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Molecular Neurobiology Jul 2017Bisphenol A (BPA) is a ubiquitous compound emerging as a possible toxicant during embryonic development. Human embryonic stem cell (hESC) promises a valuable model for...
Bisphenol A (BPA) is a ubiquitous compound emerging as a possible toxicant during embryonic development. Human embryonic stem cell (hESC) promises a valuable model for evaluating the effects of environmental chemicals on human prenatal development. In our study, 1 μM BPA were applied to hESC-derived embryoid bodies (hEBs) and effects of BPA on neural cell differentiation were investigated. The expression level of insulin-like growth factor 1 (IGF-1) and marker genes for ectoderm, neuron progenitor cells, and dopaminergic (DA) neurons were all repressed upon BPA exposure. The population of hESC-derived neural precursor cells (NPCs) and DA neurons were decreased. Furthermore, yield of DA neuron-secreted tyrosine hydroxylase (TH) and dopamine were also reduced. When recombinant IGF-1 supplied, BPA-caused repressions were partially or completely relieved. Our further methylation microarray analysis indicated that there was a higher methylation level on the promoter of SRY-related HMG-box 5 (SOX5), a possible enhancer of IGF-1. Consistently, next quantitative polymerase chain reaction (qPCR) results confirmed that SOX5 expression was downregulated. Our investigation suggests that BPA represses DA neuron differentiation mainly through downregulating IGF-1 expression, which may attribute to the altered methylation level on the promoter of IGF-1 upstream genes. Our findings first elaborate the mechanism of IGF-1-mediated BPA effects on neuronal differentiation, which is helpful to illuminate the unique mechanism of BPA toxicity on prenatal neurodevelopment.
Topics: Benzhydryl Compounds; Cell Differentiation; Cells, Cultured; DNA Methylation; Dopaminergic Neurons; Down-Regulation; Ectoderm; Epigenesis, Genetic; Human Embryonic Stem Cells; Humans; Insulin-Like Growth Factor I; Models, Biological; Neurotransmitter Agents; Phenols; SOXD Transcription Factors
PubMed: 27271280
DOI: 10.1007/s12035-016-9898-y -
Neuropsychopharmacology : Official... Mar 2015Cocaine reinforcement is mediated by increased extracellular dopamine levels in the forebrain. This neurochemical effect was thought to require inhibition of dopamine...
Cocaine reinforcement is mediated by increased extracellular dopamine levels in the forebrain. This neurochemical effect was thought to require inhibition of dopamine reuptake, but cocaine is still reinforcing even in the absence of the dopamine transporter. Here, we demonstrate that the rapid elevation in dopamine levels and motor activity elicited by cocaine involves α1 receptor activation within the ventral midbrain. Activation of α1 receptors increases dopaminergic neuron burst firing by decreasing the calcium-activated potassium channel current (SK), as well as elevates dopaminergic neuron pacemaker firing through modulation of both SK and the hyperpolarization-activated cation currents (Ih). Furthermore, we found that cocaine increases both the pacemaker and burst-firing frequency of rat ventral-midbrain dopaminergic neurons through an α1 adrenergic receptor-dependent mechanism within the ventral tegmental area and substantia nigra pars compacta. These results demonstrate the mechanism underlying the critical role of α1 adrenergic receptors in the regulation of dopamine neurotransmission and behavior by cocaine.
Topics: Action Potentials; Animals; Cocaine; Dopamine Uptake Inhibitors; Dopaminergic Neurons; Female; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Male; Microelectrodes; Motor Activity; Pars Compacta; Patch-Clamp Techniques; Potassium Channels, Calcium-Activated; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha-1; Tissue Culture Techniques; Ventral Tegmental Area
PubMed: 25374094
DOI: 10.1038/npp.2014.296 -
Molecular Neurobiology May 2024Microglia-mediated neuroinflammation plays a crucial role in the pathogenesis of Parkinson's disease (PD). Triggering receptor expressed on myeloid cells 2 (TREM2)...
Microglia-mediated neuroinflammation plays a crucial role in the pathogenesis of Parkinson's disease (PD). Triggering receptor expressed on myeloid cells 2 (TREM2) confers strong neuroprotective effects in PD by regulating the phenotype of microglia. Recent studies suggest that TREM2 regulates high glucose-induced microglial inflammation through the NLRP3 signaling pathway. This study aimed to investigate the effect of TREM2 on NLRP3 inflammasome activation and neuroinflammation in PD. Mice were injected with AAV-TREM2-shRNA into both sides of the substantia nigra using a stereotactic injection method, followed by intraperitoneal injection of MPTP to establish chronic PD mouse model. Behavioral assessments including the pole test and rotarod test were conducted to evaluate the effects of TREM2 deficiency on MPTP-induced motor dysfunction. Immunohistochemistry of TREM2 and tyrosine hydroxylase (TH), immunohistochemistry and immunofluorescence Iba1, Western blot of NLRP3 inflammasome and its downstream inflammatory factors IL-1β and IL-18, and the key pyroptosis factors GSDMD and GSDMD-N were performed to explore the effect of TREM2 on NLRP3 inflammasome and neuroinflammation. In an in vitro experiment, lentivirus was used to interfere with the expression of TREM2 in BV2 microglia, and then lipopolysaccharide (LPS) and adenopterin nucleoside triphosphate (ATP) were used to stimulate inflammation to construct a cellular inflammation model. The expression differences of NLRP3 inflammasome and its components were detected by qPCR and Western blot. In vivo, TREM2 knockdown aggravated the loss of dopaminergic neuron and the decline of motor function. After TREM2 knockdown, the number of activated microglia was significantly increased, and the expression of cleaved caspase-1, NLRP3 inflammasome, IL-1β, GSDMD, and GSDMD-N was increased. In vitro, TREM2 knockdown aggravated the inflammatory response of BV2 cells stimulated by LPS and promoted the activation of NLRP3 inflammasome through the NF-κB pathway. In addition, TREM2 knockdown also promoted the expression of TLR4/MyD88, an upstream factor of the NF-κB pathway. Our vivo and vitro data showed that TREM2 knockdown promoted NLRP3 inflammasome activation and downstream inflammatory response, promoted pyroptosis, and aggravated dopaminergic neuron loss. TREM2 acts as an anti-inflammatory in PD through the TLR4/MyD88/NF-κB pathway, which extends previous findings and supports the notion that TREM2 ameliorates neuroinflammation in PD.
Topics: Animals; Male; Mice; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Cell Line; Dopaminergic Neurons; Inflammasomes; Lipopolysaccharides; Membrane Glycoproteins; Mice, Inbred C57BL; Microglia; NLR Family, Pyrin Domain-Containing 3 Protein; Parkinson Disease; Pyroptosis; Receptors, Immunologic; Signal Transduction
PubMed: 37917301
DOI: 10.1007/s12035-023-03713-0 -
Biological Psychiatry Jan 2017Brain imaging has revealed alterations in dopamine uptake, release, and receptor levels in patients with schizophrenia that have been resolved on the scale of striatal... (Review)
Review
Brain imaging has revealed alterations in dopamine uptake, release, and receptor levels in patients with schizophrenia that have been resolved on the scale of striatal subregions. However, the underlying synaptic mechanisms are on a finer scale. Dopamine neuron synaptic actions vary across the striatum, involving variations not only in dopamine release but also in dopamine neuron connectivity, cotransmission, modulation, and activity. Optogenetic studies have revealed that dopamine neurons release dopamine in a synaptic signal mode, and that the neurons also release glutamate and gamma-aminobutyric acid as cotransmitters, with striking regional variation. Fast glutamate and gamma-aminobutyric acid cotransmission convey discrete patterns of dopamine neuron activity to striatal neurons. Glutamate may function not only in a signaling role at a subset of dopamine neuron synapses, but also in mediating vesicular synergy, contributing to regional differences in loading of dopamine into synaptic vesicles. Regional differences in dopamine neuron signaling are likely to be differentially involved in the schizophrenia disease process and likely determine the subregional specificity of the action of psychostimulants that exacerbate the disorder, and antipsychotics that ameliorate the disorder. Elucidating dopamine neuron synaptic signaling offers the potential for achieving greater pharmacological specificity through intersectional pharmacological actions targeting subsets of dopamine neuron synapses.
Topics: Animals; Corpus Striatum; Dopamine; Dopaminergic Neurons; GABAergic Neurons; Glutamic Acid; Humans; Mice; Psychotropic Drugs; Receptors, Dopamine; Schizophrenia; Synapses; Synaptic Transmission
PubMed: 27692238
DOI: 10.1016/j.biopsych.2016.07.002 -
Neurochemistry International Oct 2019Dopamine (DA) neuron projections to the striatum are functionally heterogeneous with diverse behavioral roles. We focus here on DA neuron projections to the nucleus... (Review)
Review
Dopamine (DA) neuron projections to the striatum are functionally heterogeneous with diverse behavioral roles. We focus here on DA neuron projections to the nucleus accumbens (NAc) medial Shell, their distinct anatomical and functional connections, and discuss their role in motivated behavior. We first review rodent studies showing that a subpopulation of DA neurons in the medial ventral tegmental area (VTA) project to the NAc medial Shell. Using a combinatorial strategy, we show that the majority of DA neurons projecting to the NAc Shell express vesicular glutamate transporter 2 (VGLUT2) making them capable of glutamate co-transmission (DA-GLU neurons). In the NAc dorsal medial Shell, all of the DA neuron terminals arise from DA-GLU neurons, while in the lateral NAc Shell, DA neuron terminals arise from both DA-GLU neurons and DA-only neurons, without VGLUT2. DA-GLU neurons make excitatory connections to the three major cells types, spiny projection neurons, fast-spiking interneuron and cholinergic interneurons (ChIs). The strongest DA-GLU neuron excitatory connections are to ChIs. Photostimulation of DA-GLU neuron terminals in the slice drives ChIs to burst fire. Finally, we review studies that address specially the behavioral function of this subpopulation of DA neurons in extinction learning and latent inhibition. Taking into account findings from anatomical and functional connectome studies, we propose that DA-GLU neuron connections to ChIs in the medial Shell play a crucial role in switching behavioral responses under circumstances of altered cue-reinforcer contingencies.
Topics: Action Potentials; Animals; Brain Mapping; Cholinergic Neurons; Connectome; Cues; Dopaminergic Neurons; Extinction, Psychological; Fear; Glutamic Acid; Humans; Interneurons; Mice; Nerve Endings; Nerve Tissue Proteins; Neural Pathways; Nucleus Accumbens; Reinforcement, Psychology; Ventral Tegmental Area; Vesicular Glutamate Transport Protein 2
PubMed: 31170424
DOI: 10.1016/j.neuint.2019.104482 -
Neurotoxicity Research Apr 2016Parkinson's disease (PD) is characterized by progressive degeneration of dopaminergic neurons accompanied by an inflammatory reaction. The neuron-derived chemokine...
Parkinson's disease (PD) is characterized by progressive degeneration of dopaminergic neurons accompanied by an inflammatory reaction. The neuron-derived chemokine fractalkine (CX3CL1) is an exclusive ligand for the receptor CX3CR1 expressed on microglia. The CX3CL1/CX3CR1 signaling is important for sustaining microglial activity. Using a recently developed PD model, in which the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxin is delivered intranasally, we hypothesized that CX3CR1 could play a role in neurotoxicity and glial activation. For this, we used CX3CR1 knock-in mice and compared results with those obtained using the classical PD models through intraperitonal MPTP or intrastriatal 6-hydroxydopamine (6-OHDA). The striatum from all genotypes (CX3CR1(+/+), CX3CR1(+/GFP) and CX3CR1-deficient mice) showed a significant dopaminergic depletion after intranasal MPTP inoculation. In contrast to that, we could not see differences in the number of dopaminergic neurons in the substantia nigra of CX3CR1-deficient animals. Similarly, after 6-OHDA infusion, the CX3CR1 deletion decreased the amphetamine-induced turning behavior observed in CX3CR1(+/GFP) mice. After the 6-OHDA inoculation, a minor dopaminergic neuronal loss was observed in the substantia nigra from CX3CR1-deficient mice. Distinctly, a more extensive neuronal cell loss was observed in the substantia nigra after the intraperitoneal MPTP injection in CX3CR1 disrupted animals, corroborating previous results. Intranasal and intraperitoneal MPTP inoculation induced a similar microgliosis in CX3CR1-deficient mice but a dissimilar change in the astrocyte proliferation in the substantia nigra. Nigral astrocyte proliferation was observed only after intraperitoneal MPTP inoculation. In conclusion, intranasal MPTP and 6-OHDA lesion in CX3CR1-deficient mice yield no nigral dopaminergic neuron loss, linked to the absence of astroglial proliferation.
Topics: Administration, Intranasal; Animals; Astrocytes; CX3C Chemokine Receptor 1; Corpus Striatum; Dopamine; Dopaminergic Neurons; Encephalitis; Gliosis; Injections, Intraperitoneal; Mice; Mice, Transgenic; Microglia; Oxidopamine; Parkinsonian Disorders; Receptors, Chemokine; Substantia Nigra
PubMed: 26403659
DOI: 10.1007/s12640-015-9557-5 -
Journal of Neural Transmission (Vienna,... Jun 2022The neurotoxin 6-hydroxydopamine (6-OHDA), following pretreatment with the norepinephrine transport inhibitor desipramine, selectively destroys dopaminergic neurons.... (Review)
Review
The neurotoxin 6-hydroxydopamine (6-OHDA), following pretreatment with the norepinephrine transport inhibitor desipramine, selectively destroys dopaminergic neurons. When given to rats, neonatal 6-OHDA (n6-OHDA) crosses the blood-brain barrier to destroy 90-99% of dopaminergic nerves in pars compacta substantia nigra (SNpc). The n6-OHDA-lesioned rat is posed as a reasonable animal model for PD: (a) the magnitude of dopaminergic neuronal destruction is expansive, (b) mapping of dopaminergic denervation has been defined, (c) effects on dopamine (DA) receptor alterations have been elucidated (d) as well as changes in receptor sensitivity status, (e) reactive sprouting of serotoninergic innervation (i.e. hyperinnervation) has been mapped, and (f) interplay between serotoninergic and dopaminergic systems is characterized. (g) A broad range of locomotor and stereotyped behaviors has been assessed and (h) large numbers of neurochemical assessments have been attained. (i) n6-OHDA-lesioned rats survive 6-OHDA lesioning and (j) the rat is behaviorally indistinguishable from controls. Dopaminergic destruction in early ontogeny rather in adulthood is a 'treatment liability' of this model, yet other animal models have liability issues of a serious nature-the initial one being use of a neurotoxin to produce the animal model of PD. The n6-OHDA-lesioned rat is proposed as a PD model for its value in associating the SNpc dopaminergic lesion with behavioral outcomes, also for replicability of dopaminergic destruction, and the accompanying neuronal adaptations and interplay between neuronal phenotypes in brain-which provide a means to better define and understand the range of deficits and neuronal adaptations that are likely to occur in human PD.
Topics: Animals; Disease Models, Animal; Dopamine; Dopaminergic Neurons; Neurotoxins; Oxidopamine; Parkinson Disease; Rats; Substantia Nigra
PubMed: 35279767
DOI: 10.1007/s00702-022-02479-4 -
Ecotoxicology and Environmental Safety Apr 2023Dithianon is a conventional broad-spectrum protectant fungicide widely used in agriculture, but its potential neurotoxic risk to animals remains largely unknown. In this...
Dithianon is a conventional broad-spectrum protectant fungicide widely used in agriculture, but its potential neurotoxic risk to animals remains largely unknown. In this study, neurotoxic effects of Dithianon and its underlying cellular and molecular mechanisms were investigated using the nematode, Caenorhabditis elegans, as a model system. Upon chronic exposure of C. elegans to Dithianon, dopaminergic neurons were found to be vulnerable, with significant degeneration in terms of structure and function in a concentration-dependent manner. In examining toxicity mechanisms, we observed significant Dithianon-induced increases in oxidative stress and mitochondrial fragmentation, both of which are often associated with cellular stress. The present study suggests that Dithianon exposure causes dopaminergic neurotoxicity in C. elegans, by inducing oxidative stress and mitochondrial dysfunction. These findings contribute to a better understanding of Dithianon's neurotoxic potential.
Topics: Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Oxidative Stress; Dopaminergic Neurons
PubMed: 36924561
DOI: 10.1016/j.ecoenv.2023.114752 -
Experimental Neurology Aug 2019Dopaminergic neurons express mixed lineage kinases which regulate the expression of cell death genes. In Parkinson's disease, cell death via apoptosis is prevalent, and...
Dopaminergic neurons express mixed lineage kinases which regulate the expression of cell death genes. In Parkinson's disease, cell death via apoptosis is prevalent, and previous work testing mixed lineage kinase inhibitors in animal models suggested the inhibitors had some neuroprotective potential. CLFB-1134 is a new, brain-penetrant inhibitor specific for MLK3, tested here in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of dopaminergic depletion and nigral neuron death in mice. After ensuring that treatment with CLFB-1134 did not alter conversion of MPTP to MPP+, we demonstrated CLFB-1134's inhibition of MLK3 and neuroprotective efficacy. Specifically we evaluated the integrity of the nigrostriatal dopamine system following MPTP by assessing protein expression, high performance liquid chromatography, and immunohistology with stereology. We found that CLFB-1134 achieves protection of striatal dopaminergic terminals and nigral cell bodies when dosed simultaneously or following MPTP treatment. By preventing phosphorylation of JNK and other downstream targets of MLK3, CLFB-1134 protects against the neurotoxin MPTP. Inhibition of MLK3 may be a valid target for future work investigating treatment of Parkinson's disease.
Topics: Animals; Brain; Dopaminergic Neurons; Imidazoles; MAP Kinase Kinase Kinases; Male; Mice; Mice, Inbred C57BL; Nerve Degeneration; Neuroprotective Agents; Parkinsonian Disorders; Pyridazines; Rats; Rats, Sprague-Dawley; Mitogen-Activated Protein Kinase Kinase Kinase 11
PubMed: 31077715
DOI: 10.1016/j.expneurol.2019.05.002 -
Cell Reports Nov 2014Effective approaches to neuropsychiatric disorders require detailed understanding of the cellular composition and circuitry of the complex mammalian brain. Here, we...
Effective approaches to neuropsychiatric disorders require detailed understanding of the cellular composition and circuitry of the complex mammalian brain. Here, we present a paradigm for deconstructing the diversity of neurons defined by a specific neurotransmitter using a microfluidic dynamic array to simultaneously evaluate the expression of 96 genes in single neurons. With this approach, we successfully identified multiple molecularly distinct dopamine neuron subtypes and localized them in the adult mouse brain. To validate the anatomical and functional correlates of molecular diversity, we provide evidence that one Vip+ subtype, located in the periaqueductal region, has a discrete projection field within the extended amygdala. Another Aldh1a1+ subtype, located in the substantia nigra, is especially vulnerable in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease. Overall, this rapid, cost-effective approach enables the identification and classification of multiple dopamine neuron subtypes, with distinct molecular, anatomical, and functional properties.
Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Aging; Animals; Disease Models, Animal; Dopaminergic Neurons; Gene Expression Profiling; High-Throughput Screening Assays; Mesencephalon; Mice, Inbred C57BL; Parkinson Disease
PubMed: 25437550
DOI: 10.1016/j.celrep.2014.10.008