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ENeuro Jun 2024Measuring the dynamic relationship between neuromodulators, such as dopamine, and neuronal action potentials is imperative to understand how these fundamental modes of...
Measuring the dynamic relationship between neuromodulators, such as dopamine, and neuronal action potentials is imperative to understand how these fundamental modes of neural signaling interact to mediate behavior. We developed methods to measure concurrently dopamine and extracellular action potentials (i.e., spikes) in monkeys. Standard fast-scan cyclic voltammetric (FSCV) electrochemical (EChem) and electrophysiological (EPhys) recording systems are combined and used to collect spike and dopamine signals, respectively, from an array of carbon fiber (CF) sensors implanted in the monkey striatum. FSCV requires the application of small voltages at the implanted sensors to measure redox currents generated from target molecules, such as dopamine. These applied voltages create artifacts at neighboring EPhys-measurement sensors which may lead to misclassification of these signals as physiological spikes. Therefore, simple automated temporal interpolation algorithms were designed to remove these artifacts and enable accurate spike extraction. We validated these methods using simulated artifacts and demonstrated an average spike recovery rate of 84.5%. We identified and discriminated cell-type specific units in the monkey striatum that were shown to correlate to specific behavioral task parameters related to reward size and eye-movement direction. Synchronously recorded spike and dopamine signals displayed contrasting relations to the task variables, suggesting a complex relationship between these two modes of neural signaling. Future application of our methods will help advance our understanding of the interactions between neuromodulator signaling and neuronal activity, to elucidate more detailed mechanisms of neural circuitry and plasticity mediating behaviors in health and in disease. We present a simple method for recording synchronous molecular and neuronal spike signals. Conventional electrophysiological and electrochemical instruments are combined without the need for additional hardware. A custom-designed algorithm was made and validated for extracting neuronal action potential signals with high fidelity. We were able to compute cell-type specific spike activity along with molecular dopamine signals related to reward and movement behaviors from measurements made in the monkey striatum. Such combined measurements of neurochemical and extracellular action potentials may help pave the way to elucidating mechanisms of plasticity, and how neuromodulators and neurons are orchestrated to mediate behavior.
PubMed: 38918051
DOI: 10.1523/ENEURO.0001-24.2024 -
BioRxiv : the Preprint Server For... Jun 2024The classic output pathways of the basal ganglia are known as the direct-D1 and indirect-D2, or "Go/No-Go", pathways. Balance of the activity in these canonical...
The classic output pathways of the basal ganglia are known as the direct-D1 and indirect-D2, or "Go/No-Go", pathways. Balance of the activity in these canonical direct-indirect pathways is considered a core requirement for normal movement control, and their imbalance is a major etiologic factor in movement disorders including Parkinson's disease. We present evidence for a conceptually equivalent parallel system of direct-D1 and indirect-D2 pathways that arise from striatal projection neurons (SPNs) of the striosome compartment rather than from the matrix. These striosomal direct (S-D1) and indirect (S-D2) pathways, as a pair, target dopamine-containing neurons of the substantia nigra (SNpc) instead of the motor output nuclei of the basal ganglia. The novel anatomically and functionally distinct indirect-D2 striosomal pathway targets dopaminergic SNpc cells indirectly via a core region of the external pallidum (GPe). We demonstrate that these S-D1 and S-D2 pathways oppositely modulate striatal dopamine release in freely behaving mice under open-field conditions and oppositely modulate locomotor and other movements. These S-D1 and S-D2 pathways further exhibit different, time-dependent responses during performance of a probabilistic decision-making maze task and respond differently to rewarding and aversive stimuli. These contrasts depend on mediolateral and anteroposterior striatal locations of the SPNs as are the classic direct and indirect pathways. The effects of S-D1 and S-D2 stimulation on striatal dopamine release and voluntary locomotion are nearly opposite. The parallelism of the direct-indirect circuit design motifs of the striosomal S-D and S-D2 circuits and canonical matrix M-D1 and M-D2, and their contrasting behavioral effects, call for a major reformulation of the classic direct-indirect pathway model of basal ganglia function. Given that some striosomes receive limbic and association cortical inputs, the S-D1 and S-D2 circuits likely influence motivation for action and behavioral learning, complementing and possibly reorienting the motoric activities of the canonical matrix pathways. At a fundamental level, these findings suggest a unifying framework for aligning two sets of circuits that share the organizational motif of opponent D1 and D2 regulation, but that have different outputs and can even have opposite polarities in their targets and effects, albeit conditioned by striatal topography. Our findings further delineate a potentially therapeutically important set of pathways influencing dopamine, including a D2 receptor-linked S-D2 pathway likely unknowingly targeted by administration of many therapeutic drugs including those for Parkinson's disease. The novel parallel pathway model that we propose here could help to account for the normally integrated modulatory influence of the basal ganglia on motivation for actions as well as the actions themselves.
PubMed: 38915684
DOI: 10.1101/2024.06.01.596922 -
BioRxiv : the Preprint Server For... Jun 2024Gangliosides are sialylated glycosphingolipids with essential but enigmatic functions in healthy and disease brains. GD3 is the predominant species in neural stem cells...
Gangliosides are sialylated glycosphingolipids with essential but enigmatic functions in healthy and disease brains. GD3 is the predominant species in neural stem cells (NSCs) and GD3-synthase (sialyltransferase II; ) knockout (GD3S-KO) revealed reduction of postnatal NSC pools with severe behavioral deficits including cognitive impairment, depression-like phenotypes, and olfactory dysfunction. Exogenous administration of GD3 significantly restored the NSC pools and enhanced the stemness of NSCs with multipotency and self-renewal, followed by restored neuronal functions. Our group discovered that GD3 is involved in the maintenance of NSC fate determination by interacting with epidermal growth factor receptors (EGFRs), by modulating expression of cyclin-dependent kinase (CDK) inhibitors p27 and p21, and by regulating mitochondrial dynamics via associating a mitochondrial fission protein, the dynamin-related protein-1 (Drp1). Furthermore, we discovered that nuclear GM1 promotes neuronal differentiation by an epigenetic regulatory mechanism. GM1 binds with acetylated histones on the promoter of as well as on the in differentiated neurons. In addition, epigenetic activation of the GM2S gene was detected as accompanied by an apparent induction of neuronal differentiation in NSCs responding to an exogenous supplement of GM1. Interestingly, GM1 induced epigenetic activation of the gene, with recruitment of Nurr1 and PITX3, dopaminergic neuron-associated transcription factors, to the promoter region. In this way, GM1 epigenetically regulates dopaminergic neuron specific gene expression, and it would modify Parkinson's disease. Multifunctional gangliosides significantly modulate lipid microdomains to regulate functions of important molecules on multiple sites: the plasma membrane, mitochondrial membrane, and nuclear membrane. Versatile gangliosides regulate functional neurons as well as sustain NSC functions via modulating protein and gene activities on ganglioside microdomains. Maintaining proper ganglioside microdomains benefits healthy neuronal development and millions of senior citizens with neurodegenerative diseases. Here, we introduce how to isolate GD3 and GM1 and how to administer them into the mouse brain to investigate their functions on NSC fate determination and nerve cell specification.
PubMed: 38915682
DOI: 10.1101/2024.06.09.598109 -
BioRxiv : the Preprint Server For... Jun 2024Pathological forms of the protein α-synuclein contribute to a family of disorders termed synucleinopathies, which includes Parkinson's disease (PD). Most cases of PD...
Pathological forms of the protein α-synuclein contribute to a family of disorders termed synucleinopathies, which includes Parkinson's disease (PD). Most cases of PD are believed to arise from gene-environment interactions. Microbiome composition is altered in PD, and gut bacteria are causal to symptoms and pathology in animal models. To explore how the microbiome may impact PD-associated genetic risks, we quantitatively profiled nearly 630 metabolites from 26 biochemical classes in the gut, plasma, and brain of α-synuclein-overexpressing (ASO) mice with or without microbiota. We observe tissue-specific changes driven by genotype, microbiome, and their interaction. Many differentially expressed metabolites in ASO mice are also dysregulated in human PD patients, including amine oxides, bile acids and indoles. Notably, levels of the microbial metabolite trimethylamine N-oxide (TMAO) strongly correlate from the gut to the plasma to the brain, identifying a product of gene-environment interactions that may influence PD-like outcomes in mice. TMAO is elevated in the blood and cerebral spinal fluid of PD patients. These findings uncover broad metabolomic changes that are influenced by the intersection of host genetics and the microbiome in a mouse model of PD.
PubMed: 38915679
DOI: 10.1101/2024.06.07.597975 -
BioRxiv : the Preprint Server For... Jun 2024Mutations in that increase its kinase activity are strongly linked to genetic forms of Parkinson's disease (PD). However, the regulation of endogenous wild-type (WT)...
Mutations in that increase its kinase activity are strongly linked to genetic forms of Parkinson's disease (PD). However, the regulation of endogenous wild-type (WT) LRRK2 kinase activity remains poorly understood, despite its frequent elevation in idiopathic PD (iPD) patients. Various stressors such as mitochondrial dysfunction, lysosomal dyshomeostasis, or vesicle trafficking deficits can activate WT LRRK2 kinase, but the specific molecular mechanisms are not fully understood. We found that the production of 4-hydroxynonenal (4-HNE), a lipid hydroperoxidation end-product, is a common biochemical response to these diverse stimuli. 4-HNE forms post-translational adducts with Cys2024 and Cys2025 in the kinase activation loop of WT LRRK2, significantly increasing its kinase activity. Additionally, we discovered that the 4-HNE responsible for regulating LRRK2 is generated by the action of 15-lipoxygenase (15-LO), making 15-LO an upstream regulator of the pathogenic hyperactivation of LRRK2 kinase activity. Pharmacological inhibition or genetic ablation of 15-LO prevents 4-HNE post-translational modification of LRRK2 kinase and its subsequent pathogenic hyperactivation. Therefore, 15-LO inhibitors, or methods to lower 4-HNE levels, or the targeting of Cys2024/2025 could provide new therapeutic strategies to modulate LRRK2 kinase activity and treat PD.
PubMed: 38915558
DOI: 10.1101/2024.06.12.598654 -
Frontiers in Aging Neuroscience 2024Patients with Parkinson's disease (PD) exhibit a heightened risk of falls and related fractures compared to the general population. This study aims to assess the...
BACKGROUND
Patients with Parkinson's disease (PD) exhibit a heightened risk of falls and related fractures compared to the general population. This study aims to assess the clinical characteristics associated with falls in the patient with PD and to gain further insight into these factors through Mendelian randomization analysis.
METHODS
From January 2013 to December 2023, we included 591 patients diagnosed with Parkinson's disease at Shenzhen Baoan People's Hospital. Using univariate and multivariate logistic regression analyses, we identified clinical variables associated with falls. We constructed a nomogram based on these variables and evaluated the predictive efficacy of the model. Additionally, we employed summary statistics from genome-wide association studies to conduct two-sample Mendelian randomization (MR) analyses on key variables influencing falls.
RESULTS
Compared to the control group, we identified osteoporosis, motor dysfunction, higher Hoehn and Yahr scale as significant risk factors for falls in PD patients. Conversely, treatment with levodopa and a higher level of education exhibited a protective effect against the risk of falling. MR analysis further confirmed a causal relationship between osteoporosis, education level and falls in PD patients.
CONCLUSION
Osteoporosis and educational attainment are correlated with falls in Parkinson's disease.
PubMed: 38915347
DOI: 10.3389/fnagi.2024.1420885 -
Journal of Movement Disorders Jun 2024Pain is one of the most common non-motor symptoms in Parkinson's disease (PD), with variable characteristics among populations. This multicenter Egyptian study aimed to...
OBJECTIVE
Pain is one of the most common non-motor symptoms in Parkinson's disease (PD), with variable characteristics among populations. This multicenter Egyptian study aimed to translate and validate the King's Parkinson's Disease Pain Scale (KPPS) and questionnaire (KPPQ) into Arabic versions and to investigate the pain characteristics in Egyptian people with PD (PWP).
METHODS
192 PWP and 100 sex and age-matched controls were evaluated by KPPS-Arabic and KPPQ-Arabic. Both tools were assessed for test-retest reliability, floor or ceiling effects, construct validity and convert validity. PWP were assessed also by MDS-UPDRS, Hoehn and Yahr, NMSS, PD Questionnaire-39, and the Non-Motor Fluctuation Assessment (NoMoFA).
RESULTS
KPPS-Arabic and KPPQ-Arabic showed inter and intra-rater consistency and high validity, with an acceptable ceiling effect. 188 PWP (97.9%) reported at least 1 type of pain, (p<0.001). The severity and prevalence of KPPS-Arabic domains were significantly higher in all pain domains among PWP compared to controls (p < 0.001). Fluctuation-related and musculoskeletal pains were the most common (81.3% and 80.7%, respectively). In the PD group, the total and domains of KPPS-Arabic were significantly correlated to the MDS-UPDRS total, parts I, II, III, PIGD, axial, and H &Y scores, but not age or age of onset. Predictors of KPPS-Arabic included the total MDS-UPDRS, part III-Off, disease duration, total NMSS, and NoMoFA.
CONCLUSION
The current multicentre study provided a validated Arabic versions of KPPS and KPPQ, with high reliability and validity, and demonstrated a high prevalence and severity of pain within Egyptian PWP and characterized its determinants.
PubMed: 38915261
DOI: 10.14802/jmd.24088 -
Journal of Neuroengineering and... Jun 2024Treadmill gait training has been shown to improve gait performance in People with Parkinson's Disease (PwPD), and in combination with Virtual Reality, it can be an...
BACKGROUND
Treadmill gait training has been shown to improve gait performance in People with Parkinson's Disease (PwPD), and in combination with Virtual Reality, it can be an effective tool for gait rehabilitation. The addition of gamification elements can create a more stimulating and adherent intervention. However, implementation of new technologies in healthcare can be challenging. This study aimed to develop and evaluate the feasibility of a treadmill rehabilitation program in a Gamified Virtual Reality Environment (GVRE) for PwPD.
METHODS
The GVRE was developed following a user-centered design approach, involving both PwPD and physiotherapists in the development and evaluation of the intervention. The intervention consisted of a walking simulation in three different environments (countryside, city, and park), which had a progressive increase in difficulty. To test its feasibility, three sessions were carried out with four PwPD and four physiotherapists. To assess the usability, the System Usability Scale (SUS), Assistive Technology Usability Questionnaire for people with Neurological diseases (NATU Quest) and Simulator Sickness Questionnaire (SSQ) were used. To assess the intervention's acceptability, feedback and in-game performance was collected from participants.
RESULTS
Results showed the feasibility of the intervention, with a SUS score of 74.82 ± 12.62, and a NATU Quest score of 4.49 ± 0.62, and positive acceptability feedback. Participants showed clear preferences for naturalistic environments, and gamification elements were seen as positive. Difficulty settings worked as intended, but lowered enjoyment of the experience in some cases.
CONCLUSIONS
This intervention was successfully shown as a feasible option for the training of gait under Dual Task conditions for PwPD. It offers a safe and replicable environment in which complex situations can be trained. However, further iterations of the intervention need to be improved in order to guarantee accurate tracking and a more realistic training progression.
TRIAL REGISTRATION NUMBER
NCT05243394-01/20/2022.
Topics: Humans; Parkinson Disease; Feasibility Studies; Male; Virtual Reality; Aged; Female; Middle Aged; Gait Disorders, Neurologic; Video Games; Exercise Therapy; Gait
PubMed: 38915103
DOI: 10.1186/s12984-024-01399-6 -
BMC Medicine Jun 2024People with different types of dementia may have distinct symptoms and experiences that affect their quality of life. This study investigated whether quality of life...
BACKGROUND
People with different types of dementia may have distinct symptoms and experiences that affect their quality of life. This study investigated whether quality of life varied across types of dementia and over time.
METHODS
The participants were 1555 people with mild-to-moderate dementia and 1327 carers from the IDEAL longitudinal cohort study, recruited from clinical services. As many as possible were followed for up to 6 years. Diagnoses included were Alzheimer's disease, vascular dementia, mixed Alzheimer's and vascular dementia, Parkinson's disease dementia, dementia with Lewy bodies, and frontotemporal dementia. Self- and informant-rated versions of the Quality of Life in Alzheimer's Disease scale were used. A joint model, incorporating a mixed effects model with random effects and a survival model to account for dropout, was used to examine whether quality of life varied by dementia type at the time of diagnosis and how trajectories changed over time.
RESULTS
The strongest associations between dementia type and quality of life were seen around the time of diagnosis. For both self-ratings and informant ratings, people with Parkinson's disease dementia or dementia with Lewy bodies had lower quality of life scores. Over time there was little change in self-rated scores across all dementia types (- 0.15 points per year). Informant-rated scores declined over time (- 1.63 points per year), with the greatest decline seen in ratings by informants for people with dementia with Lewy bodies (- 2.18 points per year).
CONCLUSIONS
Self-rated quality of life scores were relatively stable over time whilst informant ratings showed a steeper decline. People with Parkinson's disease dementia or dementia with Lewy bodies report particularly low levels of quality of life, indicating the importance of greater attention to the needs of these groups.
Topics: Humans; Quality of Life; Male; Female; Longitudinal Studies; Aged; Dementia; Aged, 80 and over; Middle Aged
PubMed: 38915081
DOI: 10.1186/s12916-024-03492-y -
Sheng Wu Gong Cheng Xue Bao = Chinese... Jun 2024Cytidine-5'-diphosphate choline (CDP-choline) plays a crucial role in the formation of the phospholipid bilamolecular layer in cell membranes and the stabilization of... (Review)
Review
Cytidine-5'-diphosphate choline (CDP-choline) plays a crucial role in the formation of the phospholipid bilamolecular layer in cell membranes and the stabilization of the neurotransmitter system, acting as a precursor to phosphatidylcholine and acetylcholine. CDP-choline has been found effective in treating functional and consciousness disorders resulting from brain injury, Parkinson's disease, depression and glaucoma, and other conditions. As such, CDP-choline is widely utilized in clinical medicine and health care products. The conventional chemical synthesis process of CDP-choline is gradually being replaced by biosynthesis due to the expensive and toxic reagents involved, the production of various by-products, and the high cost of industrial production. Biosynthesis of CDP-choline offers two strategies: microbial fermentation and biocatalysis. Microbial fermentation utilizes inexpensive raw materials but results in a relatively low conversion rate and requires a complex separation and purification process. Biocatalysis, on the other hand, involves two stages: the growth of a living "catalyst" and the conversion of the substrate. Although the synthetic process in biocatalysis is more complex, it offers a higher conversion ratio, and the downstream processing technique for extraction is relatively less costly. Consequently, biocatalysis is currently the primary strategy for the industrial production of CDP-choline. This review aims to summarize the progress made in both chemical synthesis and biosynthesis of CDP-choline, with particular focus on the metabolic pathway and the synthetic processes involved in biocatalysis, in order to provide insights for the industrial production of CDP-choline.
Topics: Cytidine Diphosphate Choline; Biocatalysis; Fermentation; Humans
PubMed: 38914484
DOI: 10.13345/j.cjb.230715