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Nature Communications Jul 2024Genetically-encoded dopamine (DA) sensors enable high-resolution imaging of DA release, but their ability to detect a wide range of extracellular DA levels, especially...
Genetically-encoded dopamine (DA) sensors enable high-resolution imaging of DA release, but their ability to detect a wide range of extracellular DA levels, especially tonic versus phasic DA release, is limited by their intrinsic affinity. Here we show that a human-selective dopamine receptor positive allosteric modulator (PAM) can be used to boost sensor affinity on-demand. The PAM enhances DA detection sensitivity across experimental preparations (in vitro, ex vivo and in vivo) via one-photon or two-photon imaging. In vivo photometry-based detection of optogenetically-evoked DA release revealed that DETQ administration produces a stable 31 minutes window of potentiation without effects on animal behavior. The use of the PAM revealed region-specific and metabolic state-dependent differences in tonic DA levels and enhanced single-trial detection of behavior-evoked phasic DA release in cortex and striatum. Our chemogenetic strategy can potently and flexibly tune DA imaging sensitivity and reveal multi-modal (tonic/phasic) DA signaling across preparations and imaging approaches.
Topics: Dopamine; Animals; Humans; Optogenetics; Mice; Male; Corpus Striatum; Receptors, Dopamine; Mice, Inbred C57BL; Allosteric Regulation; Photometry; HEK293 Cells
PubMed: 38956067
DOI: 10.1038/s41467-024-49442-3 -
Scientific Reports Jul 2024Ferroptosis is an iron-dependent cell death form characterized by reactive oxygen species (ROS) overgeneration and lipid peroxidation. Myricetin, a flavonoid that exists...
Ferroptosis is an iron-dependent cell death form characterized by reactive oxygen species (ROS) overgeneration and lipid peroxidation. Myricetin, a flavonoid that exists in numerous plants, exhibits potent antioxidant capacity. Given that iron accumulation and ROS-provoked dopaminergic neuron death are the two main pathological hallmarks of Parkinson's disease (PD), we aimed to investigate whether myricetin decreases neuronal death through suppressing ferroptosis. The PD models were established by intraperitoneally injecting 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into rats and by treating SH-SY5Y cells with 1-methyl-4-phenylpyridinium (MPP), respectively. Ferroptosis was identified by assessing the levels of Fe, ROS, malondialdehyde (MDA), and glutathione (GSH). The results demonstrated that myricetin treatment effectively mitigated MPTP-triggered motor impairment, dopamine neuronal death, and α-synuclein (α-Syn) accumulation in PD models. Myricetin also alleviated MPTP-induced ferroptosis, as evidenced by decreased levels of Fe, ROS, and MDA and increased levels of GSH in the substantia nigra (SN) and serum in PD models. All these changes were reversed by erastin, a ferroptosis activator. In vitro, myricetin treatment restored SH-SY5Y cell viability and alleviated MPP-induced SH-SY5Y cell ferroptosis. Mechanistically, myricetin accelerated nuclear translocation of nuclear factor E2-related factor 2 (Nrf2) and subsequent glutathione peroxidase 4 (Gpx4) expression in MPP-treated SH-SY5Y cells, two critical inhibitors of ferroptosis. Collectively, these data demonstrate that myricetin may be a potential agent for decreasing dopaminergic neuron death by inhibiting ferroptosis in PD.
Topics: Ferroptosis; Animals; Flavonoids; Rats; Disease Models, Animal; Male; Reactive Oxygen Species; Dopaminergic Neurons; Humans; Parkinson Disease; Cell Line, Tumor; Iron; alpha-Synuclein; Rats, Sprague-Dawley; Glutathione; Lipid Peroxidation; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NF-E2-Related Factor 2
PubMed: 38956066
DOI: 10.1038/s41598-024-62910-6 -
Mikrochimica Acta Jul 2024Transferrin (TRF), recognized as a glycoprotein clinical biomarker and therapeutic target, has its concentration applicable for disease diagnosis and treatment...
A double boronic acid affinity "sandwich" SERS biosensor based on magnetic boronic acid controllable-oriented imprinting for high-affinity biomimetic specific recognition and rapid detection of target glycoproteins.
Transferrin (TRF), recognized as a glycoprotein clinical biomarker and therapeutic target, has its concentration applicable for disease diagnosis and treatment monitoring. Consequently, this study developed boronic acid affinity magnetic surface molecularly imprinted polymers (B-MMIPs) with pH-responsitivity as the "capture probe" for TRF, which have high affinity similar to antibodies, with a dissociation constant of (3.82 ± 0.24) × 10 M, showing 7 times of reusability. The self-copolymerized imprinted layer synthesized with dopamine (DA) and 3-Aminophenylboronic acid (APBA) as double monomers avoided nonspecific binding sites and produced excellent adsorption properties. Taking the gold nanostar (AuNS) with a branch tip "hot spot" structure as the core, the silver-coated AuNS functionalized with the biorecognition element 4-mercaptophenylboronic acid (MPBA) was employed as a surface-enhanced Raman scattering (SERS) nanotag (AuNS@Ag-MPBA) to label TRF, thereby constructing a double boronic acid affinity "sandwich" SERS biosensor (B-MMIPs-TRF-SERS nanotag) for the highly sensitive detection of TRF. The SERS biosensor exhibited a detection limit for TRF of 0.004 ng/mL, and its application to spiked serum samples confirmed its reliability and feasibility, demonstrating significant potential for clinical TRF detection. Moreover, the SERS biosensor designed in this study offers advantages in stability, detection speed (40 min), and cost efficiency. The portable Raman instrument for SERS detection fulfills the requirements for point-of-care testing.
Topics: Boronic Acids; Biosensing Techniques; Gold; Humans; Spectrum Analysis, Raman; Silver; Metal Nanoparticles; Limit of Detection; Transferrin; Molecular Imprinting; Molecularly Imprinted Polymers; Glycoproteins; Biomimetic Materials; Dopamine; Sulfhydryl Compounds
PubMed: 38955823
DOI: 10.1007/s00604-024-06522-x -
The Journal of Neuroscience : the... Jul 2024Recent work demonstrated that activation of spinal D1 and D5 dopamine receptors (D1/D5Rs) facilitates non-Hebbian long-term potentiation (LTP) at primary afferent...
Recent work demonstrated that activation of spinal D1 and D5 dopamine receptors (D1/D5Rs) facilitates non-Hebbian long-term potentiation (LTP) at primary afferent synapses onto spinal projection neurons. However, the cellular localization of the D1/D5Rs driving non-Hebbian LTP in spinal nociceptive circuits remains unknown, and it is also unclear whether D1/D5R signaling must occur concurrently with sensory input in order to promote non-Hebbian LTP at these synapses. Here we investigate these issues using cell type-selective knockdown of D1Rs or D5Rs from lamina I spinoparabrachial neurons, dorsal root ganglion (DRG) neurons or astrocytes in adult mice of either sex using Cre recombinase-based genetic strategies. The LTP evoked by low-frequency stimulation of primary afferents in the presence of the selective D1/D5R agonist SKF82958 persisted following the knockdown of D1R or D5R in spinoparabrachial neurons, suggesting that postsynaptic D1/D5R signaling was dispensable for non-Hebbian plasticity at sensory synapses onto these key output neurons of the superficial dorsal horn (SDH). Similarly, the knockdown of D1Rs or D5Rs in DRG neurons failed to influence SKF82958-enabled LTP in lamina I projection neurons. In contrast, SKF82958-induced LTP was suppressed by the knockdown of D1R or D5R in spinal astrocytes. Furthermore, the data indicate that the activation of D1R/D5Rs in spinal astrocytes can either retroactively or proactively drive non-Hebbian LTP in spinoparabrachial neurons. Collectively, these results suggest that dopaminergic signaling in astrocytes can strongly promote activity-dependent LTP in the SDH, which is predicted to significantly enhance the amplification of ascending nociceptive transmission from the spinal cord to the brain. Long-term potentiation (LTP) of sensory synapses onto lamina I projection neurons represents a key mechanism by which the spinal superficial dorsal horn (SDH) can amplify ascending nociceptive transmission to the brain. Here we demonstrate that the activation of D1 or D5 dopamine receptors expressed in spinal astrocytes promotes non-Hebbian LTP at primary afferent inputs onto mouse spinoparabrachial neurons. Furthermore, astrocyte D1/D5R signaling not only retroactively potentiated sensory synapses that were recently active, but also proactively primed synapses to undergo LTP following subsequent stimulation. These results identify dopaminergic signaling onto astrocytes as a key regulator of synaptic metaplasticity in the SDH and suggest that astrocyte D1/D5Rs could serve as a gain control that enables the excessive amplification of spinal nociceptive transmission.
PubMed: 38955487
DOI: 10.1523/JNEUROSCI.0170-24.2024 -
The International Journal of... Jul 2024
PubMed: 38955467
DOI: 10.1093/ijnp/pyae028 -
Cell Host & Microbe Jun 2024The impact of gestational diabetes mellitus (GDM) on maternal or infant microbiome trajectory remains poorly understood. Utilizing large-scale longitudinal fecal samples...
The impact of gestational diabetes mellitus (GDM) on maternal or infant microbiome trajectory remains poorly understood. Utilizing large-scale longitudinal fecal samples from 264 mother-baby dyads, we present the gut microbiome trajectory of the mothers throughout pregnancy and infants during the first year of life. GDM mothers had a distinct microbiome diversity and composition during the gestation period. GDM leaves fingerprints on the infant's gut microbiome, which are confounded by delivery mode. Further, Clostridium species positively correlate with a larger head circumference at month 12 in male offspring but not females. The gut microbiome of GDM mothers with male fetuses displays depleted gut-brain modules, including acetate synthesis I and degradation and glutamate synthesis II. The gut microbiome of female infants of GDM mothers has higher histamine degradation and dopamine degradation. Together, our integrative analysis indicates that GDM affects maternal and infant gut composition, which is associated with sexually dimorphic infant head growth.
PubMed: 38955186
DOI: 10.1016/j.chom.2024.06.005 -
Parkinsonism & Related Disorders Jun 2024Parkinson's disease (PD) presents with a progressive decline in manual dexterity, attributed to dysfunction in the basal ganglia-thalamus-cortex loop, influenced by...
INTRODUCTION
Parkinson's disease (PD) presents with a progressive decline in manual dexterity, attributed to dysfunction in the basal ganglia-thalamus-cortex loop, influenced by dopaminergic deficits in the striatum. Recent research suggests that the motor cortex may play a pivotal role in mediating the relationship between striatal dopamine depletion and motor function in PD. Understanding this connection is crucial for comprehending the origins of manual dexterity impairments in PD. Therefore, our study aimed to explore how motor cortex activation mediates the association between striatal dopamine depletion and manual dexterity in PD.
MATERIALS AND METHODS
We enrolled 26 mildly affected PD patients in their off-medication phase to undergo [F]FDOPA scans for evaluating striatal dopaminergic function. EEG recordings were conducted during bimanual anti-phase finger tapping tasks to evaluate motor cortex activity, specifically focusing on Event-Related Desynchronization in the beta band. Manual dexterity was assessed using the Purdue Pegboard Test. Regression-based mediation analysis was conducted to examine whether motor cortex activation mediates the association between striatal dopamine depletion and manual dexterity in PD.
RESULTS
Mediation analysis revealed a significant direct effect of putamen dopamine depletion on manual dexterity for the affected hand and assembly tasks (performed with two hands), with motor cortex activity mediating this association. In contrast, while caudate nucleus dopamine depletion showed a significant direct effect on manual dexterity, motor cortex mediation on this association was not observed.
CONCLUSION
Our study confirms the association between striatum dopamine depletion and impaired manual dexterity in PD, with motor cortex activity mediating this relationship.
PubMed: 38955097
DOI: 10.1016/j.parkreldis.2024.107049 -
Biosensors & Bioelectronics Jun 2024Neurotransmitters (NTs) are molecules produced by neurons that act as the body's chemical messengers. Their abnormal levels in the human system have been associated with...
Neurotransmitters (NTs) are molecules produced by neurons that act as the body's chemical messengers. Their abnormal levels in the human system have been associated with many disorders and neurodegenerative diseases, which makes the monitoring of NTs fundamentally important. Specifically for clinical analysis and understanding of brain behavior, simultaneous detection of NTs at low levels quickly and reliably is imperative for disease prevention and early diagnosis. However, the methods currently employed are usually invasive or inappropriate for multiple NTs detection. Herein, we developed a MXene-based impedimetric electronic tongue (e-tongue) for sensitive NT monitoring, using NbC, NbC, MoC, and MoTiC MXenes as sensing units of the e-tongue, and Principal Component Analysis (PCA) as the data treatment method. The high specific surface area, distinct electrical properties, and chemical stability of the MXenes gave rise to high sensitivity and good reproducibility of the sensor array toward NT detection. Specifically, the e-tongue detected and differentiated multiple NTs (acetylcholine, dopamine, glycine, glutamate, histamine, and tyrosine) at concentrations as low as 1 nmol L and quantified NTs present in a mixture. Besides, analyses performed with interferents and actual samples confirmed the system's potential to be used in clinical diagnostics. The results demonstrate that the MXene-based e-tongue is a suitable, rapid, and simple method for NT monitoring with high accuracy and sensitivity.
PubMed: 38954905
DOI: 10.1016/j.bios.2024.116526 -
ACS Sensors Jul 2024Brain organoids are being recognized as valuable tools for drug evaluation in neurodegenerative diseases due to their similarity to the human brain's structure and...
Brain organoids are being recognized as valuable tools for drug evaluation in neurodegenerative diseases due to their similarity to the human brain's structure and function. However, a critical challenge is the lack of selective and sensitive electrochemical sensing platforms to detect the response of brain organoids, particularly changes in the neurotransmitter concentration upon drug treatment. This study introduces a 3D concave electrode patterned with a mesoporous Au nanodot for the detection of electrochemical signals of dopamine in response to drugs in brain organoids for the first time. The mesoporous Au nanodot-patterned film was fabricated using laser interference lithography and electrochemical deposition. Then, the film was attached to a polymer-based 3D concave mold to obtain a 3D concave electrode. Midbrain organoids generated from Parkinson's disease (PD) patient-derived iPSCs with gene mutations (named as PD midbrain organoid) or normal midbrain organoids were positioned on the developed 3D concave electrode. The 3D concave electrode showed a 1.4 times higher electrochemical signal of dopamine compared to the bare gold electrode. And the dopamine secreted from normal midbrain organoids or PD midbrain organoids on the 3D concave electrode could be detected electrochemically. After the treatment of PD midbrain organoids with levodopa, the drug for PD, the increase in dopamine level was detected due to the activation of dopaminergic neurons by the drug. The results suggest the potential of the proposed 3D concave electrode combined with brain organoids as a useful tool for assessing drug efficacy. This sensing system can be applied to a variety of organoids for a comprehensive drug evaluation.
PubMed: 38954790
DOI: 10.1021/acssensors.4c00476 -
Brain : a Journal of Neurology Jul 2024The ability to initiate volitional action is fundamental to human behaviour. Loss of dopaminergic neurons in Parkinson's disease is associated with impaired action...
The ability to initiate volitional action is fundamental to human behaviour. Loss of dopaminergic neurons in Parkinson's disease is associated with impaired action initiation, also termed akinesia. Both dopamine and subthalamic deep brain stimulation (DBS) can alleviate akinesia, but the underlying mechanisms are unknown. An important question is whether dopamine and DBS facilitate de novo build-up of neural dynamics for motor execution or accelerate existing cortical movement initiation signals through shared modulatory circuit effects. Answering these questions can provide the foundation for new closed-loop neurotherapies with adaptive DBS, but the objectification of neural processing delays prior to performance of volitional action remains a significant challenge. To overcome this challenge, we studied readiness potentials and trained brain signal decoders on invasive neurophysiology signals in 25 DBS patients (12 female) with Parkinson's disease during performance of self-initiated movements. Combined sensorimotor cortex electrocorticography (ECoG) and subthalamic local field potential (LFP) recordings were performed OFF therapy (N = 22), ON dopaminergic medication (N = 18) and ON subthalamic deep brain stimulation (N = 8). This allowed us to compare their therapeutic effects on neural latencies between the earliest cortical representation of movement intention as decoded by linear discriminant analysis classifiers and onset of muscle activation recorded with electromyography (EMG). In the hypodopaminergic OFF state, we observed long latencies between motor intention and motor execution for readiness potentials and machine learning classifications. Both, dopamine and DBS significantly shortened these latencies, hinting towards a shared therapeutic mechanism for alleviation of akinesia. To investigate this further, we analysed directional cortico-subthalamic oscillatory communication with multivariate granger causality. Strikingly, we found that both therapies independently shifted cortico-subthalamic oscillatory information flow from antikinetic beta (13-35 Hz) to prokinetic theta (4-10 Hz) rhythms, which was correlated with latencies in motor execution. Our study reveals a shared brain network modulation pattern of dopamine and DBS that may underlie the acceleration of neural dynamics for augmentation of movement initiation in Parkinson's disease. Instead of producing or increasing preparatory brain signals, both therapies modulate oscillatory communication. These insights provide a link between the pathophysiology of akinesia and its' therapeutic alleviation with oscillatory network changes in other non-motor and motor domains, e.g. related to hyperkinesia or effort and reward perception. In the future, our study may inspire the development of clinical brain computer interfaces based on brain signal decoders to provide temporally precise support for action initiation in patients with brain disorders.
PubMed: 38954651
DOI: 10.1093/brain/awae219