-
Neuron Oct 2022The use of body-focused repetitive behaviors (BFRBs) is conceptualized as a means of coping with stress. However, the neurological mechanism by which repetitive...
The use of body-focused repetitive behaviors (BFRBs) is conceptualized as a means of coping with stress. However, the neurological mechanism by which repetitive behaviors affect anxiety regulation is unclear. Here, we identify that the excitatory somatostatin-positive neurons in the medial paralemniscal nucleus (MPL neurons) in mice promote self-grooming and encode reward. MPL neurons display prominent grooming-related neuronal activity. Loss of function of MPL neurons impairs both self-grooming and post-stress anxiety alleviation. Activation of MPL neurons is rewarding and sufficient to drive reinforcement by activating dopamine (DA) neurons in the ventral tegmental area (VTA) and eliciting dopamine release. The neuropeptide SST facilitates the rewarding impact of MPL neurons. MPL neuron-mediated self-grooming is triggered by the input from the central amygdala (CeA). Our study reveals a dual role of CeA-MPL-VTA circuit in self-grooming and post-stress anxiety regulation and conceptualizes MPL neurons as an interface linking the stress and reward systems in mice.
Topics: Animals; Mice; Grooming; Dopamine; Reward; Ventral Tegmental Area; Dopaminergic Neurons; Pontine Tegmentum; Somatostatin
PubMed: 36070748
DOI: 10.1016/j.neuron.2022.08.010 -
Proceedings of the National Academy of... Nov 2022The neurobiological understanding of obsessive-compulsive disorder (OCD) includes dysregulated frontostriatal circuitry and altered monoamine transmission. Repetitive...
The neurobiological understanding of obsessive-compulsive disorder (OCD) includes dysregulated frontostriatal circuitry and altered monoamine transmission. Repetitive stereotyped behavior (e.g., grooming), a featured symptom in OCD, has been proposed to be associated with perturbed dopamine (DA) signaling. However, the precise brain circuits participating in DA's control over this behavioral phenotype remain elusive. Here, we identified that DA neurons in substantia nigra pars compacta (SNc) orchestrate ventromedial striatum (VMS) microcircuits as well as lateral orbitofrontal cortex (lOFC) during self-grooming behavior. SNc-VMS and SNc-lOFC dopaminergic projections modulate grooming behaviors and striatal microcircuit function differentially. Specifically, the activity of the SNc-VMS pathway promotes grooming via D1 receptors, whereas the activity of the SNc-lOFC pathway suppresses grooming via D2 receptors. SNc DA neuron activity thus controls the OCD-like behaviors via both striatal and cortical projections as dual gating. These results support both pharmacological and brain-stimulation treatments for OCD.
Topics: Animals; Dopaminergic Neurons; Corpus Striatum; Dopamine; Obsessive-Compulsive Disorder; Mesencephalon; Substantia Nigra
PubMed: 36343236
DOI: 10.1073/pnas.2207545119 -
Neurobiology of Disease Aug 2023Parkinson's disease (PD) is currently the fastest growing disabling neurological disorder worldwide, with motor and non-motor symptoms being its main clinical... (Review)
Review
Parkinson's disease (PD) is currently the fastest growing disabling neurological disorder worldwide, with motor and non-motor symptoms being its main clinical manifestations. The primary pathological features include a reduction in the number of dopaminergic neurons in the substantia nigra and decrease in dopamine levels in the nigrostriatal pathway. Existing treatments only alleviate clinical symptoms and do not stop disease progression; slowing down the loss of dopaminergic neurons and stimulating their regeneration are emerging therapies. Preclinical studies have demonstrated that transplantation of dopamine cells generated from human embryonic or induced pluripotent stem cells can restore the loss of dopamine. However, the application of cell transplantation is limited owing to ethical controversies and the restricted source of cells. Until recently, the reprogramming of astrocytes to replenish lost dopaminergic neurons has provided a promising alternative therapy for PD. In addition, repair of mitochondrial perturbations, clearance of damaged mitochondria in astrocytes, and control of astrocyte inflammation may be extensively neuroprotective and beneficial against chronic neuroinflammation in PD. Therefore, this review primarily focuses on the progress and remaining issues in astrocyte reprogramming using transcription factors (TFs) and miRNAs, as well as exploring possible new targets for treating PD by repairing astrocytic mitochondria and reducing astrocytic inflammation.
Topics: Humans; Astrocytes; Dopamine; Parkinson Disease; Dopaminergic Neurons; Inflammation
PubMed: 37433411
DOI: 10.1016/j.nbd.2023.106224 -
Neurosciences (Riyadh, Saudi Arabia) Jan 2023Parkinson's disease (PD) is a progressive widespread neurodegenerative disorder affecting the brain. It is characterized by dopaminergic neuron degeneration in the... (Review)
Review
Parkinson's disease (PD) is a progressive widespread neurodegenerative disorder affecting the brain. It is characterized by dopaminergic neuron degeneration in the substantia nigra pars compacta (SNpc). Current therapeutic options ease the symptoms of PD; however, they have multiple undesirable effects and do not slow the disease progression. Exercise by itself has many positive impacts on general health. In this review, the positive impact of different forms of exercise were found to improve motor and non-motor symptoms in PD. Exercise effects is mediate by multiple mechanisms, including the upregulation of brain-derived neurotrophic factor, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, and autophagy regulating proteins; and downregulates proinflammatory cytokines. In this review, the significance of exercise in PD, as well as in the prevention and maintenance of the disease was discussed. Many questions are left unanswered in this manuscript, including potential genetic factors underlying response to exercise. Therefore, further high-quality studies on humans are needed.
Topics: Humans; Animals; Parkinson Disease; Dopamine; Exercise; Dopaminergic Neurons; Disease Models, Animal
PubMed: 36617448
DOI: 10.17712/nsj.2023.1.20220105 -
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 -
Nature Nov 2023Resource-seeking behaviours are ordinarily constrained by physiological needs and threats of danger, and the loss of these controls is associated with pathological...
Resource-seeking behaviours are ordinarily constrained by physiological needs and threats of danger, and the loss of these controls is associated with pathological reward seeking. Although dysfunction of the dopaminergic valuation system of the brain is known to contribute towards unconstrained reward seeking, the underlying reasons for this behaviour are unclear. Here we describe dopaminergic neural mechanisms that produce reward seeking despite adverse consequences in Drosophila melanogaster. Odours paired with optogenetic activation of a defined subset of reward-encoding dopaminergic neurons become cues that starved flies seek while neglecting food and enduring electric shock punishment. Unconstrained seeking of reward is not observed after learning with sugar or synthetic engagement of other dopaminergic neuron populations. Antagonism between reward-encoding and punishment-encoding dopaminergic neurons accounts for the perseverance of reward seeking despite punishment, whereas synthetic engagement of the reward-encoding dopaminergic neurons also impairs the ordinary need-dependent dopaminergic valuation of available food. Connectome analyses reveal that the population of reward-encoding dopaminergic neurons receives highly heterogeneous input, consistent with parallel representation of diverse rewards, and recordings demonstrate state-specific gating and satiety-related signals. We propose that a similar dopaminergic valuation system dysfunction is likely to contribute to maladaptive seeking of rewards by mammals.
Topics: Animals; Dopamine; Dopaminergic Neurons; Drosophila melanogaster; Electroshock; Learning; Odorants; Optogenetics; Punishment; Reward; Starvation; Models, Animal
PubMed: 37880370
DOI: 10.1038/s41586-023-06671-8 -
Aging Cell Oct 2023Parkinson's disease (PD) is a neurodegenerative disorder associated with α-synuclein aggregation and dopaminergic neuron loss in the midbrain. There is evidence that...
Parkinson's disease (PD) is a neurodegenerative disorder associated with α-synuclein aggregation and dopaminergic neuron loss in the midbrain. There is evidence that psychological stress promotes PD progression by enhancing glucocorticoids-related oxidative damage, however, the mechanisms involved are unknown. The present study demonstrated that plasma membrane phospholipid peroxides, as determined by phospholipidomics, triggered ferroptosis in dopaminergic neurons, which in turn contributed to stress exacerbated PD-like motor disorder in mice overexpressing mutant human α-synuclein. Using hormonomics, we identified that stress stimulated corticosteroid release and promoted 15-lipoxygenase-1 (ALOX15)-mediated phospholipid peroxidation. ALOX15 was upregulated by α-synuclein overexpression and acted as a fundamental risk factor in the development of chronic stress-induced parkinsonism and neurodegeneration. Further, we demonstrated the mechanism by which corticosteroids activated the PKC pathway and induced phosphatidylethanolamine-binding protein-1 (PEBP1) to form a complex with ALOX15, thereby facilitating ALOX15 to locate on the plasma membrane phospholipids. A natural product isolated from herbs, leonurine, was screened with activities of inhibiting the ALOX15/PEBP1 interaction and thereby attenuating membrane phospholipid peroxidation. Collectively, our findings demonstrate that stress increases the susceptibility of PD by driving membrane lipid peroxidation of dopaminergic neurons and suggest the ALOX15/PEBP1 complex as a potential intervention target.
Topics: Mice; Humans; Animals; Parkinson Disease; alpha-Synuclein; Dopaminergic Neurons; Disease Susceptibility; Stress, Psychological
PubMed: 37622525
DOI: 10.1111/acel.13970 -
Nature Biomedical Engineering Apr 2023Cell therapies as potential treatments for Parkinson's disease first gained traction in the 1980s, owing to the clinical success of trials that used transplants of... (Review)
Review
Cell therapies as potential treatments for Parkinson's disease first gained traction in the 1980s, owing to the clinical success of trials that used transplants of foetal midbrain dopaminergic tissue. However, the poor standardization of the tissue for grafting, and constraints on its availability and ethical use, have hindered this treatment strategy. Recent advances in stem-cell technologies and in the understanding of the development of dopaminergic neurons have enabled preclinical advancements of promising stem-cell therapies. To move these therapies to the clinic, appropriate levels of safety screening, as well as optimization of the cell products and the scalability of their manufacturing, will be required. In this Review, we discuss how challenges pertaining to cell sources, functional and safety testing, manufacturing and storage, and clinical-trial design are being addressed to advance the translational and clinical development of cell therapies for Parkinson's disease.
Topics: Humans; Parkinson Disease; Stem Cell Transplantation; Cell- and Tissue-Based Therapy; Dopaminergic Neurons
PubMed: 36635420
DOI: 10.1038/s41551-022-00987-y -
The Journal of Neuroscience : the... Nov 2023In the brain, microRNAs (miRNAs) are believed to play a role in orchestrating synaptic plasticity at a higher level by acting as an additional mechanism of translational...
In the brain, microRNAs (miRNAs) are believed to play a role in orchestrating synaptic plasticity at a higher level by acting as an additional mechanism of translational regulation, alongside the mRNA/polysome system. Despite extensive research, our understanding of the specific contribution of individual miRNA to the function of dopaminergic neurons (DAn) remains limited. By performing a dopaminergic-specific miRNA screening, we have identified miR-218 as a critical regulator of DAn activity in male and female mice. We have found that miR-218 is specifically expressed in mesencephalic DAn and is able to promote dopaminergic differentiation of embryonic stem cells and functional maturation of transdifferentiated induced DA neurons. Midbrain-specific deletion of both genes encoding for miR-218 (referred to as miR-218-1 and mir218-2) affects the expression of a cluster of synaptic-related mRNAs and alters the intrinsic excitability of DAn, as it increases instantaneous frequencies of evoked action potentials, reduces rheobase current, affects the ionic current underlying the action potential after hyperpolarization phase, and reduces dopamine efflux in response to a single electrical stimulus. Our findings provide a comprehensive understanding of the involvement of miR-218 in the dopaminergic system and highlight its role as a modulator of dopaminergic transmission. In the past decade, several miRNAs have emerged as potential regulators of synapse activity through the modulation of specific gene expression. Among these, we have identified a dopaminergic-specific miRNA, miR-218, which is able to promote dopaminergic differentiation and regulates the translation of an entire cluster of synapse related mRNAs. Deletion of miR-218 has notable effects on dopamine release and alters the intrinsic excitability of dopaminergic neurons, indicating a direct control of dopaminergic activity by miR-218.
Topics: Mice; Male; Female; Animals; Dopamine; Cell Differentiation; Dopaminergic Neurons; MicroRNAs; Neurotransmitter Agents
PubMed: 37816598
DOI: 10.1523/JNEUROSCI.0431-23.2023 -
International Journal of Molecular... Dec 2023Parkinson's disease (PD) is a complex neurodegenerative disease characterized by the progressive loss of dopaminergic neurons in the substantia nigra and the widespread... (Review)
Review
Parkinson's disease (PD) is a complex neurodegenerative disease characterized by the progressive loss of dopaminergic neurons in the substantia nigra and the widespread accumulation of alpha-synuclein (αSyn) protein aggregates. αSyn aggregation disrupts critical cellular processes, including synaptic function, mitochondrial integrity, and proteostasis, which culminate in neuronal cell death. Importantly, αSyn pathology extends beyond neurons-it also encompasses spreading throughout the neuronal environment and internalization by microglia and astrocytes. Once internalized, glia can act as neuroprotective scavengers, which limit the spread of αSyn. However, they can also become reactive, thereby contributing to neuroinflammation and the progression of PD. Recent advances in αSyn research have enabled the molecular diagnosis of PD and accelerated the development of targeted therapies. Nevertheless, despite more than two decades of research, the cellular function, aggregation mechanisms, and induction of cellular damage by αSyn remain incompletely understood. Unraveling the interplay between αSyn, neurons, and glia may provide insights into disease initiation and progression, which may bring us closer to exploring new effective therapeutic strategies. Herein, we provide an overview of recent studies emphasizing the multifaceted nature of αSyn and its impact on both neuron and glial cell damage.
Topics: alpha-Synuclein; Dopaminergic Neurons; Neurodegenerative Diseases; Neuroglia; Parkinson Disease
PubMed: 38203531
DOI: 10.3390/ijms25010360