Prosocial behaviour, as a facet of social behaviour across species, entails voluntary actions that benefit others, including helping and comforting behaviours. To explain how external sensory information is integrated to generate motivation and ultimately govern prosocial action, we organize its emergence into three interacting components: a social orientation process centered on the superior colliculus (SC), which selects and evaluates social cues and calibrates attention and arousal; a framework formed by the medial prefrontal cortex (mPFC) and the anterior cingulate cortex (ACC), which transforms perceived distress into internal representations, forming empathic memory that guides subsequent behavior; and neuromodulatory systems (e.g., oxytocin and dopamine) together with projections linking the insular cortex (IC), thalamus, and ventral tegmental area (VTA), that compose social motivation, assign value to prosocial acts and promote helping. Evidence across these processes suggests alignment and potential generalisation in autism spectrum disorder (ASD), which is marked by atypical attention to social signals and diminished responsiveness to social reward. We define prosocial neural network mapping as the characterisation of interregional projections and their neuromodulatory regulation to explain how social information is organised and transformed, offering new insights into circuit-level pathology in ASD and helping identify therapeutic targets aimed at restoring social salience and enhancing social motivation.

Generalization, the ability to apply learned rules to novel situations, is a fundamental cognitive process, yet its underlying neural mechanisms remain incompletely understood. The posterior parietal cortex (PPC) is considered a key hub for extracting abstract rules from specific experiences, yet its precise role in generalization requires further elucidation. In this study, we developed a five-hole operant paradigm to demonstrate that mice exhibit robust memory generalization, as reflected by graded success rates across tasks of varying difficulty. Fiber photometry revealed that PPC neurons are selectively activated during correct choices in generalization tasks. Chemogenetic inhibition of PPC neurons significantly impaired this generalization ability, particularly for the most difficult tasks. local infusion of NMDA receptor antagonists into the PPC, but not AMPA or acetylcholine receptor antagonists, specifically disrupted generalization, indicating a critical role for PPC NMDA receptors. Importantly, blockade of the NR2B subunit of NMDA receptors reproduced this impairment, whereas NR2A antagonism had no effect. Together, our findings establish that PPC neurons and NR2B-containing NMDA receptors within the PPC are essential for memory generalization in mice, providing new insights into the circuit and molecular mechanisms underlying adaptive behavior.

Olfactory dysfunction has emerged as a promising target for the early diagnosis and treatment of Alzheimer’s disease (AD). However, the mechanisms underlying neural circuit disruption associated with olfactory dysfunction in AD remain poorly understood. We conducted single-cell RNA sequencing (RNA-seq) and ex vivo electrophysiological studies to determine the link between olfactory memory in AD and dynamic synaptic transmission disorders in PCx-IL engram cell circuits. Clinical functional magnetic resonance imaging (fMRI) data revealed that connectivity between the piriform cortex (PCx) and the infralimbic cortex (IL) was impaired during the early mild cognitive impairment (MCI) stage of AD. Optogenetic stimulation of IL-projecting PCx engram neurons successfully improved olfactory memory retrieval in 5xFAD mice. In addition, single-cell RNA sequencing was employed to investigate the mechanisms of damage in IL engram cells, which revealed increased glutamate expression and impaired synaptic function as key alterations. Guided by single-cell sequencing data, we analyzed glutamatergic synaptic transmission in the PCx-IL engram cell circuit in 5xFAD mice. These results indicated dynamic impairments in AMPA receptor-associated synaptic transmission within this circuit. Optical long-term potentiation (LTP) of synaptic transmission restored directional engram synaptic transmission and prevented olfactory memory decline. Therefore, dynamic impairment of synaptic transmission in the PCx-IL engram cell circuit underlies the early decline in olfactory memory in AD. Impairment of PCx-IL functional connectivity may represent a new target for the diagnosis and treatment of early-stage AD.

Memory generalization is essential for adaption to novel circumstances through experiential learning, leading to behavioral flexibility and survival capability. However, its underlying neural mechanisms remain to be elucidated. This study designed 8-arm-maze-based tasks to reveal how the hippocampal CA3 associates with the generalization of spatial working memory. Mice successfully transferred the learned rule to novel task configurations, but the efficiency was inversely correlated with task difficulty. In vivo electrophysiological recordings of the CA3 showed that single-unit and population activity in the CA3 reflected this behavioral transition. On testing day 1, neuronal firing and population trajectories robustly distinguished in relatively simple tasks, but not in more difficult tasks. On testing day 2, as behavioral performance improved, the representational differences of the CA3 neuronal population across different tasks gradually decreased. Decoding analysis revealed that task discriminability based on population activity decreased over time, indicating CA3 neural coding is shifting toward a more generalized pattern. Feature elimination analysis further demonstrated that CA3 neurons employ a sparse but redundant coding scheme to support generalization. Together, the observed neural and behavioral changes are consistent with the emergence of generalized task representations, indicating experience-dependent reorganization of CA3 population activity during memory generalization across task configurations.

Sleep is a critical physiological process for maintaining the cognitive function of brain, particularly about memory consolidation. This review systematically elaborates on the multiscale regulatory mechanisms of the sleep-wake cycle, with a focus on the neural circuits involved in sleep-dependent memory consolidation, such as the hippocampus-prefrontal-thalamus network, characteristic neural oscillations, and microglia-mediated synaptic changes. Building upon these foundations, the article delves into Alzheimer's disease (AD), providing an in-depth analysis of the complex bidirectional relationship between sleep disturbances and the core pathologies of AD. Early vulnerable brain regions in AD, including the entorhinal cortex, hippocampus, thalamus, and locus coeruleus, coincide precisely with key hubs of the sleep-memory circuitry. Pathological damage in these regions leads to disrupted sleep architecture and impaired memory consolidation, creating a vicious cycle that accelerates memory impairment and cognitive decline. Interventions targeting the sleep-memory circuitry may thus offer a promising new strategy for early intervention in AD.

Background Microglia undergo extensive transcriptional remodeling in Alzheimer’s disease (AD), particularly within plaque-associated environments enriched in lipid-rich debris and phagocytic cargo. Although lipid handling and lysosomal processing are prominent features of disease-associated microglia, whether these processes constitute a coordinated remodeling program associated with neuropathological severity and plaque-associated spatial niches remains challenging. We investigated the cellular, pathological, and spatial organization of coupled lipid–lysosome remodeling in AD. Methods The study analyzed 236,044 Microglia/PVM-lineage single-nucleus transcriptomic profiles from 84 donors across 10 brain regions in the Seattle Alzheimer’s Disease Brain Cell Atlas (SEA-AD). Lipid–lysosome (LL) remodeling was characterized using continuous module scores and a Context-Aware Dual-Graph Lipid–Lysosome Remodeling framework (CA-DGLLR) integrating cellular context and biologically structured gene features. Robustness was evaluated using label-free clustering, canonical-program adjustment, threshold and gene-set sensitivity analyses, alternative scoring methods, strict microglial filtering, and held-out validation. Independent validation included four external transcriptomic datasets, human GeoMx plaque-zone transcriptomics, and mouse STARmap plaque-distance data. Statistical analyses included Spearman correlations, rank-based comparisons, Cohen’s d effect sizes, predictive performance metrics, and false-discovery-rate correction for multiple testing. Results LL remodeling comprised 13.34% of the primary discovery compartment and formed a continuous transcriptional landscape. Donor-level LL scores correlated with cognitive and neuropathological severity, including CERAD (ρ = 0.357, FDR = 0.00295) and Braak stage (ρ = 0.321, FDR = 0.00685). The LL-remodeled fraction remained similar across five transcriptomic datasets (12.47–15.22%), with strong human–mouse program-level conservation ( r = 0.96, P = 4.8×10⁻⁴). Spatial analyses further localized this conserved program to plaque-associated tissue environments. Human GeoMx analysis showed strong plaque-core LL enrichment (Cohen’s d = 1.25, FDR = 4.41×10⁻¹⁰), while independent STARmap analysis demonstrated a corresponding spatial gradient, with LL scores decreasing with plaque distance (Spearman ρ=−0.388, FDR = 8.79×10⁻⁹³). Conclusions LL remodeling defines a reproducible microglial response landscape that tracks AD severity and localizes preferentially to plaque-associated niches. By linking lipid handling and lysosomal processing within a shared cellular and spatial framework, these findings provide a cross-platform and cross-species view of microglial metabolic remodeling in AD and nominate candidates for future mechanistic and therapeutic investigation.

Chemotherapy resistance remains a primary cause of treatment failure in breast cancer, yet the global proteomic landscape driving this phenotype has not been completely understood. In this study, we employed a systematic multiomics approach, integrating quantitative proteomics of doxorubicin-resistant cells with transcriptomic and proteomic data from large-scale clinical cohorts (TCGA and FUSCC). Our analysis revealed a fundamental functional dichotomy in resistant cells, where a downregulation of metabolic processes contrasts with a robust upregulation of cytoskeletal and focal adhesion complexes. Through machine learning and interaction network analyses, we identified the focal adhesion scaffold paxillin (PXN) as a central hub driving resistance and a robust prognostic marker for poor recurrence-free survival in chemotherapy-treated patients. Mechanistically, PXN orchestrates a "cell adhesion-mediated drug resistance" program by an extracellular matrix-focal adhesion-cytoskeleton axis, driving extensive extracellular matrix remodeling and stiffening via the upregulation of cross-linking enzymes and protease inhibitors. This structural remodeling reprograms the tumor microenvironment, inducing an immunosuppressive state where PXN-high tumors exhibit increased CD8+ T cell infiltration, but these lymphocytes are functionally exhausted and fail to execute cytotoxic responses. In summary, our findings reveal a novel resistance axis where PXN connects the intracellular cytoskeleton and extracellular matrix remodeling. This reprograms the tumor microenvironment and immune cell cytotoxicity, highlighting PXN as a critical target for overcoming chemoresistance.

Neuroinflammation has emerged as a crucial factor in the pathogenesis of Alzheimer's disease (AD), paving the way for promising therapeutic interventions. Increasing evidence highlights the interplay between the peripheral immune system and the central nervous system (CNS) in driving neuroinflammation, with T lymphocytes playing a vital role in both regulatory and effector functions. Aberrant activation of T cells during the early stages of neuroinflammation perpetuates inflammatory responses by interacting with CNS glial cells and releasing pro-inflammatory mediators, such as IFN-γ, TNF-α, and IL-17. Studies have documented significant T cell activation and infiltration into the brain parenchyma in AD, contributing to disease progression. However, the specific mechanisms by which T cells mediate AD pathogenesis remain unclear. This comprehensive review synthesizes the current understanding of T cell involvement in AD pathology, emphasizing their aberrant activation, interactions with microglia, tau protein pathology, and the influence of gut microbiota. Finally, we propose potential treatment modalities for AD, highlighting the promise of T cellbased therapies currently under investigation in clinical trials. Understanding the critical role of T cells in intercellular communication and disease progression may enhance our comprehension of the pathophysiology of AD.

Cognitive impairments are common clinical manifestation of Alzheimer’s disease, vascular dementia, type 2 diabetes mellitus, and autoimmune diseases. Emerging evidence has suggested a strong correlation between peripheral chronic inflammation and cognitive impairments. For example, nearly 40

How do brains take what they have learned and apply it to new situations? This fundamental question sits at the core of cognitive generalization—a crucial ability that allows organisms to adapt to novel circumstances by drawing on prior experiences. While this mental flexibility enhances survival across species, the underlying neural mechanisms connecting different brain regions in rodents, primates, and humans remain poorly understood. Our review maps these neural pathways of generalization from hippocampus to cortex across the evolutionary spectrum. We show how hippocampal remapping and replay processes create abstract rules during generalization, with different hippocampal subregions handling distinct memory types. The prefrontal cortex emerges as essential for rule-based categorization across all species studied, while the orbitofrontal cortex drives value-based decision-making, and the posterior parietal cortex guides generalization through perceptual processing of past experiences. We explore the neural circuitry connecting these regions and examine how similar these brain structures and their associated behaviors are across species. Additionally, we discuss how disruptions to cognitive generalization manifest in various neurological conditions and their corresponding brain regions. This comprehensive analysis not only clarifies the neural foundations of cognitive generalization but also suggests promising directions for interventions targeting related neurological disorders.

The complex pathogenesis of Alzheimer’s disease (AD) has resulted in limited current biomarkers for its classification and diagnosis, necessitating further investigation into reliable universal biomarkers or combinations. In this work, we collect multiple CSF proteomics datasets and build a universal diagnose model by SVM-RFECV method combined with equal sample size and standard normalization design. The model was training in 297_CSF and then test the effect in other datasets. Utilizing machine learning, we identify a 12-protein panel from cerebrospinal fluid proteomic datasets. The universal diagnosis model demonstrated strong diagnostic capability and high accuracy across ten different AD cohorts across different countries and different detection technologies. These proteins involved in various biological processes related to AD and shows a tight correlation with established AD pathogenic biomarkers, including amyloid-β, tau/p-tau, and the Montreal Cognitive Assessment score. The high accuracy in the model may due to multiple protein combination based on comprehensive pathogenesis and different AD progress. Furthermore, it effectively differentiates AD from mild cognitive impairment (MCI) and other neurodegenerative disorders, especially the frontotemporal dementia (FTD), which share similar pathogenesis as AD. This study highlights a high accuracy, robustness and compatibility model of 12-protein panel whose detection is even based on label-free, TMT and DIA mass spectrometry or ELISA technologies, implicating its potential prospect in clinical application.

Cathepsin B (CatB), a protease in endosomal and lysosomal compartments, plays a key role in neuronal protein processing and degradation, but its function in brain development remains unclear. In this study, we found that CatB is highly expressed in the cortex of E12.5-E16.5 mice. Morphological analysis revealed significant defects in cortical development in CatB knockout (KO) mice, particularly in layer 6. In vitro experiments showed that CatB deficiency notably impaired neuronal migration and development. Behaviorally, CatB KO mice displayed prominent depressive-like behaviors, and electrophysiological recordings demonstrated significantly reduced neuronal activity in layer 6 of the medial prefrontal cortex. Mechanistically, proteomics analysis revealed that CatB KO affected neuronal migration and axonal growth, and decreased the expression of key transcription factors involved in neuronal development, particularly PEG3. Deficiency of PEG3 also significantly impaired neuronal migration and development. Our findings uncover a role for CatB in cortical development and suggest a mechanism linking CatB deficiency with depression and developmental defects through the destabilization of PEG3.

Hippocampus (HPC)-associated spatial memory deficits are one of the earliest symptoms of Alzheimer’s disease (AD). Current pharmacological treatments only alleviate the symptoms but do not prevent disease progression. The emergence of neuromodulation technology suggests that specific neural circuits are potential therapeutic targets for AD. Current studies have analyzed the medial septum (MS)–HPC and the HPC–lateral septum (LS) circuitries separately. A comprehensive understanding of their synergistic effects and overall dysregulation in AD remains limited. In this review, we will integrate anatomical and functional evidence to give an overview of the role of the MS–HPC–LS circuitry in spatial memory, the mechanisms of AD-related dysregulation, and therapeutic strategies targeting the circuitry, specially focusing on molecular interventions (receptor modulation) and bioengineering strategies (circuit-specific stimulation).

The deposition of toxic aggregated amyloid-β (Aβ), resulting from continuous cleavage of amyloid precursor protein (APP) by β-site APP cleaving enzyme 1 (BACE1) and γ-secretase, is a key pathogenic event in Alzheimer's disease (AD). Small interfering RNAs (siRNA) have shown great potential for disease treatment by specifically silencing target genes. However, the poor brain delivery efficiency of siRNAs limits their therapeutic efficacy against AD. We designed a simplified and effective BACE1 siRNA (siBACE1) delivery system, namely, dendritic polyamidoamine modified with the neurotropic virus-derived peptide RVG29 and polyethylene glycol (PPR@siBACE1). PPR@siBACE1 crossed the blood–brain barrier efficiently and entered brain parenchyma in large amount, with subsequent neurotropism and potential microglia-targeting ability. Both in vitro and in vivo studies validated the effective brain delivery of siBACE1 and strong BACE1 silencing efficiency. Treatment of AD mice with PPR@siBACE1 inhibited the production of Aβ, potentiated Aβ phagocytosis by microglia, improved the memory deficits and reduced neuroinflammatory response in AD mice. This study provides a reliable delivery platform for gene therapies for AD.

Social isolation during adolescence negatively impacts the development of adult social behaviors. However, the exact link between social experiences during adolescence and social behaviors in adulthood is not fully understood. In the present study, we investigated how isolation during juvenility affects harm avoidance behavior in a mouse model of juvenile social isolation. We found that mice subjected to social isolation as juveniles display atypical harm avoidance behaviors and that neurons in the anterior cingulate cortex are involved in these abnormal behaviors. Furthermore, we discovered that the chemogenetic activation of anterior cingulate cortex pyramidal neurons can rescue impaired harm-avoidance behaviors in these mice. Our findings provide valuable insights into the potential mechanisms underlying the impact of social experiences on behavior and brain function. Understanding how social isolation during crucial developmental periods can lead to alterations in behavior opens up new avenues for exploring therapeutic interventions for neuropsychiatric disorders characterized by impaired prosocial behaviors.

The approval of anti-amyloid β (Aβ) monoclonal antibodies (lecanemab) for the treatment of patients with early preclinical stage of Alzheimer's disease (AD) by the Food and Drug Administration, suggests the reliability and importance of brain Aβ clearance for AD therapy. Microglia are the main phagocytes that clear Aβ in the brain, but the underlying regulatory mechanism is unclear. Here, we investigate the critical role of cathepsin B (CatB) in modulating microglial Aβ clearance from mouse brain. Wild-type or CatB-/- mice were injected with Aβ into the hippocampus from 1 to 3 weeks. Mice were evaluated for cognitive change, Aβ metabolism, neuroinflammation. Microglia and neuron cultures were prepared to verify the in vivo results. The statistical analyses were performed by student's t test, one-way ANOVA with a post hoc Tukey's test using the GraphPad Prism software package. CatB deficiency significantly reduces Aβ clearance efficiency and aggravates mouse cognitive decline. Exogenous Aβ markedly increases CatB expression in activated microglia. Transcriptome analysis and in vitro cell culture experiments demonstrate that CatB is associated with gene clusters involved in migration, phagocytosis, and inflammation. In addition, transcriptome analysis and immunoblotting suggest that CatB modulates microglial Aβ clearance via PI3K-AKT activation. Our study unveils a previously unknown role of CatB in promoting microglial functionality during Aβ clearance.

We previously discovered WS-6 as a new antidepressant in correlation to its function of stimulating neurogenesis. Herein, several different scaffolds (stilbene, 1,3-diphenyl 1-propene, 1,3-diphenyl 2-propene, 1,2-diphenyl acrylo-1-nitrile, 1,2-diphenyl acrylo-2-nitrile, 1,3-diphenyl trimethylamine), further varied through substitutions of twelve amide substituents plus the addition of a methylene unit and an inverted amide, were examined to elucidate the SARs for promoting adult rat neurogenesis. Most of the compounds could stimulate proliferation of progenitors, but just a few chemicals possessing a specific structural profile, exemplified by diphenyl acrylonitrile 29b, 32a, and 32b, showed better activity than the clinical drug NSI-189 in promoting newborn cells differentiation into mature neurons. The most potent diphenyl acrylonitrile 32b had an excellent brain AUC to plasma AUC ratio (B/P = 1.6), suggesting its potential for further development as a new lead.

The blood-brain barrier (BBB) is a highly selective interface between the blood and the brain parenchyma. It plays an essential role in maintaining a specialized environment for central nervous system function and homeostasis. The BBB disrupts with age, which contributes to the development of many age-related disorders due to central and peripheral toxic factors or BBB dysfunction. Microglia, the resident innate immune cells of the brain, have recently been explored for their ability to directly and indirectly regulate the integrity of the BBB. This review will focus on the current understanding of the molecular mechanisms utilized by microglia to regulate BBB integrity and how this becomes disrupted in aging and age-associated diseases. We will also discuss the rationale for considering microglia as a therapeutic target to prevent or slow down neurodegeneration.

Alzheimer’s disease (AD) is the most common neurodegenerative disease often associated with olfactory dysfunction. Aβ is a typical AD hall marker, but Aβ-induced molecular alterations in olfactory memory remain unclear. In this study, we used a 5xFAD mouse model to investigate Aβ-induced olfactory changes. Results showed that 4-month-old 5xFAD have olfactory memory impairment accompanied by piriform cortex neuron activity decline and no sound or working memory impairment. In addition, synapse and glia functional alteration is consistent across different ages at the proteomic level. Microglia and astrocyte specific proteins showed strong interactions in the conserved co-expression network module. Moreover, this interaction declines only in mild cognitive impairment patients in human postmortem brain proteomic data. This suggests that astrocytes-microglia interaction may play a leading role in the early stage of Aβ-induced olfactory memory impairment, and the decreasing of their synergy may accelerate the neurodegeneration.

Depression is a common mental disorder that seriously affects the quality of life and leads to an increasing global suicide rate. Macro, micro, and trace elements are the main components that maintain normal physiological functions of the brain. Depression is manifested in abnormal brain functions, which are considered to be tightly related to the imbalance of elements. Elements associated with depression include glucose, fatty acids, amino acids, and mineral elements such as lithium, zinc, magnesium, copper, iron, and selenium. To explore the relationship between these elements and depression, the main literature in the last decade was mainly searched and summarized on PubMed, Google Scholar, Scopus, Web of Science, and other electronic databases with the keywords "depression, sugar, fat, protein, lithium, zinc, magnesium, copper, iron, and selenium". These elements aggravate or alleviate depression by regulating a series of physiological processes, including the transmission of neural signals, inflammation, oxidative stress, neurogenesis, and synaptic plasticity, which thus affect the expression or activity of physiological components such as neurotransmitters, neurotrophic factors, receptors, cytokines, and ion-binding proteins in the body. For example, excessive fat intake can lead to depression, with possible mechanisms including inflammation, increased oxidative stress, reduced synaptic plasticity, and decreased expression of 5-Hydroxytryptamine (5-HT), Brain Derived Neurotrophic Factor (BDNF), Postsynaptic density protein 95(PSD-95), etc. Supplementing mineral elements, such as selenium, zinc, magnesium, or lithium as a psychotropic medication is mostly used as an auxiliary method to improve depression with other antidepressants. In general, appropriate nutritional elements are essential to treat depression and prevent the risk of depression.