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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 -
Neuroscience Dec 2014The midbrain dopamine (DA) neurons play a central role in developing appropriate goal-directed behaviors, including the motivation and cognition to develop appropriate... (Review)
Review
The midbrain dopamine (DA) neurons play a central role in developing appropriate goal-directed behaviors, including the motivation and cognition to develop appropriate actions to obtain a specific outcome. Indeed, subpopulations of DA neurons have been associated with these different functions: the mesolimbic, mesocortical, and nigrostriatal pathways. The mesolimbic and nigrostriatal pathways are an integral part of the basal ganglia through its reciprocal connections to the ventral and dorsal striatum respectively. This chapter reviews the connections of the midbrain DA cells and their role in integrating information across limbic, cognitive and motor functions. Emphasis is placed on the interface between these functional domains within the striatum through corticostriatal connections, through the striato-nigro-striatal connection, and through the lateral habenula projection to the midbrain.
Topics: Animals; Basal Ganglia; Cerebral Cortex; Dopamine; Dopaminergic Neurons; Mesencephalon; Neural Pathways
PubMed: 25445194
DOI: 10.1016/j.neuroscience.2014.10.008 -
ENeuro 2019Midbrain dopamine seems to play an outsized role in motivated behavior and learning. Widely associated with mediating reward-related behavior, decision making, and... (Review)
Review
Midbrain dopamine seems to play an outsized role in motivated behavior and learning. Widely associated with mediating reward-related behavior, decision making, and learning, dopamine continues to generate controversies in the field. While many studies and theories focus on what dopamine cells encode, the question of how the midbrain derives the information it encodes is poorly understood and comparatively less addressed. Recent anatomical studies suggest greater diversity and complexity of afferent inputs than previously appreciated, requiring rethinking of prior models. Here, we elaborate a hypothesis that construes midbrain dopamine as implementing a Bayesian selector in which individual dopamine cells sample afferent activity across distributed brain substrates, comprising evidence to be evaluated on the extent to which stimuli in the on-going sensorimotor stream organizes distributed, parallel processing, reflecting implicit value. To effectively generate a temporally resolved phasic signal, a population of dopamine cells must exhibit synchronous activity. We argue that synchronous activity across a population of dopamine cells signals consensus across distributed afferent substrates, invigorating responding to recognized opportunities and facilitating further learning. In framing our hypothesis, we shift from the question of how value is computed to the broader question of how the brain achieves coordination across distributed, parallel processing. We posit the midbrain is part of an "axis of agency" in which the prefrontal cortex (PFC), basal ganglia (BGS), and midbrain form an axis mediating control, coordination, and consensus, respectively.
Topics: Animals; Basal Ganglia; Dopamine; Dopaminergic Neurons; Humans; Learning; Mesencephalon; Prefrontal Cortex; Signal Transduction
PubMed: 31053604
DOI: 10.1523/ENEURO.0345-18.2019 -
Gut Jan 2023Idiopathic Parkinson's disease (PD) is characterised by alpha-synuclein (aSyn) aggregation and death of dopaminergic neurons in the midbrain. Recent evidence posits that...
OBJECTIVE
Idiopathic Parkinson's disease (PD) is characterised by alpha-synuclein (aSyn) aggregation and death of dopaminergic neurons in the midbrain. Recent evidence posits that PD may initiate in the gut by microbes or their toxins that promote chronic gut inflammation that will ultimately impact the brain. In this work, we sought to demonstrate that the effects of the microbial toxin β--methylamino-L-alanine (BMAA) in the gut may trigger some PD cases, which is especially worrying as this toxin is present in certain foods but not routinely monitored by public health authorities.
DESIGN
To test the hypothesis, we treated wild-type mice, primary neuronal cultures, cell lines and isolated mitochondria with BMAA, and analysed its impact on gut microbiota composition, barrier permeability, inflammation and aSyn aggregation as well as in brain inflammation, dopaminergic neuronal loss and motor behaviour. To further examine the key role of mitochondria, we also determined the specific effects of BMAA on mitochondrial function and on inflammasome activation.
RESULTS
BMAA induced extensive depletion of segmented filamentous bacteria (SFB) that regulate gut immunity, thus triggering gut dysbiosis, immune cell migration, increased intestinal inflammation, loss of barrier integrity and caudo-rostral progression of aSyn. Additionally, BMAA induced and mitochondrial dysfunction with cardiolipin exposure and consequent activation of neuronal innate immunity. These events primed neuroinflammation, dopaminergic neuronal loss and motor deficits.
CONCLUSION
Taken together, our results demonstrate that chronic exposure to dietary BMAA can trigger a chain of events that recapitulate the evolution of the PD pathology from the gut to the brain, which is consistent with 'gut-first' PD.
Topics: Mice; Animals; Gastrointestinal Microbiome; Mesencephalon; Parkinson Disease; Inflammation; Mitochondria
PubMed: 34836918
DOI: 10.1136/gutjnl-2021-326023 -
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