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Biomolecules Sep 2020Midbrain dopamine neurons have crucial functions in motor and emotional control and their degeneration leads to several neurological dysfunctions such as Parkinson's... (Review)
Review
Midbrain dopamine neurons have crucial functions in motor and emotional control and their degeneration leads to several neurological dysfunctions such as Parkinson's disease, addiction, depression, schizophrenia, and others. Despite advances in the understanding of specific altered proteins and coding genes, little is known about cumulative changes in the transcriptional landscape of noncoding genes in midbrain dopamine neurons. Noncoding RNAs-specifically microRNAs and long noncoding RNAs-are emerging as crucial post-transcriptional regulators of gene expression in the brain. The identification of noncoding RNA networks underlying all stages of dopamine neuron development and plasticity is an essential step to deeply understand their physiological role and also their involvement in the etiology of dopaminergic diseases. Here, we provide an update about noncoding RNAs involved in dopaminergic development and metabolism, and the related evidence of these biomolecules for applications in potential treatments for dopaminergic neurodegeneration.
Topics: Animals; Dopamine; Dopaminergic Neurons; Gene Expression Regulation; Humans; Mesencephalon; Parkinson Disease; RNA, Untranslated
PubMed: 32899172
DOI: 10.3390/biom10091269 -
Molecules (Basel, Switzerland) Nov 2020Ayahuasca is a beverage consumed at shamanic ceremonies and currently has gained popularity on recreational scenarios. It contains beta-carboline alkaloids and...
Ayahuasca is a beverage consumed at shamanic ceremonies and currently has gained popularity on recreational scenarios. It contains beta-carboline alkaloids and ,-dimethyltryptamine, which possesses hallucinogenic effects. Only a few studies have elicited the psychoactive effects and the dose of such compounds on neurological dopaminergic cells or animals. In this work, we aimed to study the cytotoxic effects of these compounds present in ayahuasca beverages and on five different teas (, , , and Dc Ab (commercial name)) preparations on dopaminergic immortalized cell lines. Moreover, a characterization of the derivative alkaloids was also performed. All the extracts were characterized by chromatographic systems and the effect of those compounds in cell viability and total protein levels were analyzed in N27 dopaminergic neurons cell line. This is the first article where cytotoxicity of ayahuasca tea is studied on neurological dopaminergic cells. Overall, results showed that both cell viability and protein contents decreased when cells were exposed to the individual compounds, as well as to the teas and to the two mixtures based on the traditional ayahuasca beverages.
Topics: Animals; Apoptosis; Banisteriopsis; Beverages; Cells, Cultured; Cytotoxins; Dopaminergic Neurons; Mesencephalon; Plant Extracts; Rats
PubMed: 33260723
DOI: 10.3390/molecules25235594 -
ELife Aug 2022Repeated exposure to drugs of abuse results in an upregulation of cAMP signaling in the mesolimbic dopamine system, a molecular adaptation thought to be critically...
Repeated exposure to drugs of abuse results in an upregulation of cAMP signaling in the mesolimbic dopamine system, a molecular adaptation thought to be critically involved in the development of drug dependence. Exchange protein directly activated by cAMP (Epac2) is a major cAMP effector abundantly expressed in the brain. However, it remains unknown whether Epac2 contributes to cocaine reinforcement. Here, we report that Epac2 in the mesolimbic dopamine system promotes cocaine reinforcement via enhancement of dopamine release. Conditional knockout of Epac2 from midbrain dopamine neurons (Epac2-cKO) and the selective Epac2 inhibitor ESI-05 decreased cocaine self-administration in mice under both fixed-ratio and progressive-ratio reinforcement schedules and across a broad range of cocaine doses. In addition, Epac2-cKO led to reduced evoked dopamine release, whereas Epac2 agonism robustly enhanced dopamine release in the nucleus accumbens in vitro. This mechanism is central to the behavioral effects of Epac2 disruption, as chemogenetic stimulation of ventral tegmental area (VTA) dopamine neurons via deschloroclozapine (DCZ)-induced activation of Gs-DREADD increased dopamine release and reversed the impairment of cocaine self-administration in Epac2-cKO mice. Conversely, chemogenetic inhibition of VTA dopamine neurons with Gi-DREADD reduced dopamine release and cocaine self-administration in wild-type mice. Epac2-mediated enhancement of dopamine release may therefore represent a novel and powerful mechanism that contributes to cocaine reinforcement.
Topics: Animals; Cocaine; Dopamine; Dopaminergic Neurons; Mesencephalon; Mice; Ventral Tegmental Area
PubMed: 35993549
DOI: 10.7554/eLife.80747 -
Hearing Research Nov 2021Cholinergic axons from the pedunculopontine tegmental nucleus (PPT) innervate the inferior colliculus where they are positioned to modulate both excitatory and...
Cholinergic axons from the pedunculopontine tegmental nucleus (PPT) innervate the inferior colliculus where they are positioned to modulate both excitatory and inhibitory circuits across the central nucleus and adjacent cortical regions. More rostral regions of the auditory midbrain include the nucleus of the brachium of the inferior colliculus (NBIC), the intercollicular tegmentum (ICt) and the rostral pole of the inferior colliculus (ICrp). These regions appear especially important for multisensory integration and contribute to orienting behavior and many aspects of auditory perception. These regions appear to receive cholinergic innervation but little is known about the distribution of cholinergic axons in these regions or the cells that they contact. The present study used immunostaining to examine the distribution of cholinergic axons and then used chemically-specific viral tracing to examine cholinergic projections from the PPT to the intercollicular areas in male and female transgenic rats. Staining with antibodies against vesicular acetylcholine transporter revealed dense cholinergic innervation throughout the NBIC, ICt and ICrp. Deposits of viral vector into the PPT labeled cholinergic axons bilaterally in the NBIC, ICt and ICrp. In each area, the projections were denser on the ipsilateral side. The axons appeared morphologically similar across the three areas. In each area, en passant and terminal boutons from these axons appeared in the neuropil and also in close apposition to cell bodies. Immunostaining with a marker for GABAergic cells suggested that the cholinergic axons likely contact both GABAergic and non-GABAergic cells in the NBIC, ICt and ICrp. Thus, the cholinergic axons could affect multisensory processing by modulating excitatory and inhibitory circuits in the NBIC, ICt and ICrp. The similarity of axons and their targets suggests there may be a common function for cholinergic innervation across the three areas. Given what is known about the PPT, such functions could be associated with arousal, sleep-wake cycle, reward and plasticity.
Topics: Animals; Axons; Cholinergic Agents; Female; Inferior Colliculi; Male; Mesencephalon; Rats; Tegmentum Mesencephali
PubMed: 34564033
DOI: 10.1016/j.heares.2021.108352 -
FEBS Letters Dec 2015Glial cell line-derived neurotrophic factor (GDNF) and its canonical receptor Ret can signal together or independently to fulfill many important functions in the... (Review)
Review
Glial cell line-derived neurotrophic factor (GDNF) and its canonical receptor Ret can signal together or independently to fulfill many important functions in the midbrain dopaminergic (DA) system. While Ret signaling clearly impacts on the development, maintenance and regeneration of the mesostriatal DA system, the physiological functions of GDNF for the DA system are still unclear. Nevertheless, GDNF is still considered to be an excellent candidate to protect and/or regenerate the mesostriatal DA system in Parkinson disease (PD). Clinical trials with GDNF on PD patients are, however, so far inconclusive. Here, we review the current knowledge of GDNF and Ret signaling and function in the midbrain DA system, and their crosstalk with proteins and signaling pathways associated with PD.
Topics: Animals; Dopamine; Dopaminergic Neurons; Glial Cell Line-Derived Neurotrophic Factor; Humans; Mesencephalon; Parkinson Disease; Proto-Oncogene Proteins c-ret; Synaptic Transmission
PubMed: 26555190
DOI: 10.1016/j.febslet.2015.11.006 -
Biomolecular Concepts Oct 2014Midbrain GABA neurons, endowed with multiple morphological, physiological and molecular characteristics as well as projection patterns are key players interacting with... (Review)
Review
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 -
Cellular and Molecular Life Sciences :... Dec 2014Dopaminergic (DA) neurons in the ventral mesodiencephalon control locomotion and emotion and are affected in psychiatric and neurodegenerative diseases, such as... (Review)
Review
Dopaminergic (DA) neurons in the ventral mesodiencephalon control locomotion and emotion and are affected in psychiatric and neurodegenerative diseases, such as Parkinson's disease (PD). A clinical hallmark of PD is the specific degeneration of DA neurons located within the substantia nigra (SNc), whereas neurons in the ventral tegmental area remain unaffected. Recent advances have highlighted that the selective vulnerability of the SNc may originate in subset-specific molecular programming during DA neuron development, and significantly increased our understanding of the molecular code that drives specific SNc development. We here present an up-to-date overview of molecular mechanisms that direct DA subset specification, integrating our current knowledge about subset-specific roles of transcription factors, signaling pathways and morphogenes. We discuss strategies to further unravel subset-specific gene-regulatory networks, and the clinical promise of fundamental knowledge about subset specification of DA neurons, with regards to cell replacement therapy and cell-type-specific vulnerability in PD.
Topics: Animals; Dopaminergic Neurons; Gene Expression; Gene Regulatory Networks; Humans; Mesencephalon; Models, Genetic; Models, Neurological; Signal Transduction; Transcription Factors
PubMed: 25064061
DOI: 10.1007/s00018-014-1681-5 -
Trends in Neurosciences Nov 2018Selective attention is central to cognition. Dramatic advances have been made in understanding the neural circuits that mediate selective attention. Forebrain networks,... (Review)
Review
Selective attention is central to cognition. Dramatic advances have been made in understanding the neural circuits that mediate selective attention. Forebrain networks, most elaborated in primates, control all forms of attention based on task demands and the physical salience of stimuli. These networks contain circuits that distribute top-down signals to sensory processing areas and enhance information processing in those areas. A midbrain network, most elaborated in birds, controls spatial attention. It contains circuits that continuously compute the highest priority stimulus location and route sensory information from the selected location to forebrain networks that make cognitive decisions. The identification of these circuits, their functions and mechanisms represent a major advance in our understanding of how the vertebrate brain mediates selective attention.
Topics: Animals; Attention; Brain; Cognition; Decision Making; Humans; Mesencephalon; Visual Perception
PubMed: 30075867
DOI: 10.1016/j.tins.2018.06.006 -
Cell Reports. Medicine Feb 2023Roussel et al. provide new insight into mecencephalic locomotor region (MLR) stimulation to treat spinal cord injury in mice. Previously, it was unclear which part of...
Roussel et al. provide new insight into mecencephalic locomotor region (MLR) stimulation to treat spinal cord injury in mice. Previously, it was unclear which part of the MLR to target. Now, evidence converges on cuneiform nucleus activation.
Topics: Mice; Animals; Locomotion; Mesencephalon
PubMed: 36812884
DOI: 10.1016/j.xcrm.2023.100948 -
The Journal of Neuroscience : the... Dec 2022Motivation is a powerful driver of learning and memory. Functional MRI studies show that interactions among the dopaminergic midbrain substantia nigra/ventral tegmental... (Randomized Controlled Trial)
Randomized Controlled Trial
Motivation is a powerful driver of learning and memory. Functional MRI studies show that interactions among the dopaminergic midbrain substantia nigra/ventral tegmental area (SN/VTA), hippocampus, and nucleus accumbens (NAc) are critical for motivated memory encoding. However, it is not known whether these effects are transient and purely functional, or whether individual differences in the structure of this circuit underlie motivated memory encoding. To quantify individual differences in structure, diffusion-weighted MRI and probabilistic tractography were used to quantify SN/VTA-striatum and SN/VTA-hippocampus pathways associated with motivated memory encoding in humans. Male and female participants completed a motivated source memory paradigm. During encoding, words were randomly assigned to one of three conditions, reward ($1.00), control ($0.00), or punishment (-$1.00). During retrieval, participants were asked to retrieve item and source information of the previously studied words and were rewarded or penalized according to their performance. Source memory for words assigned to both reward and punishment conditions was greater than those for control words, but there were no differences in item memory based on value. Anatomically, probabilistic tractography results revealed a heterogeneous, topological arrangement of the SN/VTA. Tract density measures of SN/VTA-hippocampus pathways were positively correlated with individual differences in reward-and-punishment-modulated memory performance, whereas density of SN/VTA-striatum pathways showed no association. This novel finding suggests that pathways emerging from the human SV/VTA are anatomically separable and functionally heterogeneous. Individual differences in structural connectivity of the dopaminergic hippocampus-VTA loop are selectively associated with motivated memory encoding. Functional MRI studies show that interactions among the SN/VTA, hippocampus, and NAc are critical for motivated memory encoding. This has led to competing theories that posit either SN/VTA-NAc reward prediction errors or SN/VTA-hippocampus signals underlie motivated memory encoding. Additionally, it is not known whether these effects are transient and purely functional or whether individual differences in the structure of these circuits underlie motivated memory encoding. Using diffusion-weighted MRI and probabilistic tractography, we show that tract density measures of SN/VTA-hippocampus pathways are positively correlated with motivated memory performance, whereas density of SN/VTA-striatum pathways show no association. This finding suggests that anatomic individual differences of the dopaminergic hippocampus-VTA loop are selectively associated with motivated memory encoding.
Topics: Female; Humans; Male; Dopamine; Hippocampus; Magnetic Resonance Imaging; Mesencephalon; Reward; Substantia Nigra; Ventral Tegmental Area
PubMed: 36332978
DOI: 10.1523/JNEUROSCI.0945-22.2022