This study aimed to investigate the effect of Ubiquitin-Specific Peptidase 22 (USP22) on the inflammatory response mediated by BV-2 mouse microglia and explore the role of the PU box binding protein 1 (PU.1)/NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome in the USP22-induced polarization of BV-2 cells.

Using a chronic unpredictable mild stress (CUMS) combined with multi-platform water environment sleep deprivation (SD) as an animal model, the occurrence and development of human depression combined with insomnia were simulated. The abnormal mitochondrial autophagy signaling caused by the putative kinase 1/Parkin E3 ubiquitin protein ligase (Pink1/Parkin) signaling pathway directly affects the normal secretion of melatonin by the pineal gland, which may explain the pathogenesis of depression combined with insomnia. This study aims to explore the depression-like behavior, sleep changes, central oxidative stress response, pineal mitochondrial autophagy damage, melatonin secretion, histopathological changes of the pineal gland, and the expression of Pink1/Parkin signaling-related factors in CUMS+SD rats. The results showed that the levels of reactive oxygen species (ROS) in cerebrospinal fluid of CUMS+SD rats significantly increased along with the inflammatory factors Interleukin-1β (IL-1β) and nuclear factor kappa-B (NF-κB) in cerebrospinal fluid. In addition, the number of pineal gland cells significantly decreased, cell boundaries became blurred, cell volume shrank, and apoptotic bodies appeared in the pineal gland tissue under HE staining, indicating pineal gland inflammation. Sleep deprivation further disrupted the levels of autophagy damage factors, including histamine (MDA), glutathione (GSH), and catalase (CAT), in the cerebrospinal fluid of CUMS + SD rats. Transmission electron microscopy of the pineal gland in CUMS+SD rats revealed damage to mitochondrial autophagy. The levels of 5-hydroxytryptamine (5-HT) and aromatic amine-N-acetyltransferase (AANAT) in the cerebrospinal fluid, as well as melatonin levels in the pineal gland, were significantly decreased. Additionally, the expression of IL-1β, NF-κB, Pink1, and Parkin in the pineal gland of CUMS+SD rats significantly increased. The expression of microtubule-associated protein 1 light chain 3-β (LC3), selective autophagy adaptor protein (P62), cytochrome c oxidase IV (COXIV), and mitochondrial outer membrane translocation enzyme 20 (TOM20) proteins downstream of the Pink1/Parkin signaling pathway was enhanced, while the expression of downstream brain-derived neurotrophic factor (BDNF), Beclin 1, and BCL2 interacting protein 3 (BNIP3) proteins was negatively regulated. Pink1/Parkin signaling may specifically respond to mitochondrial autophagy damage in the pineal gland, affecting the normal synthesis and secretion of melatonin in the pineal gland. In summary, mitochondrial autophagy damage in the pineal gland affects the normal secretion of melatonin in CUMS+SD rats, which is closely related to the specific autophagy signaling impairment of Pink1/Parkin pathway, which may mediate the occurrence of depression combined with insomnia.

Further studies are necessary to investigate the neural mechanisms elemental of subcortical vascular mild cognitive impairment (svMCI), which is considered as precursor to vascular dementia (VaD). This objective of this research was to investigate the alterations in gray matter volume and brain iron deposition in patients with svMCI.

Spinal cord injury (SCI) is a debilitating condition that often results in paralysis and lifelong medical challenges. Research has shown that epigenetic modifications, particularly histone acetylation, play a role in neuroprotection following hypoxic-ischemic events in SCI. The objective of this study was to explore the effects of histone H3K27 acetylation, along with its underlying mechanisms, on the tolerance to hypoxia and ischemia in SCI.

Neurocognitive Disorders (NCDs) primarily affect cognitive functions, including learning, memory, perception, and problem-solving. They predominantly arise as pathological sequelae of central nervous system (CNS) disorders. Emerging evidence suggests that microglial inflammatory activation within the hippocampus underlies the pathogenesis of cognitive impairment. Triggering receptor expressed on myeloid cells 1 (TREM1), a pattern-recognition receptor on microglia, becomes upregulated in response to injury and synergistically amplifies inflammatory responses mediated by other pattern-recognition receptors, leading to uncontrolled inflammation. While TREM1 is lowly expressed in the resting state, its upregulation upon exposure to injurious inflammatory stimuli promotes microglial activation and contributes to the development of NCDs. Consequently, TREM1 may serve as a critical receptor in microglia-mediated inflammation. This article reviews the current understanding of TREM1 and its role in NCDs pathogenesis.

Opioids are the most effective and potent analgesics available for acute pain management. With no viable alternative for treating chronic or post operative pain, it is not surprising that over 10 million people misuse opioids. This study explores the developmental influence of the microbiome on resistance to opioid addictive behavior and functional connectivity.

Motor imagery (MI) encompasses kinesthetic motor imagery (KMI), internal visual-motor motor imagery (IVMI), and external visual-motor motor imagery (EVMI). This study explored α/β oscillations during MI of left-/right-hand movement from KMI/IVMI/EVMI perspectives in a group of left- (N = 20) and right-handed (N = 20), volunteers selected based on their laterality quotient (RH > 80; LH > -80). We analyzed changes in the power of α/β oscillations from visual- and motor-related clusters of independent components, connectivity (imaginary part of coherence; ICOH) between electroencephalographic activity from selected regions of interest (ROIs), and the correctness of the MI. The left-handed individuals showed more robust α/β activity in visual-related ROI during EVMI for their non-dominant hand, compared during IVMI. However, they did not show a difference in brain activity for EVMI/IVMI compared with KMI and connectivity variance across EVMI/IVMI and KMI. The right-handed individuals exhibited visual area suppression during KMI, which could signify focusing on internal sensations and blocking visual processing in this condition. ICOH connectivity in the RH group varied depending on the task and hand involved, with more robust connections for EVMI of the non-dominant hand compared with IVMI and stronger connections for EVMI and KMI of the non-dominant hand compared with the dominant hand. The results suggest that left-handed individuals rely more on visual representations during MI, especially for their non-dominant hand. At the same time, right-handed people may create more multimodal images during the same tasks.

Hippocampal-dependent cognitive impairments are consequences of temporal lobe epilepsy. This study aimed to assess the modulatory effects of fenoprofen on Pentylenetetrazol (PTZ)-induced cognitive dysfunction in the rat model of epilepsy. Male Wistar rats were randomly divided into five groups. Except for the control group, the kindling model was induced by intraperitoneal (IP) injection of PTZ (35 mg/kg) every other day for a month. Three groups received fenoprofen (10, 20, and 40 mg/kg) before each PTZ injection. One week after kindling development, rats were challenged with PTZ (70 mg/kg). The Morris Water Maze, Shuttle Box, and Elevated Plus Maze tests were applied to assess cognitive functions. Rats' serum and brain samples were prepared for biochemical, histological, and gene expression studies. Fenoprofen pretreatment effectively reduced the mean seizure score, and treated rats had better cognitive performance than the PTZ group in passive avoidance and spatial memory and learning tests; they also showed less anxiety-like behaviors. Its administration also showed anti-oxidative properties. So the serum level of Nitric oxide was significantly reduced while Glutathione and Catalase increased significantly. It also diminished the expression of inflammatory genes (Tumor Necrosis Factor alpha (TNF-α) and Nuclear Factor Kappa B (NF-kB)) in the hippocampus, these results were confirmed by histological observation from Hematoxylin & Eosin staining. These results show the ability of fenoprofen to reduce cognitive impairments caused by epilepsy induction. These effects seem to be through the modulation of inflammatory mediators and oxidative stress.

A slowly moving dark spot imitating the shadow of a hovering bird of prey has been shown to induce freezing in rodents. Such visually triggered behaviours are usually initiated in the superior colliculus (SC); therefore, it is likely that such slowly moving dark spots can produce responses in SC neurons. In SC, two types of visual responses are typically distinguished: ON responses are produced by an increase in image brightness, and OFF responses are produced by a decrease in image brightness. Typically, OFF responses are very brief, lasting only a few hundred milliseconds, and may be poorly suited for the detection of slowly moving dark spots. Here, we report that, in the majority of SC neurons of urethane-anaesthetized rats, in addition to these brief OFF responses, very slow OFF responses lasting over 5s were present; thus, OFF responses that occurred >1s after the stimulus offset were termed 'slow OFF' response, while brief, less than 1s long OFF responses were called 'fast OFF' response. Although the slow OFF responses were of similar amplitude as the fast OFF responses (~5Hz), the optimal size (producing the maximal response) was larger for the slow OFF responses (20° for the slow and 10° for the fast OFF responses). Correlation analysis revealed that both the fast and the slow components of the OFF response contribute to the response to a slowly moving spot. Elimination of visual cortex inputs increased the amplitude and duration of the slow OFF responses, indicating that they originate in the retina. It is concluded that in rodent SC, a new type of OFF response that is well suited for predator detection is present.

Recent clinical trials targeting tau protein aggregation have heightened interest in tau-based therapies for dementia. Success of such treatments depends crucially on translation from non-clinical animal models. Here, we present the age profile of the PLB2 knock-in model of fronto-temporal dementia in terms of cognition, and by utilising a directly translatable magnetic resonance imaging approach. Separate cohorts of mice aged 3, 6 and 12 months were tested in an object recognition protocol interrogating visual, spatial, and temporal discrimination in consecutive tests. Upon completion of their behavioural testing, animals were recorded in a 7T MRI for brain structural integrity and diffusion tensor imaging (DTI) analysis. We report that PLB2 mice presented with an age-dependent deficit in novel object discrimination relative to wild-type controls at 6 and 12 months. Spatial and temporal discrimination, though not significantly different from controls, appeared extremely challenging for PLB2 subjects, especially at 12 months, since they explored objects less than controls and were devoid of memory. Controls readily recalled all relevant object-related information. At the same time, the T2 weighted voxel-based image analysis revealed a progressive shrinkage of total brain volumes in 6- and 12-month-old PLB2 mice as well as relative striatal, but not hippocampal volumes. A regional DTI analysis yielded only reduced mean diffusivity of the fimbria, but not CA1 or dentate gyrus, amygdala, cingulate cortex, or corpus callosum. These data confirm the PLB2 mouse as a translationally useful model for dementia research and suggest the importance of the hippocampal input as a determinant for novel object discrimination.

Depression is a debilitating mental disease that inflicts significant harm upon individuals and society, yet effective treatment options remain elusive. At present, the pathogenesis of multiple depression is not fully clear, but its occurrence can be related to biological or environmental pathways, among which Brain-derived neurotrophic factor (BDNF) can unequivocally act on two downstream receptors, tyrosine kinase receptor (TrkB) and the p75 neurotrophin receptor (p75NTR), then affect the related signal pathways, affecting the occurrence and development of depression. Accumulating studies have revealed that BDNF-related pathways are critical in the pathophysiology of depression, and their interaction can further influence the efficacy of depression treatment. In this review, we mainly summarized the signaling pathways associated with BDNF and classified them according to different receptors and related molecules, providing promising insights and future directions in the treatment of depression.

Kaempferol (KF), the main active ingredient in identifying the authenticity of safflower, has a variety of pharmacological activities and neuroprotective effects. However, the mechanism of KF in the treatment of epilepsy remains unclear. This study aimed to investigate the protective effects of KF on epilepsy and its related mechanisms.

Repetitive transcranial magnetic stimulation (rTMS) to the left dorsolateral prefrontal cortex (L-DLPFC) has an improving effect in cognitive function, but it is still not clear in what specific cognitive domains. We here combined a single session of TMS (HF-rTMS/iTBS) with electroencephalography (EEG) to clarify the effects of magnetic stimulation techniques on executive function, working memory, and visuospatial attention in healthy participants, and to investigate the underlying neurophysiological mechanisms.

Peripheral nerve injuries are extremely severe and may lead to permanent disability, despite the regenerative capacity of the peripheral nervous system (PNS). To date, there is no established pharmacological therapy capable of predicting functional recovery and alleviation of trauma-related symptoms such as neuropathic pain, inflammation and weakness, which are the main targets for current therapies. In this work we provide new evidence for a therapeutic use of valproic acid (VPA) upon ischiatic nerve injury. Ischiatic nerve-injured mice treated with VPA after lesion, displayed an improvement in pain and motor function associated with an increase in the number of myelinated nerve fibers, and exhibited a more organized microenvironment during regeneration. In addition, VPA treatment also promoted an immunomodulatory capacity, leading to a significant enhancement of neutrophils in the peritoneal cavity, suggesting its role on the sensory and motor recovery after ischiatic nerve injury. This highlights the physiological role of VPA during ischiatic nerve regeneration and contributes to the characterization of innovative pharmacological epigenetic therapy capable of accelerating peripheral nerve regeneration with critical impacts on the clinical practice.

Mental workload could affect human performance. An inappropriate workload level, whether too high or too low, leads to discomfort and decreased task performance. Auditory stimuli have been shown to act as an emotional medium to influence the workload. For example, the 'Mozart effect' has been shown to enhance performance in spatial reasoning tasks. However, the impact of auditory stimuli on task performance and brain activity remains unclear. This study examined the effects of three different environments-quiet, music, and white noise-on task performance and EEG activities. The N-back task was employed to induce mental workload, and the Psychomotor Vigilance Task assessed participants' alertness. We proposed a novel, statistically-based method to construct the brain functional network, avoiding issues associated with subjective threshold selection. This method systematically analyzed the connectivity patterns under different environments. Our analysis revealed that white noise negatively affected participants, primarily impacting brain activity in high-frequency ranges. This study provided deeper insights into the relationship between auditory stimuli and mental workload, offering a robust framework for future research on mental workload regulation.

The positive hemodynamic response (PHR) during stimulation often co-occurs with a strong, sustained negative hemodynamic response (NHR). However, the characteristics and neurophysiological mechanisms of the NHR, especially in regions distal to the PHR, remain incompletely understood. Using intrinsic optical imaging (OI) and two-photon imaging, we observed that forelimb electrical stimulation evoked strong PHR signals in the forelimb region of the primary somatosensory cortex (S1FL). Meanwhile, NHR signals primarily appeared in the primary visual cortex (V1), with a delayed onset and lower amplitude relative to the PHR signals. Additionally, stimulation led to a reduction in cerebral blood flow (CBF) in the NHR region. Notably, there was an overall suppression of the calcium response in the NHR region, although a small proportion (14 %) of neurons exhibited concurrent activation. Axon tracing revealed cortico-cortical projections from S1FL to V1. These findings suggest that neuronal deactivation significantly contributes to the origin of the NHR, offering additional insights into the specific inhibitory mechanisms underlying the NHR.

Intracerebral hemorrhage (ICH) is a condition with high mortality and disability. Secondary injury processes following ICH include neuroinflammation, oxidative stress, and neuronal apoptosis. Human platelet lysate (HPL), derived from crushed platelets, is rich in cytokines and has demonstrated therapeutic potential in neurological disorders in several studies. However, studies on HPL for ICH remain limited. In this study, we prepared HPL for intranasal administration in ICH treatment. We determined the concentration of growth factors in HPL, validated the targeting of HPL, and established a mouse model of ICH. We observed that HPL improved neuromotor deficits in ICH mice. Barnes maze training showed that HPL enhanced spatial memory and learning ability in mice. Furthermore, HPL reduced neuroinflammation, brain edema, oxidative stress, neuronal apoptosis, and neural axonal damage. Additionally, 5 % HPL demonstrated potent functional activity with no cytotoxicity in SH-5YSY cell cultures. These findings indicate that HPL is a promising therapeutic approach for mitigating secondary brain injury following ICH.

Autism spectrum disorders (ASD) are characterized by social skill deficits and behavior impairments. Exposure to valproic acid (VPA) has been linked to ASD in humans and ASD-like behaviors in rodents. Clinical evidence suggests that immunological damage can worsen ASD symptoms in humans.

Spinal cord injury (SCI) is a devastating disease characterized by neuroinflammation and irreversible neuronal loss. The basic helix-loop-helix family member e40 (Bhlhe40) is a stress-responsive transcription factor involved in the pathological process of inflammation. However, Bhlhe40 expression and its role in SCI are largely unknown. SCI rat models were established with an aneurysm clip and then the rats were injected with lentiviral Bhlhe40 shRNA to knock down Bhlhe40 expression. In vitro, BV2 microglia cells were stimulated with LPS and IFN-γ to promote M1 microglia polarization. The results showed that Bhlhe40 expression was significantly elevated in the injured spinal cord tissue. Bhlhe40 deficiency reduced neuroinflammation and neuronal loss, and then promoted the recovery of neurological function. Additionally, Bhlhe40 knockdown alleviated neuronal apoptosis by regulating microglia polarization. In our study, Bhlhe40 knockdown inhibited M1 microglia polarization and the secretion of pro-inflammatory factors (TNF-α, IL-1β, and IL-6). Meanwhile, the NF-κB pathway was inhibited after the Bhlhe40 knockdown in SCI rats. To further explore the functional role of Bhlhe40, we performed in vitro experiments. Bhlhe40 knockdown decreased M1 microglia polarization by inhibiting the NF-κB pathway. In conclusion, our study indicates that Bhlhe40 knockdown can alleviate the progression of SCI and its underlying mechanism in regulating macrophage polarization through the NF-κB pathway.

Alzheimer's disease (AD) poses a major societal challenge, yet no definitive cure exists. Noninvasive brain stimulation methods, such as transcranial magnetic stimulation and transcranial direct current stimulation, have shown promise in alleviating cognitive symptoms associated with neurodegenerative disorders. This study investigated the effects of 40 Hz vibrotactile stimulation on AD-related cellular responses using SH-SY5Y neuroblastoma cells, primary human brain pericytes, and BV2 microglia. SH-SY5Y cells and brain pericytes treated with oligomeric beta-amyloid (Aβ) underwent 40 Hz vibrational stimulation for varying durations. Cell viability was determined via the CCK-8 assay, while intracellular calcium levels in pericytes were assessed. Protein expression was measured using western blotting, and gene expression was quantified via a real-time quantitative polymerase chain reaction. Detailed vibrational parameters were employed to ensure precise stimulation. Notably, 40 Hz vibrotactile stimulation improved cell viability in Aβ-exposed SH-SY5Y cells, reduced intracellular calcium ion (Ca2+) levels in Aβ-treated pericytes, activated autophagy, and mitigated tau hyperphosphorylation in SH-SY5Y cells. Additionally, it exhibited anti-neuroinflammatory properties in BV2 microglia. These findings highlight the potential of 40 Hz vibrotactile stimulation as a therapeutic strategy for AD.

This study explores the molecular mechanism of METTL14 regulating microglial function post ischemic stroke. A murine model was established by tMCAO. The neurological function was evaluated by mNSS. The cerebral infarct size and pathological changes were observed by TTC and H&E staining. M1 and M2 microglia in brain tissues were detected by flow cytometry. BV2 cells were subjected to OGD/R to establish an in vitro model. qRT-PCR and Western blot were used for detecting METTL14, PAX6, YTHDF2, TREM2, iNOS, and Arg1 expressions. The m6A level was quantitatively analyzed, and the binding of YTHDF2 or m6A to PAX6 was analyzed by RIP. PAX6 mRNA stability was assessed after actinomycin D treatment. ChIP was utilized for determining the enrichment of PAX6 on TREM2 promoter. The binding relationship between TREM2 and PAX6 was verified by dual-luciferase reporter assay. METTL14 was highly expressed after tMCAO, and silence of METTL14 alleviated symptoms of tMCAO mice and promoted microglial M2 polarization. METTL14 enhanced PAX6 mRNA m6A modification to promote YTHDF2 binding to PAX6 mRNA and its degradation. PAX6 bound to TREM2 promoter and facilitated its transcription and expression. In conclusion, METTL14-mediated m6A modification aggravates ischemic stroke by promoting microglial M1 polarization via YTHDF2/PAX6/TREM2 axis.