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Frontiers in Medicine 2024Parkinson's disease (PD) is a chronic neurodegenerative disease associated with a progressive loss of dopaminergic neurons, clinically characterized by motor and... (Review)
Review
Parkinson's disease (PD) is a chronic neurodegenerative disease associated with a progressive loss of dopaminergic neurons, clinically characterized by motor and non-motor signs. Frailty is a clinical condition of increased vulnerability and negative health outcomes due to the loss of multiple physiological reserves. Chronic hyperglycemia and insulin resistance, which characterize diabetes mellitus (DM), have been reported to alter dopaminergic activity, increase the risk of PD, and influence the development of frailty. Even though diabetes may facilitate the development of frailty in patients with PD, this relationship is not established and a revision of the current knowledge is necessary. Furthermore, the synergy between DM, PD, and frailty may drive clinical complexity, worse outcomes, and under-representation of these populations in the research. In this review, we aimed to discuss the role of diabetes in the development of frailty among patients with PD. We summarized the clinical characteristics and outcomes of patients with concomitant DM, PD, and frailty. Finally, interventions to prevent frailty in this population are discussed.
PubMed: 38882667
DOI: 10.3389/fmed.2024.1377975 -
Ecotoxicology and Environmental Safety Jun 2024Manganese (Mn) exposure is a common environmental risk factor for Parkinson's disease (PD), with pathogenic mechanisms associated with dopaminergic neuron damage and...
Small extracellular vesicles-derived from 3d cultured human nasal mucosal mesenchymal stem cells during differentiation to dopaminergic progenitors promote neural damage repair via miR-494-3p after manganese exposed mice.
Manganese (Mn) exposure is a common environmental risk factor for Parkinson's disease (PD), with pathogenic mechanisms associated with dopaminergic neuron damage and neuroinflammation. Mesenchymal stem cells (MSCs)-derived small extracellular vesicles (sEVs) have emerged as a novel therapeutic approach for neural damage repair. The functional sEVs released from MSCs when they are induced into dopaminergic progenitors may have a better repair effect on neural injury. Therefore, we collected sEVs obtained from primary human nasal mucosal mesenchymal stem cells (hnmMSC-sEVs) or cells in the process of dopaminergic progenitor cell differentiation (da-hnmMSC-sEVs), which were cultured in a 3D dynamic system, and observed their repair effects and mechanisms of Mn-induced neural damage by intranasal administration of sEVs. In Mn-exposed mice, sEVs could reach the site of brain injury after intranasal administration, da-hnmMSC enhanced the repair effects of sEVs in neural damage and behavioral competence, as evidenced by restoration of motor dysfunction, enhanced neurogenesis, decreased microglia activation, up-regulation of anti-inflammatory factors, and down-regulation of pro-inflammatory factors. The transcriptomics of hnmMSC-sEVs and da-hnmMSC-sEVs revealed that miRNAs, especially miR-494-3p in sEVs were involved in neuroprotective and anti-inflammatory effects. Overexpression of miR-494-3p in sEVs inhibited Mn-induced inflammation and neural injury, and its repair mechanism might be related to the down-regulation of CMPK2 and NLRP3 in vitro experiments. Thus, intranasal delivery of da-hnmMSC-sEVs is an effective strategy for the treatment of neural injury repair.
PubMed: 38878331
DOI: 10.1016/j.ecoenv.2024.116569 -
Learning & Memory (Cold Spring Harbor,... May 2024The brain constantly compares past and present experiences to predict the future, thereby enabling instantaneous and future behavioral adjustments. Integration of... (Review)
Review
The brain constantly compares past and present experiences to predict the future, thereby enabling instantaneous and future behavioral adjustments. Integration of external information with the animal's current internal needs and behavioral state represents a key challenge of the nervous system. Recent advancements in dissecting the function of the mushroom body (MB) at the single-cell level have uncovered its three-layered logic and parallel systems conveying positive and negative values during associative learning. This review explores a lesser-known role of the MB in detecting and integrating body states such as hunger, thirst, and sleep, ultimately modulating motivation and sensory-driven decisions based on the physiological state of the fly. State-dependent signals predominantly affect the activity of modulatory MB input neurons (dopaminergic, serotoninergic, and octopaminergic), but also induce plastic changes directly at the level of the MB intrinsic and output neurons. Thus, the MB emerges as a tightly regulated relay station in the insect brain, orchestrating neuroadaptations due to current internal and behavioral states leading to short- but also long-lasting changes in behavior. While these adaptations are crucial to ensure fitness and survival, recent findings also underscore how circuit motifs in the MB may reflect fundamental design principles that contribute to maladaptive behaviors such as addiction or depression-like symptoms.
Topics: Animals; Mushroom Bodies; Behavior, Animal; Sleep; Hunger; Drosophila; Thirst; Neurons
PubMed: 38876486
DOI: 10.1101/lm.053918.124 -
IBRO Neuroscience Reports Dec 2024Parkinson's disease (PD) is a neurodegenerative disease characterized by death of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Death of... (Review)
Review
Parkinson's disease (PD) is a neurodegenerative disease characterized by death of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Death of dopaminergic cells in the SNpc leads to manifestations of motor dysfunction and non-motor symptoms of PD. The progression of PD symptoms severely affects the quality of life of patients and poses socio-economic problems to families and society at large. The clinical and neuropathological characteristics of PD are triggered by multiple factors such as oxidative stress, neuroinflammation, mitochondrial dysfunction, and protein aggregation. Notwithstanding the advancements in pharmacological therapy in PD management, there is burgeoning interest in alternative and complementary approaches, essentially nutrition and plant extracts strategies. This review gives widespread analysis of the role of nutrition and plant extracts in the management of PD. Studies that investigated the effects of various dietary compounds and plant extract on PD symptoms and progression were reviewed from existing literatures. Nutraceuticals, including vitamins and phytochemicals such as have shown potential neuroprotective functions in preclinical and clinical studies. Indeed, these strategies ameliorate mitochondrial dysfunction, oxidative stress, and neuroinflammation, all which are implicated in the pathogenesis of PD. The neuroprotective mechanisms of nutrition and plant extracts in PD, with emphasis on their capacity to target multiple pathways implicated in PD are discussed. Additionally, challenges and limitations related with translating preclinical findings into clinical practice including standardization of dosing regimens, bioavailability, and inter-individual variability are discussed. Largely, this review elucidates on the role of nutrition and plant extracts as adjunctive therapy in PD management.
PubMed: 38872839
DOI: 10.1016/j.ibneur.2024.05.011 -
ENeuro Jun 2024CRISPR/Cas9 gene editing represents an exciting avenue to study genes of unknown function, and can be combined with genetically-encoded tools such as fluorescent...
CRISPR/Cas9 gene editing represents an exciting avenue to study genes of unknown function, and can be combined with genetically-encoded tools such as fluorescent proteins, channelrhodopsins, DREADDs, and various biosensors to more deeply probe the function of these genes in different cell types. However, current strategies to also manipulate or visualize edited cells are challenging due to the large size of Cas9 proteins and the limited packaging capacity of adeno-associated viruses (AAVs). To overcome these constraints, we developed an alternative gene editing strategy using a single AAV vector and mouse lines that express Cre-dependent Cas9 to achieve efficient cell-type specific editing across the nervous system. Expressing Cre-dependent Cas9 from a genomic locus affords space to package guide RNAs for gene editing together with Cre-dependent, genetically encoded tools to manipulate, map, or monitor neurons using a single virus.We validated this strategy with three common tools in neuroscience: ChRonos, a channelrhodopsin, for studying synaptic transmission using optogenetics; GCaMP8f for recording Ca2+ transients using photometry, and mCherry for tracing axonal projections. We tested these tools in multiple brain regions and cell types, including GABAergic neurons in the nucleus accumbens, glutamatergic neurons projecting from the ventral pallidum to the lateral habenula, dopaminergic neurons in the ventral tegmental area, and proprioceptive neurons in the periphery. This flexible approach could help identify and test the function of novel genes affecting synaptic transmission, circuit activity, or morphology with a single viral injection. Our CRISPR/Cas9 approach is the first to use a single vector to both knock-down genes of interest and express tools to monitor, map, and manipulate neurons. We demonstrate its utility in the central nervous system and describe the first systemic CRISPR/Cas9 gene editing with co-expressed reporters in the peripheral nervous system. Our approach fills a significant gap in the neuronal gene editing toolkit, allowing high-throughput study of genes of unknown function in the nervous system, and has broad utility for loss-of-function studies in other biological fields. This tool has great translational potential: it can be used to screen risk factor genes identified through genome-wide association studies, or knock-down native gene expression and reintroduce mutant variants identified in clinical settings.
PubMed: 38871457
DOI: 10.1523/ENEURO.0438-23.2024 -
Nan Fang Yi Ke Da Xue Xue Bao = Journal... May 2024To investigate the mechanisms that mediate the neuroprotective effect of the intestinal microbial metabolite sodium butyrate (NaB) in a mouse model of Parkinson's...
OBJECTIVE
To investigate the mechanisms that mediate the neuroprotective effect of the intestinal microbial metabolite sodium butyrate (NaB) in a mouse model of Parkinson's disease (PD) the gut-brain axis.
METHODS
Thirty-nine 7-week-old male C57BL/6J mice were randomized equally into control group, PD model group, and NaB treatment group. In the latter two groups, PD models were established by intraperitoneal injection of 30 mg/kg 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) once daily for 5 consecutive days, and normal saline was injected in the control group. After modeling, the mice received daily gavage of NaB (300 mg/kg) or an equal volume of saline for 14 days. Behavioral tests were carried out to assess the changes in motor function of the mice, and Western blotting was performed to detect the expressions of tyrosine hydroxylase (TH) and -synuclein (-syn) in the striatum and nuclear factor-κB (NF-κB), tumor necrosis factor (TNF-), interleukin 6 (IL-6), and the tight junction proteins ZO-1, Occludin, and Claudinin the colon. HE staining was used to observe inflammatory cell infiltration in the colon of the mice. RNA sequencing analysis was performed to identify the differentially expressed genes in mouse colon tissues, and their expressions were verified using qRT-PCR and Western blotting.
RESULTS
The mouse models of PD with NaB treatment showed significantly increased movement speed and pulling strength of the limbs with obviously upregulated expressions of TH, Occludin, and Claudin and downregulated expressions of -syn, NF-κB, TNF-, and IL-6 (all < 0.05). HE staining showed that NaB treatment significantly ameliorated inflammatory cell infiltration in the colon of the PD mice. RNA sequencing suggested that Bmal1 gene probably mediated the neuroprotective effect of NaB in PD mice ( < 0.05).
CONCLUSION
NaB can improve motor dysfunction, reduce dopaminergic neuron loss in the striatum, and ameliorate colonic inflammation in PD mice possibly through a mechanism involving Bmal1.
Topics: Animals; Mice; Butyric Acid; Male; Mice, Inbred C57BL; Neuroprotective Agents; Disease Models, Animal; Parkinson Disease; alpha-Synuclein; Tumor Necrosis Factor-alpha; NF-kappa B; Interleukin-6; Tyrosine 3-Monooxygenase; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Corpus Striatum; Occludin; Brain-Gut Axis
PubMed: 38862445
DOI: 10.12122/j.issn.1673-4254.2024.05.09 -
Learning & Memory (Cold Spring Harbor,... May 2024Associative learning enables the adaptive adjustment of behavioral decisions based on acquired, predicted outcomes. The valence of what is learned is influenced not only...
Associative learning enables the adaptive adjustment of behavioral decisions based on acquired, predicted outcomes. The valence of what is learned is influenced not only by the learned stimuli and their temporal relations, but also by prior experiences and internal states. In this study, we used the fruit fly to demonstrate that neuronal circuits involved in associative olfactory learning undergo restructuring during extended periods of low-caloric food intake. Specifically, we observed a decrease in the connections between specific dopaminergic neurons (DANs) and Kenyon cells at distinct compartments of the mushroom body. This structural synaptic plasticity was contingent upon the presence of allatostatin A receptors in specific DANs and could be mimicked optogenetically by expressing a light-activated adenylate cyclase in exactly these DANs. Importantly, we found that this rearrangement in synaptic connections influenced aversive, punishment-induced olfactory learning but did not impact appetitive, reward-based learning. Whether induced by prolonged low-caloric conditions or optogenetic manipulation of cAMP levels, this synaptic rearrangement resulted in a reduction of aversive associative learning. Consequently, the balance between positive and negative reinforcing signals shifted, diminishing the ability to learn to avoid odor cues signaling negative outcomes. These results exemplify how a neuronal circuit required for learning and memory undergoes structural plasticity dependent on prior experiences of the nutritional value of food.
Topics: Animals; Mushroom Bodies; Drosophila melanogaster; Neuronal Plasticity; Dopaminergic Neurons; Eating; Optogenetics; Association Learning; Smell; Olfactory Perception; Reward; Animals, Genetically Modified
PubMed: 38862177
DOI: 10.1101/lm.053997.124 -
Learning & Memory (Cold Spring Harbor,... May 2024Across animal species, dopamine-operated memory systems comprise anatomically segregated, functionally diverse subsystems. Although individual subsystems could operate... (Review)
Review
Across animal species, dopamine-operated memory systems comprise anatomically segregated, functionally diverse subsystems. Although individual subsystems could operate independently to support distinct types of memory, the logical interplay between subsystems is expected to enable more complex memory processing by allowing existing memory to influence future learning. Recent comprehensive ultrastructural analysis of the mushroom body revealed intricate networks interconnecting the dopamine subsystems-the mushroom body compartments. Here, we review the functions of some of these connections that are beginning to be understood. Memory consolidation is mediated by two different forms of network: A recurrent feedback loop within a compartment maintains sustained dopamine activity required for consolidation, whereas feed-forward connections across compartments allow short-term memory formation in one compartment to open the gate for long-term memory formation in another compartment. Extinction and reversal of aversive memory rely on a similar feed-forward circuit motif that signals omission of punishment as a reward, which triggers plasticity that counteracts the original aversive memory trace. Finally, indirect feed-forward connections from a long-term memory compartment to short-term memory compartments mediate higher-order conditioning. Collectively, these emerging studies indicate that feedback control and hierarchical connectivity allow the dopamine subsystems to work cooperatively to support diverse and complex forms of learning.
Topics: Animals; Dopamine; Mushroom Bodies; Drosophila; Feedback, Physiological; Memory Consolidation; Nerve Net; Dopaminergic Neurons; Neural Pathways
PubMed: 38862171
DOI: 10.1101/lm.053807.123 -
Learning & Memory (Cold Spring Harbor,... May 2024Octopamine, the functional analog of noradrenaline, modulates many different behaviors and physiological processes in invertebrates. In the central nervous system, a few... (Review)
Review
Octopamine, the functional analog of noradrenaline, modulates many different behaviors and physiological processes in invertebrates. In the central nervous system, a few octopaminergic neurons project throughout the brain and innervate almost all neuropils. The center of memory formation in insects, the mushroom bodies, receive octopaminergic innervations in all insects investigated so far. Different octopamine receptors, either increasing or decreasing cAMP or calcium levels in the cell, are localized in Kenyon cells, further supporting the release of octopamine in the mushroom bodies. In addition, different mushroom body (MB) output neurons, projection neurons, and dopaminergic PAM cells are targets of octopaminergic neurons, enabling the modulation of learning circuits at different neural sites. For some years, the theory persisted that octopamine mediates rewarding stimuli, whereas dopamine (DA) represents aversive stimuli. This simple picture has been challenged by the finding that DA is required for both appetitive and aversive learning. Furthermore, octopamine is also involved in aversive learning and a rather complex interaction between these biogenic amines seems to modulate learning and memory. This review summarizes the role of octopamine in MB function, focusing on the anatomical principles and the role of the biogenic amine in learning and memory.
Topics: Octopamine; Mushroom Bodies; Animals; Memory; Learning; Dopamine; Insecta; Neurons
PubMed: 38862169
DOI: 10.1101/lm.053839.123 -
Molecular Brain Jun 2024Chronic perturbations of neuronal activity can evoke homeostatic and new setpoints for neurotransmission. Using chemogenetics to probe the relationship between neuronal...
Chronic perturbations of neuronal activity can evoke homeostatic and new setpoints for neurotransmission. Using chemogenetics to probe the relationship between neuronal cell types and behavior, we recently found reversible decreases in dopamine (DA) transmission, basal behavior, and amphetamine (AMPH) response following repeated stimulation of DA neurons in adult mice. It is unclear, however, whether altering DA neuronal activity via chemogenetics early in development leads to behavioral phenotypes that are reversible, as alterations of neuronal activity during developmentally sensitive periods might be expected to induce persistent effects on behavior. To examine the impact of developmental perturbation of DA neuron activity on basal and AMPH behavior, we expressed excitatory hM3D(Gq) in postnatal DA neurons in TH-Cre and WT mice. Basal and CNO- or AMPH-induced locomotion and stereotypy was evaluated in a longitudinal design, with clozapine N-oxide (CNO, 1.0 mg/kg) administered across adolescence (postnatal days 15-47). Repeated CNO administration did not impact basal behavior and only minimally reduced AMPH-induced hyperlocomotor response in adolescent TH-Cre mice relative to WT littermate controls. Following repeated CNO administration, however, AMPH-induced stereotypic behavior robustly decreased in adolescent TH-Cre mice relative to controls. A two-month CNO washout period rescued the diminished AMPH-induced stereotypic behavior. Our findings indicate that the homeostatic compensations that take place in response to chronic hM3D(Gq) stimulation during adolescence are temporary and are dependent on ongoing chemogenetic stimulation.
Topics: Animals; Amphetamine; Dopaminergic Neurons; Stereotyped Behavior; Clozapine; Locomotion; Mice; Male; Motor Activity; Mice, Transgenic; Tyrosine 3-Monooxygenase; Behavior, Animal; Integrases
PubMed: 38858755
DOI: 10.1186/s13041-024-01110-9