dopamine neurons by transplanting donor dopamine neural progenitor cells. Cell therapy for PD has been performed in the clinic since the 1980s and uses donor cells from the mesencephalon of aborted embryos. Regenerative medicine for PD using induced pluripotent stem (iPS) cell technology is drawing attention, because it offers a limitless and more advantageous source of donor cells than aborted embryos.
Topics: Animals; Cell- and Tissue-Based Therapy; Dopamine; Humans; Induced Pluripotent Stem Cells; Mesencephalon; Parkinson Disease
PubMed: 26912295
DOI: 10.2176/nmc.ra.2015-0303 -
Trends in Neurosciences Feb 2019The trade-off between reward and effort is at the heart of most behavioral theories, from ecology to economics. Compared to reward, however, effort remains poorly... (Review)
Review
The trade-off between reward and effort is at the heart of most behavioral theories, from ecology to economics. Compared to reward, however, effort remains poorly understood, both at the behavioral and neurophysiological levels. This is important because unwillingness to overcome effort to gain reward is a common feature of many neuropsychiatric and neurological disorders. A recent surge in interest in the neurobiological basis of effort has led to seemingly conflicting results regarding the role of dopamine. We argue here that, upon closer examination, there is actually striking consensus across studies: dopamine primarily codes for future reward but is less sensitive to anticipated effort cost. This strong association between dopamine and the incentive effects of rewards places dopamine in a key position to promote reward-directed action.
Topics: Animals; Decision Making; Dopamine; Humans; Mesencephalon; Motivation; Physical Exertion; Reward
PubMed: 30391016
DOI: 10.1016/j.tins.2018.10.001 -
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 -
Frontiers in Neural Circuits 2023The pedunculopontine nucleus (PPN) is the major part of the mesencephalic locomotor region, involved in the control of gait and locomotion. The PPN contains... (Review)
Review
The pedunculopontine nucleus (PPN) is the major part of the mesencephalic locomotor region, involved in the control of gait and locomotion. The PPN contains glutamatergic, cholinergic, and GABAergic neurons that all make local connections, but also have long-range ascending and descending connections. While initially thought of as a region only involved in gait and locomotion, recent evidence is showing that this structure also participates in decision-making to initiate movement. Clinically, the PPN has been used as a target for deep brain stimulation to manage freezing of gait in late Parkinson's disease. In this review, we will discuss current thinking on the role of the PPN in locomotor control. We will focus on the cytoarchitecture and functional connectivity of the PPN in relationship to motor control.
Topics: Humans; Parkinson Disease; Deep Brain Stimulation; Gait Disorders, Neurologic; Locomotion; Mesencephalon; Pedunculopontine Tegmental Nucleus
PubMed: 36925563
DOI: 10.3389/fncir.2023.1095441 -
Nature Communications Aug 2023The modulation of dopamine release from midbrain projections to the striatum has long been demonstrated in reward-based learning, but the synaptic basis of aversive...
The modulation of dopamine release from midbrain projections to the striatum has long been demonstrated in reward-based learning, but the synaptic basis of aversive learning is far less characterized. The cerebellum receives axonal projections from the locus coeruleus, and norepinephrine release is implicated in states of arousal and stress, but whether aversive learning relies on plastic changes in norepinephrine release in the cerebellum is unknown. Here we report that in mice, norepinephrine is released in the cerebellum following an unpredicted noxious event (a foot-shock) and that this norepinephrine release is potentiated powerfully with fear acquisition as animals learn that a previously neutral stimulus (tone) predicts the aversive event. Importantly, both chemogenetic and optogenetic inhibition of the locus coeruleus-cerebellum pathway block fear memory without impairing motor function. Thus, norepinephrine release in the cerebellum is modulated by experience and underlies aversive learning.
Topics: Mice; Animals; Avoidance Learning; Norepinephrine; Locus Coeruleus; Cerebellum; Mesencephalon
PubMed: 37563141
DOI: 10.1038/s41467-023-40548-8 -
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