Negative biases in cognition have been documented consistently in major depressive disorder (MDD), including difficulties in the ability to control the processing of negative material. Although negative information-processing biases have been studied using both behavioral and neuroimaging paradigms, relatively little research has been conducted examining the difficulties of depressed persons with inhibiting the retrieval of negative information from long-term memory. In this study, we used the think/no-think paradigm and functional magnetic resonance imaging to assess the cognitive and neural consequences of memory suppression in individuals diagnosed with depression and in healthy controls. The participants showed typical behavioral forgetting effects, but contrary to our hypotheses, there were no differences between the depressed and nondepressed participants or between neutral and negative memories. Relative to controls, depressed individuals exhibited greater activity in right middle frontal gyrus during memory suppression, regardless of the valence of the suppressed stimuli, and differential activity in the amygdala and hippocampus during memory suppression involving negatively valenced stimuli. These findings indicate that depressed individuals are characterized by neural anomalies during the suppression of long-term memories, increasing our understanding of the brain bases of negative cognitive biases in MDD.

Successful encoding of episodic memories is thought to depend on contributions from prefrontal and temporal lobe structures. Neural processes that contribute to successful encoding have been extensively explored through univariate analyses of neuroimaging data that compare mean activity levels elicited during the encoding of events that are subsequently remembered vs. those subsequently forgotten. Here, we applied pattern classification to fMRI data to assess the degree to which distributed patterns of activity within prefrontal and temporal lobe structures elicited during the encoding of word-image pairs were diagnostic of the visual category (Face or Scene) of the encoded image. We then assessed whether representation of category information was predictive of subsequent memory. Classification analyses indicated that temporal lobe structures contained information robustly diagnostic of visual category. Information in prefrontal cortex was less diagnostic of visual category, but was nonetheless associated with highly reliable classifier-based evidence for category representation. Critically, trials associated with greater classifier-based estimates of category representation in temporal and prefrontal regions were associated with a higher probability of subsequent remembering. Finally, consideration of trial-by-trial variance in classifier-based measures of category representation revealed positive correlations between prefrontal and temporal lobe representations, with the strength of these correlations varying as a function of the category of image being encoded. Together, these results indicate that multi-voxel representations of encoded information can provide unique insights into how visual experiences are transformed into episodic memories.

Prior knowledge structures (or schemas) confer multiple behavioral benefits. First, when we encounter information that fits with prior knowledge structures, this information is generally better learned and remembered. Second, prior knowledge can support prospective planning. In humans, memory enhancements related to prior knowledge have been suggested to be supported, in part, by computations in prefrontal and medial temporal lobe (MTL) cortex. Moreover, animal studies further implicate a role for the hippocampus in schema-based facilitation and in the emergence of prospective planning signals following new learning. To date, convergence across the schema-enhanced learning and memory literature may be constrained by the predominant use of hippocampally dependent spatial navigation paradigms in rodents, and non-spatial list-based learning paradigms in humans. Here, we targeted this missing link by examining the effects of prior knowledge on human navigational learning in a hippocampally dependent virtual navigation paradigm that closely relates to foundational studies in rodents. Outside the scanner, participants overlearned Old Paired Associates (OPA- item-location associations) in multiple spatial environments, and they subsequently learned New Paired Associates (NPA-new item-location associations) in the environments while undergoing fMRI. We hypothesized that greater OPA knowledge precision would positively affect NPA learning, and that the hippocampus would be instrumental in translating this new learning into prospective planning of navigational paths to NPA locations. Behavioral results revealed that OPA knowledge predicted one-shot learning of NPA locations, and neural results indicated that one-shot learning was predicted by the rapid emergence of performance-predictive prospective planning signals in hippocampus. Prospective memory relationships were not significant in parahippocampal cortex and were marginally dissociable from the primary hippocampal effect. Collectively, these results extend understanding of how schemas impact learning and performance, showing that the precision of prior spatial knowledge is important for future learning in humans, and that the hippocampus is involved in translating this knowledge into new goal-directed behaviors.

The neuronal microtubule-associated protein tau becomes hyperphosphorylated and forms aggregates in tauopathies but the processes leading to this pathological hallmark are not understood. Because tauopathies are accompanied by neuroinflammation and the complement cascade forms a key innate immune pathway, we asked whether the complement system has a role in the development of tau pathology.

Mild traumatic brain injury (mTBI, also referred to as concussion) accounts for the majority of all traumatic brain injuries. The consequences of repetitive mTBI have become of particular concern for individuals engaged in certain sports or in military operations. Many mTBI patients suffer long-lasting neurobehavioral impairments. In order to expedite pre-clinical research and therapy development, there is a need for animal models that reflect the long-term cognitive and pathological features seen in patients. In the present study, we developed and characterized a mouse model of repetitive mTBI, induced onto the closed head over the left frontal hemisphere with an electromagnetic stereotaxic impact device. Using GFAP-luciferase bioluminescence reporter mice that provide a readout of astrocyte activation, we observed an increase in bioluminescence relative to the force delivered by the impactor after single impact and cumulative effects of repetitive mTBI. Using the injury parameters established in the reporter mice, we induced a repetitive mTBI in wild-type C57BL/6J mice and characterized the long-term outcome. Animals received repetitive mTBI showed a significant impairment in spatial learning and memory when tested at 2 and 6 months after injury. A robust astrogliosis and increased p-Tau immunoreactivity were observed upon post-mortem pathological examinations. These findings are consistent with the deficits and pathology associated with mTBI in humans and support the use of this model to evaluate potential therapeutic approaches.

The p75 neurotrophin receptor (p75(NTR)) is associated with multiple mechanisms linked to Alzheimer's disease (AD); hence, modulating its function might confer therapeutic effects. In previous in vitro work, we developed small molecule p75(NTR) ligands that inhibited amyloid-β-induced degenerative signaling and prevented neurite degeneration. In the present study, a prototype p75(NTR) ligand, LM11A-31, was administered orally to the Thy-1 hAPP(Lond/Swe) (APP(L/S)) AD mouse model. LM11A-31 reached brain concentrations known to inhibit degenerative signaling without toxicity or induction of hyperalgesia. It prevented deficits in novel object recognition after 2.5 months and, in a separate cohort, deficits in Y-maze performance after 3 months of treatment. Stereology studies found that the number and size of basal forebrain cholinergic neurons, which are normal in APP(L/S) mice, were unaffected. Neuritic dystrophy, however, was readily apparent in the basal forebrain, hippocampus and cortex, and was significantly reduced by LM11A-31, with no effect on amyloid levels. These studies reveal that p75(NTR) is an important and tractable in vivo drug target for AD, with LM11A-31 representing a novel class of therapeutic candidates.

In the central nervous system, ageing results in a precipitous decline in adult neural stem/progenitor cells and neurogenesis, with concomitant impairments in cognitive functions. Interestingly, such impairments can be ameliorated through systemic perturbations such as exercise. Here, using heterochronic parabiosis we show that blood-borne factors present in the systemic milieu can inhibit or promote adult neurogenesis in an age-dependent fashion in mice. Accordingly, exposing a young mouse to an old systemic environment or to plasma from old mice decreased synaptic plasticity, and impaired contextual fear conditioning and spatial learning and memory. We identify chemokines--including CCL11 (also known as eotaxin)--the plasma levels of which correlate with reduced neurogenesis in heterochronic parabionts and aged mice, and the levels of which are increased in the plasma and cerebrospinal fluid of healthy ageing humans. Lastly, increasing peripheral CCL11 chemokine levels in vivo in young mice decreased adult neurogenesis and impaired learning and memory. Together our data indicate that the decline in neurogenesis and cognitive impairments observed during ageing can be in part attributed to changes in blood-borne factors.

Phagocytosis controls CNS homeostasis by facilitating the removal of unwanted cellular debris. Accordingly, impairments in different receptors or proteins involved in phagocytosis result in enhanced inflammation and neurodegeneration. While various studies have identified extrinsic factors that modulate phagocytosis in health and disease, key intracellular regulators are less understood. Here we show that the autophagy protein beclin 1 is required for efficient phagocytosis in vitro and in mouse brains. Furthermore, we show that beclin 1-mediated impairments in phagocytosis are associated with dysfunctional recruitment of retromer to phagosomal membranes, reduced retromer levels, and impaired recycling of phagocytic receptors CD36 and Trem2. Interestingly, microglia isolated from human Alzheimer's disease (AD) brains show significantly reduced beclin 1 and retromer protein levels. These findings position beclin 1 as a link between autophagy, retromer trafficking, and receptor-mediated phagocytosis and provide insight into mechanisms by which phagocytosis is regulated and how it may become impaired in AD.

Decisions are often guided by generalizing from past experiences. Fundamental questions remain regarding the cognitive and neural mechanisms by which generalization takes place. Prior data suggest that generalization may stem from inference-based processes at the time of generalization. By contrast, generalization may emerge from mnemonic processes occurring while premise events are encoded. Here, participants engaged in a two-phase learning and generalization task, wherein they learned a series of overlapping associations and subsequently generalized what they learned to novel stimulus combinations. Functional MRI revealed that successful generalization was associated with coupled changes in learning-phase activity in the hippocampus and midbrain (ventral tegmental area/substantia nigra). These findings provide evidence for generalization based on integrative encoding, whereby overlapping past events are integrated into a linked mnemonic representation. Hippocampal-midbrain interactions support the dynamic integration of experiences, providing a powerful mechanism for building a rich associative history that extends beyond individual events.

Secreted polypeptides are a fundamental axis of intercellular and endocrine communication. However, a global understanding of the composition and dynamics of cellular secretomes in intact mammalian organisms has been lacking. Here, we introduce a proximity biotinylation strategy that enables labeling, detection and enrichment of secreted polypeptides in a cell type-selective manner in mice. We generate a proteomic atlas of hepatocyte, myocyte, pericyte and myeloid cell secretomes by direct purification of biotinylated secreted proteins from blood plasma. Our secretome dataset validates known cell type-protein pairs, reveals secreted polypeptides that distinguish between cell types and identifies new cellular sources for classical plasma proteins. Lastly, we uncover a dynamic and previously undescribed nutrient-dependent reprogramming of the hepatocyte secretome characterized by the increased unconventional secretion of the cytosolic enzyme betaine-homocysteine S-methyltransferase (BHMT). This secretome profiling strategy enables dynamic and cell type-specific dissection of the plasma proteome and the secreted polypeptides that mediate intercellular signaling.

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.

The ability to remember an episode from our past is often hindered by competition from similar events. For example, if we want to remember the article a colleague recommended during the last lab meeting, we may need to resolve interference from other article recommendations from the same colleague. This study investigates if the contextual features specifying the encoding episodes are incidentally reinstated during competitive memory retrieval. Competition between memories was created through the AB/AC interference paradigm. Individual word-pairs were presented embedded in a slowly drifting real-word-like context. Multivariate pattern analysis (MVPA) of high temporal-resolution electroencephalographic (EEG) data was used to investigate context reactivation during memory retrieval. Behaviorally, we observed proactive (but not retroactive) interference; that is, performance for AC competitive retrieval was worse compared with a control DE noncompetitive retrieval, whereas AB retrieval did not suffer from competition. Neurally, proactive interference was accompanied by an early reinstatement of the competitor context and interference resolution was associated with the ensuing reinstatement of the target context. Together, these findings provide novel evidence showing that the encoding contexts of competing discrete events are incidentally reinstated during competitive retrieval and that such reinstatement tracks retrieval competition and subsequent interference resolution.

Cerebrospinal fluid (CSF) contains a tightly regulated immune system. However, knowledge is lacking about how CSF immunity is altered with aging or neurodegenerative disease. Here, we performed single-cell RNA sequencing on CSF from 45 cognitively normal subjects ranging from 54 to 82 years old. We uncovered an upregulation of lipid transport genes in monocytes with age. We then compared this cohort with 14 cognitively impaired subjects. In cognitively impaired subjects, downregulation of lipid transport genes in monocytes occurred concomitantly with altered cytokine signaling to CD8 T cells. Clonal CD8 T effector memory cells upregulated C-X-C motif chemokine receptor 6 (CXCR6) in cognitively impaired subjects. The CXCR6 ligand, C-X-C motif chemokine ligand 16 (CXCL16), was elevated in the CSF of cognitively impaired subjects, suggesting CXCL16-CXCR6 signaling as a mechanism for antigen-specific T cell entry into the brain. Cumulatively, these results reveal cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment.

Alzheimer's Disease (AD) is the most prevalent neurodegenerative disorder. Despite advances in the understanding of its pathophysiology, none of the available therapies prevents disease progression. Excess glutamate plays an important role in excitotoxicity by activating ionotropic receptors. However, the mechanisms modulating neuronal cell survival/death via metabotropic glutamate receptors (mGluRs) are not completely understood. Recent data indicates that CDPPB, a positive allosteric modulator of mGluR5, has neuroprotective effects. Thus, this work aimed to investigate CDPPB treatment effects on amyloid-β (Aβ) induced pathological alterations in vitro and in vivo and in a transgenic mouse model of AD (T41 mice). Aβ induced cell death in primary cultures of hippocampal neurons, which was prevented by CDPPB. Male C57BL/6 mice underwent stereotaxic surgery for unilateral intra-hippocampal Aβ injection, which induced memory deficits, neurodegeneration, neuronal viability reduction and decrease of doublecortin-positive cells, a marker of immature neurons and neuronal proliferation. Treatment with CDPPB for 8 days reversed neurodegeneration and doublecortin-positive cells loss and recovered memory function. Fourteen months old T41 mice presented cognitive deficits, neuronal viability reduction, gliosis and Aβ accumulation. Treatment with CDPPB for 28 days increased neuronal viability (32.2% increase in NeuN+ cells) and reduced gliosis in CA1 region (Iba-1+ area by 31.3% and GFAP+ area by 37.5%) in transgenic animals, without inducing hepatotoxicity. However, it did not reverse cognitive deficit. Despite a four-week treatment did not prevent memory loss in aged transgenic mice, CDPPB is protective against Aβ stimulus. Therefore, this drug represents a potential candidate for further investigations as AD treatment.

Aging is a key risk factor for chronic diseases of the elderly. MicroRNAs regulate post-transcriptional gene silencing through base-pair binding on their target mRNAs. We identified nonlinear changes in age-related microRNAs by analyzing whole blood from 1334 healthy individuals. We observed a larger influence of the age as compared to the sex and provide evidence for a shift to the 5' mature form of miRNAs in healthy aging. The addition of 3059 diseased patients uncovered pan-disease and disease-specific alterations in aging profiles. Disease biomarker sets for all diseases were different between young and old patients. Computational deconvolution of whole-blood miRNAs into blood cell types suggests that cell intrinsic gene expression changes may impart greater significance than cell abundance changes to the whole blood miRNA profile. Altogether, these data provide a foundation for understanding the relationship between healthy aging and disease, and for the development of age-specific disease biomarkers.

We present GeneTrail 3, a major extension of our web service GeneTrail that offers rich functionality for the identification, analysis, and visualization of deregulated biological processes. Our web service provides a comprehensive collection of biological processes and signaling pathways for 12 model organisms that can be analyzed with a powerful framework for enrichment and network analysis of transcriptomic, miRNomic, proteomic, and genomic data sets. Moreover, GeneTrail offers novel workflows for the analysis of epigenetic marks, time series experiments, and single cell data. We demonstrate the capabilities of our web service in two case-studies, which highlight that GeneTrail is well equipped for uncovering complex molecular mechanisms. GeneTrail is freely accessible at: http://genetrail.bioinf.uni-sb.de.

With the explosion of digital media and technologies, scholars, educators and the public have become increasingly vocal about the role that an 'attention economy' has in our lives1. The rise of the current digital culture coincides with longstanding scientific questions about why humans sometimes remember and sometimes forget, and why some individuals remember better than others2-6. Here we examine whether spontaneous attention lapses-in the moment7-12, across individuals13-15 and as a function of everyday media multitasking16-19-negatively correlate with remembering. Electroencephalography and pupillometry measures of attention20,21 were recorded as eighty young adults (mean age, 21.7 years) performed a goal-directed episodic encoding and retrieval task22. Trait-level sustained attention was further quantified using task-based23 and questionnaire measures24,25. Using trial-to-trial retrieval data, we show that tonic lapses in attention in the moment before remembering, assayed by posterior alpha power and pupil diameter, were correlated with reductions in neural signals of goal coding and memory, along with behavioural forgetting. Independent measures of trait-level attention lapsing mediated the relationship between neural assays of lapsing and memory performance, and between media multitasking and memory. Attention lapses partially account for why we remember or forget in the moment, and why some individuals remember better than others. Heavier media multitasking is associated with a propensity to have attention lapses and forget.

Exercise confers protection against obesity, type 2 diabetes and other cardiometabolic diseases1-5. However, the molecular and cellular mechanisms that mediate the metabolic benefits of physical activity remain unclear6. Here we show that exercise stimulates the production of N-lactoyl-phenylalanine (Lac-Phe), a blood-borne signalling metabolite that suppresses feeding and obesity. The biosynthesis of Lac-Phe from lactate and phenylalanine occurs in CNDP2+ cells, including macrophages, monocytes and other immune and epithelial cells localized to diverse organs. In diet-induced obese mice, pharmacological-mediated increases in Lac-Phe reduces food intake without affecting movement or energy expenditure. Chronic administration of Lac-Phe decreases adiposity and body weight and improves glucose homeostasis. Conversely, genetic ablation of Lac-Phe biosynthesis in mice increases food intake and obesity following exercise training. Last, large activity-inducible increases in circulating Lac-Phe are also observed in humans and racehorses, establishing this metabolite as a molecular effector associated with physical activity across multiple activity modalities and mammalian species. These data define a conserved exercise-inducible metabolite that controls food intake and influences systemic energy balance.

Massively-parallel single-cell and single-nucleus RNA sequencing (scRNA-seq, snRNA-seq) requires extensive sequencing to achieve proper per-cell coverage, making sequencing resources and availability of sequencers critical factors for conducting deep transcriptional profiling. CoolMPS is a novel sequencing-by-synthesis approach that relies on nucleotide labeling by re-usable antibodies, but whether it is applicable to snRNA-seq has not been tested. Here, we use a low-cost and off-the-shelf protocol to chemically convert libraries generated with the widely-used Chromium 10X technology to be sequenceable with CoolMPS technology. To assess the quality and performance of converted libraries sequenced with CoolMPS, we generated a snRNA-seq dataset from the hippocampus of young and old mice. Native libraries were sequenced on an Illumina Novaseq and libraries that were converted to be compatible with CoolMPS were sequenced on a DNBSEQ-400RS. CoolMPS-derived data faithfully replicated key characteristics of the native library dataset, including correct estimation of ambient RNA-contamination, detection of captured cells, cell clustering results, spatial marker gene expression, inter- and intra-replicate differences and gene expression changes during aging. In conclusion, our results show that CoolMPS provides a viable alternative to standard sequencing of RNA from droplet-based libraries.

Genetic association studies have demonstrated the critical involvement of the microglial immune response in Alzheimer's disease (AD) pathogenesis. Phospholipase C-gamma-2 (PLCG2) is selectively expressed by microglia and functions in many immune receptor signaling pathways. In AD, PLCG2 is induced uniquely in plaque-associated microglia. A genetic variant of PLCG2, PLCG2P522R, is a mild hypermorph that attenuates AD risk. Here, we identified a loss-of-function PLCG2 variant, PLCG2M28L, that confers an increased AD risk. PLCG2P522R attenuated disease in an amyloidogenic murine AD model, whereas PLCG2M28L exacerbated the plaque burden associated with altered phagocytosis and Aβ clearance. The variants bidirectionally modulated disease pathology by inducing distinct transcriptional programs that identified microglial subpopulations associated with protective or detrimental phenotypes. These findings identify PLCG2M28L as a potential AD risk variant and demonstrate that PLCG2 variants can differentially orchestrate microglial responses in AD pathogenesis that can be therapeutically targeted.