Spontaneous Activity Research Articles

EXPRESS: Advanced cancer perineural invasion induces profound peripheral neuronal plasticity, pain, and somatosensory mechanical deactivation, unmitigated by the lack of TNFR1. Part. 1: Behavior and single-cell in vivo electrophysiology.

Patients with cancer perineural invasion (PNI) report greater spontaneous pain and mechanical allodynia. Here, we examine the impact of the disease on the peripheral sensory system, the excitability changes induced by PNI at the dorsal root ganglia, and the potential protective role of the absence of Tumor Necrosis Factor-α Receptor 1 (TNFR1). To study these effects, we use a murine model generated by injecting mouse oral cancer squamous cell carcinoma (MOC2) into the sciatic nerve (MOC2-PNI) in both male and female mice. We found that MOC2-PNI induces a profound change in the somatosensory landscape by deactivating/blocking the peripheral inputs while modulating the afferent's sensibility (tactile desensitization with concurrent nociceptive sensitization) and demyelination without inducing spontaneous activity. All these changes caused by MOC2-PNI are unmitigated by the absence of TNFR1. We conclude that MOC2-PNI induces an aberrant neuronal excitability state and triggers extreme gender-specific neuronal plasticity. These data allow us to speculate on the role of such plasticity as a powerful defense mechanism to prevent terminal sensory dysfunction, the rise of chronic pain, and extend animals' survivability.

Sequence-dependent activity and compartmentalization of foreign DNA in a eukaryotic nucleus.

In eukaryotes, DNA-associated protein complexes coevolve with genomic sequences to orchestrate chromatin folding. We investigate the relationship between DNA sequence and the spontaneous loading and activity of chromatin components in the absence of coevolution. Using bacterial genomes integrated into Saccharomyces cerevisiae, which diverged from yeast more than 2 billion years ago, we show that nucleosomes, cohesins, and associated transcriptional machinery can lead to the formation of two different chromatin archetypes, one transcribed and the other silent, independently of heterochromatin formation. These two archetypes also form on eukaryotic exogenous sequences, depend on sequence composition, and can be predicted using neural networks trained on the native genome. They do not mix in the nucleus, leading to a bipartite nuclear compartmentalization, reminiscent of the organization of vertebrate nuclei.

Impaired hippocampal neurogenesis associated with regulatory ceRNA network in a mouse model of postoperative cognitive dysfunction

BackgroundPostoperative cognitive dysfunction (POCD) represents a post-surgical complication that features progressive cognitive impairment and memory loss, often occurring in elderly patients. This study aimed to investigate the potential biological mechanisms underlying POCD.MethodsMale C57BL/6 mice (2 and 17 months old) were randomly assigned to surgery or control groups. The surgery group underwent laparotomy under 1.5% isoflurane anesthesia, while controls received no intervention. Cognitive function was assessed 7–10 days post-surgery using open field, Y-maze, and novel object recognition tests.Hippocampal mRNA expression was analyzed using Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment. A competing endogenous RNA (ceRNA) network was constructed using microRNA (miRNA) target prediction databases (miRanda, miRTarbase, miRcode) and sequencing results. Key findings were validated by RT-qPCR and immunofluorescence. The Connectivity Map (CMap) database was queried to predict potential POCD treatments.ResultsAging significantly affected mice’s spontaneous activity in the open field test (F1, 28 = 8.933, P < 0.01) and the proportion of time spent in the center area (F1, 28 = 5.387, P < 0.05). Surgery significantly reduced the rate of spontaneous alternations in the Y-maze (F1, 28 = 16.94, P < 0.001) and the recognition index in novel object recognition test (F1, 28 = 6.839, P < 0.05) in aging mice, but had no effect on young mice. Transcriptome analysis revealed that aging and surgery downregulated multiple neurogenesis-related genes in the hippocampus. Doublecortin (DCX) immunofluorescence staining confirmed reduced hippocampal neurogenesis in aging mice, which was further decreased after surgery. We identified several key lncRNAs and miRNAs implicated in neurogenesis regulation. Additionally, drugs were predicted as potential therapeutic candidates for POCD treatment.ConclusionBoth aging and surgery have complex effects on the hippocampal transcriptome in mice. The significant decrease in neurogenesis may be a potential reason for the increased susceptibility of aging mice to POCD. The identified key regulatory lncRNAs, miRNAs, and drugs provide potential therapeutic targets for POCD prevention and treatment.

Microbial metabolites tune amygdala neuronal hyperexcitability and anxiety-linked behaviors.

Changes in gut microbiota composition have been linked to anxiety behavior in rodents. However, the underlying neural circuitry linking microbiota and their metabolites to anxiety behavior remains unknown. Using male C57BL/6J germ-free (GF) mice, not exposed to live microbes, increased anxiety-related behavior was observed correlating with a significant increase in the immediate early c-Fos gene in the basolateral amygdala (BLA). This phenomenon coincided with increased intrinsic excitability and spontaneous synaptic activity of BLA pyramidal neurons associated with reduced small conductance calcium-activated potassium (SK) channel currents. Importantly, colonizing GF mice to live microbes or the microbial-derived metabolite indoles reverted SK channel activities in BLA pyramidal neurons and reduced the anxiety behavioral phenotype. These results are consistent with a molecular mechanism by which microbes and or microbial-derived indoles, regulate functional changes in the BLA neurons. Moreover, this microbe metabolite regulation of anxiety links these results to ancient evolutionarily conserved defense mechanisms associated with anxiety-related behaviors in mammals.

Multimodal abnormalities of brain function in chronic low back pain: a systematic review and meta-analysis of neuroimaging studies

ObjectivesNeuroimaging investigations into chronic low back pain (CLBP) have detected functional abnormalities across a spectrum of brain regions, yet the findings have often been inconsistent. In this meta-analysis, we integrated the existing data, delineating a pattern of coherent results from the encompassed studies.MethodsA systematic search of neuroimaging studies investigating the brain activity differences between CLBP and Healthy controls (HCs) was conducted in seven databases up to December 22, 2024. An anisotropic effect-size signed differential mapping (AES-SDM)-based meta-analysis was carried out to report the results and perform a multimodal analysis.ResultsA total of 20 publications reporting on 24 experiments in this meta-analysis. The ReHo meta-analysis showed abnormal spontaneous activity of left inferior temporal gyrus (ITG), left superior frontal gyrus (SFG), right middle frontal gyrus (MFG), right precuneus, right fusiform gyrus and bilateral postcentral gyrus (PoCG) in CLBP patients. The ALFF meta-analysis demonstrated functional alterations in the right rolandic operculum (extending to the right insula and right IFG), left ITG, left middle occipital gyrus (MOG), left paracentral lobule, left PoCG and bilateral cuneus cortex in CLBP patients. The results of the functional group meta-analysis revealed that patients with CLBP displayed new decreased functional activity in the right thalamus, right precentral gyrus (PreCG) and right lingual gyrus.ConclusionPatients with CLBP exhibit extensive multimodal functional neuroimaging abnormalities, involving brain regions related to pain perception, emotional processing, cognitive functions, and both the visual and motor cortices. These meta-analysis findings might provide a valuable reference for the identification of potential therapeutic targets for CLBP in the brain.

The developmental emergence of reliable cortical representations.

The fundamental structure of cortical networks arises early in development before the onset of sensory experience. However, how endogenously generated networks respond to the onset of sensory experience and how they form mature sensory representations with experience remain unclear. In this study, we examined this 'nature-nurture transform' at the single-trial level using chronic in vivo calcium imaging in ferret visual cortex. At eye opening, visual stimulation evokes robust patterns of modular cortical network activity that are highly variable within and across trials, severely limiting stimulus discriminability. These initial stimulus-evoked modular patterns are distinct from spontaneous network activity patterns present before and at the time of eye opening. Within a week of normal visual experience, cortical networks develop low-dimensional, highly reliable stimulus representations that correspond with reorganized patterns of spontaneous activity. Using a computational model, we propose that reliable visual representations derive from the alignment of feedforward and recurrent cortical networks shaped by novel patterns of visually driven activity.

Similarities and Differences in Resting-State Brain Activity Changes of Distinct Chronic Pain Types.

To explore neural similarities and differences between visceral and somatic pain by comparing spontaneous brain activity in patients with chronic temporomandibular disorder (TMD) and irritable bowel syndrome (IBS). Twenty eight IBS patients, 21 TMD patients, and 28 healthy controls (HC) underwent resting-state fMRI and behavioral assessments. The correlations between fMRI metrics such as the amplitude of low-frequency fluctuations (ALFF), regional homogeneity (ReHo), functional connectivity (FC), and clinical manifestations were further analyzed. Compared with HC, both patient groups demonstrated increased ALFF in right parahippocampal gyrus (PHG), insula, medial superior frontal gyrus (SFGmed), precentral gyrus (PreCG), and increased ReHo in right SFGmed and left supplementary motor area (SMA). Compared with IBS patients, TMD patients exhibited reduced ALFF in right SFGmed and insula, increased ALFF in right PHG and PreCG, decreased ReHo in right SFGmed and left lingual gyrus, and increased ReHo in left SMA. Both patient groups exhibited enhanced right PHG-related FC in left precuneus and right cingulate gyrus, and right insula-related FC in left superior temporal gyrus and right paracentral lobule. Specifically, IBS patients showed higher FC between right PHG and orbitofrontal cortex than TMD patients, which was negatively correlated with mood and gastrointestinal symptoms. Mediation analysis revealed that pain in TMD and gastrointestinal symptoms in IBS mediated these relationships. Visceral and somatic pain share abnormal activity in multiple brain networks. Abnormalities in affective region present potential neuroimaging markers for pain disorders, with depression in somatic pain linked to pain intensity and in visceral pain to gastrointestinal symptoms.

Ligand-Independent Spontaneous Activation of Purinergic P2Y6 Receptor Under Cell Culture Soft Substrate

G protein-coupled receptors (GPCRs) exist in the conformational equilibrium between inactive state and active state, where the proportion of active state in the absence of a ligand determines the basal activity of GPCRs. Although many GPCRs have different basal activity, it is still unclear whether physiological stresses such as substrate stiffness affect the basal activity of GPCRs. In this study, we identified that purinergic P2Y6 receptor (P2Y6R) induced spontaneous Ca2+ oscillation without a nucleotide ligand when cells were cultured in a silicon chamber. This P2Y6R-dependent Ca2+ oscillation was absent in cells cultured in glass dishes. Coating substrates, including collagen, laminin, and fibronectin, did not affect the P2Y6R spontaneous activity. Mutation of the extracellular Arg-Gly-Asp (RGD) motif of P2Y6R inhibited spontaneous activity. Additionally, extracellular Ca2+ was required for P2Y6R-dependent spontaneous Ca2+ oscillation. The GPCR screening assay identified cells expressing 10 GPCRs, including purinergic P2Y1R, P2Y2R, and P2Y6R, that exhibited spontaneous Ca2+ oscillation under cell culture soft substrate. Our results suggest that stiffness of the cell adhesion surface modulates spontaneous activities of several GPCRs, including P2Y6R, through a ligand-independent mechanism.

Translaminar synchronous neuronal activity is required for columnar synaptic strengthening in the mouse neocortex

Synchronous neuronal activity is a hallmark of the developing mouse primary somatosensory cortex. While the patterns of synchronous neuronal activity in cortical layer 2/3 have been well described, the source of the robust layer 2/3 activity is still unknown. Using a novel microprism preparation and in vivo 2-photon imaging in neonatal mice, we show that synchronous neuronal activity is organized in barrel columns across layers. Monosynaptic rabies tracing and slice electrophysiology experiments reveal that layer 2/3 pyramidal neurons receive significant layer 5 inputs during the first postnatal week, and silencing layer 5 synaptic outputs results in a significant reduction in spontaneous activity, abnormal sensory-evoked activity and disrupted layer 4-layer 2/3 connectivity. Our results demonstrate that translaminar layer 5-layer 2/3 connectivity plays an important role in synchronizing the developing barrel column to ensure the strengthening of layer 4-layer 2/3 connections, supporting the formation of the canonical cortical organization in barrel cortex.

Differed brain spontaneous neural activity between limb-onset and bulbar-onset amyotrophic lateral sclerosis patients.

To investigate the differences in brain spontaneous neural activity between limb-onset and bulbar-onset amyotrophic lateral sclerosis (ALS-L and ALS-B, respectively) patients using resting-state functional MRI (rs-fMRI) with amplitude of low-frequency fluctuation (ALFF) and regional homogeneity (ReHo). The rs-fMRI data were collected from 41 ALS patients (11 ALS-B and 30 ALS-L) and 25 healthy controls (HC). ALFF and ReHo values were calculated, and group differences were assessed using one-way ANCOVA and two-sample t-tests. Correlation analyses with clinical measures were conducted. Support vector machine (SVM) analysis was performed to distinguish ALS subtypes. Compared with ALS-L, ALS-B showed increased ALFF values in the right gyrus rectus/ orbital part of right middle frontal gyrus, orbital part of left middle frontal gyrus and left dorsolateral superior frontal gyrus/ left medial superior frontal gyrus and decreased ALFF values in the left superior occipital gyrus (FDR-corrected, P < 0.05). Both ALS subtypes demonstrated distinct ALFF alterations compared to HC. Differences in ReHo values were only found between ALS-B and HC. Correlation analyses revealed associations between ALFF in specific brain regions and ALS clinical scores. SVM analysis achieved an accuracy of 90.2 %, with an AUC of 0.909 in differentiating ALS-B and ALS-L. ALS-B and ALS-L patients had distinct alterations in brain spontaneous neural activity, which could serve as potential biomarkers for accurately distinguishing these two subtypes. Our findings offer a new insight into the neural mechanism of ALS, underscoring the importance of personalized diagnostic approaches for this complex neurological disorder.

Time-Varying Spatial Propagation of Brain Networks in fMRI Data.

Spontaneous neural activity coherently relays information across the brain. Several efforts have been made to understand how spontaneous neural activity evolves at the macro-scale level as measured by resting-state functional magnetic resonance imaging (rsfMRI). Previous studies observe the global patterns and flow of information in rsfMRI using methods such as sliding window or temporal lags. However, to our knowledge, no studies have examined spatial propagation patterns evolving with time across multiple overlapping 4D networks. Here, we propose a novel approach to study how dynamic states of the brain networks spatially propagate and evaluate whether these propagating states contain information relevant to mental illness. We implement a lagged windowed correlation approach to capture voxel-wise network-specific spatial propagation patterns in dynamic states. Results show systematic spatial state changes over time, which we confirmed are replicable across multiple scan sessions using human connectome project data. We observe networks varying in propagation speed; for example, the default mode network (DMN) propagates slowly and remains positively correlated with blood oxygenation level-dependent (BOLD) signal for 6-8 s, whereas the visual network propagates much quicker. We also show that summaries of network-specific propagative patterns are linked to schizophrenia. More specifically, we find significant group differences in multiple dynamic parameters between patients with schizophrenia and controls within four large-scale networks: default mode, temporal lobe, subcortical, and visual network. Individuals with schizophrenia spend more time in certain propagating states. In summary, this study introduces a promising general approach to exploring the spatial propagation in dynamic states of brain networks and their associated complexity and reveals novel insights into the neurobiology of schizophrenia.

Oxaliplatin reversibly and differentially affects electrogenic activity of small IB4(+) of male and female rat sensory neurons.

Oxaliplatin-induced peripheral neuropathy (OIPN) is a prevalent drug side effect with unclear molecular mechanism and sex differences. We report that a 48-hour exposure of 1 µg·mL-1 oxaliplatin potently and reversibly increased the excitability of IB4(+) male and female nociceptors. In females, oxaliplatin augmented spontaneous and tonic activity, increased the overshoot and amplitude of action potentials, depolarized the membrane potential, reduced the rheobase, and raised the firing frequency, primarily due to the depolarization of KV currents and a mild up-regulation of TTX-resistant (TTX-r) NaV currents. In males, oxaliplatin reduced the rheobase, augmented the firing frequency, and prolonged the action potential peak time, mediated by increased TTX-r NaV currents, hyperpolarization of their activation curve, and a faster recovery from inactivation. Oxaliplatin also up-regulated TRPV1 currents in male and female IB4(+) nociceptors and augmented TRPA1 responses in male IB4(+) neurons. These findings highlight NaV1.8, TRPV1, and TRPA1 as therapeutic targets to mitigate OIPN and validate the use of long-term nociceptor cultures as preclinical models for studying peripheral neuropathies.

Automatic detection and characterization of maturational neurobiomarkers identified as nested oscillations in premature newborns using high-density electroencephalography

Neural development leads to the evolution of electroencephalographic (EEG) characteristics during the third trimester of gestation. Theta activity in coalescence with slow waves (TA-SW) and delta brushes (DB) are key clinical neurobiomarkers in the evaluation of neurodevelopment in infants prior to full-term gestation. Both neurobiomarkers exhibit nested oscillations, a key feature of intrinsic spontaneous oscillatory activity, allowing the investigation of neural interaction development in the underlying circuits. In the present study, we propose an automatic approach for the detection and characterization of neurobiomarkers that (1) leverages high-density EEG (HD-EEG), (2) incorporates temporal dynamics and spatial distributions, and (3) evaluates the characteristics of nested oscillations. This method evaluates both slow and rapid neural activity, along with their cross-frequency coupling. Our results are in good agreement with those of clinical experts, achieving ROC performances and overall accuracies of 91 %/84 % and 83 %/75 % for TA-SW/DB events, respectively. Following detection and validation, we characterized and compared these two neurobiomarkers. Correlation-based spatial clustering showed that DB patterns were more symmetric and diffuse, whereas TA-SW patterns were more localized in the right and left temporal areas. Comparisons revealed (1) greater variability in spatial patterns for DB than for TA-SW, and that (2) while slow-wave coupling to fast oscillations showed similar characteristics for both neurobiomarkers, differences emerged in the amplitude and descending slope of the underlying slow waves. These findings suggested potential differences in the mechanisms underlying their generation, particularly in the modulation of slow oscillations. This approach represents a promising avenue for the quantitative evaluation of EEG signatures pertinent to early neural development in premature neonates.

Sequence of episodic memory-related behavioral and brain-imaging abnormalities in type 2 diabetes.

Episodic memory decline is a common complication of type 2 diabetes (T2D). To comprehensively explore the neural mechanisms underlying it, we aimed to explore the sequence that episodic memory-related behavioral and brain-imaging biomarkers appear abnormal in the progression of T2D. We enrolled 62 healthy controls and 110 patients with T2D. The California Verbal Learning Test, Montreal cognitive assessment, and Stroop color word test was used to assess the episodic memory, general cognitive function, and executive function. Principal component analysis was applied to extract behavioral biomarkers. Imaging biomarkers included structural and functional MRI features of the entorhinal cortex-hippocampus and hippocampus-anterior cingulate cortex pathways. We used a novel discriminative event-based model to determine the sequence that memory-related biomarkers appear abnormal and estimate the stage of memory decline. T2D patients exhibited poorer memory, general cognitive function, and executive function compared to healthy controls after controlling age, sex, and education level. In the progression of T2D, functional interaction between brain regions showed abnormalities first, followed by memory tests, the cerebral spontaneous neural activity, and finally the gray matter volume. Besides, abnormalities appeared earlier in the entorhinal cortex than in the anterior cingulate cortex. Later stage of memory decline was distributed in older patients with T2D and was associated with higher systolic blood pressure, postprandial blood glucose, and low-density lipoprotein. In T2D, behavioral and brain imaging biomarkers of episodic memory appear abnormal in a specific sequence, and the stage of memory decline was closely associated with old age and vascular risk factors. NCT02420470, ClinicalTrials.gov ( https://www. gov/ ).

Small fiber pathology in fibromyalgia syndrome.

About 50% of women with fibromyalgia syndrome have reduced skin innervation. This finding is consistent in patient cohorts from different regions of the world. Small fiber function may also be affected, as shown by various studies using different methods, such as quantitative sensory testing or special small fiber neurophysiology such as C-fiber microneurography. Microneurography in particular has shown increased spontaneous activity, mechanosensitivity, and enhanced activity-induced slowing in C fibers of patients with fibromyalgia. Generalized reduction of skin innervation, ie, proximally and distally, was associated with higher symptom severity and more pronounced central nervous system changes as seen in magnetic resonance tomography. The question whether peripheral or central nervous system changes come first, or whether both are signs of an underlying pathology, has not been resolved yet. For clinical practice, it is important to note that reduced skin innervation in fibromyalgia must not be confused with small fiber neuropathy, which is a separate entity with different characteristics and pathophysiology. Further prospective research is warranted to transfer these findings in the peripheral nervous system into clinical fibromyalgia patient management.

Altered local spontaneous activity and functional connectivity density in major depressive disorder patients with anhedonia.

The purpose of this study was to investigate the alterations of intrinsic brain function in major depressive disorder (MDD) patients with and without anhedonia based on whole-brain level by using two novel measures, four-dimensional spatial-temporal consistency of local neural activity (FOCA) and local functional connectivity density (lFCD). A total of 26 MDD patients with anhedonia (MDD-WA), 29 MDD patients without anhedonia (MDD-WoA), and 30 healthy controls (HCs) were recruited and underwent resting-state functional magnetic resonance imaging (rs-fMRI) scanning and intrinsic brain function was explored by FOCA and lFCD. A two-sample t-test was conducted to explore FOCA and lFCD differences between MDD patients and HCs, then analysis of covariance (ANCOVA) and post hoc tests were performed to obtain brain regions with significant differences among three groups. Finally, the diagnostic performance of FOCA and lFCD values with significant inter-group difference was evaluated using receiver operating characteristic (ROC) curves. Compared to HCs, MDD patients showed decreased FOCA in the right cuneus (CUN) and left postcentral gyrus (PoCG), as well as diminished lFCD in the right CUN and left calcarine fissure and surrounding cortex (CAL). Interestingly, the MDD-WA group was more likely to exhibit decreased FOCA in the left PoCG and reduced lFCD in the left CAL after consideration for the effect of anhedonia in MDD patients. The MDD-WA group further showed increased FOCA in the bilateral caudate (CAU) and right ventral anterior nucleus (VA) when comparing to HCs. Additionally, as compared with MDD-WoA group, the MDD-WA group presented decreased FOCA in the right middle occipital gyrus (MOG), which was also negatively associated with the severity of anhedonia in MDD patients. Finally, FOCA values of the right MOG exhibited excellent discriminant validity in differentiating MDD-WA from MDD-WoA, and the other individual or combined indices of FOCA or lFCD values in the aforementioned distinct brain regions presented significant utility in distinguishing between MDD or MDD-WA and HCs. The present findings suggest that aberrant intrinsic brain function in the left CAL, left PoCG, bilateral CAU, right VA, and, especially the right MOG may be associated with anhedonia in patients with MDD. Altered FOCA in the right MOG may have the potential to be a diagnostic neuroimaging biomarker for MDD patients with anhedonia.

Abstract TMP118: Validation and Reliability of the SPAN Score for Assessing Neurological Function in Mouse Stroke Models following MCAO

Introduction: Neuroanatomy-based functional examinations are crucial for understanding the extent and effects of infarcts in stroke studies. Despite the importance of correlating neurological function with brain anatomy, a comprehensive neurological score that correlates with infarction volume and location following middle cerebral artery occlusion (MCAO) in mice is lacking. During the pilot phase of the Stroke Preclinical Assessment Network (SPAN), a new scoring system—SPAN score—was developed. This study aims to evaluate the reliability and validity of the SPAN score, a 9-item tool rated on a 0-3 Likert scale. Methods: The SPAN 2.0 pilot database was utilized for analysis. Reliability was assessed using Cronbach's alpha (α) and intraclass correlation coefficient (ICC) for individual items and the total score. Multivariate regression was performed for item selection and to determine the weight of each item. Concurrent validity was examined by correlating post-operative day 2 infarction volume, as measured by MRI, with the SPAN score. Results: The total SPAN score demonstrated acceptable reliability, with Cronbach's α and ICC both at 0.751. Item-total correlation coefficients of each item ranged from 0.092 to 0.638. The Pearson correlation coefficient between the total SPAN score and infarction volume was 0.539. Notably, spontaneous activity showed a reversed relationship with other items; excluding this item increased Cronbach's α to 0.766. Conclusion: The SPAN score proves to be a reliable and valid tool for neuroanatomy-based functional assessment in mouse stroke models following MCAO. Ongoing analysis will focus on refining the score by reducing the number of items, adjusting the Likert scale, incorporating lesion area, and further exploring item relationships.

Unveiling the Potential Biological and Chemical Mechanism of Pergularia tomentosa Extracts by Liquid Chromatography-Electrospray Ionisation-High-Resolution Tandem Mass Spectrometry, In-Vitro and In-Vivo Pharmacological Studies.

By means of this investigation, we were able to ascertain some hitherto undiscovered biological activities of Pergularia tomentosa. In this study, the chemical composition of P. tomentosa extracts (aqueous PtAE and hydroalcoholic PtHE) was investigated by liquid chromatography-electrospray ionisation-high-resolution tandem mass spectrometry (LC-ESI-HR-MS/MS) analysis. The extracts were evaluated for various biological features in vitro, including antioxidant, anti-inflammatory, urease inhibitory, and sun protection factor (SPF) capabilities. To assess the antioxidant activity of PtAE and PtHE, which was expressed as 50% inhibition and absorbance at 0.5 values, 1,1-diphenyl-2-picrylhydrazyl (DPPH•) and 2,2'-azino-bis(3 ethylbenzothiazoline-6-sulfonic acid) (ABTS•+) scavenging, ferric reducing power, and silver nanoparticle-based assays were performed. The in vitro anti-inflammatory impact was investigated to assess the inhibitory effect of PtAE and PtHE on albumin denaturation. Also, we established, for the first time, P. tomentosa's urease inhibitory capacity and SPF. In order to assess the in vivo biological features of PtAE and PtHE, experiments were conducted to evaluate their acute toxicity, anti-inflammatory effects and sedative properties, which are determined for the first time. The outcomes revealed that these extracts are prolific in flavonoids and cardenolides, among other secondary metabolites. Some of these compounds are identified for the first time in the P. tomentosa plant. The findings demonstrated that PtHE was potent against DPPH● (244.43 ± 1.44µg/mL), ABTS●+ (18.30 ± 2.11µg/mL), and PtAE was strongly active against ferric reducing power (4.56 ± 0.80µg/mL) and SNP (44.81 ± 1.13µg/mL). The anti-inflammatory potential of PtAE and PtHE is significant, and their inhibition percentages (61.57% for PtAE and 43.77% for PtHE) are comparable to the reference ibuprofen. All treated mice did not exhibit any signs of intoxication after receiving a single dose of 2000mg/kg of PtAE and PtHE oral alternatively. PtAE and PtHE have potent anti-inflammatory with inhibition percentages of 77.25% and 43.00%, respectively. Emphasising the sedative effect of both P. tomentosa extracts, the oral administration of the extracts produced a decrease in movement of 49.77% for the PtAE and 60.00% for the PtHE. These highlights prove the ability of PtAE and PtHE to suppress the formation of paw oedema and lower spontaneous locomotor activity in treated mice. The data gathered suggest that P. tomentosa has potential use in the pharmaceutical industries as an alternative therapy for different physiological disorders and diseases and as a therapeutic agent.

Glia control experience-dependent plasticity in an olfactory critical period.

Sensory experience during developmental critical periods has lifelong consequences for circuit function and behavior, but the molecular and cellular mechanisms through which experience causes these changes are not well understood. The Drosophila antennal lobe houses synapses between olfactory sensory neurons (OSNs) and downstream projection neurons (PNs) in stereotyped glomeruli. Many glomeruli exhibit structural plasticity in response to early-life odor exposure, indicating a general sensitivity of the fly olfactory circuitry to early sensory experience. We recently found that glia shape antennal lobe development in young adults, leading us to ask if glia also drive experience-dependent plasticity during this period. Here, we define a critical period for structural and functional plasticity of OSN-PN synapses in the ethyl butyrate (EB)-sensitive glomerulus VM7. EB exposure for the first 2 days post-eclosion drives large-scale reductions in glomerular volume, presynapse number, and post- synaptic activity. Crucially, pruning during the critical period has long-term consequences for circuit function since both OSN-PN synapse number and spontaneous activity of PNs remain persistently decreased following early-life odor exposure. The highly conserved engulfment receptor Draper is required for this critical period plasticity as ensheathing glia upregulate Draper, invade the VM7 glomerulus, and phagocytose OSN presynaptic terminals in response to critical-period EB exposure. Loss of Draper fully suppresses the morphological and physiological consequences of critical period odor exposure, arguing that phagocytic glia engulf intact synaptic terminals. These data demonstrate experience-dependent pruning of synapses and argue that Drosophila olfactory circuitry is a powerful model for defining the function of glia in critical period plasticity.

Glia control experience-dependent plasticity in an olfactory critical period

Sensory experience during developmental critical periods has lifelong consequences for circuit function and behavior, but the molecular and cellular mechanisms through which experience causes these changes are not well understood. The Drosophila antennal lobe houses synapses between olfactory sensory neurons (OSNs) and downstream projection neurons (PNs) in stereotyped glomeruli. Many glomeruli exhibit structural plasticity in response to early-life odor exposure, indicating a general sensitivity of the fly olfactory circuitry to early sensory experience. We recently found that glia shape antennal lobe development in young adults, leading us to ask if glia also drive experience-dependent plasticity during this period. Here, we define a critical period for structural and functional plasticity of OSN-PN synapses in the ethyl butyrate (EB)-sensitive glomerulus VM7. EB exposure for the first 2 days post-eclosion drives large-scale reductions in glomerular volume, presynapse number, and post- synaptic activity. Crucially, pruning during the critical period has long-term consequences for circuit function since both OSN-PN synapse number and spontaneous activity of PNs remain persistently decreased following early-life odor exposure. The highly conserved engulfment receptor Draper is required for this critical period plasticity as ensheathing glia upregulate Draper, invade the VM7 glomerulus, and phagocytose OSN presynaptic terminals in response to critical-period EB exposure. Loss of Draper fully suppresses the morphological and physiological consequences of critical period odor exposure, arguing that phagocytic glia engulf intact synaptic terminals. These data demonstrate experience-dependent pruning of synapses and argue that Drosophila olfactory circuitry is a powerful model for defining the function of glia in critical period plasticity.