Subjective memory complaints in young people; their relationship withobjective cognitive performance and the role of neuroticism / Quejas subjetivas de memoria en jóvenes; su relación con el rendimiento cognitivo objetivo y el papel del neuroticismo

Las percepciones de olvidos recurrentes o episodios de distracción en la vida diaria se denominan quejas subjetivas de memoria (QSM). Su naturaleza se ha estudiado ampliamente en adultos mayores, pero su importancia y relación con el rendimiento neurocognitivo no se han abordado por completo en adultos más jóvenes. Se han sugerido algunos rasgos psicológicos como posibles moderadores de la asociación entre el rendimiento de la memoria objetiva y subjetiva. El primer objetivo de este estudio fue analizar la correspondencia entre la percepción objetiva y subjetiva de los fallos de memoria en jóvenes. En segundo lugar, estudiamos si el rasgo psicológico del neuroticismo podría estar influyendo en esta relación. Para ello, medimos QSM, diferentes dominios cognitivos (memoria episódica y de trabajo y funciones ejecutivas) y neuroticismo en 80 hombres y mujeres jóvenes. Los resultados mostraron que solo la memoria episódica inmediata estaba estadísticamente relacionada con los QSM. Curiosamente, las relaciones negativas entre el rendimiento de la memoria objetiva y subjetiva solo aparecieron en participantes con mayor neuroticismo. Por lo tanto, las quejas de memoria reportadas por los jóvenes podrían reflejar un peor rendimiento de la memoria episódica inmediata, mientras que el neuroticismo jugaría un papel principal en la asociación entre los déficits de memoria y las QSM. Este estudio proporciona datos que pueden ayudar a comprender mejor las QSM en los jóvenes.(AU)

Perceptions of recurrent forgetfulness or episodes of distraction in daily life are referred to as subjective memory complaints (SMCs). Their nature has been extensively studied in older adults, but their significance and relationship with neurocognitive performance have not been fully ad-dressed in younger adults. Some psychological traits have been suggested as possible moderators of the association between objective and subjective memory performance. The first aim of this study was to analyze the corre-spondence between the objective and subjective perception of memory failures in young people. Second, we studied whether the psychological trait of neuroticism could be influencing this relationship. Todo this, we measured SMCs, different cognitive domains (episodic and working memory and executive functions), and neuroticism in 80 young men and women. Results showed that only immediate episodic memory was statisti-cally related to SMCs. Interestingly, the negative relationships between ob-jective and subjective memory performance only appeared in participants with higher neuroticism. Thus, memory complaints reported by young people could reflect poorer immediate episodic memory performance, whereas neuroticism would play a main role in the association between memory deficits and SMCs. This study provides data that can help to bet-ter understand SMCs in young people.(AU)

A decision support system based on recurrent neural networks to predict medication dosage for patients with Parkinson's disease.

Using deep learning has demonstrated significant potential in making informed decisions based on clinical evidence. In this study, we deal with optimizing medication and quantitatively present the role of deep learning in predicting the medication dosage for patients with Parkinson's disease (PD). The proposed method is based on recurrent neural networks (RNNs) and tries to predict the dosage of five critical medication types for PD, including levodopa, dopamine agonists, monoamine oxidase-B inhibitors, catechol-O-methyltransferase inhibitors, and amantadine. Recurrent neural networks have memory blocks that retain crucial information from previous patient visits. This feature is helpful for patients with PD, as the neurologist can refer to the patient's previous state and the prescribed medication to make informed decisions. We employed data from the Parkinson's Progression Markers Initiative. The dataset included information on the Unified Parkinson's Disease Rating Scale, Activities of Daily Living, Hoehn and Yahr scale, demographic details, and medication use logs for each patient. We evaluated several models, such as multi-layer perceptron (MLP), Simple-RNN, long short-term memory (LSTM), and gated recurrent units (GRU). Our analysis found that recurrent neural networks (LSTM and GRU) performed the best. More specifically, when using LSTM, we were able to predict levodopa and dopamine agonist dosage with a mean squared error of 0.009 and 0.003, mean absolute error of 0.062 and 0.030, root mean square error of 0.099 and 0.053, and R-squared of 0.514 and 0.711, respectively.

Constitutive knockout of interleukin-6 ameliorates memory deficits and entorhinal astrocytosis in the MRL/lpr mouse model of neuropsychiatric lupus.

BACKGROUND: Neuropsychiatric lupus (NPSLE) describes the cognitive, memory, and affective emotional burdens faced by many lupus patients. While NPSLE's pathogenesis has not been fully elucidated, clinical imaging studies and cerebrospinal fluid (CSF) findings, namely elevated interleukin-6 (IL-6) levels, point to ongoing neuroinflammation in affected patients. Not only linked to systemic autoimmunity, IL-6 can also activate neurotoxic glial cells the brain. A prior pre-clinical study demonstrated that IL-6 can acutely induce a loss of sucrose preference; the present study sought to assess the necessity of chronic IL-6 exposure in the NPSLE-like disease of MRL/lpr lupus mice. METHODS: We quantified 1308 proteins in individual serum or pooled CSF samples from MRL/lpr and control MRL/mpj mice using protein microarrays. Serum IL-6 levels were plotted against characteristic NPSLE neurobehavioral deficits. Next, IL-6 knockout MRL/lpr (IL-6 KO; n = 15) and IL-6 wildtype MRL/lpr mice (IL-6 WT; n = 15) underwent behavioral testing, focusing on murine correlates of learning and memory deficits, depression, and anxiety. Using qPCR, we quantified the expression of inflammatory genes in the cortex and hippocampus of MRL/lpr IL-6 KO and WT mice. Immunofluorescent staining was performed to quantify numbers of microglia (Iba1 +) and astrocytes (GFAP +) in multiple cortical regions, the hippocampus, and the amygdala. RESULTS: MRL/lpr CSF analyses revealed increases in IL-17, MCP-1, TNF-α, and IL-6 (a priori p-value < 0.1). Serum levels of IL-6 correlated with learning and memory performance (R2 = 0.58; p = 0.03), but not motivated behavior, in MRL/lpr mice. Compared to MRL/lpr IL-6 WT, IL-6 KO mice exhibited improved novelty preference on object placement (45.4% vs 60.2%, p < 0.0001) and object recognition (48.9% vs 67.9%, p = 0.002) but equivalent performance in tests for anxiety-like disease and depression-like behavior. IL-6 KO mice displayed decreased cortical expression of aif1 (microglia; p = 0.049) and gfap (astrocytes; p = 0.044). Correspondingly, IL-6 KO mice exhibited decreased density of GFAP + cells compared to IL-6 WT in the entorhinal cortex (89 vs 148 cells/mm2, p = 0.037), an area vital to memory. CONCLUSIONS: The inflammatory composition of MRL/lpr CSF resembles that of human NPSLE patients. Increased in the CNS, IL-6 is necessary to the development of learning and memory deficits in the MRL/lpr model of NPSLE. Furthermore, the stimulation of entorhinal astrocytosis appears to be a key mechanism by which IL-6 promotes these behavioral deficits.

Mismatch novelty exploration training shifts VPAC1 receptor-mediated modulation of hippocampal synaptic plasticity by endogenous VIP in male rats.

Novelty influences hippocampal-dependent memory through metaplasticity. Mismatch novelty detection activates the human hippocampal CA1 area and enhances rat hippocampal-dependent learning and exploration. Remarkably, mismatch novelty training (NT) also enhances rodent hippocampal synaptic plasticity while inhibition of VIP interneurons promotes rodent exploration. Since VIP, acting on VPAC1 receptors (Rs), restrains hippocampal LTP and depotentiation by modulating disinhibition, we now investigated the impact of NT on VPAC1 modulation of hippocampal synaptic plasticity in male Wistar rats. NT enhanced both CA1 hippocampal LTP and depotentiation unlike exploring an empty holeboard (HT) or a fixed configuration of objects (FT). Blocking VIP VPAC1Rs with PG 97269 (100 nM) enhanced both LTP and depotentiation in naïve animals, but this effect was less effective in NT rats. Altered endogenous VIP modulation of LTP was absent in animals exposed to the empty environment (HT). HT and FT animals showed mildly enhanced synaptic VPAC1R levels, but neither VIP nor VPAC1R levels were altered in NT animals. Conversely, NT enhanced the GluA1/GluA2 AMPAR ratio and gephyrin synaptic content but not PSD-95 excitatory synaptic marker. In conclusion, NT influences hippocampal synaptic plasticity by reshaping brain circuits modulating disinhibition and its control by VIP-expressing hippocampal interneurons while upregulation of VIP VPAC1Rs is associated with the maintenance of VIP control of LTP in FT and HT animals. This suggests VIP receptor ligands may be relevant to co-adjuvate cognitive recovery therapies in aging or epilepsy, where LTP/LTD imbalance occurs.

The IC87201 (a PSD95/nNOS Inhibitor) Attenuates Post- Stroke Injuries.

N-methyl-D-aspartate receptor-dependent excitotoxicity is one of the most important mechanisms underlying stroke injury and the resulting neuronal death. In the present study, in order to reduce post-stroke brain injury and improve behavioral performance, a new molecule named IC87201, which acts as an inhibitor of PSD95/nNOS interaction in the intracellular signaling pathway of NMDA receptors, was administered. Using the middle cerebral artery occlusion (MCAO) technique, 24 adult male rats were subjected to one hour of cerebral ischemia. Animals were randomly divided into sham, MCAO, MCAO + DXM, and MCAO + IC87201 groups, and in the last two groups, intraperitoneal injection of dextromethorphan hydrobromide monohydrate (DXM), as an NMDA antagonist, and IC87201 was performed after ischemia. Neurobehavioral scores were evaluated for seven days, and on the last two days, the rats' memory performance was appraised using the passive avoidance test. On seventh day, the brain tissue was properly prepared for stereological analysis. Stereological studies of the hippocampus CA1 and CA3 regions revealed that changes in the total and infarcted volumes, total number of neurons, non-neurons, and dead neurons are the consequences of cerebral ischemia. Also, following cerebral ischemia, neurobehavioral and memory function impairments which were assessed by modified neurological severity scores (mNSS) and passive avoidance test, were observed. The aforementioned impairments were recovered after administration of IC87201 significantly and more potently than DXM. Based on our findings, IC87201 successfully attenuated post-ischemia damages. Therefore, this molecule can be considered as a new therapeutic approach in future research.

Age Deficits in Associative Memory are not Alleviated by Multisensory Paradigms.

OBJECTIVES: Age deficits in memory are widespread, this impacts individuals at a personal level, and investigating memory has been a key focus in cognitive ageing research. Age deficits occur in memory for an episode, where information from the environment is integrated through the senses into an episodic event via associative memory. Associating items in memory has been shown to be particularly difficult for older adults but can often be alleviated by providing support from the external environment. The current investigation explored the potential for increased sensory input (multimodal stimuli) to alleviate age deficits in associative memory. Here, we present compelling evidence, supported by Bayesian analysis, for a null age-by-modality interaction. METHODS: Across three pre-registered studies, young and older adults (n = 860) completed associative memory tasks either in single modalities or in multimodal formats. Study 1 used either visual text (unimodal) or video introductions (multimodal) to test memory for name-face associations. Studies 2 and 3 tested memory for paired associates. Study 2 used unimodal visual presentation or cross modal visual-auditory word pairs in a cued recall paradigm. Study 3 presented word pairs as visual only, auditory only or audiovisual and tested memory separately for items (individual words) or associations (word pairings). RESULTS: Typical age deficits in associative memory emerged, but these were not alleviated by multimodal presentation. DISCUSSION: The lack of multimodal support for associative memory indicates that perceptual manipulations are less effective than other forms of environmental support at alleviating age deficits in associative memory.

Bile acid metabolism is altered in learning and memory impairment induced by chronic lead exposure.

Lead is a neurotoxic contaminant that exists widely in the environment. Although lead neurotoxicity has been found to be tightly linked to gut microbiota disturbance, the effect of host metabolic disorders caused by gut microbiota disturbance on lead neurotoxicity has not been investigated. In this work, the results of new object recognition tests and Morris water maze tests showed that chronic low-dose lead exposure caused learning and memory dysfunction in mice. The results of 16 S rRNA sequencing of cecal contents and fecal microbiota transplantation showed that the neurotoxicity of lead could be transmitted through gut microbiota. The results of untargeted metabolomics and bile acid targeted metabolism analysis showed that the serum bile acid metabolism profile of lead-exposed mice was significantly changed. In addition, supplementation with TUDCA or INT-777 significantly alleviated chronic lead exposure-induced learning and memory impairment, primarily through inhibition of the NLRP3 inflammasome in the hippocampus to relieve neuroinflammation. In conclusion, our findings suggested that dysregulation of host bile acid metabolism may be one of the mechanisms of lead-induced neurotoxicity, and supplementation of specific bile acids may be a possible therapeutic strategy for lead-induced neurotoxicity.

Improving usual care outcomes in major depression in youth by targeting memory specificity: A randomized controlled trial of adjunct computerized memory specificity training (c-MeST).

OBJECTIVE: Extending on previous findings that computerized MeST (c-MeST) improves memory specificity and depressive symptoms in Major Depressive Disorder (MDD) in adults, this study aimed to assess the effects of c-MeST in youth with MDD on memory specificity and depression in addition to other treatment. METHODS: Participants aged 15-25 (N = 359, 76 % female; M age = 19.2, SD = 3.1), receiving predominantly psychological therapy or counseling (85 %) and/or antidepressants (52 %) were randomized to usual care and c-MeST or usual care. Cognitive and clinical outcomes were assessed at baseline and at one, three, and six-month follow-ups. RESULTS: The usual care and c-MeST group reported higher memory specificity at one-month (d = 0.42, p = .022), but not at three or six months (d's < 0.15, p's > 0.05). The rate of MDE was numerically lower in the c-MeST group at each follow-up time-point, but group was not a statistically significant predictor at one month (64 % usual care and c-MeST vs. 68 % usual care, OR = 0.81, p = .606), three months (67 % usual care and c-MeST vs. 72 % usual care, OR = 0.64, p = .327) or six months (55 % usual care and c-MeST vs. 68 % usual care, OR = 0.56, p = .266). The usual care and c-MeST group did report lower depressive symptoms at one month (d = 0.42, p = .023) and six-months (d = 0.84, p = .001), but not three-months (d = 0.13, p > .05). CONCLUSIONS: c-MeST may reduce symptoms in youth with MDD when provided alongside other treatments. However, there are significant limitations to this inference, including high attrition in the study and a need for more data on the acceptability of the intervention.

A natural language model to automate scoring of autobiographical memories.

Biases in the retrieval of personal, autobiographical memories are a core feature of multiple mental health disorders, and are associated with poor clinical prognosis. However, current assessments of memory bias are either reliant on human scoring, restricting their administration in clinical settings, or when computerized, are only able to identify one memory type. Here, we developed a natural language model able to classify text-based memories as one of five different autobiographical memory types (specific, categoric, extended, semantic associate, omission), allowing easy assessment of a wider range of memory biases, including reduced memory specificity and impaired memory flexibility. Our model was trained on 17,632 text-based, human-scored memories obtained from individuals with and without experience of memory bias and mental health challenges, which was then tested on a dataset of 5880 memories. We used 20-fold cross-validation setup, and the model was fine-tuned over BERT. Relative to benchmarking and an existing support vector model, our model achieved high accuracy (95.7%) and precision (91.0%). We provide an open-source version of the model which is able to be used without further coding, by those with no coding experience, to facilitate the assessment of autobiographical memory bias in clinical settings, and aid implementation of memory-based interventions within treatment services.

Probing the content of affective semantic memory following caregiving-related early adversity.

Cognitive science has demonstrated that we construct knowledge about the world by abstracting patterns from routinely encountered experiences and storing them as semantic memories. This preregistered study tested the hypothesis that caregiving-related early adversities (crEAs) shape affective semantic memories to reflect the content of those adverse interpersonal-affective experiences. We also tested the hypothesis that because affective semantic memories may continue to evolve in response to later-occurring positive experiences, child-perceived attachment security will inform their content. The sample comprised 160 children (ages 6-12 at Visit 1; 87F/73 M), 66% of whom experienced crEAs (n = 105). At Visit 1, crEA exposure prior to study enrollment was operationalized as parental-reports endorsing a history of crEAs (abuse/neglect, permanent/significant parent-child separation); while child-reports assessed concurrent attachment security. A false memory task was administered online ∼2.5 years later (Visit 2) to probe the content of affective semantic memories-specifically attachment schemas. Results showed that crEA exposure (vs. no exposure) was associated with a higher likelihood of falsely endorsing insecure (vs. secure) schema scenes. Attachment security moderated the association between crEA exposure and insecure schema-based false recognition. Findings suggest that interpersonal-affective semantic schemas include representations of parent-child interactions that may capture the quality of one's own attachment experiences and that these representations shape how children remember attachment-relevant narrative events. Findings are also consistent with the hypothesis that these affective semantic memories can be modified by later experiences. Moving forward, the approach taken in this study provides a means of operationalizing Bowlby's notion of internal working models within a cognitive neuroscience framework. RESEARCH HIGHLIGHTS: Affective semantic memories representing insecure schema knowledge (child needs + needs-not-met) may be more salient, elaborated, and persistent among youths exposed to early caregiving adversity. All youths, irrespective of early caregiving adversity exposure, may possess affective semantic memories that represent knowledge of secure schemas (child needs + needs-met). Establishing secure relationships with parents following early-occurring caregiving adversity may attenuate the expression of insecure semantic memories, suggesting potential malleability. Affective semantic memories include schema representations of parent-child interactions that may capture the quality of one's own attachment experiences and shape how youths remember attachment-relevant events.

Growth of Atomic layer-deposited Monoclinic Molybdenum Dioxide Films Stabilized by Tin Oxide Doping for DRAM Capacitor Electrode Applications.

Dynamic random-access memory (DRAM) capacitor electrodes, exemplified by TiN, face performance limitations owing to their relatively low work functions in addition to the formation of a low-k interfacial layer caused by their insufficient chemical stability. With recent advances in device scaling, these issues have become increasingly problematic, prompting the exploration of alternative electrode materials to replace TiN. Molybdenum dioxide (MoO2) has emerged as a promising candidate for this application, outperforming TiN due to its low resistivity, high work function (>5 eV), and excellent chemical stability. Moreover, monoclinic MoO2 exhibits a distorted rutile structure, enabling the in situ growth of high-k rutile TiO2 on MoO2 at low deposition temperatures. However, MoO2 deposition poses challenges because of its metastable nature compared to the more stable molybdenum oxide (MoOx) phases, such as MoO3 and Mo4O11. In this work, we successfully fabricated Sn-doped MoOx (TMO) films by atomic layer deposition (ALD) at 300 °C. A stabilized monoclinic MoO2 phase was achieved using ALD by incorporating SnOx into MoOx on both SiO2 and TiN substrates. The ALD TMO process comprised MoOx and SnOx subcycles, and the MoOx:SnOx subcycle ratio was varied from 100:1 to 20:1. High growth rates ranging from 0.19 to 0.34 nm/cycle were achieved for ALD TMO with varying the MoOx:SnOx subcycle ratio from 20:1 to 100:0. After post-deposition annealing at 500 °C, polycrystalline TMO films were obtained with smooth surface morphology. ALD TMO exhibited excellent interface quality with ALD TiO2, possessing a negligible low-k interfacial layer. Moreover, a rutile TiO2 film with a high dielectric constant of 136 was successfully grown on a 20% Sn-TMO electrode. Overall, this study provides a strategy to stabilize metastable MoO2 films using ALD, and it demonstrates the superiority of ALD TMO as a promising DRAM capacitor electrode material.

Revisiting plant stress memory: mechanisms and contribution to stress adaptation.

Highly repetitive adverse environmental conditions are encountered by plants multiple times during their lifecycle. These repetitive encounters with stresses provide plants an opportunity to remember and recall the experiences of past stress-associated responses, resulting in better adaptation towards those stresses. In general, this phenomenon is known as plant stress memory. According to our current understanding, epigenetic mechanisms play a major role in plants stress memory through DNA methylation, histone, and chromatin remodeling, and modulating non-coding RNAs. In addition, transcriptional, hormonal, and metabolic-based regulations of stress memory establishment also exist for various biotic and abiotic stresses. Plant memory can also be generated by priming the plants using various stressors that improve plants' tolerance towards unfavorable conditions. Additionally, the application of priming agents has been demonstrated to successfully establish stress memory. However, the interconnection of all aspects of the underlying mechanisms of plant stress memory is not yet fully understood, which limits their proper utilization to improve the stress adaptations in plants. This review summarizes the recent understanding of plant stress memory and its potential applications in improving plant tolerance towards biotic and abiotic stresses.

Relationship of plasma biomarkers to digital cognitive tests in Alzheimer's disease.

INTRODUCTION: A major limitation in Alzheimer's disease (AD) research is the lack of the ability to measure cognitive performance at scale-robustly, remotely, and frequently. Currently, there are no established online digital platforms validated against plasma biomarkers of AD. METHODS: We used a novel web-based platform that assessed different cognitive functions in AD patients (N = 46) and elderly controls (N = 53) who were also evaluated for plasma biomarkers (amyloid beta 42/40 ratio, phosphorylated tau ([p-tau]181, glial fibrillary acidic protein, neurofilament light chain). Their cognitive performance was compared to a second, larger group of elderly controls (N = 352). RESULTS: Patients with AD were significantly impaired across all digital cognitive tests, with performance correlating with plasma biomarker levels, particularly p-tau181. The combination of p-tau181 and the single best-performing digital test achieved high accuracy in group classification. DISCUSSION: These findings show how online testing can now be deployed in patients with AD to measure cognitive function effectively and related to blood biomarkers of the disease. Highlights: This is the first study comparing online digital testing to plasma biomarkers.Alzheimer's disease patients and two independent cohorts of elderly controls were assessed.Cognitive performance correlated with plasma biomarkers, particularly phosphorylated tau (p-tau)181.Glial fibrillary acidic protein and neurofilament light chain, and less so the amyloid beta 42/40 ratio, were also associated with performance.The best cognitive metric performed at par to p-tau181 in group classification.

Distinct brain network organizations between club players and novices under different difficulty levels.

SIGNIFICANT: Chunk memory is one of the essential cognitive functions for high-expertise (HE) player to make efficient decisions. However, it remains unknown how the neural mechanisms of chunk memory processes mediate or alter chess players' performance when facing different opponents. AIM: This study aimed at inspecting the significant brain networks associated with chunk memory, which would vary between club players and novices. APPROACH: Functional networks and topological features of 20 club players (HE) and 20 novice players (LE) were compared at different levels of difficulty by means of functional near-infrared spectroscopy. RESULTS: Behavioral performance indicated that the club player group was unaffected by differences in difficulty. Furthermore, the club player group demonstrated functional connectivity among the dorsolateral prefrontal cortex, the frontopolar cortex, the supramarginal gyrus, and the subcentral gyrus, as well as higher clustering coefficients and lower path lengths in the high-difficulty task. CONCLUSIONS: The club player group illustrated significant frontal-parietal functional connectivity patterns and topological characteristics, suggesting enhanced chunking processes for improved chess performance.

Dysregulation of CD4+ and CD8+ resident memory T, myeloid, and stromal cells in steroid-experienced, checkpoint inhibitor colitis.

BACKGROUND: Colitis caused by checkpoint inhibitors (CPI) is frequent and is treated with empiric steroids, but CPI colitis mechanisms in steroid-experienced or refractory disease are unclear. METHODS: Using colon biopsies and blood from predominantly steroid-experienced CPI colitis patients, we performed multiplexed single-cell transcriptomics and proteomics to nominate contributing populations. RESULTS: CPI colitis biopsies showed enrichment of CD4+resident memory (RM) T cells in addition to CD8+ RM and cytotoxic CD8+ T cells. Matching T cell receptor (TCR) clonotypes suggested that both RMs are progenitors that yield cytotoxic effectors. Activated, CD38+ HLA-DR+ CD4+ RM and cytotoxic CD8+ T cells were enriched in steroid-experienced and a validation data set of steroid-naïve CPI colitis, underscoring their pathogenic potential across steroid exposure. Distinct from ulcerative colitis, CPI colitis exhibited perturbed stromal metabolism (NAD+, tryptophan) impacting epithelial survival and inflammation. Endothelial cells in CPI colitis after anti-TNF and anti-cytotoxic T-lymphocyte-associated antigen 4 (anti-CTLA-4) upregulated the integrin α4ß7 ligand molecular vascular addressin cell adhesion molecule 1 (MAdCAM-1), which may preferentially respond to vedolizumab (anti-α4ß7). CONCLUSIONS: These findings nominate CD4+ RM and MAdCAM-1+ endothelial cells for targeting in specific subsets of CPI colitis patients.

LRP1 in GABAergic neurons is a key link between obesity and memory function.

OBJECTIVE: Low-density lipoprotein receptor-related protein-1 (LRP1) regulates energy homeostasis, blood-brain barrier integrity, and metabolic signaling in the brain. Deficiency of LRP1 in inhibitory gamma-aminobutyric acid (GABA)ergic neurons causes severe obesity in mice. However, the impact of LRP1 in inhibitory neurons on memory function and cognition in the context of obesity is poorly understood. METHODS: Mice lacking LRP1 in GABAergic neurons (Vgat-Cre; LRP1loxP/loxP) underwent behavioral tests for locomotor activity and motor coordination, short/long-term and spatial memory, and fear learning/memory. This study evaluated the relationships between behavior and metabolic risk factors and followed the mice at 16 and 32 weeks of age. RESULTS: Deletion of LRP1 in GABAergic neurons caused a significant impairment in memory function in 32-week-old mice. In the spatial Y-maze test, Vgat-Cre; LRP1loxP/loxP mice exhibited decreased travel distance and duration in the novel arm compared with controls (LRP1loxP/loxP mice). In addition, GABAergic neuron-specific LRP1-deficient mice showed a diminished capacity for performing learning and memory tasks during the water T-maze test. Moreover, reduced freezing time was observed in these mice during the contextual and cued fear conditioning tests. These effects were accompanied by increased neuronal necrosis and satellitosis in the hippocampus. Importantly, the distance and duration in the novel arm, as well as the performance of the reversal water T-maze test, negatively correlated with metabolic risk parameters, including body weight, serum leptin, insulin, and apolipoprotein J. However, in 16-week-old Vgat-Cre; LRP1loxP/loxP mice, there were no differences in the behavioral tests or correlations between metabolic parameters and cognition. CONCLUSIONS: Our findings demonstrate that LRP1 from GABAergic neurons is important in regulating normal learning and memory. Metabolically, obesity caused by GABAergic LRP1 deletion negatively regulates memory and cognitive function in an age-dependent manner. Thus, LRP1 in GABAergic neurons may play a crucial role in maintaining normal excitatory/inhibitory balance, impacting memory function, and reinforcing the potential importance of LRP1 in neural system integrity.

Bone marrow CD8+ Trm cells induced by IL-15 and CD16+ monocytes contribute to HSPC destruction in human severe aplastic anemia.

Idiopathic severe aplastic anemia (SAA) is a disease of bone marrow failure caused by T-cell-induced destruction of hematopoietic stem and progenitor cells (HSPCs), however the mechanism remains unclear. We performed single-cell RNA sequencing of PBMCs and BMMCs from SAA patients and healthy donors and identified a CD8+ T cell subset with a tissue residency phenotype (Trm) in bone marrow that exhibit high IFN-γ and FasL expression and have a higher ability to induce apoptosis in HSPCs in vitro through FasL expression. CD8+ Trm cells were induced by IL-15 presented by IL-15Rα on monocytes, especially CD16+ monocytes, which were increased in SAA patients. CD16+ monocytes contributed to IL-15-induced CD38+CXCR6+ pre-Trm differentiation into CD8+ Trm cells, which can be inhibited by the CD38 inhibitor 78c. Our results demonstrate that IL-15-induced CD8+ Trm cells are pathogenic cells that mediate HSPC destruction in SAA patients and are therapeutic targets for future treatments.

Class I HDAC inhibitors enhance antitumor efficacy and persistence of CAR-T cells by activation of the Wnt pathway.

Epigenetic modification shapes differentiation trajectory and regulates the exhaustion state of chimeric antigen receptor T (CAR-T) cells. Limited efficacy induced by terminal exhaustion closely ties with intrinsic transcriptional regulation. However, the comprehensive regulatory mechanisms remain largely elusive. Here, we identify class I histone deacetylase inhibitors (HDACi) as boosters of CAR-T cell function by high-throughput screening of chromatin-modifying drugs, in which M344 and chidamide enhance memory maintenance and resistance to exhaustion of CAR-T cells that induce sustained antitumor efficacy both in vitro and in vivo. Mechanistically, HDACi decrease HDAC1 expression and enhance H3K27ac activity. Multi-omics analyses from RNA-seq, ATAC-seq, and H3K27ac CUT&Tag-seq show that HDACi upregulate expression of TCF4, LEF1, and CTNNB1, which subsequently activate the canonical Wnt/ß-catenin pathway. Collectively, our findings elucidate the functional roles of class I HDACi in enhancing CAR-T cell function, which provides the basis and therapeutic targets for synergic combination of CAR-T cell therapy and HDACi treatment.

The 5HT2b Receptor in Alzheimer's Disease: Increased Levels in Patient Brains and Antagonist Attenuation of Amyloid and Tau Induced Dysfunction.

BACKGROUND: Background: Neurodegenerative diseases manifest behavioral dysfunction with disease progression. Intervention with neuropsychiatric drugs is part of most multi-drug treatment paradigms. However, only a fraction of patients responds to the treatments and those responding must deal with drug-drug interactions and tolerance issues generally attributed to off-target activities. Recent efforts have focused on the identification of underexplored targets and exploration of improved outcomes by treatment with selective molecular probes. Objective: As part of ongoing efforts to identify and validate additional targets amenable to therapeutic intervention, we examined levels of the serotonin 5-HT2b receptor (5-HT2bR) in Alzheimer's disease (AD) brains and the potential of a selective 5-HT2bR antagonist to counteract synaptic plasticity and memory damage induced by AD-related proteins, amyloid-ß, and tau. Methods: This work used a combination of biochemical, chemical biology, electrophysiological, and behavioral techniques. Biochemical methods included analysis of protein levels. Chemical biology methods included the use of an in vivo molecular probe MW071, a selective antagonist for the 5HT2bR. Electrophysiological methods included assessment of long-term potentiation (LTP), a type of synaptic plasticity thought to underlie memory formation. Behavioral studies investigated spatial memory and associative memory. Results: 5HT2bR levels are increased in brain specimens of AD patients compared to controls. 5HT2bR antagonist treatment rescued amyloid-ß and tau oligomer-induced impairment of synaptic plasticity and memory. Conclusions: The increased levels of 5HT-2bR in AD patient brains and the attenuation of disease-related synaptic and behavioral dysfunctions by MW071 treatment suggest that the 5HT-2bR is a molecular target worth pursuing as a potential therapeutic target.

A hybrid 1D CNN-BiLSTM model for epileptic seizure detection using multichannel EEG feature fusion.

Epilepsy, a chronic non-communicable disease is characterized by repeated unprovoked seizures, which are transient episodes of abnormal electrical activity in the brain. While Electroencephalography (EEG) is considered as the gold standard for diagnosis in current clinical practice, manual inspection of EEG is time consuming and biased. This paper presents a novel hybrid 1D CNN-Bi LSTM feature fusion model for automatically detecting seizures. The proposed model leverages spatial features extracted by one dimensional convolutional neural network and temporal features extracted by bi directional long short-term memory network. Ictal and inter ictal data is first acquired from the long multichannel EEG record. The acquired data is segmented and labelled using small fixed windows. Signal features are then extracted from the segments concurrently by the parallel combination of CNN and Bi-LSTM. The spatial and temporal features thus captured are then fused to enhance classification accuracy of model. The approach is validated using benchmark CHB-MIT dataset and 5-fold cross validation which resulted in an average accuracy of 95.90%, with precision 94.78%, F1 score 95.95%. Notably model achieved average sensitivity of 97.18% with false positivity rate at 0.05/hr. The significantly lower false positivity and false negativity rates indicate that the proposed model is a promising tool for detecting seizures in epilepsy patients. The employed parallel path network benefits from memory function of Bi-LSTM and strong feature extraction capabilities of CNN. Moreover, eliminating the need for any domain transformation or additional preprocessing steps, model effectively reduces complexity and enhances efficiency, making it suitable for use by clinicians during the epilepsy diagnostic process.