BDNF Val66Met gene polymorphism modulates brain activity following rTMS-induced memory impairment

The BDNF Val66Met gene polymorphism is a relevant factor explaining inter-individual differences to TMS responses in studies of the motor system. However, whether this variant also contributes to TMS-induced memory effects, as well as their underlying brain mechanisms, remains unexplored. In this investigation, we applied rTMS during encoding of a visual memory task either over the left frontal cortex (LFC; experimental condition) or the cranial vertex (control condition). Subsequently, individuals underwent a recognition memory phase during a functional MRI acquisition. We included 43 young volunteers and classified them as 19 Met allele carriers and 24 as Val/Val individuals. The results revealed that rTMS delivered over LFC compared to vertex stimulation resulted in reduced memory performance only amongst Val/Val allele carriers. This genetic group also exhibited greater fMRI brain activity during memory recognition, mainly over frontal regions, which was positively associated with cognitive performance. We concluded that BDNF Val66Met gene polymorphism, known to exert a significant effect on neuroplasticity, modulates the impact of rTMS both at the cognitive as well as at the associated brain networks expression levels. This data provides new insights on the brain mechanisms explaining cognitive inter-individual differences to TMS, and may inform future, more individually-tailored rTMS interventions.

Amyloid-Beta Influences Memory via Functional Connectivity During Memory Retrieval in Alzheimer's Disease

Objective: Amnesia in Alzheimer's disease (AD) appears early and could be caused by encoding deficiency, consolidation dysfunction, and/or impairment in the retrieval of stored memory information. The relationship between AD pathology biomarker β-amyloid and memory dysfunction is unclear.Method: The memory task functional MRI and amyloid PET were simultaneously performed to investigate the relationship between memory performance, memory phase-related functional connectivity, and cortical β-amyloid deposition. We clustered functional networks during memory maintenance and compared network connectivity between groups in each memory phase. Mediation analysis was performed to investigate the mediator between β-amyloid and related cognitive performance.Results: Alzheimer's disease was primarily characterized by decreased functional connectivity in a data-driven network composed of an a priori default mode network, limbic network, and frontoparietal network during the memory maintenance (0.205 vs. 0.236, p = 0.04) and retrieval phase (0.159 vs. 0.183, p = 0.017). Within the network, AD had more regions with reduced connectivity during the retrieval than the maintenance and encoding phases (chi-square p = 0.01 and < 0.001). Furthermore, the global cortical β-amyloid negatively correlated with network connectivity during the memory retrieval phase (R = – 0.247, p = 0.032), with this relationship mediating the effect of cortical β-amyloid on memory performance (average causal mediation effect = – 0.05, p = 0.035).Conclusion: We demonstrated that AD had decreased connectivity in specific networks during the memory retrieval phase. Impaired functional connectivity during memory retrieval mediated the adverse effect of β-amyloid on memory. These findings help to elucidate the involvement of cortical β-amyloid (Aβ) in the memory performance in the early stages of AD.

The rodent object-in-context task: A systematic review and meta-analysis of important variables

Environmental information plays an important role in remembering events. Information about stable aspects of the environment (here referred to as ‘context’) and the event are combined by the hippocampal system and stored as context-dependent memory. In rodents (such as rats and mice), context-dependent memory is often investigated with the object-in-context task. However, the implementation and interpretation of this task varies considerably across studies. This variation hampers the comparison between studies and—for those who design a new experiment or carry out pilot experiments–the estimation of whether observed behavior is within the expected range. Also, it is currently unclear which of the variables critically influence the outcome of the task. To address these issues, we carried out a preregistered systematic review (PROSPERO CRD42020191340) and provide an up-to-date overview of the animal-, task-, and protocol-related variations in the object-in-context task for rodents. Using a data-driven explorative meta-analysis we next identified critical factors influencing the outcome of this task, such as sex, testbox size and the delay between the learning trials. Based on these observations we provide recommendations on sex, strain, prior arousal, context (size, walls, shape, etc.) and timing (habituation, learning, and memory phase) to create more consensus in the set-up, procedure, and interpretation of the object-in-context task for rodents. This could contribute to a more robust and evidence-based design in future animal experiments.

Gait Analysis under Spatial Navigation Task in Elderly People—A Pilot Study

A decline in the Spatial Navigation (SN) abilities has been observed in the course of healthy aging. Walking is an inseparable part of the navigation process; however, research tasks overlook this aspect in studies involving seniors. The present study was designed to overcome this limitation by recording gait parameters during natural environment navigation and to determine gait indicators that most accurately assign the participants to the proper age category. Thirteen elderly (mean age = 69.1 ± 5.4 year) and sixteen young women (mean age = 21.5 ± 2.2 year) equipped with gait sensors were asked to learn a path while walking in a real building (Learning Phase), reproduce the path (Memory Phase) and reach targets after a 30 min delay (Delayed Phase). The Receiver Operating Characteristics (ROC) analysis showed that our self-developed Gait Style Change indicator, that is, the difference in the probability of feet landing between particular SN task phases, classified the participants into either the elderly or the young group with the highest accuracy (0.91). The second most important indicator, the Task-Related (step counts in each SN task phase), achieved the accuracy discrimination of 0.83. The gait indicators, comprising single gait parameters measured while navigating, might be considered as accurately differentiating older from younger people.

Post-Encoding Stress Does Not Enhance Memory Consolidation: The Role of Cortisol and Testosterone Reactivity

In contrast to the large body of research on the effects of stress-induced cortisol on memory consolidation in young people, far less attention has been devoted to understanding the effects of stress-induced testosterone on this memory phase. This study examined the psychobiological (i.e., anxiety, cortisol, and testosterone) response to the Maastricht Acute Stress Test and its impact on free recall and recognition for emotional and neutral material. Thirty-seven healthy young men and women were exposed to a stress (MAST) or control task post-encoding, and 24 h later, they had to recall the material previously learned. Results indicated that the MAST increased anxiety and cortisol levels, but it did not significantly change the testosterone levels. Post-encoding MAST did not affect memory consolidation for emotional and neutral pictures. Interestingly, however, cortisol reactivity was negatively related to free recall for negative low-arousal pictures, whereas testosterone reactivity was positively related to free recall for negative-high arousal and total pictures. This study provides preliminary evidence about a different reactivity of testosterone and cortisol to the MAST as well as on their effects on consolidation. Our results suggest a different pattern of relationships between these steroid hormones and the arousal of the negative images.

Long-lived T follicular helper cells retain plasticity and help sustain humoral immunity

CD4+ memory T cells play an important role in protective immunity and are a key target in vaccine development. Many studies have focused on T central memory (Tcm) cells, whereas the existence and functional significance of long-lived T follicular helper (Tfh) cells are controversial. Here, we show that Tfh cells are highly susceptible to NAD-induced cell death (NICD) during isolation from tissues, leading to their underrepresentation in prior studies. NICD blockade reveals the persistence of abundant Tfh cells with high expression of hallmark Tfh markers to at least 400 days after infection, by which time Tcm cells are no longer found. Using single-cell RNA-seq, we demonstrate that long-lived Tfh cells are transcriptionally distinct from Tcm cells, maintain stemness and self-renewal gene expression, and, in contrast to Tcm cells, are multipotent after recall. At the protein level, we show that folate receptor 4 (FR4) robustly discriminates long-lived Tfh cells from Tcm cells. Unexpectedly, long-lived Tfh cells concurrently express a distinct glycolytic signature similar to trained immune cells, including elevated expression of mTOR-, HIF-1–, and cAMP-regulated genes. Late disruption of glycolysis/ICOS signaling leads to Tfh cell depletion concomitant with decreased splenic plasma cells and circulating antibody titers, demonstrating both unique homeostatic regulation of Tfh and their sustained function during the memory phase of the immune response. These results highlight the metabolic heterogeneity underlying distinct long-lived T cell subsets and establish Tfh cells as an attractive target for the induction of durable adaptive immunity.

Interleukin-10 (IL-10) Produced by Mutant Toxic Shock Syndrome Toxin 1 Vaccine-Induced Memory T Cells Downregulates IL-17 Production and Abrogates the Protective Effect against Staphylococcus aureus Infection

ABSTRACT Development of long-term memory is crucial for vaccine-induced adaptive immunity against infectious diseases such as Staphylococcus aureus infection. Toxic shock syndrome toxin 1 (TSST-1), one of the superantigens produced by S. aureus, is a possible vaccine candidate against infectious diseases caused by this pathogen. We previously reported that vaccination with less toxic mutant TSST-1 (mTSST-1) induced T helper 17 (Th17) cells and elicited interleukin-17A (IL-17A)-mediated protection against S. aureus infection 1 week after vaccination. In the present study, we investigated the host immune response induced by mTSST-1 vaccination in the memory phase, 12 weeks after the final vaccination. The protective effect and IL-17A production after vaccination with mTSST-1 were eliminated because of IL-10 production. In the presence of IL-10-neutralizing monoclonal antibody (mAb), IL-17A production was restored in culture supernatants of CD4+ T cells and macrophages sorted from the spleens of vaccinated mice. Vaccinated mice treated with anti-IL-10 mAb were protected against systemic S. aureus infection in the memory phase. From these results, it was suggested that IL-10 produced in the memory phase suppresses the IL-17A-dependent vaccine effect through downregulation of IL-17A production.

PD-1hi CD8+ resident memory T cells balance immunity and fibrotic sequelae

CD8+ tissue-resident memory T (TRM) cells provide frontline immunity in mucosal tissues. The mechanisms regulating CD8+ TRM maintenance, heterogeneity, and protective and pathological functions are largely elusive. Here, we identify a population of CD8+ TRM cells that is maintained by major histocompatibility complex class I (MHC-I) signaling, and CD80 and CD86 costimulation after acute influenza infection. These TRM cells have both exhausted-like phenotypes and memory features and provide heterologous immunity against secondary infection. PD-L1 blockade after the resolution of primary infection promotes the rejuvenation of these exhausted-like TRM cells, restoring protective immunity at the cost of promoting postinfection inflammatory and fibrotic sequelae. Thus, PD-1 serves to limit the pathogenic capacity of exhausted-like TRM cells at the memory phase. Our data indicate that TRM cell exhaustion is the result of a tissue-specific cellular adaptation that balances fibrotic sequelae with protective immunity.