Human learning of hierarchical graphs.

Humans are exposed to sequences of events in the environment, and the interevent transition probabilities in these sequences can be modeled as a graph or network. Many real-world networks are organized hierarchically and while much is known about how humans learn basic transition graph topology, whether and to what degree humans can learn hierarchical structures in such graphs remains unknown. We probe the mental estimates of transition probabilities via the surprisal effect phenomenon: humans react more slowly to less expected transitions. Using mean-field predictions and numerical simulations, we show that surprisal effects are stronger for finer-level than coarser-level hierarchical transitions, and that surprisal effects at coarser levels are difficult to detect for limited learning times or in small samples. Using a serial response experiment with human participants (n=100), we replicate our predictions by detecting a surprisal effect at the finer level of the hierarchy but not at the coarser level of the hierarchy. We then evaluate the presence of a trade-off in learning, whereby humans who learned the finer level of the hierarchy better also tended to learn the coarser level worse, and vice versa. This study elucidates the processes by which humans learn sequential events in hierarchical contexts. More broadly, our work charts a road map for future investigation of the neural underpinnings and behavioral manifestations of graph learning.

Human Learning of Hierarchical Graphs.

Humans are constantly exposed to sequences of events in the environment. Those sequences frequently evince statistical regularities, such as the probabilities with which one event transitions to another. Collectively, inter-event transition probabilities can be modeled as a graph or network. Many real-world networks are organized hierarchically and understanding how these networks are learned by humans is an ongoing aim of current investigations. While much is known about how humans learn basic transition graph topology, whether and to what degree humans can learn hierarchical structures in such graphs remains unknown. Here, we investigate how humans learn hierarchical graphs of the Sierpinski family using computer simulations and behavioral laboratory experiments. We probe the mental estimates of transition probabilities via the surprisal effect: a phenomenon in which humans react more slowly to less expected transitions, such as those between communities or modules in the network. Using mean-field predictions and numerical simulations, we show that surprisal effects are stronger for finer-level than coarser-level hierarchical transitions. Notably, surprisal effects at coarser levels of the hierarchy are difficult to detect for limited learning times or in small samples. Using a serial response experiment with human participants (n=100), we replicate our predictions by detecting a surprisal effect at the finer-level of the hierarchy but not at the coarser-level of the hierarchy. To further explain our findings, we evaluate the presence of a trade-off in learning, whereby humans who learned the finer-level of the hierarchy better tended to learn the coarser-level worse, and vice versa. Taken together, our computational and experimental studies elucidate the processes by which humans learn sequential events in hierarchical contexts. More broadly, our work charts a road map for future investigation of the neural underpinnings and behavioral manifestations of graph learning.

Glutaminase 1 deficiency confined in forebrain neurons causes autism spectrum disorder-like behaviors.

An abnormal glutamate signaling pathway has been proposed in the mechanisms of autism spectrum disorder (ASD). However, less is known about the involvement of alterations of glutaminase 1 (GLS1) in the pathophysiology of ASD. We show that the transcript level of GLS1 is significantly decreased in the postmortem frontal cortex and peripheral blood of ASD subjects. Mice lacking Gls1 in CamKIIα-positive neurons display a series of ASD-like behaviors, synaptic excitatory and inhibitory (E/I) imbalance, higher spine density, and glutamate receptor expression in the prefrontal cortex, as well as a compromised expression pattern of genes involved in synapse pruning and less engulfed synaptic puncta in microglia. A low dose of lipopolysaccharide treatment restores microglial synapse pruning, corrects synaptic neurotransmission, and rescues behavioral deficits in these mice. In summary, these findings provide mechanistic insights into Gls1 loss in ASD symptoms and identify Gls1 as a target for the treatment of ASD.

Neural stem/progenitor cell-derived extracellular vesicles: A novel therapy for neurological diseases and beyond.

As bilayer lipid membrane vesicles secreted by neural stem/progenitor cells (NSCs), NSC-derived extracellular vesicles (NSC-EVs) have attracted growing attention for their promising potential to serve as novel therapeutic agents in treatment of neurological diseases due to their unique physicochemical characteristics and biological functions. NSC-EVs exhibit advantages such as stable physical and chemical properties, low immunogenicity, and high penetration capacity to cross blood-brain barrier to avoid predicaments of the clinical applications of NSCs that include autoimmune responses, ethical/religious concerns, and the problematic logistics of acquiring fetal tissues. More importantly, NSC-EVs inherit excellent neuroprotective and neuroregenerative potential and immunomodulatory capabilities from parent cells, and display outstanding therapeutic effects on mitigating behavioral alterations and pathological phenotypes of patients or animals with neurological diseases. In this review, we first comprehensively summarize the progress in functional research and application of NSC-EVs in different neurological diseases, including neurodegenerative diseases, acute neurological diseases, dementia/cognitive dysfunction, and peripheral diseases. Next, we provide our thoughts on current limitations/concerns as well as tremendous potential of NSC-EVs in clinical applications. Last, we discuss future directions of further investigations on NSC-EVs and their probable applications in both basic and clinical research.

Internal m7G methylation: A novel epitranscriptomic contributor in brain development and diseases.

In recent years, N7-methylguanosine (m7G) methylation, originally considered as messenger RNA (mRNA) 5' caps modifications, has been identified at defined internal positions within multiple types of RNAs, including transfer RNAs, ribosomal RNAs, miRNA, and mRNAs. Scientists have put substantial efforts to discover m7G methyltransferases and methylated sites in RNAs to unveil the essential roles of m7G modifications in the regulation of gene expression and determine the association of m7G dysregulation in various diseases, including neurological disorders. Here, we review recent findings regarding the distribution, abundance, biogenesis, modifiers, and functions of m7G modifications. We also provide an up-to-date summary of m7G detection and profile mapping techniques, databases for validated and predicted m7G RNA sites, and web servers for m7G methylation prediction. Furthermore, we discuss the pathological roles of METTL1/WDR-driven m7G methylation in neurological disorders. Last, we outline a roadmap for future directions and trends of m7G modification research, particularly in the central nervous system.

Extracellular vesicles, from the pathogenesis to the therapy of neurodegenerative diseases.

Extracellular vesicles (EVs) are small bilipid layer-enclosed vesicles that can be secreted by all tested types of brain cells. Being a key intercellular communicator, EVs have emerged as a key contributor to the pathogenesis of various neurodegenerative diseases (NDs) including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease through delivery of bioactive cargos within the central nervous system (CNS). Importantly, CNS cell-derived EVs can be purified via immunoprecipitation, and EV cargos with altered levels have been identified as potential biomarkers for the diagnosis and prognosis of NDs. Given the essential impact of EVs on the pathogenesis of NDs, pathological EVs have been considered as therapeutic targets and EVs with therapeutic effects have been utilized as potential therapeutic agents or drug delivery platforms for the treatment of NDs. In this review, we focus on recent research progress on the pathological roles of EVs released from CNS cells in the pathogenesis of NDs, summarize findings that identify CNS-derived EV cargos as potential biomarkers to diagnose NDs, and comprehensively discuss promising potential of EVs as therapeutic targets, agents, and drug delivery systems in treating NDs, together with current concerns and challenges for basic research and clinical applications of EVs regarding NDs.

Circulating extracellular vesicle-containing microRNAs reveal potential pathogenesis of Alzheimer's disease.

The pathogenesis of Alzheimer's disease (AD) remains unknown till today, hindering the research and development of AD therapeutics and diagnostics. Circulating extracellular vesicles (EVs) can be utilized as a new window to spy upon AD pathogenesis. Altered microRNA profiles were noted in both the cerebrospinal fluid (CSF)- and blood-isolated EVs of AD patients, implying the outstanding potential of circulating EV-containing miRNAs (CEmiRs) to serve as important regulators in AD pathogenesis. Although several CEmiRs were found to play a part in AD, the association of globally altered miRNA profiles in patients' serum-derived EVs with AD pathogenesis remains unclear. In this study, we first investigated the miRNA profile in serum-derived EVs from AD, mild cognitive impairment (MCI) patients, and healthy individuals. We observed differential expression patterns of CEmiRs and classified them into 10 clusters. We identified the predicted targets of these differentially expressed CEmiRs (DECEmiRs) and analyzed their biological functions and interactions. Our study revealed the temporal regulation of complex and precise signaling networks on AD pathogenesis, shedding light on the development of novel therapeutic strategies, including multi-target drug combination for AD treatment.

Mitochondrial dysfunction in microglia: a novel perspective for pathogenesis of Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease in the elderly globally. Emerging evidence has demonstrated microglia-driven neuroinflammation as a key contributor to the onset and progression of AD, however, the mechanisms that mediate neuroinflammation remain largely unknown. Recent studies have suggested mitochondrial dysfunction including mitochondrial DNA (mtDNA) damage, metabolic defects, and quality control (QC) disorders precedes microglial activation and subsequent neuroinflammation. Therefore, an in-depth understanding of the relationship between mitochondrial dysfunction and microglial activation in AD is important to unveil the pathogenesis of AD and develop effective approaches for early AD diagnosis and treatment. In this review, we summarized current progress in the roles of mtDNA, mitochondrial metabolism, mitochondrial QC changes in microglial activation in AD, and provide comprehensive thoughts for targeting microglial mitochondria as potential therapeutic strategies of AD.

Mechanisms of Ferroptosis and Emerging Links to the Pathology of Neurodegenerative Diseases.

Neurodegenerative diseases are a diverse class of diseases attributed to chronic progressive neuronal degeneration and synaptic loss in the brain and/or spinal cord, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and multiple sclerosis. The pathogenesis of neurodegenerative diseases is complex and diverse, often involving mitochondrial dysfunction, neuroinflammation, and epigenetic changes. However, the pathogenesis of neurodegenerative diseases has not been fully elucidated. Recently, accumulating evidence revealed that ferroptosis, a newly discovered iron-dependent and lipid peroxidation-driven type of programmed cell death, provides another explanation for the occurrence and progression of neurodegenerative diseases. Here, we provide an overview of the process and regulation mechanisms of ferroptosis, and summarize current research progresses that support the contribution of ferroptosis to the pathogenesis of neurodegenerative diseases. A comprehensive understanding of the emerging roles of ferroptosis in neurodegenerative diseases will shed light on the development of novel therapeutic technologies and strategies for slowing down the progression of these diseases.

Astrocytes: GABAceptive and GABAergic Cells in the Brain.

Astrocytes, the most numerous glial cells in the brain, play an important role in preserving normal neural functions and mediating the pathogenesis of neurological disorders. Recent studies have shown that astrocytes are GABAceptive and GABAergic astrocytes express GABAA receptors, GABAB receptors, and GABA transporter proteins to capture and internalize GABA. GABAceptive astrocytes thus influence both inhibitory and excitatory neurotransmission by controlling the levels of extracellular GABA. Furthermore, astrocytes synthesize and release GABA to directly regulate brain functions. In this review, we highlight recent research progresses that support astrocytes as GABAceptive and GABAergic cells. We also summarize the roles of GABAceptive and GABAergic astrocytes that serve as an inhibitory node in the intercellular communication in the brain. Besides, we discuss future directions for further expanding our knowledge on the GABAceptive and GABAergic astrocyte signaling.

Insulin-incubated palladium clusters promote recovery after brain injury.

Traumatic brain injury (TBI) is a cause of disability and death worldwide, but there are currently no specific treatments for this condition. Release of excess reactive oxygen species (ROS) in the injured brain leads to a series of pathological changes; thus, eliminating ROS could be a potential therapeutic strategy. Herein, we synthesized insulin-incubated ultrasmall palladium (Pd@insulin) clusters via green biomimetic chemistry. The Pd@insulin clusters, which were 3.2 nm in diameter, exhibited marked multiple ROS-scavenging ability testified by the theoretical calculation. Pd@insulin could be rapidly excreted via kidney-urine metabolism and induce negligible adverse effects after a long-time treatment in vivo. In a TBI mouse model, intravenously injected Pd@insulin clusters aggregated in the injured cortex, effectively suppressed excessive ROS production, and significantly rescued motor function, cognition and spatial memory. We found that the positive therapeutic effects of the Pd@insulin clusters were mainly attributed to their ROS-scavenging ability, as they inhibited excessive neuroinflammation, reduced cell apoptosis, and prevented neuronal loss. Therefore, the ability of Pd@insulin clusters to effectively eliminate ROS, as well as their simple structure, easy synthesis, low toxicity, and rapid metabolism may facilitate their clinical translation for TBI treatment.

m6A Reader Igf2bp1 Regulates the Inflammatory Responses of Microglia by Stabilizing Gbp11 and Cp mRNAs.

Microglia are brain resident cells that function as brain phagocytic macrophages. The inflammatory responses of microglia induced by pathologic insults are key regulators in the progression of various neurological disorders. Currently, little is known about how these responses are regulated intrinsically. Here, it is observed that LPS-activated microglia exhibit distinct N6-methyladenosine (m6A) methylation patterns that are positively correlated with the expression patterns of corresponding mRNAs. High-throughput analyses and molecular studies both identified Igf2bp1 as the most significantly regulated m6A modifiers in activated microglia. Perturbation of function approaches further indicated Igf2bp1 as a key mediator for LPS-induced m6A modification and microglial activation presumably via enhancing the m6A methylation and stability of Gbp11 and Cp mRNAs. Thus, our study provides a possible mechanism for the m6A methylation-mediated microglia regulation and identifies Igf2bp1 as a potential target for modulating the inflammatory responses of microglia.

ROS-Targeted Depression Therapy via BSA-Incubated Ceria Nanoclusters.

Depression is one of the most fatal mental diseases, and there is currently a lack of efficient drugs for the treatment of depression. Emerging evidence has indicated oxidative stress as a key pathological feature of depression. We targeted reactive oxygen species (ROS) and synthesized CeO2@BSA nanoclusters as a novel antidepression nanodrug via a convenient, green, and highly effective bovine serum albumin (BSA) incubation strategy. CeO2@BSA has ultrasmall size (2 nm) with outstanding ROS scavenging and blood-brain barrier crossing capacity, rapid metabolism, and negligible adverse effects in vitro and in vivo. CeO2@BSA administration alleviates depressive behaviors and depression-related pathological changes of the chronic restraint stress-induced depressive model, suggesting promising therapeutic effects of CeO2@BSA for the treatment of depression. Our study proved the validity by directly using nanodrugs as antidepression drugs instead of using them as a nanocarrier, which greatly expands the application of nanomaterials in depression treatment.

Exosomes Mediate APP Dysregulation via APP-miR-185-5p Axis.

APP misexpression plays a crucial role in triggering a complex pathological cascade, leading to Alzheimer's disease (AD). But how the expression of APP is regulated in pathological conditions remains poorly understood. In this study, we found that the exosomes isolated from AD mouse brain promoted APP expression in neuronal N2a cells. Moreover, exosomes derived from N2a cells with ectopic expression of APP (APP-EXO) also induced APP dysregulation in normal N2a cells. Surprisingly, the effects of APP-EXO on APP expression in recipient cells were not mediated by the direct transferring of APP gene products. Instead, the effects of APP-EXO were highly likely mediated by the reduction of the expression levels of exosomal miR-185-5p. We found that the 3'UTR of APP transcripts binds to miR-185-5p, therefore inhibiting the sorting of miR-185-5p to exosomes. N2a cell-derived exosomes with less amount of miR-185-5p exert similar roles in APP expression to APP-EXO. Lastly, we demonstrated a significant decline of serum exosomal miR-185-5p in AD patients and AD mice, versus the corresponding controls. Together, our results demonstrate a novel mechanism in the exosome-dependent regulation of APP, implying exosomes and exosomal miRNAs as potential therapeutic targets and biomarkers for AD treatment and diagnosis, respectively.