Neurobiology of cataplexy

Zhou

et al. 2022

IJERPH

In this study, 16 PAHs were selected as the priority control pollutants to summarize their environmental metabolism and transformation processes, including photolysis, plant degradation, bacterial degradation, fungal degradation, microalgae degradation, and human metabolic transformation. Meanwhile, a total of 473 PAHs by-products generated during their transformation and degradation in different environmental media were considered. Then, a comprehensive system was established for evaluating the PAHs by-products’ neurotoxicity, immunotoxicity, phytotoxicity, developmental toxicity, genotoxicity, carcinogenicity, and endocrine-disrupting effect through molecular docking, molecular dynamics simulation, 3D-QSAR model, TOPKAT method, and VEGA platform. Finally, the potential environmental risk (phytotoxicity) and human health risks (neurotoxicity, immunotoxicity, genotoxicity, carcinogenicity, developmental toxicity, and endocrine-disrupting toxicity) during PAHs metabolism and transformation were comprehensively evaluated. Among the 473 PAH’s metabolized and transformed products, all PAHs by-products excluding ACY, CHR, and DahA had higher neurotoxicity, 152 PAHs by-products had higher immunotoxicity, and 222 PAHs by-products had higher phytotoxicity than their precursors during biological metabolism and environmental transformation. Based on the TOPKAT model, 152 PAH by-products possessed potential developmental toxicity, and 138 PAH by-products had higher genotoxicity than their precursors. VEGA predicted that 247 kinds of PAH derivatives had carcinogenic activity, and only the natural transformation products of ACY did not have carcinogenicity. In addition to ACY, 15 PAHs produced 123 endocrine-disrupting substances during metabolism and transformation. Finally, the potential environmental and human health risks of PAHs metabolism and transformation products were evaluated using metabolic and transformation pathway probability and degree of toxic risk as indicators. Accordingly, the priority control strategy for PAHs was constructed based on the risk entropy method by screening the priority control pathways. This paper assesses the potential human health and environmental risks of PAHs in different environmental media with the help of models and toxicological modules for the toxicity prediction of PAHs by-products, and thus designs a risk priority control evaluation system for PAHs.

Section: Resultsmentioning

confidence: 99%

Potential Toxicity Risk Assessment and Priority Control Strategy for PAHs Metabolism and Transformation Behaviors in the Environment

Zhou

et al. 2022

IJERPH

“…It appears that the norepinephrine neurotransmission is particularly sensitive to MG deficiency, as both the levels of norepinephrine metabolites and the corresponding receptors are significantly affected by MG depletion. Norepinephrine is implicated in both wakefulness 21 and sleep regulation 57, 58 , and it has been suggested that microglial surveillance process relies heavily on norepinephrine signaling 59, 60 . Additionally, we observed a decrease in the expression of neurotransmitter precursors such as L-serine, which was mirrored by changes in the concentrations of glycine, asparagine, and glutamic acid.…”

Section: Discussionmentioning

confidence: 99%

“…VS regulation and sleep oscillatory patterns rely on a complex CNS connectivity, and different cell types, mainly neuronal populations interact with each other (via synaptic connections and neurotransmitter release) to fine-tune the regulation of VS and brain oscillations. Among the major neuropeptides and neurotransmitters involved in VS regulation are hypocretin/orexin (HCRT) and melanin-concentrating hormone neurons (MCH) in the lateral hypothalamus (LH), serotonin (5HT) and noradrenaline (NA) in the brainstem (BS), and acetylcholine in the BS and basal forebrain (BF), and midbrain dopaminergic neurons 20, 21 .…”

Section: Introductionmentioning

confidence: 99%

Embryo-derived brain-resident macrophages sustain sleep-wake circuits

Seifinejad,

Bandarabadi,

Haddar

et al. 2024

Preprint

Self Cite

SummaryBrain resident macrophages such as microglia and CNS-associated macrophages (CAMs) are already established before birth and play therefore a crucial role for normal brain functioning during development. However, their involvement in fine-tuning complex physiological functions such as vigilance states (VS) after birth remains poorly understood. Here, we investigated the reciprocal interaction of microglia and VS using multimodal high throughput transcriptional, electrophysiological and metabolomic profiling in mice. We found that sleep deprivation caused severe transcriptional changes in microglia and CAMs and absence of the wake-promoting neuropeptides hypocretin/orexin intensified these effects. Depletion of embryonic microglia robustly increased sleep quantity during the active period, while decreased sleep quality that was reflected in reduced power of brain sleep oscillations. Unexpectedly, subsequent repopulation by postnatal microglia failed to reestablish normal sleep-wake patterns, and even induced additional abnormalities such as sleep fragmentation. Moreover, we found a substantial excitatory-inhibitory synaptic imbalance following microglia depletion, which was not normalized after microglial repopulation and even lead to an increase of inhibitory synapses in the brain. At the metabolite level, we observed a distinct metabolite pattern after microglia depletion, which largely returned to normal levels after repopulation. Our findings suggest a so far largely unknown interaction between microglia and brain VS and emphasizes striking functional differences between embryonic and postnatal-derived microglia, thereby potentially paving the way for the further exploration of microglia of different origin and their roles in sleep disorders and synaptic connectivity.

“…In narcolepsy patients, cataplexy is sudden muscle paralysis triggered by generally positive emotions [ 6 ]. Furthermore, mood disorders have been linked to shortened nocturnal REM sleep latency, nocturnal sleep fragmentation, and episodic hallucinations in NT1 [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

“…The fibers from hypothalamic secretin neurons project densely onto the cortical and subcortical brain areas, regulating cyclical changes in sleep and wakefulness. In NT1, the areas involved in orexin deficiency extend beyond the hypothalamus to include a wide range of the brain [ 6 , 7 ]. Recently, increasing neuroimaging studies have attempted to confirm the structural and functional abnormalities of the cranial brain in narcolepsy, but their results remained controversial [ 8 , 9 , 10 , 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

Abnormal Regional Spontaneous Neural Activity and Functional Connectivity in Unmedicated Patients with Narcolepsy Type 1: A Resting-State fMRI Study

Zhan²,

Liu³

et al. 2022

IJERPH

Background: Previous Resting-state functional magnetic resonance imaging (fMRI) studies have mainly focused on cerebral functional alteration in processing different emotional stimuli in patients with narcolepsy type 1 (NT1), but were short of exploration of characteristic brain activity and its remote interaction patterns. This study aimed to investigate the spontaneous blood oxygen fluctuations at rest and to elucidate the neural mechanisms underlying neuropsychiatric behavior. Method: A total of 18 unmedicated patients with NT1 and matched healthy individuals were recruited in a resting-state fMRI study. Magnetic resonance imaging (MRI) data were first analyzed using fractional low-frequency amplitude of low-frequency fluctuation (fALFF) to detect changes in local neural activity, and regions with group differences were taken as regions of interest (ROIs). Secondly, functional connectivity (FC) analysis was used to explore altered connectivity between ROIs and other areas. Lastly, the relationship between functional brain activity and neuropsychiatric behaviors was analyzed with correlation analysis. Results: fALFF analysis revealed enhanced neural activity in bilateral fusiform gyrus (FFG), right precentral gyrus, and left postcentral gyrus (PoCG) in the NT1 group. The patients indicated reduced activity in the bilateral temporal pole middle temporal gyrus (TPOmid), left caudate nucleus (CAU), left parahippocampus, left precuneus (PCUN), right amygdala, and right anterior cingulate and paracingulate gyri. ESS score was negatively correlated with fALFF in the right FFG. The NT1 group revealed decreased connectivity between left TPOmid and right PoCG, the bilateral middle frontal gyrus, left superior frontal gyrus, medial, and right supramarginal gyrus. Epworth Sleepiness Scale (ESS) was negatively correlated with FC of the left TPOmid with left putamen (PUT) in NT1. Compared with healthy controls (HCs), enhanced FC of the left CAU with right FFG was positively associated with MSLT-SOREMPs in patients. Furthermore, increased FC of the left PCUN with right PoCG was positively correlated with SDS score. Conclusions: We found that multiple functional activities related to the processing of emotional regulation and sensory information processing were abnormal, and some were related to clinical characteristics. fALFF in the left postcentral or right precentral gyrus may be used as a biomarker of narcolepsy, whereas fALFF in the right fusiform and the FC strength of the left temporal pole middle temporal gyrus with the putamen may be clinical indicators to assess the drowsiness severity of narcolepsy.