Erratum: Hematologic DNMT3A reduction and high-fat diet synergize to promote weight gain and tissue inflammation.

[This corrects the article DOI: 10.1016/j.isci.2024.109122.].

The well-worn route revisited: Striatal and hippocampal system contributions to familiar route navigation.

Classic research has shown a division in the neuroanatomical structures that support flexible (e.g., short-cutting) and habitual (e.g., familiar route following) navigational behavior, with hippocampal-caudate systems associated with the former and putamen systems with the latter. There is, however, disagreement about whether the neural structures involved in navigation process particular forms of spatial information, such as associations between constellations of cues forming a cognitive map, versus single landmark-action associations, or alternatively, perform particular reinforcement learning algorithms that allow the use of different spatial strategies, so-called model-based (flexible) or model-free (habitual) forms of learning. We sought to test these theories by asking participants (N = 24) to navigate within a virtual environment through a previously learned, 9-junction route with distinctive landmarks at each junction while undergoing functional magnetic resonance imaging (fMRI). In a series of probe trials, we distinguished knowledge of individual landmark-action associations along the route versus knowledge of the correct sequence of landmark-action associations, either by having absent landmarks, or "out-of-sequence" landmarks. Under a map-based perspective, sequence knowledge would not require hippocampal systems, because there are no constellations of cues available for cognitive map formation. Within a learning-based model, however, responding based on knowledge of sequence would require hippocampal systems because prior context has to be utilized. We found that hippocampal-caudate systems were more active in probes requiring sequence knowledge, supporting the learning-based model. However, we also found greater putamen activation in probes where navigation based purely on sequence memory could be planned, supporting models of putamen function that emphasize its role in action sequencing.

Restoration of neuronal progenitors by partial reprogramming in the aged neurogenic niche.

Partial reprogramming (pulsed expression of reprogramming transcription factors) improves the function of several tissues in old mice. However, it remains largely unknown how partial reprogramming impacts the old brain. Here we use single-cell transcriptomics to systematically examine how partial reprogramming influences the subventricular zone neurogenic niche in aged mouse brains. Whole-body partial reprogramming mainly improves neuroblasts (cells committed to give rise to new neurons) in the old neurogenic niche, restoring neuroblast proportion to more youthful levels. Interestingly, targeting partial reprogramming specifically to the neurogenic niche also boosts the proportion of neuroblasts and their precursors (neural stem cells) in old mice and improves several molecular signatures of aging, suggesting that the beneficial effects of reprogramming are niche intrinsic. In old neural stem cell cultures, partial reprogramming cell autonomously restores the proportion of neuroblasts during differentiation and blunts some age-related transcriptomic changes. Importantly, partial reprogramming improves the production of new neurons in vitro and in old brains. Our work suggests that partial reprogramming could be used to rejuvenate the neurogenic niche and counter brain decline in old individuals.

Hematologic DNMT3A reduction and high-fat diet synergize to promote weight gain and tissue inflammation.

During aging, blood cell production becomes dominated by a limited number of variant hematopoietic stem cell (HSC) clones. Differentiated progeny of variant HSCs are thought to mediate the detrimental effects of such clonal hematopoiesis on organismal health, but the mechanisms are poorly understood. While somatic mutations in DNA methyltransferase 3A (DNMT3A) frequently drive clonal dominance, the aging milieu also likely contributes. Here, we examined in mice the interaction between high-fat diet (HFD) and reduced DNMT3A in hematopoietic cells; strikingly, this combination led to weight gain. HFD amplified pro-inflammatory pathways and upregulated inflammation-associated genes in mutant cells along a pro-myeloid trajectory. Aberrant DNA methylation during myeloid differentiation and in response to HFD led to pro-inflammatory activation and maintenance of stemness genes. These findings suggest that reduced DNMT3A in hematopoietic cells contributes to weight gain, inflammation, and metabolic dysfunction, highlighting a role for DNMT3A loss in the development of metabolic disorders.

Exercise reprograms the inflammatory landscape of multiple stem cell compartments during mammalian aging.

Exercise has the ability to rejuvenate stem cells and improve tissue regeneration in aging animals. However, the cellular and molecular changes elicited by exercise have not been systematically studied across a broad range of cell types in stem cell compartments. We subjected young and old mice to aerobic exercise and generated a single-cell transcriptomic atlas of muscle, neural, and hematopoietic stem cells with their niche cells and progeny, complemented by whole transcriptome analysis of single myofibers. We found that exercise ameliorated the upregulation of a number of inflammatory pathways associated with old age and restored aspects of intercellular communication mediated by immune cells within these stem cell compartments. Exercise has a profound impact on the composition and transcriptomic landscape of circulating and tissue-resident immune cells. Our study provides a comprehensive view of the coordinated responses of multiple aged stem cells and niche cells to exercise at the transcriptomic level.

Cell-type-specific aging clocks to quantify aging and rejuvenation in neurogenic regions of the brain.

The diversity of cell types is a challenge for quantifying aging and its reversal. Here we develop 'aging clocks' based on single-cell transcriptomics to characterize cell-type-specific aging and rejuvenation. We generated single-cell transcriptomes from the subventricular zone neurogenic region of 28 mice, tiling ages from young to old. We trained single-cell-based regression models to predict chronological age and biological age (neural stem cell proliferation capacity). These aging clocks are generalizable to independent cohorts of mice, other regions of the brains, and other species. To determine if these aging clocks could quantify transcriptomic rejuvenation, we generated single-cell transcriptomic datasets of neurogenic regions for two interventions-heterochronic parabiosis and exercise. Aging clocks revealed that heterochronic parabiosis and exercise reverse transcriptomic aging in neurogenic regions, but in different ways. This study represents the first development of high-resolution aging clocks from single-cell transcriptomic data and demonstrates their application to quantify transcriptomic rejuvenation.

The developmental trajectories of children's reorientation to global and local properties of environmental geometry.

The way in which organisms represent the shape of their environments during navigation has been debated in cognitive, comparative, and developmental psychology. While there is evidence that adult humans encode the entire boundary shape of an environment (a global-shape representation), there are also data demonstrating that organisms reorient using only segments of the boundary that signal a goal location (a local-shape representation). Developmental studies offer unique insights into this debate; however, most studies have used designs that cannot dissociate the type of boundary-shape representation that children use to guide reorientation. Thus, we examined the developmental trajectories of children's reorientation according to local and global boundary shape. Participants aged 6-12 years were trained to find a goal hidden in one corner of a virtual arena, after which they were required to reorient in a novel test arena. From 10.5 years, children performed above chance when the test arena permitted reorientation based only on local-shape (Experiment 2), or only global-shape (Experiment 3) information. Moreover, when these responses were placed into conflict, older children reoriented with respect to global-shape information (Experiment 4). These age-related findings were not due to older children being better able to reorient in virtual environments per se: when trained and tested within the same environment (Experiment 1), children performed above chance from 6 years. Together, our results suggest (a) the ability to reorient on the basis of global- and local-shape representations develops in parallel, and (b) shape-based information is weighted to determine which representation informs reorientation. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

The spatial layout of doorways and environmental boundaries shape the content of event memories.

Physical boundaries in our environment have been observed to define separate events in episodic memory. To date, however, there is little evidence that the spatial properties of boundaries exert any control over event memories. To examine this possibility, we conducted four experiments that took manipulations involving boundaries that have been demonstrated to influence spatial representations, and adapted them for use in an episodic object memory paradigm. Here, participants were given 15 min to freely explore an environment that contained 36 objects, equally dispersed among six discriminable buildings. In a subsequent test of object-location binding, participants were required to indicate where they remembered encountering the objects. In Experiment 1 the spatial properties of the building boundaries were identical; however, in Experiment 2 the boundaries were differentiated by their geometric shape and the location of the doorways in the buildings. In the test phases of these experiments, we observed a shift from a bias towards remembering the positions of objects within a building but not the building itself (Experiment 1), to a bias towards remembering which building an object was in but not the location within the building (Experiment 2). In Experiment 3, the buildings shared the same geometry but were differentiated by the locations of doorways, and we observed no significant differences between response types. Finally, in Experiment 4, the buildings were uniquely shaped but shared the same doorway location, and we observed a bias towards remembering the positions of objects within a building. In addition, exploratory analyses of non-spatial interference revealed more correct recall for objects housed in the first building a participant visited during exploration, compared to all other buildings. Together, our data indicates that the location of doorways in boundaries and, to a lesser extent, boundary geometries influence event models, and that a primacy effect can be observed in the recall of multiple object-location bindings.

Temporal and spatial contiguity are necessary for competition between events.

Over the last 50 years, cue competition phenomena have shaped theoretical developments in animal and human learning. However, recent failures to observe competition effects in standard conditioning procedures, as well as the lengthy and ongoing debate surrounding cue competition in the spatial learning literature, have cast doubts on the generality of these phenomena. In the present study, we manipulated temporal contiguity between simultaneously trained predictors and outcomes (Experiments 1-4), and spatial contiguity between landmarks and goals in spatial learning (Supplemental Experiments 1 and 2; Experiment 5). Across different parametric variations, we observed overshadowing when temporal and spatial contiguity were strong, but no overshadowing when contiguity was weak. Thus, across temporal and spatial domains, we observed that contiguity is necessary for competition to occur, and that competition between cues presented simultaneously during learning is absent when these cues were either spatially or temporally discontiguous from the outcome. Consequently, we advance a model in which the contiguity between events is accounted for and which explains these results and reconciles the previously contradictory findings observed in spatial learning. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Males induce premature demise of the opposite sex by multifaceted strategies.

Interactions between the sexes negatively impact health in many species. In Caenorhabditis, males shorten the lifespan of the opposite sex-hermaphrodites or females. Here we use transcriptomic profiling and targeted screens to systematically uncover conserved genes involved in male-induced demise in C. elegans. Some genes (for example, delm-2, acbp-3), when knocked down, are specifically protective against male-induced demise. Others (for example, sri-40), when knocked down, extend lifespan with and without males, suggesting general mechanisms of protection. In contrast, many classical long-lived mutants are impacted more negatively than wild type by the presence of males, highlighting the importance of sexual environment for longevity. Interestingly, genes induced by males are triggered by specific male components (seminal fluid, sperm and pheromone), and manipulating these genes in combination in hermaphrodites induces stronger protection. One of these genes, the conserved ion channel delm-2, acts in the nervous system and intestine to regulate lipid metabolism. Our analysis reveals striking differences in longevity in single sex versus mixed sex environments and uncovers elaborate strategies elicited by sexual interactions that could extend to other species.

A Fructo-Oligosaccharide Prebiotic Is Well Tolerated in Adults Undergoing Allogeneic Hematopoietic Stem Cell Transplantation: A Phase I Dose-Escalation Trial.

Alterations of the gut microbiota after allogeneic hematopoietic cell transplantation (allo-HCT) are a key factor in the development of transplant-related complications such as graft-versus-host disease (GVHD). Interventions that preserve the gut microbiome hold promise to improve HCT-associated morbidity and mortality. Murine models demonstrate that prebiotics such as fructo-oligosaccharides (FOSs) may increase gut levels of short-chain fatty acids (SCFAs) such as butyrate and consequently induce proliferation of immunomodulatory FOXP3+CD4+ regulatory T cells (Tregs), which impact GVHD risk. We conducted a pilot phase I trial to investigate the maximum tolerated dose of FOS in patients undergoing reduced-intensity allo-HCT (n = 15) compared with concurrent controls (n = 16). We administered the FOS starting at pretransplant conditioning and continuing for a total of 21 days. We characterized the gut microbiome using shotgun metagenomic sequencing, measured stool short-chain fatty acids (SCFAs) using liquid chromatography-mass spectrometry, and determined peripheral T cell concentrations using cytometry by time-of-flight. We found that FOS was safe and well-tolerated at 10 g/d without significant adverse effects in patients undergoing allo-HCT. Community-level gut microbiota composition differed significantly on the day of transplant (day 0) between patients receiving FOS and concurrent controls; however, FOS-associated alterations of the gut microbiota were not sustained after transplant. Although the impact of FOS was fleeting, transplantation itself impacted a substantial number of taxa over time. In our small pilot trial, no significant differences were observed in gut microbial metabolic pathways, stool SCFAs, or peripheral Tregs, although Tregs trended higher in those patients who received FOS. A marker of CD4+ T cell activation (namely, CTLA4+) was significantly higher in patients receiving FOS, whereas a non-significant trend existed for FOP3+CD4+ Treg cells, which were higher in those receiving FOS compared with controls. FOS is well tolerated at 10 g/d in patients undergoing reduced-intensity allo-HCT. Although the alterations in gut microbiota and peripheral immune cell composition in those receiving FOS are intriguing, additional studies are required to investigate the use of prebiotics in HCT recipients.

The effects of spatial stability and cue type on spatial learning: Implications for theories of parallel memory systems.

Some theories of spatial learning predict that associative rules apply under only limited circumstances. For example, learning based on a boundary has been claimed to be immune to cue competition effects because boundary information is the basis for the formation of a cognitive map, whilst landmark learning does not involve cognitive mapping. This is referred to as the cue type hypothesis. However, it has also been claimed that cue stability is a prerequisite for the formation of a cognitive map, meaning that whichever cue type was perceived as stable would enter a cognitive map and thus be immune to cue competition, while unstable cues will be subject to cue competition, regardless of cue type. In experiments 1 and 2 we manipulated the stability of boundary and landmark cues when learning the location of two hidden goals. One goal location was constant with respect to the boundary, and the other constant with respect to the landmark cues. For both cue types, the presence of distal orientation cues provided directional information. For half the participants the landmark cues were unstable relative to the boundary and orientation cues, whereas for the remainder of the participants the boundary was unstable relative to landmarks and orientation cues. In a second stage of training, all cues remained stable so that both goal locations could be learned with respect to both landmark and boundary information. According to the cue type hypothesis, boundary information should block learning about landmarks regardless of cue stability. According to the cue stability hypothesis, however, landmarks should block learning about the boundary when the landmarks appear stable relative to the boundary. Regardless of cue type or stability the results showed reciprocal blocking, contrary to both formulations of incidental cognitive mapping. Experiment 3 established that the results of Experiments 1 and 2 could not be explained in terms of difficulty in learning certain locations with respect to different cue types. In a final experiment, following training in which both landmarks and boundary cues signalled two goal locations, a new goal location was established with respect to the landmark cues, before testing with the boundary, which had never been used to define the new goal location. The results of this novel test of the interaction between boundary and landmark cues indicated that new learning with respect to the landmark had a profound effect on navigation with respect to the boundary, counter to the predictions of incidental cognitive mapping of boundaries.

Individual differences in theta-band oscillations in a spatial memory network revealed by electroencephalography predict rapid place learning.

Spatial memory has been closely related to the medial temporal lobe and theta oscillations are thought to play a key role. However, it remains difficult to investigate medial temporal lobe activation related to spatial memory with non-invasive electrophysiological methods in humans. Here, we combined the virtual delayed-matching-to-place task, reverse-translated from the watermaze delayed-matching-to-place task in rats, with high-density electroencephalography recordings. Healthy young volunteers performed this computerised task in a virtual circular arena, which contained a hidden target whose location moved to a new place every four trials, allowing the assessment of rapid memory formation. Using behavioural measures as predictor variables for source reconstructed frequency-specific electroencephalography power, we found that inter-individual differences in 'search preference' during 'probe trials', a measure of one-trial place learning known from rodent studies to be particularly hippocampus-dependent, correlated predominantly with distinct theta-band oscillations (approximately 7 Hz), particularly in the right temporal lobe, the right striatum and inferior occipital cortex or cerebellum. This pattern was found during both encoding and retrieval/expression, but not in control analyses and could not be explained by motor confounds. Alpha-activity in sensorimotor and parietal cortex contralateral to the hand used for navigation also correlated (inversely) with search preference. This latter finding likely reflects movement-related factors associated with task performance, as well as a frequency difference in (ongoing) alpha-rhythm for high-performers versus low-performers that may contribute to these results indirectly. Relating inter-individual differences in ongoing brain activity to behaviour in a continuous rapid place-learning task that is suitable for a variety of populations, we could demonstrate that memory-related theta-band activity in temporal lobe can be measured with electroencephalography recordings. This approach holds great potential for further studies investigating the interactions within this network during encoding and retrieval, as well as neuromodulatory impacts and age-related changes.

Diagnostic biomarkers for obsessive-compulsive disorder: A reasonable quest or ignis fatuus?

Obsessive-compulsive disorder (OCD) has been associated with a wide range of biological and neurocognitive findings, which could assist in the search for biomarkers. We conducted an umbrella review of systematic reviews and meta-analyses to assess and grade the strength of the evidence of the association between OCD and several potential diagnostic biomarkers while controlling for several potential biases. Twenty-four systematic reviews and meta-analyses were included, comprising 352 individual studies, more than 10,000 individuals with OCD, and covering 73 potential biomarkers. OCD was significantly associated with several neurocognitive biomarkers, with varying degrees of evidence, ranging from weak to convincing. A number of biochemical, neurophysiological, and neuroimaging biomarkers also showed statistically significant, albeit weak, associations with OCD. Analyses in unmedicated samples (123 studies) weakened the strength of the evidence for most biomarkers or rendered them non-significant. None of the biomarkers seem to have sufficient sensitivity and specificity to become a diagnostic biomarker. A more promising avenue for future biomarker research in OCD might be the prediction of clinical outcomes rather than diagnosis.

Single-cell analysis reveals T cell infiltration in old neurogenic niches.

The mammalian brain contains neurogenic niches that comprise neural stem cells and other cell types. Neurogenic niches become less functional with age, but how they change during ageing remains unclear. Here we perform single-cell RNA sequencing of young and old neurogenic niches in mice. The analysis of 14,685 single-cell transcriptomes reveals a decrease in activated neural stem cells, changes in endothelial cells and microglia, and an infiltration of T cells in old neurogenic niches. T cells in old brains are clonally expanded and are generally distinct from those in old blood, which suggests that they may experience specific antigens. T cells in old brains also express interferon-γ, and the subset of neural stem cells that has a high interferon response shows decreased proliferation in vivo. We find that T cells can inhibit the proliferation of neural stem cells in co-cultures and in vivo, in part by secreting interferon-γ. Our study reveals an interaction between T cells and neural stem cells in old brains, opening potential avenues through which to counteract age-related decline in brain function.

Crossing boundaries: Global reorientation following transfer from the inside to the outside of an arena.

In 2 spatial navigation experiments, human participants were asked to find a hidden goal (a WiFi signal) that was located in 1 of the right-angled corners of a kite-shaped (Experiment 1) or a cross-shaped (Experiment 2) virtual environment. Goal location was defined solely with respect to the geometry of the environment. Following this training, in a test conducted in extinction, participants were placed onto the outside of the same environments and asked to locate the WiFi signal. The results of both experiments revealed that participants spent more time searching in regions on the outside of the environments that were closest to where the WiFi signal was located during training. These results are difficult to explain in terms of analyses of spatial navigation and reorientation that emphasize the role of local representational encoding or view matching. Instead, we suggest that these results are better understood in terms of a global representation of the shape of the environment. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Walking through doorways differentially affects recall and familiarity.

Previous research has reported that walking through a doorway to a new location makes memory for objects and events experienced in the previous location less accurate. This effect, termed the location updating effect, has been used to suggest that location changes are used to mark boundaries between events in memory: memories for objects encountered within the current event are more available than those from beyond an event boundary. Within a computer-generated memory task, participants navigated through virtual rooms, walking through doorways, and interacting with objects. The accuracy and their subjective experience of their memory for the objects (remember/know and confidence) were assessed. The findings showed that shifts in location decreased accurate responses associated with the subjective experience of remembering but not those associated with the experience of knowing, even when considering only the most confident responses in each condition. These findings demonstrate that a shift in location selectively impacts recollection and so contributes to our understanding of boundaries in event memory.

Thinking outside of the box II: Disrupting the cognitive map.

A number of influential spatial learning theories posit that organisms encode a viewpoint independent (i.e. allocentric) representation of the global boundary shape of their environment in order to support spatial reorientation and place learning. In contrast to the trial and error learning mechanisms that support domain-general processes, a representation of the global-shape of the environment is thought to be encoded automatically as part of a cognitive map, and without interference from other spatial cues. To date, however, this core theoretical assumption has not been appropriately examined. This is because previous attempts to address this question have failed to employ tasks that fully dissociate reorientation based on an allocentric representation of global-shape from egocentric reorientation strategies. Here, we address this issue in two experiments. Participants were trained to navigate to a hidden goal on one side of a virtual arena (e.g. the inside) before being required to find the same point on the alternative side (e.g. the outside). At test, performing the correct search behaviour requires an allocentric representation of the global boundary-shape. Using established associative learning procedures of overshadowing and blocking, we find that search behaviour at test is disrupted when participants were able to form landmark-goal associations during training. These results demonstrate that encoding of an allocentric representation of boundary information is susceptible to interference from landmark cues, and is not acquired through special means. Instead, the results suggest that allocentric representations of environmental boundaries are acquired through the same kind of error-correction mechanisms that support domain-general non-spatial learning.

A new human delayed-matching-to-place test in a virtual environment reverse-translated from the rodent watermaze paradigm: Characterization of performance measures and sex differences.

Watermaze tests of place learning and memory in rodents and corresponding reverse-translated human paradigms in real or virtual environments are key tools to study hippocampal function. In common variants, the animal or human participant has to find a hidden goal that remains in the same place over many trials, allowing for incremental learning of the place with reference to distal cues surrounding the circular, featureless maze. Although the hippocampus is involved in incremental place learning, rodent studies have shown that the delayed-matching-to-place (DMP) watermaze test is a more sensitive assay of hippocampal function. On the DMP test, the goal location changes every four trials, requiring the rapid updating of place memory. Here, we developed a virtual DMP test reverse-translated from the rat watermaze DMP paradigm. In two replications, participants showed 1-trial place learning, evidenced by marked latency and path length savings between Trials 1 and 2 to the same goal location, and by search preference for the vicinity of the goal when Trial 2 was run as probe trial (during which the goal was removed). The performance was remarkably similar to rats' performance on the watermaze DMP test. In both replications, male participants showed greater savings and search preferences compared to female participants. Male participants also showed better mental rotation performance, although mental rotation scores did not consistently correlate with DMP performance measures, pointing to distinct neurocognitive mechanisms. The remarkable similarity between rodent and human DMP performance suggests similar underlying neuro-psychological mechanisms, including hippocampus dependence. The new virtual DMP test may, therefore, provide a sensitive tool to probe human hippocampal function.

Collapsed Dark Matter Structures.

The distributions of dark matter and baryons in the Universe are known to be very different: The dark matter resides in extended halos, while a significant fraction of the baryons have radiated away much of their initial energy and fallen deep into the potential wells. This difference in morphology leads to the widely held conclusion that dark matter cannot cool and collapse on any scale. We revisit this assumption and show that a simple model where dark matter is charged under a "dark electromagnetism" can allow dark matter to form gravitationally collapsed objects with characteristic mass scales much smaller than that of a Milky-Way-type galaxy. Though the majority of the dark matter in spiral galaxies would remain in the halo, such a model opens the possibility that galaxies and their associated dark matter play host to a significant number of collapsed substructures. The observational signatures of such structures are not well explored but potentially interesting.