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Nature Aug 2022Memory formation involves binding of contextual features into a unitary representation, whereas memory recall can occur using partial combinations of these contextual...
Memory formation involves binding of contextual features into a unitary representation, whereas memory recall can occur using partial combinations of these contextual features. The neural basis underlying the relationship between a contextual memory and its constituent features is not well understood; in particular, where features are represented in the brain and how they drive recall. Here, to gain insight into this question, we developed a behavioural task in which mice use features to recall an associated contextual memory. We performed longitudinal imaging in hippocampus as mice performed this task and identified robust representations of global context but not of individual features. To identify putative brain regions that provide feature inputs to hippocampus, we inhibited cortical afferents while imaging hippocampus during behaviour. We found that whereas inhibition of entorhinal cortex led to broad silencing of hippocampus, inhibition of prefrontal anterior cingulate led to a highly specific silencing of context neurons and deficits in feature-based recall. We next developed a preparation for simultaneous imaging of anterior cingulate and hippocampus during behaviour, which revealed robust population-level representation of features in anterior cingulate, that lag hippocampus context representations during training but dynamically reorganize to lead and target recruitment of context ensembles in hippocampus during recall. Together, we provide the first mechanistic insights into where contextual features are represented in the brain, how they emerge, and how they access long-range episodic representations to drive memory recall.
Topics: Animals; Brain Mapping; Entorhinal Cortex; Gyrus Cinguli; Hippocampus; Longitudinal Studies; Mental Recall; Mice; Models, Neurological; Neural Inhibition
PubMed: 35831504
DOI: 10.1038/s41586-022-04936-2 -
Alzheimer's Research & Therapy May 2023Studies on DNA methylation (DNAm) in Alzheimer's disease (AD) have recently highlighted several genomic loci showing association with disease onset and progression. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Studies on DNA methylation (DNAm) in Alzheimer's disease (AD) have recently highlighted several genomic loci showing association with disease onset and progression.
METHODS
Here, we conducted an epigenome-wide association study (EWAS) using DNAm profiles in entorhinal cortex (EC) from 149 AD patients and control brains and combined these with two previously published EC datasets by meta-analysis (total n = 337).
RESULTS
We identified 12 cytosine-phosphate-guanine (CpG) sites showing epigenome-wide significant association with either case-control status or Braak's tau-staging. Four of these CpGs, located in proximity to CNFN/LIPE, TENT5A, PALD1/PRF1, and DIRAS1, represent novel findings. Integrating DNAm levels with RNA sequencing-based mRNA expression data generated in the same individuals showed significant DNAm-mRNA correlations for 6 of the 12 significant CpGs. Lastly, by calculating rates of epigenetic age acceleration using two recently proposed "epigenetic clock" estimators we found a significant association with accelerated epigenetic aging in the brains of AD patients vs. controls.
CONCLUSION
In summary, our study represents the hitherto most comprehensive EWAS in AD using EC and highlights several novel differentially methylated loci with potential effects on gene expression.
Topics: Humans; Epigenome; Epigenesis, Genetic; Alzheimer Disease; Entorhinal Cortex; CpG Islands; DNA Methylation; Genome-Wide Association Study; GTP Phosphohydrolases; Tumor Suppressor Proteins
PubMed: 37149695
DOI: 10.1186/s13195-023-01232-7 -
Scientific Reports Oct 2023The pathological features of Alzheimer's disease are the formation of amyloid plaques and entanglement of nerve fibers. Studies have shown that Cu may be involved in the...
The pathological features of Alzheimer's disease are the formation of amyloid plaques and entanglement of nerve fibers. Studies have shown that Cu may be involved in the formation of amyloid plaques. However, their role has been controversial. The aim of this study was to explore the role of Cu in AD. We applied the "R" software for our differential analysis. Differentially expressed genes were screened using the limma package. Copper metabolism-related genes and the intersection set of differential genes with GSE5281 were searched; functional annotation was performed. The protein-protein interaction network was constructed using several modules to analyse the most significant hub genes. The hub genes were then qualified, and a database was used to screen for small-molecule AD drugs. We identified 87 DEGs. gene ontology analysis focused on homeostatic processes, response to toxic substances, positive regulation of transport, and secretion. The enriched molecular functions are mainly related to copper ion binding, molecular function regulators, protein-containing complex binding, identical protein binding and signalling receptor binding. The KEGG database is mainly involved in central carbon metabolism in various cancers, Parkinson's disease and melanoma. We identified five hub genes, FGF2, B2M, PTPRC, CD44 and SPP1, and identified the corresponding small molecule drugs. Our study identified key genes possibly related to energy metabolism in the pathological mechanism of AD and explored potential targets for AD treatment by establishing interaction networks.
Topics: Humans; Gene Expression Profiling; Entorhinal Cortex; Copper; Alzheimer Disease; Plaque, Amyloid
PubMed: 37838728
DOI: 10.1038/s41598-023-44656-9 -
Cells Jun 2023The enormous, 2-3-million-year evolutionary expansion of hominin neocortices to the current enormity enabled humans to take over the planet. However, there appears to... (Review)
Review
The enormous, 2-3-million-year evolutionary expansion of hominin neocortices to the current enormity enabled humans to take over the planet. However, there appears to have been a glitch, and it occurred without a compensatory expansion of the entorhinal cortical (EC) gateway to the hippocampal memory-encoding system needed to manage the processing of the increasing volume of neocortical data converging on it. The resulting age-dependent connectopathic glitch was unnoticed by the early short-lived populations. It has now surfaced as Alzheimer's disease (AD) in today's long-lived populations. With advancing age, processing of the converging neocortical data by the neurons of the relatively small lateral entorhinal cortex (LEC) inflicts persistent strain and high energy costs on these cells. This may result in their hyper-release of harmless Aβ monomers into the interstitial fluid, where they seed the formation of toxic amyloid-β oligomers (AβOs) that initiate AD. At the core of connectopathic AD are the postsynaptic cellular prion protein (PrPC). Electrostatic binding of the negatively charged AβOs to the positively charged N-terminus of PrPC induces hyperphosphorylation of tau that destroys synapses. The spread of these accumulating AβOs from ground zero is supported by Aβ's own production mediated by target cells' Ca2+-sensing receptors (CaSRs). These data suggest that an early administration of a strongly positively charged, AβOs-interacting peptide or protein, plus an inhibitor of CaSR, might be an effective AD-arresting therapeutic combination.
Topics: Humans; Alzheimer Disease; Amyloid beta-Peptides; Hippocampus; Neurons; Entorhinal Cortex; Prion Proteins
PubMed: 37371088
DOI: 10.3390/cells12121618 -
Cell Reports Dec 2021Specific classes of GABAergic neurons play specific roles in regulating information processing in the brain. In the hippocampus, two major classes,...
Specific classes of GABAergic neurons play specific roles in regulating information processing in the brain. In the hippocampus, two major classes, parvalbumin-expressing (PV) and somatostatin-expressing (SST), differentially regulate endogenous firing patterns and target subcellular compartments of principal cells. How these classes regulate the flow of information throughout the hippocampus is poorly understood. We hypothesize that PV and SST interneurons in the dentate gyrus (DG) and CA3 differentially modulate CA3 patterns of output, thereby altering the influence of CA3 on CA1. We find that while suppressing either interneuron class increases DG and CA3 output, the effects on CA1 were very different. Suppressing PV interneurons increases local field potential signatures of coupling from CA3 to CA1 and decreases signatures of coupling from entorhinal cortex to CA1; suppressing SST interneurons has the opposite effect. Thus, DG and CA3 PV and SST interneurons bidirectionally modulate the flow of information through the hippocampal circuit.
Topics: Action Potentials; Animals; CA1 Region, Hippocampal; CA3 Region, Hippocampal; Dentate Gyrus; Entorhinal Cortex; Female; GABAergic Neurons; Interneurons; Male; Mice; Mice, Inbred C57BL; Somatostatin
PubMed: 34965435
DOI: 10.1016/j.celrep.2021.110159 -
Social Cognitive and Affective... Nov 2020Despite aggression being detrimental to children's physical health, mental health and social development, the dispositional and neurological antecedents of aggression in...
Despite aggression being detrimental to children's physical health, mental health and social development, the dispositional and neurological antecedents of aggression in the child are poorly understood. Here we examined the relationship between trait aggression as measured by Buss and Warren's Aggression Questionnaire and personality traits measured with Big Five Questionnaire for Children in 77 primary-school children and recorded resting-state brain activity (fractional amplitude of low-frequency fluctuations [fALFF]) and resting-state functional connectivity (rsFC) using functional magnetic resonance imaging. The present results showed that trait aggression was negatively correlated with agreeableness and positively correlated with neuroticism. The brain analyses showed that children with a higher propensity for aggression had a lower fALFF mainly in the left superior temporal gyrus, right parahippocampal gyrus and left supramarginal gyrus. Physical and total aggressions were negatively associated with rsFC between the right parahippocampal gyrus and the right putamen. Further analysis revealed that this rsFC could moderate the influence of neuroticism on total aggression. Moreover, the results suggest the presence of a sex difference in the neurodevelopmental mechanisms underlying aggression in middle childhood. Overall, our findings indicate that aggressive children have lower agreeableness and higher neuroticism, and the underlying neural systems are mainly implicated in social judgment and empathy.
Topics: Aggression; Brain; Brain Mapping; Child; Female; Humans; Magnetic Resonance Imaging; Male; Personality; Sex Characteristics
PubMed: 32991698
DOI: 10.1093/scan/nsaa134 -
Neuroscience and Biobehavioral Reviews Jan 2020Ants who have successfully navigated the long distance between their foraging spot and their nest dozens of times will drastically overshoot their destination if the... (Review)
Review
Ants who have successfully navigated the long distance between their foraging spot and their nest dozens of times will drastically overshoot their destination if the size of their legs is doubled by the addition of stilts. This observation reflects a navigational strategy called path integration, a strategy also utilized by mammals. Path integration necessitates that animals keep track of their movement speed and use it to precisely and instantly modify where they think they are and where they want to go. Here we review the neural circuitry that has evolved to integrate speed and space. We start with the rate and temporal codes for speed in the hippocampus and work backwards towards the motor and sensory systems. We highlight the need for experiments designed to differentiate the respective contributions of motor efference copy versus sensory inputs. In particular, we discuss the importance of high-resolution tracking of the latency of speed-encoding as a precise way to disentangle the sensory versus motor computations that enable successful spatial navigation at very different speeds.
Topics: Animals; Brain Waves; Entorhinal Cortex; Hippocampus; Mesencephalon; Motor Cortex; Nerve Net; Spatial Memory; Spatial Navigation; Time Perception; Walking Speed
PubMed: 31760048
DOI: 10.1016/j.neubiorev.2019.11.013 -
Military Medicine Sep 2020The purpose of this study was to explore the effect of low testosterone level on whole-brain resting state (RS) connectivity in male veterans with symptoms such as sleep...
INTRODUCTION
The purpose of this study was to explore the effect of low testosterone level on whole-brain resting state (RS) connectivity in male veterans with symptoms such as sleep disturbance, fatiguability, pain, anxiety, irritability, or aggressiveness persisting after mild traumatic brain injury (mTBI). Follow-up analyses were performed to determine if sleep scores affected the results.
MATERIALS AND METHODS
In our cross-sectional design study, RS magnetic resonance imaging scans on 28 veterans were performed, and testosterone, sleep quality, mood, and post-traumatic stress symptoms were measured. For each participant, we computed the average correlation of each voxel's time-series with the rest of the voxels in the brain, then used AFNI's 3dttest++ on the group data to determine whether the effects of testosterone level on whole-brain connectivity were significant. We then performed follow-up region of interest-based RS analyses of testosterone, with and without sleep quality as a covariate. The study protocol was approved by the National Institute of Health's Combined Neuroscience Institutional Review Board.
RESULTS
Sixteen participants reported repeated blast exposure in theater, leading to symptoms; the rest reported exposure to a single blast or a nonblast TBI. Thirty-three percent had testosterone levels <300 ng/dL. Testosterone level was lower in participants who screened positive for post-traumatic stress disorder compared to those who screened negative, but it did not reach statistical significance. Whole-brain connectivity and testosterone level were positively correlated in the left parahippocampal gyrus (LPhG), especially in its connectivity with frontal areas, the lingual gyrus, cingulate, insula, caudate, and right parahippocampal gyrus. Further analysis revealed that the effect of testosterone on LPhG connectivity is only partially mediated by sleep quality. Sleep quality by itself had an effect on connectivity of the thalamus, cerebellum, precuneus, and posterior cingulate.
CONCLUSION
Lower testosterone levels were correlated with lower connectivity of the LPhG. Weaknesses of this study include a retrospective design based on self-report of mTBI and the lack of a control group without TBI. Without a control group or pre-injury testosterone measures, we were not able to attribute the rate of low testosterone in our participants to TBI per se. Also testosterone levels were checked only once. The high rate of low testosterone level that we found suggests there may be an association between low testosterone level and greater post-traumatic stress disorder symptoms following deployment, but the causality of the relationships between TBI and deployment stress, testosterone level, behavioral symptomatology, and LPhG connectivity remains to be determined. Our study on men with persistent symptoms postdeployment and post-mTBI may help us understand the role of low testosterone and sleep quality in persistent symptoms and may be important in developing therapeutic interventions. Our results highlight the role of the LPhG, as we found that whole-brain connectivity in that region was positively associated with testosterone level, with only a limited portion of that effect attributable to sleep quality.
Topics: Adult; Brain; Brain Concussion; Humans; Magnetic Resonance Imaging; Male; Parahippocampal Gyrus; Retrospective Studies; Testosterone
PubMed: 32776114
DOI: 10.1093/milmed/usaa142 -
ENeuro 2021We propose a model of the main rhythms in the hippocampal CA1 field: theta rhythm; slow, middle, and fast gamma rhythms; and ripple oscillations. We have based this on...
We propose a model of the main rhythms in the hippocampal CA1 field: theta rhythm; slow, middle, and fast gamma rhythms; and ripple oscillations. We have based this on data obtained from animals behaving freely. We have considered the modes of neuronal discharges and the occurrence of local field potential oscillations in the theta and non-theta states at different inputs from the CA3 field, the medial entorhinal cortex, and the medial septum. In our work, we tried to reproduce the main experimental phenomena about rhythms in the CA1 field: the coupling of neurons to the phase of rhythms, cross-rhythm phase-phase coupling, and phase-amplitude coupling. Using computational experiments, we have proved the hypothesis that the descending phase of the theta rhythm in the CA1 field is formed by the input from the CA3 field via the Shaffer collaterals, and the ascending phase of the theta rhythm is formed by the IPSPs from CCK basket cells. The slow gamma rhythm is coupled to the descending phase of the theta rhythm, since it also depends on the arrival of the signal via the Shaffer collaterals. The middle gamma rhythm is formed by the EPSPs of the principal neurons of the third layer of the entorhinal cortex, corresponds to experimental data. We were able to unite in a single mathematical model several theoretical ideas about the mechanisms of rhythmic processes in the CA1 field of the hippocampus.
Topics: Animals; CA1 Region, Hippocampal; Entorhinal Cortex; Gamma Rhythm; Hippocampus; Theta Rhythm
PubMed: 34670820
DOI: 10.1523/ENEURO.0192-21.2021 -
Nature Neuroscience Feb 2020The entorhinal cortex contains neurons that represent self-location, including grid cells that fire in periodic locations and velocity signals that encode running speed...
The entorhinal cortex contains neurons that represent self-location, including grid cells that fire in periodic locations and velocity signals that encode running speed and head direction. Although the size and shape of the environment influence grid patterns, whether entorhinal velocity signals are equally influenced or provide a universal metric for self-motion across environments remains unknown. Here we report that speed cells rescale after changes to the size and shape of the environment. Moreover, head direction cells reorganize in an experience-dependent manner to align with the axis of environmental change. A knockout mouse model allows dissociation of the coordination between cell types, with grid and speed cells, but not head direction cells, responding in concert to environmental change. These results point to malleability in the coding features of multiple entorhinal cell types and have implications for which cell types contribute to the velocity signal used by computational models of grid cells.
Topics: Animals; Computer Simulation; Entorhinal Cortex; Grid Cells; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Neurological; Space Perception; Spatial Navigation
PubMed: 31932764
DOI: 10.1038/s41593-019-0562-5