Fast-Specific Fluorescent Probes to Visualize Norepinephrine Signaling Pathways and Its Flux in the Epileptic Mice Brain

Journal of the American Chemical Society, Год журнала: 2023, Номер 145(5), С. 3229 - 3237

Опубликована: Янв. 26, 2023

Norepinephrine (NE) is synthesized in the locus coeruleus and widely projected throughout brain spinal cord. It regulates various actions consciousness linked to a variety of neurological diseases. A "hunting-shooting" strategy was proposed this work improve specificity response rate an NE fluorescent probe: 2-(cyclohex-2-en-1-ylidene)malononitrile derivatives were chosen as fluorophore. To create dual-site probe, aldehyde group added ortho ester (or benzene sulfonate). Because its excellent electrophilic activity, could rapidly "hunt" amino then form intramolecular five-membered ring via nucleophilic reaction with β-hydroxyl group. The -NH- "shoots" adjacent group, releasing fluorophore allowing for rapid specific detection. release reuptake ″emetic″-″swallow″ transient process captured visualized under action primary receptor drug. Furthermore, by introducing halogen into lengthen absorption wavelength, lipid solubility, adjust pKa appropriately, probe successfully penetrated blood-brain barrier (BBB). In situ synchronous imaging used detect level brains epileptic normal mice, abnormal expression discovered during epilepsy. Brain anatomy examine distribution changes regions before after This research provides useful tools theoretical foundation diagnosing treating central nervous system diseases early.

Язык: Английский

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Dual-3DM³AD: Mixed Transformer Based Semantic Segmentation and Triplet Pre-Processing for Early Multi-Class Alzheimer’s Diagnosis

IEEE Transactions on Neural Systems and Rehabilitation Engineering, Год журнала: 2024, Номер 32, С. 696 - 707

Опубликована: Янв. 1, 2024

Alzheimer's Disease (AD) is a widespread, chronic, irreversible, and degenerative condition, its early detection during the prodromal stage of utmost importance. Typically, AD studies rely on single data modalities, such as MRI or PET, for making predictions. Nevertheless, combining metabolic structural can offer comprehensive perspective staging analysis. To address this goal, paper introduces an innovative multi-modal fusion-based approach named Dual-3DM ³ -AD. This model proposed accurate diagnosis by considering both PET image scans. Initially, we pre-process images in terms noise reduction, skull stripping 3D conversion using Quaternion Non-local Means Denoising Algorithm (QNLM), Morphology function Block Divider Model (BDM), respectively, which enhances quality. Furthermore, have adapted Mixed-transformer with Furthered U-Net performing semantic segmentation minimizing complexity. -AD consisted multi-scale feature extraction module extracting appropriate features from segmented images. The extracted are then aggregated Densely Connected Feature Aggregator Module (DCFAM) to utilize features. Finally, multi-head attention mechanism dimensionality softmax layer applied multi-class diagnosis. compared several baseline approaches help performance metrics. final results unveil that work achieves 98% accuracy, 97.8% sensitivity, 97.5% specificity, 98.2% f-measure, better ROC curves, outperforms other existing models multiclass

Язык: Английский

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Activation of locus coeruleus noradrenergic neurons rapidly drives homeostatic sleep pressure

Science Advances, Год журнала: 2025, Номер 11(3)

Опубликована: Янв. 17, 2025

Homeostatic sleep regulation is essential for optimizing the amount and timing of its revitalizing function, but mechanism underlying homeostasis remains poorly understood. Here, we show that optogenetic activation locus coeruleus (LC) noradrenergic neurons immediately increased propensity following a transient wakefulness, contrasting with many other arousal-promoting whose induces sustained wakefulness. Fiber photometry showed repeated or sensory stimulation caused rapid reduction calcium activity in LC steep declines noradrenaline/norepinephrine (NE) release both medial prefrontal cortex (mPFC). Knockdown α 2 A adrenergic receptors mitigated decline NE induced by repetitive extended demonstrating an important role receptor–mediated auto-suppression release. Together, these results suggest functional fatigue neurons, which reduces their wake-promoting capacity, contributes to pressure.

Язык: Английский

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Recent update on the heterogeneity of the Alzheimer’s disease spectrum

Journal of Neural Transmission, Год журнала: 2021, Номер 129(1), С. 1 - 24

Опубликована: Дек. 17, 2021

Язык: Английский

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Mitochondrial complex I as a therapeutic target for Alzheimer's disease

Acta Pharmaceutica Sinica B, Год журнала: 2021, Номер 12(2), С. 483 - 495

Опубликована: Ноя. 9, 2021

Alzheimer's disease (AD), the most prominent form of dementia in elderly, has no cure. Strategies focused on reduction amyloid beta or hyperphosphorylated Tau protein have largely failed clinical trials. Novel therapeutic targets and strategies are urgently needed. Emerging data suggest that response to environmental stress, mitochondria initiate an integrated stress (ISR) shown be beneficial for healthy aging neuroprotection. Here, we review implicate mitochondrial electron transport complexes involved oxidative phosphorylation as a hub small molecule-targeted therapeutics could induce ISR. Specifically, partial inhibition complex I been exploited novel strategy multiple human conditions, including AD, with several molecules being tested We discuss current understanding molecular mechanisms this counterintuitive approach. Since also enhance health life span, development safe efficacious inhibitors promote aging, delaying onset age-related neurodegenerative diseases.

Язык: Английский

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Astrocytes Render Memory Flexible by Releasing D-Serine and Regulating NMDA Receptor Tone in the Hippocampus

Biological Psychiatry, Год журнала: 2021, Номер 91(8), С. 740 - 752

Опубликована: Окт. 21, 2021

Язык: Английский

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Locus Coeruleus Integrity from 7 T MRI Relates to Apathy and Cognition in Parkinsonian Disorders

Movement Disorders, Год журнала: 2022, Номер 37(8), С. 1663 - 1672

Опубликована: Май 16, 2022

Abstract Background Neurodegeneration in the locus coeruleus (LC) contributes to neuropsychiatric symptoms both Parkinson's disease (PD) and progressive supranuclear palsy (PSP). Spatial precision of LC imaging is improved with ultrahigh field 7 T magnetic resonance imaging. Objectives This study aimed characterize spatial patterns pathological change PD PSP transdiagnostic relationship between signals symptoms. Methods Twenty‐five people idiopathic PD, 14 probable PSP‐Richardson's syndrome, 24 age‐matched healthy controls were recruited. Participants underwent clinical assessments high‐resolution (0.08 mm 3 ) T‐magnetization‐transfer measure integrity vivo. obtained using subregional mean contrast ratios significant clusters; we further correlated measures apathy cognition, mixed‐effect models voxelwise analyses. Results groups showed degeneration caudal subregion relative controls. Mixed‐effect revealed a interaction disease‐group apathy‐related correlations ( β = 0.46, SE [standard error] 0.17, F (1, 35) 7.46, P 0.01), driven by strong correlation −0.58, 0.21, t (35) −2.76, 0.009). Across groups, analyses indicated that lower was associated worse cognition higher scores. Conclusions The nonmotor highlights role for noradrenergic dysfunction across PSP, confirming potential therapeutic strategies address cognitive behavioral features neurodegenerative disease. © 2022 Authors. Movement Disorders published Wiley Periodicals LLC on behalf International Parkinson Disorder Society

Язык: Английский

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Cerebrospinal fluid catecholamines in Alzheimer’s disease patients with and without biological disease

Translational Psychiatry, Год журнала: 2022, Номер 12(1)

Опубликована: Апрель 9, 2022

Abstract Noradrenergic and dopaminergic neurons are involved in cognitive functions, relate to behavioral psychological symptoms dementia affected Alzheimer’s disease (AD). Amyloid plaques (A), neurofibrillary tangles (T) neurodegeneration (N) hallmarks the AD neuropathology. Today, AT(N) pathophysiology can be assessed through biomarkers. Previous studies report cerebrospinal fluid (CSF) catecholamine concentrations patients without biomarker refinement. We explored if CSF catecholamines clinical presentation or neuropathology as reflected by were analyzed at mild impairment (MCI; n = 54) stage ( 240) cognitively unimpaired 113). biomarkers determined AT status indicated synaptic damage (neurogranin). The 294) had higher noradrenaline adrenaline concentrations, but lower dopamine compared MCI of similar concentrations. In neurogranin positively associated with not dopamine. Adjusted regression analyses including status, neurogranin, age, gender, APOEε4 verified findings. restricted comparing A+T+ A−T− unimpaired, findings for remained significant p < 0.001) 0.07) 0.33). There no differences between unimpaired. Thus, we find alterations symptomatic adrenergic transmitters increase simultaneously indexed neurogranin.

Язык: Английский

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Associations among locus coeruleus catecholamines, tau pathology, and memory in aging

Neuropsychopharmacology, Год журнала: 2022, Номер 47(5), С. 1106 - 1113

Опубликована: Янв. 15, 2022

Язык: Английский

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Noradrenergic and cholinergic systems take centre stage in neuropsychiatric diseases of ageing

Neuroscience & Biobehavioral Reviews, Год журнала: 2023, Номер 149, С. 105167 - 105167

Опубликована: Апрель 11, 2023

Noradrenergic and cholinergic systems are among the most vulnerable brain in neuropsychiatric diseases of ageing, including Alzheimer's disease, Parkinson's Lewy body dementia, progressive supranuclear palsy. As these fail, they contribute directly to many characteristic cognitive psychiatric symptoms. However, their contribution symptoms is not sufficiently understood, pharmacological interventions targeting noradrenergic have met with mixed success. Part challenge complex neurobiology systems, operating across multiple timescales, non-linear changes adult lifespan disease course. We address challenges a detailed review outlining roles cognition behaviour, how influence disease. By bridging levels analysis, we highlight opportunities for improving drug therapies pursuing personalised medicine strategies.

Язык: Английский

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