Mammalian neonates are born in an immature state and require caregiving from conspecific adults for survival. A growing body of evidence indicates that multiple neuronal populations and hormonal factors regulate parental caregiving behavior. Among these, arginine vasopressin (AVP) and oxytocin (OT) have received particular attention. While the role of OT has been extensively investigated, the functional contributions of AVP remain comparatively less understood. Recent neurobiological studies in rodents have begun to elucidate the molecular, cellular, and circuit-level mechanisms through which AVP regulates caregiving behavior. In this review, I first summarize the properties of AVP and its receptors, with particular emphasis on vasopressin-to-oxytocin receptor crosstalk, a phenomenon in which AVP can activate non-canonical oxytocin receptors. I then review past and recent findings on the role of AVP signaling in parental caregiving behavior, highlighting evidence that receptor crosstalk contributes to these effects. Based on these findings, I propose a hypothetical circuit model integrating AVP and OT signaling in the regulation of caregiving behavior. Finally, I discuss unresolved questions regarding receptor specificity, temporal dynamics, and circuit mechanisms, as well as the potential relevance of these findings to human parenting.
Social interaction facilitates vocal learning more effectively than passive exposure, but the neural signals that reflect the social context of auditory experience remain unclear. Midbrain dopaminergic circuits broadcast motivational and learning-related signals, raising the possibility that VTA/SNc activity may reflect both tutor-song auditory input and tutor presence during juvenile vocal development. We tested this idea in juvenile zebra finches by recording single-unit activity during the same tutor-song playback under tutor-absent and tutor-present conditions; in the tutor-present condition, a live tutor was present but remained silent. Among 185 VTA/SNc neurons from 8 birds, tutor presence bidirectionally modulated auditory responses. Type-1 neurons showed enhancement (46/185, 24.9%), whereas Type-2 neurons showed suppression (29/185, 15.7%). Both profiles were observed in all birds, and bird-level analyses supported consistent modulation. Type-1 neurons showed increased baseline firing and a further enhancement of baseline-subtracted song-evoked responses, whereas Type-2 suppression occurred without reduced baseline firing. Using spike waveform and firing rate criteria, we found that the tutor-enhanced Type-1 population included neurons with putative dopaminergic features. In naturalistic recordings, these neurons also showed increased activity during live tutor singing. These findings suggest that socially modulated VTA/SNc activity may link tutor presence to auditory processing relevant to vocal learning.
Pubertal maturation drives brain development, yet longitudinal evidence linking it to resting-state functional connectivity (rs-FC) in early adolescence remains limited, and adolescent mental-health trajectories differ by sex, motivating sex-specific analyses. In a general-population cohort (255 adolescents scanned at Time 1; 68 girls and 70 boys with analysable two-wave data), we examined longitudinal change in rs-FC between ages ~11.5 and ~13.6 years, separately by sex. Whole-brain analyses were applied without predefined regions of interest, using principal component analysis (PCA) as a data-driven screen and network-based statistics (NBS) to localize subnetworks associated with pubertal stage (Tanner stage). Among girls, Tanner breast stage at Time 2 was significantly associated with the fingerprint stability (within-individual similarity) of whole-brain rs-FC. NBS identified a subnetwork positively associated with Tanner breast stage, linking the thalamus to visual, auditory, and motor areas and the prefrontal operculum to frontoparietal association areas, with the PCA screen converging on thalamic involvement. No comparable associations were observed in boys. These findings suggest that the level of pubertal maturation is associated with the longitudinal stability of large-scale brain networks in girls.
After ischemic stroke, microglia rapidly respond to brain tissue injury, triggering acute inflammation and secondary tissue damage through the production of inflammatory mediators and the phagocytosis of neurons. Several days after ischemic stroke onset, microglia resolve inflammation by clearing damage-associated molecular patterns and necrotic tissue debris. Microglia also support neural repair and functional recovery after ischemic stroke by producing neurotrophic factors, promoting white matter repair and vascular remodeling. These reparative functions diminish within a few months after stroke onset due to epigenetic mechanisms that turn reparative microglia into dysfunctional ones. In this review, we discuss the time-dependent functional changes in microglia after ischemic stroke, from inflammatory activation to the acquisition and subsequent loss of reparative properties, together with the molecular mechanisms underlying these transitions.
Tiling across the central nervous system, astrocytes contact synapses, blood vessels and other glial cells through highly specialised processes, allowing them to regulate local brain environments across multiple spatial and temporal scales. These anatomical and signalling features make astrocytes attractive substrates for modulating brain function and repair. Here, we frame "astrocyte engineering" as the intentional design of molecular access, sensing and effector modules in astrocytes to interrogate or modify local brain states. This Review focuses on how astrocyte interface biology can be converted into engineering logic, from genetic access and signalling perturbation to emerging sensor-effector designs. We first outline how astrocyte morphology, diversity and intercellular interactions shape the logic of cell-specific targeting. We then summarise tools for astrocyte-specific gene delivery and signalling control, including adeno-associated virus (AAV)-based strategies and G-protein coupled receptor (GPCR) signalling modulation approaches that can alter disease-relevant phenotypes. Further, we discuss recent proof-of-concept studies that equip astrocytes with new recognition or effector functions, including chimeric antigen receptor (CAR) astrocytes, synNotch-based systems, and trophic-factor delivery. We propose that future astrocyte engineering should be guided by omics-based design principles that link cell state, molecular access, input recognition, and effector selection.
Perioperative neurocognitive disorder (PND) is a common complication after anesthesia and surgery, particularly in older individuals, and is associated with oxidative stress and ferroptosis. Krüppel-like factor 4 (KLF4) has been implicated in neuronal injury, but its role in PND remains unclear. Using a mouse model of sevoflurane anesthesia plus tibial fracture surgery and sevoflurane-exposed HT22 cells, we found that KLF4 was upregulated in the hippocampus after anesthesia and surgery, as well as in HT22 cells. KLF4 knockdown alleviated cognitive impairment and neuronal injury in vivo and improved cell viability while reducing apoptosis in vitro. Mechanistically, KLF4 depletion attenuated oxidative stress and ferroptosis-related changes, including reduced ROS, iron accumulation, MDA, LDH, and ACSL4 expression, together with restored GSH, antioxidant activity, GPX4, and SLC7A11 levels. Multiplex immunofluorescence showed that surgery-induced GPX4 loss and ACSL4 upregulation occurred predominantly in hippocampal neurons, whereas 4-HNE accumulation was observed in both neurons and microglia. KLF4 directly bound to the SMAD7 promoter and enhanced SMAD7 transcription. Rescue experiments showed that KLF4 overexpression reversed the protective effects of SMAD7 knockdown, and in the absence of sevoflurane, KLF4 overexpression alone induced toxicity that was only partially rescued by SMAD7 knockdown. Together, these findings suggest that KLF4 is associated with PND-related neuronal injury, potentially through SMAD7-linked oxidative stress and ferroptosis-related signaling.
Temperature profoundly influences brain physiology and pathology. Accumulating evidence indicates that microglia, the resident immune cells of the central nervous system, are highly sensitive to temperature changes. Experimental evidence indicates that temperature modulates microglial motility, inflammatory signaling, and phagocytic activity through thermosensitive ion channels and, potentially, through broader biophysical mechanisms. In parallel, advances in intracellular thermometry have revealed the potential for local heat generation within organelles and heat propagation between subcellular compartments, raising the possibility that temperature may function not only as a consequence of cellular activity but also as a biologically meaningful signal. Although direct evidence for microglial heat generation remains limited, the unique metabolic and lysosomal activities of microglia make them a compelling target for investigating how local thermal dynamics are generated and regulated within the brain. In this review, we summarize current knowledge regarding the bidirectional relationship between temperature and microglial biology. We discuss temperature-dependent microglial responses and their underlying mechanisms, examine temperature dynamics in physiological and pathological conditions, and review recent advances in thermal measurement and interventions. Finally, we highlight key unresolved questions and future directions for understanding temperature-microglia interactions and their therapeutic implications.
Mechanical stimulation to periodontal ligament (PDL) by orthodontic force is received by the peripheral mechanoreceptors of trigeminal ganglion (TG) neurons and/or trigeminal mesencephalic nucleus (MesV) neurons, which are the primary sensory neurons. In this study, we examined changes in the expression of mechanosensitive plasma membrane proteins in TG and MesV neurons innervating the PDL labeled with cholera toxin B subunit (CTB) in response to orthodontic force as a sustained mechanical stimulation of molar tooth in nine-week-old Wistar rats. We also evaluated changes in body weight and food intake in non-orthodontic force-treated and orthodontic force-treated rats. In CTB-positive TG neurons innervating the PDL, we observed significantly higher expression levels of ion channels involved in mechanical sensing. Notably, in CTB-labeled MesV neurons, we observed that the expression level of Piezo2 channels was significantly higher in the group subjected to orthodontic force than in those not subjected to orthodontic force. Body weight did not change after 3 days of orthodontic force application, but food intake decreased. These results suggest that continuous mechanical stimulation by orthodontic force increases the mechanosensitive response in the PDL during proprioception via Piezo2-positive MesV neuron activation.
Dementia poses a substantial global health burden, necessitating public health focus on modifiable risk factors. While sleep duration has been linked to dementia risk, studies specifically addressing middle-aged and older Chinese adults remain limited. Using cross-sectional (n = 12,187) and longitudinal (n = 9030, 4-year follow-up) data from CHARLS, along with two-sample Mendelian randomization (MR), we examined associations between sleep duration and dementia, and causality between insomnia and dementia. We observed the strongest dementia risk among individuals reporting extreme sleep durations (<5 h or >10 h), both cross-sectional (OR=2.99, 95% CI: 2.47-3.62, P < 0.001) and longitudinally (HR=1.55, 95% CI: 1.25-1.91, P < 0.001). Restricted cubic spline analyses demonstrated a significant U-shaped dose-response association (P for nonlinearity <0.001). MR findings provided suggestive evidence for a potential causal effect of insomnia on dementia risk (OR=1.06, 95% CI: 1.01-1.13, P = 0.029). Sensitivity analyses confirmed robustness. Optimizing sleep duration and managing insomnia may help reduce dementia risk in Chinese middle-aged and older adults.
Decoding visual information based on machine learning has the potential to reveal the neural mechanisms of visual information processing in the brain. Although most highly precise decoding methods require highly invasive electrodes, these electrodes make long-term use difficult because they cause brain damage. To address this issue, we recorded local field potentials (LFPs) from the mouse cortex using custom-made low-invasive electrodes (ECoG with six recording sites) and verified how convolutional neural network (CNN) can decode visual stimulus positions from the LFP signals recorded by these electrodes. We found that the discrimination accuracies based on the cross-validation (39–70%) were significantly higher than the chance level (25%) for all animals. This confirmed that CNNs can extract the neural features of visual stimulus positions, even from low-spatial-resolution LFPs. Furthermore, we showed that visual positional information was primarily encoded during specific time periods of LFPs by using surrogate datasets. Our findings suggest that CNN enables low-invasive electrodes to analyze the visual information processing system and provide tools to understand the neural mechanisms in the brain.
Myelin, a multilamellar membrane structure enwrapping axons, is essential for rapid saltatory conduction, metabolic support, and long-term axonal integrity in the central nervous system (CNS). Myelination by oligodendrocytes (OLs) constitutes a highly dynamic and orchestrated process, encompassing distinct stages: target axon recognition, axonal wrapping, membrane expansion, and compaction. This review comprehensively summarizes recent advances in understanding the dynamics of CNS myelination which is spatiotemporally regulated through a complex interplay of membrane protein interaction, neuronal activity, metabolic checkpoints, and mechanosensory mechanisms. We highlight how adhesive molecules, cytoskeletal dynamics, and polarized membrane trafficking collectively drive the precise spiraling of myelin around axons. Furthermore, we emphasize the indispensable non-cell autonomous roles of astrocytes and microglia, which contribute critically through lipid transfer, phagocytic refinement, and modulation of the extracellular matrix. Beyond development, we discuss mechanisms that sustain myelin homeostasis, such as autophagy-lysosomal clearance. By integrating these mechanistic insights, we not only underscore the exquisite precision of CNS myelination but also illuminate potential therapeutic targets for demyelinating disorders.
Microtubules support neuronal morphology, intracellular transport, and neurite growth, but how microtubule turnover is regulated across neuronal compartments remains incompletely understood. To examine microtubule dynamics under physiological expression conditions, we expressed EGFP-tagged βIII-tubulin from the endogenous Tubb3 locus in cultured rat hippocampal neurons and measured tubulin turnover using fluorescence recovery after photobleaching (FRAP). FRAP analysis revealed pronounced spatial differences in microtubule dynamics at 9 days in vitro (DIV), with the highest turnover observed in growth cones and substantially slower turnover in dendrites, axons, and the axon initial segment (AIS). Microtubule turnover further decreased between 9 and 17 DIV in dendrites and axons, indicating progressive stabilization during neuronal maturation, whereas turnover in the AIS remained largely unchanged. Analysis of EB3 comet dynamics suggested that microtubule polymerization contributes substantially to tubulin turnover. In addition, manipulation of the dendritic microtubule-associated protein MAP-2 altered tubulin FRAP, indicating that MAP-2 contributes to the regulation of neuronal microtubule dynamics. Together, these results demonstrate that microtubule turnover is spatially and developmentally regulated in neurons.
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by elevated concentrations of amyloid β1-42 (Aβ1-42) in the brain, where it exerts neurotoxic effects. A recent study demonstrated that medium flow at approximately 10 μm/s reduces Aβ1-42 neurotoxicity in explant brain cultures containing neurons and beating ependymal cilia; however, the underlying mechanisms remain unclear. Neurons migrating from the explant and located within 300 μm of the beating cilia were exposed to cilia-generated medium flow, allowing analysis of Aβ1-42 toxicity under fluid flow conditions. Aβ1-42-containing putative EV-related extracellular particles (putative EV-related Eps), with diameters of 100-400 nm were detected in the culture medium and exhibited neurotoxic effects. Pharmacological inhibition of EV release and endocytosis reduced intracellular accumulation of Aβ1-42 and attenuated neuronal toxicity. Under medium flow, fewer putative EV-related EPs bound to neurons, and their binding duration was significantly shortened. Rhodamine-conjugated concanavalin A staining revealed enhanced cell-surface glycan labeling in damaged neurons on the non-ciliated side compared with neurons on the ciliated side. These results suggest that shear stress reduces neuronal accumulation of Aβ1-42-containing putative EV-related EPs, likely through modulation of cell-surface glycosylation composition.
How damaged mitochondrial DNA (mtDNA) affects gene expression in mtDNA-related diseases is not well understood. Here, we investigated the changes in the transcriptome and chromatin modifications associated with the accumulation of mtDNA mutations in a proof-reading-deficient mitochondrial DNA polymerase transgenic mouse (Polg1 mutant mice), which accumulate mtDNA mutations preferentially in the paraventricular thalamic nucleus (PVT) and exhibit depressive-like episodes. We examined PVT neurons that were positive or negative for cytochrome oxidase (COX) in the mutant mice in depressive-like or euthymic states. The genes that were upregulated in the COX-negative PVT neurons during the depressive-like state were enriched for mitophagy or interferon signalling pathways. We observed no differentially accessible regions between WT and Polg1 mutant mice by ATAC (Assay for Transposase-Accessible Chromatin), but the loss of H3K27Ac signal in Polg1 mutant mice was associated with a higher number of ATAC tags. The change in H3K27Ac signal was seen only in brain regions that accumulate mtDNA mutations. In addition, we found that mtDNA, especially partially deleted mtDNA, was released from mitochondria upon opening of the mitochondrial permeability transition pore. These findings altogether suggest that mutated mtDNA molecules are released from mitochondria, which may contribute to the depression-specific transcriptomic alterations in the PVT neurons of the mood disorder animal model.
This study proposes an electroencephalography (EEG) analysis method using second-order derivatives of the alpha-band envelope to characterize task-related brain dynamics. An open dataset including EEG data from 60 healthy participants was analyzed during rest and three eyes-closed tasks: calculation, memory, and music. Sixty-second epochs were extracted, alpha-band activity (8-13 Hz) was filtered, and amplitude envelopes were computed via the Hilbert transform. Second-order derivatives were derived and separated into positive (Ap) and negative (An) components. Source-localized EEG signals were mapped to 68 cortical regions using the Desikan-Killiany atlas. Regional differences in Ap, An, their ratio, envelope amplitude, and peak alpha frequency were tested using corrected Wilcoxon signed-rank tests. The calculation task increased Ap, An, and amplitude in prefrontal and cingulate cortices, while reducing An in medial parietal regions. The memory task showed increased An in the left fusiform gyrus, whereas the music task showed no significant changes. Peak alpha frequency and Ap-An ratio were unchanged. These results suggest that derivative-based features capture task- and region-specific brain dynamics not detected by conventional measures, providing complementary descriptors of EEG activity in healthy individuals. Conceptual illustration of the present study. We hypothesized that the second-order derivatives of fluctuations in the alpha-band envelope, which are relatively preserved after the Fourier-based filtering process, may contain biologically relevant information. In this study, we examined whether the second-order derivatives (force, shown in red), in addition to conventional amplitude (green) and frequency (blue) measures, exhibit task-related changes in healthy individuals. By incorporating second-order derivative measures into node-wise functional descriptors of brain regions within an intracerebral network framework, the present results provide a complementary perspective for characterizing brain function. Ap and An denote the positive and negative components of the second-order derivative, respectively.
