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Evidence from previous studies suggests that physical activity (PA) may contribute to functional and structural changes in the hippocampus throughout the lifespan. However, there is limited evidence available regarding the young adult population. Additionally, the personality traits that may influence this association remain unclear. With a sample of 84 young adults (43 women; age 22.7 ± 2.8y; range 18-29), the main aim of the current study was to analyze the association between objective and self-reported measures of daily PA and hippocampus subfield gray matter volumes, and to examine the role of the personality trait of punishment sensitivity in this association. Our results showed that only moderate to vigorous levels of objectively measured PA were positively associated with the hippocampal CA2/CA3 volume. Moreover, punishment sensitivity correlated negatively with the objective measure of sedentarism and with self-reported measures of PA. However, regression analyses did not find any interaction between punishment sensitivity and PA in explaining individual differences in hippocampal volumes. Thus, our data suggest that intense PA may contribute to enhancing the hippocampal CA2/CA3 volume in young adults.

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A zoonotic disease called brucellosis can cause flu-like symptoms and heart inflammation. The bacteria responsible for this disease can also enter the brain, causing a condition called neurobrucellosis that can result in long-term neurological problems. In this study, researchers aimed to determine the changes in the hippocampal cells of rats infected with Brucella. For the study, 24 adult male albino rats were inoculated with 1 × 106 CFU Brucella abortus 544. The rats were then deeply anesthetized, and their hippocampus samples were taken for stereological, histological, and molecular studies. The results showed that the infected rats had increased microgliosis and astrogliosis. Furthermore, a high level of caspase-3 in their hippocampal tissue indicated their susceptibility to apoptosis. Additionally, there was a decrease in expression of Ki67, which further supported this. Sholl's analysis confirmed a significant failure in glial morphology. The study demonstrated that the pathogen has the ability to destroy the hippocampus and potentially affect its normal physiology. However, more research is needed to clarify various aspects of neurobrucellosis.

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Diazinon (DZN), a persistent organophosphate insecticide, has been associated with neurotoxic effects, particularly in the hippocampus. However, the specific molecular mechanisms of DZN-induced hippocampal toxicity remain unknown. In this study, we analyzed the mRNA and miRNA expression patterns of HT22 cells following exposure to DZN (125 µM), and the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted subsequently. The integration of miRNA sequencing (miRNA-seq) and mRNA sequencing (mRNA-seq) data identified 33 differentially expressed miRNAs (DEMIs, 15 up-regulated and 18 down-regulated) and 271 differentially expressed mRNAs (DEMs, 69 up-regulated and 202 down-regulated) targeted by the DEMIs. Moreover, the 3 most central mRNAs (ITGAV, FN1, and EGFR) and 7 associated miRNAs (mmu-miR-700-5p, mmu-miR-26a-2-3p, mmu-miR-452-3p, mmu-miR-25-3p, mmu-miR-582-5p, mmu-miR-467a-5p, and mmu-miR-467b-5p) were screened and validated using quantitative real-time PCR. Furthermore, the GO analysis revealed that the identified DEMs were enriched in biological adhesion extracellular matrix, and growth factor binding, while the KEGG analysis suggested that the enriched DEMs were involved in ECM-receptor interaction, mTOR signaling pathway, MAPK signaling pathway, and AMPK signaling pathway. Our results may aid in elucidating the underlying mechanisms associated with DZN-induced hippocampal toxicity and provide valuable insights into the pathogenesis of neurotoxicity triggered by other organophosphorus pesticides.

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BACKGROUND: Standard antidepressant treatments often take weeks to reach efficacy and are ineffective for many patients. (R,S)-ketamine, an N-methyl-D-aspartate (NMDA) antagonist, has been shown to be a rapid-acting antidepressant and to decrease depressive symptoms within hours of administration. While previous studies have shown the importance of the GluN2B subunit of the NMDA receptor (NMDAR) on interneurons in the medial prefrontal cortex (mPFC), no study has investigated the influence of GluN2B-expressing adult-born granule cells (abGCs). METHODS: Here, we examined whether (R,S)-ketamine's efficacy depends upon these adult-born hippocampal neurons using a genetic strategy to selectively ablate the GluN2B subunit of the NMDAR from Nestin+ cells in male and female mice, tested across an array of standard behavioral assays. RESULTS: We report that in male mice, GluN2B expression on 6-week-old adult-born neurons is necessary for (R,S)-ketamine's effects on behavioral despair in the forced swim test (FST) and on hyponeophagia in the novelty suppressed feeding (NSF) paradigm, as well on fear behavior following contextual fear conditioning (CFC). In female mice, GluN2B expression is necessary for effects on hyponeophagia in the NSF. These effects were not replicated when ablating GluN2B from 2-week-old adult-born neurons. We also find that ablating neurogenesis increases fear expression in CFC, which is buffered by (R,S)-ketamine administration. CONCLUSIONS: In line with previous studies, these results suggest that 6-week-old adult-born hippocampal neurons expressing GluN2B partially modulate (R,S)-ketamine's rapid-acting effects. Future work targeting these 6-week-old adult-born neurons may prove beneficial for increasing the efficacy of (R,S)-ketamine.

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The hippocampus is involved in many cognitive domains which are difficult for autistic individuals. Our previous study using a Structural Learning task that has been shown to depend on hippocampal functioning found that structural learning is diminished in autistic adults (Ring et al., 2017). The aim of the present study was to examine whether those results can be replicated in and extended to a sample of autistic and non-autistic children. We tested 43 autistic children and 38 non-autistic children with a subsample of 25 autistic and 28 non-autistic children who were well-matched on IQ. The children took part in a Simple Discrimination task which a simpler form of compound learning, and a Structural Learning task. We expected both groups to perform similarly in Simple Discrimination but reduced performance by the autism group on the Structural Learning task, which is what we found in both the well-matched and the non-matched sample. However, contrary to our prediction and the findings from autistic adults in our previous study, autistic children demonstrated a capacity for Structural Learning and showed an overall better performance in the tasks than was seen in earlier studies. We discuss developmental differences in autism as well as the role of executive functions that may have contributed to better than predicted task performance in this study.

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Background: Obstetric brachial plexus palsy (OBPP) is a condition impairing limb function caused by birth injury. In 20 to 30% of cases, severe OBPP can cause life constraints in feeding, grooming, and clothing tasks. Objective: The present study, using voxel- and surface-based morphometry (VBM and SBM), examined the brain structure of pediatric OBPP patients to better understand the effects of this peripheral motor deficit on early brain development. Methods: Thirty-six T1-weighted images of 18 patients (2-17 years old, mean age = 11.3, 8 females) and 18 healthy controls (2-17 years old, mean age = 10.1, 8 females) were collected for this study. MRI data were processed and analyzed using the Statistical Parametric Mapping 12 (SPM12) toolbox. The custom pediatric tissue probability map was created with the CerebroMatic (COM) toolbox. The results were considered significant if they survived whole-brain family-wise error correction (P < .05). Results: We have found differences in grey matter volumes in the bilateral anterior hippocampus (left P < .001 and right P = .01) and left cerebellum exterior (Crus I) (P < .001). We have also found differences in cortical thickness in the bilateral parahippocampal gyri (left P = .001 and right P = .005) and right orbitofrontal cortex (OFC) (P < .001). Conclusions: These structural differences might be linked to the altered environmental adaptation that children with OBPP face due to their primary motor deficit. Our findings hint at a complex interplay between motor capabilities, brain structure development, and cognitive functions. However, more research combining neuroimaging, behavioral, cognitive, and clinical data is needed to support stronger conclusions on this subject.

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Introduction: Electrical stimulation of the brain has shown promising prospects in treating various brain diseases. Although biphasic pulse stimulation remains the predominant clinical approach, there has been increasing interest in exploring alternative stimulation waveforms, such as sinusoidal stimulation, to improve the effectiveness of brain stimulation and to expand its application to a wider range of brain disorders. Despite this growing attention, the effects of sinusoidal stimulation on neurons, especially on their nonlinear firing characteristics, remains unclear. Methods: To address the question, 50 Hz sinusoidal stimulation was applied on Schaffer collaterals of the rat hippocampal CA1 region in vivo. Single unit activity of both pyramidal cells and interneurons in the downstream CA1 region was recorded and analyzed. Two fractal indexes, namely the Fano factor and Hurst exponent, were used to evaluate changes in the long-range correlations, a manifestation of nonlinear dynamics, in spike sequences of neuronal firing. Results: The results demonstrate that sinusoidal electrical stimulation increased the firing rates of both pyramidal cells and interneurons, as well as altered their firing to stimulation-related patterns. Importantly, the sinusoidal stimulation increased, rather than decreased the scaling exponents of both Fano factor and Hurst exponent, indicating an increase in the long-range correlations of both pyramidal cells and interneurons. Discussion: The results firstly reported that periodic sinusoidal stimulation without long-range correlations can increase the long-range correlations of neurons in the downstream post-synaptic area. These results provide new nonlinear mechanisms of brain sinusoidal stimulation and facilitate the development of new stimulation modes.

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BACKGROUND: Acrylamide (ACR), a common industrial chemical, is a strong neurotoxic material. The hippocampus is a brain area of interest mostly affected by Alzheimer's disease. Mesenchymal stem cells (MSCs) usefulness in various neurological diseases including Alzheimer's is being debated. In this work, the authors aim to explore the role of MSCs in ACR-induced hippocampal neurodegeneration and elucidate the mediating mechanism. MATERIALS AND METHODS: For this purpose, ten rats served as control, another ten were injected ACR (i.p. 50 mg/kg/day for 2 weeks), and the last ten rats were injected ACR in addition to MSCs (i.p. 1 × 107 MSCs single injection). RESULTS: ACR induced neurodegenerative histopathological hippocampal changes and adversely altered hippocampal oxidative stress markers SOD, MDA, and GSH. ACR had induced hippocampal demyelination as detected by silver staining. ACR significantly (P < 0.05) up-regulated the ELISA hippocampal TNF-alpha and IL-6 and produced microglial & astrocyte activation (as tracked by Iba1 & GFAP immunohistochemistry respectively). ACR significantly reduced hippocampal PCR gene expression of IGF 1 (insulin growth factor-1), BDNF (brain-derived neurotrophic factor), and NGF (nerve growth factor). MSCs administration had mitigated all the previous deleterious changes. CONCLUSIONS: Acrylamide caused detrimental effects on the hippocampus and demonstrably altered the hippocampal architecture. Bone marrow mesenchymal stem cells offered a promising therapeutic role against these neurotoxic effects of acrylamide, presumably through modulation of IGF 1, BDNF, and NGF gene expressions.

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Neurodegenerative diseases such as Alzheimer´s (AD) and physiological ageing are characterized by a decline in neurogenesis and in the polysialylated isoforms of neural cell adhesion molecule (PSA-NCAM) expression within the hippocampus and specifically in the dentate gyrus (DG). In the 3xTG-AD mouse model, which mimics the human disease in both pathological and behavioral features, this decline in PSA-NCAM is associated with the presence of Aß plaques at 9 months and Tau tangles at 12-15 months. In this work we studied the presence of PSA-NCAM at early ages (1-6 months) in the same model. Our results demonstrated that even as early as the first month of age there is a strong decrease in PSA-NCAM dendritic tree mainly altering the molecular layer (MolL) coverage affecting the synaptic plasticity and furthermore confirmed by the reduction of PSA-NCAM area density (Sv) in the 3xTG-AD. Similar and more marked early changes were seen during aging in both NTG and 3xTg-AD animals. Our results demonstrate for the first time a precipitate decrease of PSA-NCAM cells at such very early phases of the disease. This result suggests an early effect of the disease in the progression of immature and pluripotent cells resulting in an ulterior and early diminution of neurogenesis and therefore an impaired hippocampal cellular and synaptic plasticity.

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Depression and cognitive deficits present at higher rates among people with spinal cord injury (SCI) compared to the general population, yet these SCI comorbidities are poorly addressed. Sex and age appear to play roles in depression incidence, but consensus on the direction of their effects is limited. Systemic and cortical inflammation and disruptions in hippocampal neurogenesis have been identified as potential treatment targets, but a comprehensive understanding of these mechanisms remains elusive. We used a rodent SCI model to interrogate these gaps in knowledge. We examined post-injury depression-like behavior and cognitive deficits, as well as the association between affect, cognition, chronic hippocampal inflammation and hippocampal neurogenesis, in young and middle-aged male and female Sprague-Dawley rats. Depression-like behavior manifested in male and female subsets of SCI rats irrespective of age, at rates commensurate with the incidence of clinical depression. Changes in components of behavior were driven by sex and age, and affective outcomes were independent of common post-injury pathophysiological outcomes including locomotor functional deficits and spinal lesion severity. Interestingly, however, only male depression-like SCI rats exhibited deficits in hippocampal-associated spatial cognition. Neurogenesis was also disrupted in only SCI males in regions of the hippocampus responsible for affective outcomes. Decreased neurogenesis among middle-aged male subjects coincided with increases in numbers of the pro-inflammatory markers CD86 and iNOS, while middle-aged females had increased numbers of cells expressing Iba-1 and anti-inflammatory marker CD206. Overall, the present data suggest that post-SCI depression and cognition may be affected, in part, by sex- and age-dependent changes in hippocampal neurogenesis and inflammation. Hippocampal neurogenesis is a potential target to address psychological wellbeing after SCI, but therapeutic strategies must carefully consider sex and age as biological variables.

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One of Clayton's major contributions to our understanding of animal minds has been her work on episodic-like memory. A central reason for the success of this work was its focus on ecological validity: rather than looking for episodic memory for arbitrary stimuli in artificial contexts, focussing on contexts in which episodic memory would serve a biological function such as food caching. This review aims to deepen this insight by surveying the numerous functions that have been proposed for episodic memory, articulating a philosophically grounded framework for understanding what exactly functions are, and drawing on these to make suggestions for future directions in the comparative cognitive psychology of episodic memory. Our review suggests four key insights. First, episodic memory may have more than one function and may have different functions in different species. Second, cross-disciplinary work is key to developing a functional account of episodic memory. Third, there is scope for further theoretical elaboration of proposals relating episodic memory to food caching and, in particular, future-oriented cognition. Finally, learning-related functions suggested by AI (artificial intelligence)-based models are a fruitful avenue for future behavioural research.

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The transition to adolescence is a critical period for mental health development. Socio-experiential environments play an important role in the emergence of depressive symptoms with some adolescents showing more sensitivity to social contexts than others. Drawing on recent developmental neuroscience advances, we examined whether hippocampal volume amplifies social context effects in the transition to adolescence. We analyzed 2-y longitudinal data from the Adolescent Brain Cognitive Development (ABCD®) study in a diverse sample of 11,832 youth (mean age: 9.914 y; range: 8.917 to 11.083 y; 47.8% girls) from 21 sites across the United States. Socio-experiential environments (i.e., family conflict, primary caregiver's depressive symptoms, parental warmth, peer victimization, and prosocial school environment), hippocampal volume, and a wide range of demographic characteristics were measured at baseline. Youth's symptoms of major depressive disorder were assessed at both baseline and 2 y later. Multilevel mixed-effects linear regression analyses showed that negative social environments (i.e., family conflict, primary caregiver's depressive symptoms, and peer victimization) and the absence of positive social environments (i.e., parental warmth and prosocial school environment) predicted greater increases in youth's depressive symptoms over 2 y. Importantly, left hippocampal volume amplified social context effects such that youth with larger left hippocampal volume experienced greater increases in depressive symptoms in more negative and less positive social environments. Consistent with brain-environment interaction models of mental health, these findings underscore the importance of families, peers, and schools in the development of depression during the transition to adolescence and show how neural structure amplifies social context sensitivity.

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Depresión , Hipocampo , Humanos , Hipocampo/diagnóstico por imagen , Femenino , Masculino , Adolescente , Niño , Medio Social , Estudios Longitudinales , Imagen por Resonancia Magnética , Estados Unidos

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Kynurenic acid (KYNA), a tryptophan metabolite, is believed to exert neuromodulatory and neuroprotective effects in the brain. This study aimed to examine KYNA's capacity to modify gene expression and the activity of cellular antioxidant enzymes in specific structures of the sheep brain. Anestrous sheep were infused intracerebroventricularly with two KYNA doses-lower (4 × 5 µg/60 µL/30 min, KYNA20) and higher (4 × 25 µg/60 µL/30 min, KYNA100)-at 30 min intervals. The abundance of superoxide dismutase 2 (SOD2), catalase (CAT), and glutathione peroxidase 1 (GPx1) mRNA, as well as enzyme activities, were determined in the medial-basal hypothalamus (MBH), the preoptic (POA) area of the hypothalamus, and in the hippocampal CA1 field. Both doses of KYNA caused a decrease (p < 0.01) in the expression of SOD2 and CAT mRNA in all structures examined compared to the control group (except for CAT in the POA at the KYNA100 dose). Furthermore, lower levels of SOD2 mRNA (p < 0.05) and CAT mRNA (p < 0.01) were found in the MBH and POA and in the POA and CA, respectively, in sheep administered with the KYNA20 dose. Different stimulatory effects on GPx1 mRNA expression were observed for both doses (p < 0.05-p < 0.01). KYNA exerted stimulatory but dose-dependent effects on SOD2, CAT, and GPx1 activities (p < 0.05-p < 0.001) in all brain tissues examined. The results indicate that KYNA may influence the level of oxidative stress in individual brain structures in sheep by modulating the expression of genes and the activity of at least SOD2, CAT, and GPx1. The present findings also expand the general knowledge about the potential neuroprotective properties of KYNA in the central nervous system.

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Antioxidantes , Catalasa , Glutatión Peroxidasa GPX1 , Glutatión Peroxidasa , Hipocampo , Hipotálamo , Ácido Quinurénico , Superóxido Dismutasa , Animales , Ovinos , Ácido Quinurénico/metabolismo , Ácido Quinurénico/farmacología , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Hipotálamo/metabolismo , Hipotálamo/efectos de los fármacos , Catalasa/metabolismo , Catalasa/genética , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa/genética , Antioxidantes/metabolismo , Antioxidantes/farmacología , Glutatión Peroxidasa/metabolismo , Glutatión Peroxidasa/genética , ARN Mensajero/metabolismo , ARN Mensajero/genética , Regulación de la Expresión Génica/efectos de los fármacos , Femenino

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Alzheimer's disease (AD), the leading cause of dementia, is a multifactorial disease influenced by aging, genetics, and environmental factors. miRNAs are crucial regulators of gene expression and play significant roles in AD onset and progression. This exploratory study analyzed the expression levels of 28 genes and 5 miRNAs (miR-124-3p, miR-125b-5p, miR-21-5p, miR-146a-5p, and miR-155-5p) related to AD pathology and neuroimmune responses using RT-qPCR. Analyses were conducted in the prefrontal cortex (PFC) and the hippocampus (HPC) of the 5xFAD mouse AD model at 6 and 9 months old. Data highlighted upregulated genes encoding for glial fibrillary acidic protein (Gfap), triggering receptor expressed on myeloid cells (Trem2) and cystatin F (Cst7), in the 5xFAD mice at both regions and ages highlighting their roles as critical disease players and potential biomarkers. Overexpression of genes encoding for CCAAT enhancer-binding protein alpha (Cebpa) and myelin proteolipid protein (Plp) in the PFC, as well as for BCL2 apoptosis regulator (Bcl2) and purinergic receptor P2Y12 (P2yr12) in the HPC, together with upregulated microRNA(miR)-146a-5p in the PFC, prevailed in 9-month-old animals. miR-155 positively correlated with miR-146a and miR-21 in the PFC, and miR-125b positively correlated with miR-155, miR-21, while miR-146a in the HPC. Correlations between genes and miRNAs were dynamic, varying by genotype, region, and age, suggesting an intricate, disease-modulated interaction between miRNAs and target pathways. These findings contribute to our understanding of miRNAs as therapeutic targets for AD, given their multifaceted effects on neurons and glial cells.

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Enfermedad de Alzheimer , Modelos Animales de Enfermedad , Hipocampo , MicroARNs , Neuroglía , Neuronas , Animales , MicroARNs/genética , MicroARNs/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Ratones , Neuronas/metabolismo , Neuroglía/metabolismo , Hipocampo/metabolismo , Ratones Transgénicos , Receptores Inmunológicos/genética , Receptores Inmunológicos/metabolismo , Regulación de la Expresión Génica , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Corteza Prefrontal/metabolismo , Proteína Ácida Fibrilar de la Glía/metabolismo , Proteína Ácida Fibrilar de la Glía/genética , Masculino

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Coffee intake is increasingly recognized as a life-style factor associated with the preservation of health, but there is still a debate on the relative effects of caffeinated and decaffeinated coffee. We now tested how the regular drinking of caffeinated and decaffeinated coffee for 3 weeks impacted on the behavior of male and female adult mice. Males drinking caffeinated coffee displayed statistically significant lower weight gain, increased sensorimotor coordination, greater motivation in the splash test, more struggling in the forced swimming test, faster onset of nest building, more marble burying and greater sociability. Females drinking caffeinated coffee displayed statistically significant increased hierarchy fighting, greater self-care and motivation in the splash test and faster onset of nest building. A post-hoc two-way ANOVA revealed sex-differences in the effects of caffeinated coffee (p values for interaction between the effect of caffeinated coffee and sex) on the hierarchy in the tube test (p = 0.044; dominance), in the time socializing (p = 0.044) and in the latency to grooming (p = 0.048; selfcare), but not in the marble burying test (p = 0.089). Intake of decaffeinated coffee was devoid of effects in males and females. Since caffeine targets adenosine receptors, we verified that caffeinated but not decaffeinated coffee intake increased the density of adenosine A1 receptors (A1R) and increased A1R-mediated tonic inhibition of synaptic transmission in the dorsolateral striatum and ventral but not dorsal hippocampus, the effects being more evident in the ventral hippocampus of females and striatum of males. In contrast, caffeinated and decaffeinated coffee both ameliorated the antioxidant status in the frontal cortex. It is concluded that caffeinated coffee increases A1R-mediated inhibition in mood-related areas bolstering wellbeing of both males and females, with increased sociability in males and hierarchy struggling and self-care in females.

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Conducta Animal , Cafeína , Café , Animales , Masculino , Femenino , Cafeína/farmacología , Ratones , Conducta Animal/efectos de los fármacos , Receptor de Adenosina A1/metabolismo , Factores Sexuales , Ratones Endogámicos C57BL

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The commonly used lipopolysaccharide (LPS)-induced depression models often evaluate depression-like behaviors in the acute phase after a single intraperitoneal injection of LPS, and are not suitable for examining long-term depression-like behaviors. To overcome this limitation, we developed a mice LPS model for elucidating the long-term pathophysiology of depression. Using the tail-suspension test, we show that a single intraperitoneal injection of a high dose (1.66 mg/kg) of LPS prolonged depression-like behavior to 14 days after LPS administration unlike 4 days after administration for the most commonly used LPS dose (0.83 mg/kg). Upon high-LPS dose administration, TNF-α levels in the cerebrospinal fluid were increased only on the first day after administration. Moreover, LPS-induced depression-like behavior on day 10 after LPS administration was prevented by imipramine or minocycline. Immunohistochemical analysis revealed reduced neurogenesis in the hippocampal dentate gyrus of LPS-treated mice on day 10 of LPS administration. The LPS model, in which a single intraperitoneal administration of LPS at a dose double of the standard dose used currently, exhibits depression-like behavior via reduced neurogenesis mediated by neuroinflammation, and should be useful for elucidating the long-term pathophysiology of depression and for studying antidepressant drugs.

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AIMS: Cerebral small vessel disease (CSVD) is a complex condition characterized by a combination of microcirculation disorders and neurodegenerative processes, CSVD is associated with structural abnormalities in multiple brain regions. However, the progressive pattern of structural changes remains unknown. METHODS: In order to detail the progressive structural changes in CSVD patients according to the degree of cognitive impairment, we recruited 121 CSVD patients and 104 healthy controls (HCs). Voxel-based morphometry was employed to measure the gray matter volume (GMV) of each participant. According to the VICCCS-2 diagnostic criteria, patients were initially divided into three stage groups, then we investigated the GMV changes in each stage and their causal relationships using causal structure covariance network (CaSCN) analysis. RESULTS: Overall, patients with CSVD presented stage-specific GMV alterations compared with HCs. With the worsening of cognitive impairment, the decrease in gray matter volume starts from the right hippocampus and gradually spreads to the cortical-subcortical brain regions. Importantly, the right hippocampus in CSVD patients plays a driving role in the directional network and forms both positive and negative causal effect networks with cortical-subcortical brain regions. CONCLUSIONS: This study reveals the significance of the right hippocampus as an early pathological area in CSVD patients and its causal impact on brain GMV changes with disease progression, shedding light on structural brain damage hierarchy and compensatory mechanisms.

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The concept of episodic memory (EM) faces significant challenges by two claims: EM might not be a distinct memory system, and EM might be an epiphenomenon of a more general capacity for mental time travel (MTT). Nevertheless, the observations leading to these arguments do not preclude the existence of a mechanically and functionally distinct EM system. First, modular systems, like cognition, can have distinct subsystems that may not be distinguishable in the system's final output. EM could be such a subsystem, even though its effects may be difficult to distinguish from those of other subsystems. Second, EM could have a distinct and consistent low-level function, which is used in diverse high-level functions such as MTT. This article introduces the scenario construction framework, proposing that EM crucially rests on memory traces containing the gist of an episodic experience. During retrieval, EM traces trigger the reconstruction of semantic representations, which were active during the remembered episode, and are further enriched with semantic information, to generate a scenario of the past experience. This conceptualization of EM is consistent with studies on the neural basis of EM and resolves the two challenges while retaining the key properties associated with EM. This article is part of the theme issue 'Elements of episodic memory: lessons from 40 years of research'.

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Memoria Episódica , Humanos , Cognición/fisiología , Recuerdo Mental/fisiología

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How consciousness is lost in states such as sleep or anesthesia remains a mystery. To gain insight into this phenomenon, concurrent recordings of electrophysiology signals in the anterior cingulate cortex and whole-brain functional magnetic resonance imaging (fMRI) are conducted in rats exposed to graded propofol, undergoing the transition from consciousness to unconsciousness. The results reveal that upon the loss of consciousness (LOC), there is a sharp increase in low-frequency power of the electrophysiological signal. Additionally, fMRI signals exhibit a cascade of deactivation across a pathway including the hippocampus, thalamus, and medial prefrontal cortex (mPFC) surrounding the moment of LOC, followed by a broader increase in brain activity across the cortex during sustained unconsciousness. Furthermore, sliding window analysis demonstrates a temporary increase in synchrony of fMRI signals across the hippocampus-thalamus-mPFC pathway preceding LOC. These data suggest that LOC may be triggered by sequential activities in the hippocampus, thalamus, and mPFC, while wide-spread activity increases in other cortical regions commonly observed during anesthesia-induced unconsciousness may be a consequence, rather than a cause of LOC. Taken together, the study identifies a cascade of neural events unfolding as the brain transitions into unconsciousness, offering insight into the systems-level neural mechanisms underpinning LOC.

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Subarachnoid hemorrhage (SAH) often leads to long-term cognitive deficits in patients, particularly due to injury to brain regions such as the hippocampus. This study aims to investigate the role of the triggering receptor expressed on myeloid cells 2 (TREM2) in mitigating hippocampal injury and associated cognitive impairments following SAH. To explore the protective effects of TREM2, we utilized the TREM2 agonist COG1410 to upregulate TREM2 expression and employed TREM2 knockout (KO) mice to verify the necessity of TREM2 for this protective role. The study further examined the involvement of the PI3K/Akt signaling pathway in TREM2-mediated neuroprotection. Our findings indicate that the upregulation of TREM2 significantly alleviated long-term cognitive deficits and promoted the recovery of hippocampal neural activity post-SAH. The neuroprotective effects were linked to reduced microglial activation and decreased secretion of inflammatory factors within the hippocampus. In contrast, TREM2 KO mice did not exhibit these protective effects. Furthermore, inhibition of the PI3K/Akt pathway also diminished these protective effects of TREM2 upregulation and worsened cognitive outcomes. In conclusion, TREM2 upregulation mitigates long-term cognitive dysfunction following SAH by attenuating hippocampal neuroinflammation via the PI3K/Akt signaling pathway. These findings suggest that TREM2 could be a potential therapeutic target for improving cognitive outcomes after SAH.