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NeuroImage Apr 2024In Alzheimer's disease (AD), early diagnosis facilitates treatment options and leads to beneficial outcomes for patients, their carers and the healthcare system. The...
INTRODUCTION
In Alzheimer's disease (AD), early diagnosis facilitates treatment options and leads to beneficial outcomes for patients, their carers and the healthcare system. The neuropsychological battery of the Uniform Data Set (UDSNB3.0) assesses cognition in ageing and dementia, by measuring scores across different cognitive domains such as attention, memory, processing speed, executive function and language. However, its neuroanatomical correlates have not been investigated using 7 Tesla MRI (7T MRI).
METHODS
We used 7T MRI to investigate the correlations between hippocampal subfield volumes and the UDSNB3.0 in 24 individuals with Amyloidβ-status AD and 18 age-matched controls, with respective age ranges of 60 (42-76) and 62 (52-79) years. AD participants with a Medial Temporal Atrophy scale of higher than 2 on 3T MRI were excluded from the study.
RESULTS
A significant difference in the entire hippocampal volume was observed in the AD group compared to healthy controls (HC), primarily influenced by CA1, the largest hippocampal subfield. Notably, no significant difference in whole brain volume between the groups implied that hippocampal volume loss was not merely reflective of overall brain atrophy. UDSNB3.0 cognitive scores showed significant differences between AD and HC, particularly in Memory, Language, and Visuospatial domains. The volume of the Dentate Gyrus (DG) showed a significant association with the Memory and Executive domain scores in AD patients as assessed by the UDSNB3.0.. The data also suggested a non-significant trend for CA1 volume associated with UDSNB3.0 Memory, Executive, and Language domain scores in AD. In a reassessment focusing on hippocampal subfields and MoCA memory subdomains in AD, associations were observed between the DG and Cued, Uncued, and Recognition Memory subscores, whereas CA1 and Tail showed associations only with Cued memory.
DISCUSSION
This study reveals differences in the hippocampal volumes measured using 7T MRI, between individuals with early symptomatic AD compared with healthy controls. This highlights the potential of 7T MRI as a valuable tool for early AD diagnosis and the real-time monitoring of AD progression and treatment efficacy.
CLINICALTRIALS
GOV: ID NCT04992975 (Clinicaltrial.gov 2023).
Topics: Humans; Alzheimer Disease; Male; Magnetic Resonance Imaging; Female; Aged; Dentate Gyrus; Middle Aged; CA1 Region, Hippocampal; Memory Disorders; Adult; Amyloid beta-Peptides
PubMed: 38614372
DOI: 10.1016/j.neuroimage.2024.120607 -
Cell Reports Jan 2022During exploration, animals form an internal map of an environment by combining information about landmarks and the animal's movement, a process that depends on the...
During exploration, animals form an internal map of an environment by combining information about landmarks and the animal's movement, a process that depends on the hippocampus. The dentate gyrus (DG) is the first stage of the hippocampal circuit where self-motion ("where") and sensory cue information ("what") are integrated, but it remains unknown how DG neurons encode this information during cognitive map formation. Using two-photon calcium imaging in mice running on a treadmill along with online cue manipulation, we identify robust sensory cue responses in DG granule cells. Cue cell responses are stable, stimulus-specific, and accompanied by inhibition of nearby neurons. This demonstrates the existence of "cue cells" in addition to better characterized "place cells" in the DG. We hypothesize that the DG supports parallel channels of spatial and non-spatial information that contribute distinctly to downstream computations and affect roles of the DG in spatial navigation and episodic memory.
Topics: Animals; Cues; Dentate Gyrus; Mice; Neurons; Spatial Learning; Spatial Navigation
PubMed: 35045280
DOI: 10.1016/j.celrep.2021.110257 -
ELife Jul 2023The theta rhythm, a quasi-periodic 4-10 Hz oscillation, is observed during memory processing in the hippocampus, with different phases of theta hypothesized to separate...
The theta rhythm, a quasi-periodic 4-10 Hz oscillation, is observed during memory processing in the hippocampus, with different phases of theta hypothesized to separate independent streams of information related to the encoding and recall of memories. At the cellular level, the discovery of hippocampal memory cells (engram neurons), as well as the modulation of memory recall through optogenetic activation of these cells, has provided evidence that certain memories are stored, in part, in a sparse ensemble of neurons in the hippocampus. In previous research, however, engram reactivation has been carried out using open-loop stimulation at fixed frequencies; the relationship between engram neuron reactivation and ongoing network oscillations has not been taken into consideration. To address this concern, we implemented a closed-loop reactivation of engram neurons that enabled phase-specific stimulation relative to theta oscillations in the local field potential in CA1. Using this real-time approach, we tested the impact of activating dentate gyrus engram neurons during the peak (encoding phase) and trough (recall phase) of theta oscillations. Consistent with previously hypothesized functions of theta oscillations in memory function, we show that stimulating dentate gyrus engram neurons at the trough of theta is more effective in eliciting behavioral recall than either fixed-frequency stimulation or stimulation at the peak of theta. Moreover, phase-specific trough stimulation is accompanied by an increase in the coupling between gamma and theta oscillations in CA1 hippocampus. Our results provide a causal link between phase-specific activation of engram cells and the behavioral expression of memory.
Topics: Mice; Animals; Mice, Inbred C57BL; Neurons; Hippocampus; Memory; Theta Rhythm; Dentate Gyrus
PubMed: 37401757
DOI: 10.7554/eLife.82697 -
Neuroscience Jul 2023Neurogenesis occurs throughout adulthood within the dentate gyrus, and evidence indicates that these new neurons play a critical role in both spatial and social memory....
Neurogenesis occurs throughout adulthood within the dentate gyrus, and evidence indicates that these new neurons play a critical role in both spatial and social memory. However, a vast majority of past research on adult neurogenesis has involved experiments with captive mice and rats, making the generalizability of results to natural settings questionable. We assessed the connection between adult neurogenesis and memory by measuring the home range size of wild-caught, free-ranging meadow voles (Microtus pennsylvanicus). Adult male voles (n = 18) were captured, fitted with radio collars, and released back into their natural habitat, where each vole's home range was assessed using 40 radio-telemetry fixes over the course of 5 evenings. Voles were then recaptured, and brain tissue was collected. Cellular markers of cell proliferation (pHisH3, Ki67), neurogenesis (DCX), and pyknosis were labeled on histological sections and then quantified using either fluorescent or light microscopy. Voles with larger home ranges had significantly higher pHisH3+ cell densities within the granule cell layer and subgranular zone (GCL + SGZ) of the dentate gyrus and higher Ki67+ cell densities in the dorsal GCL + SGZ. Voles with larger ranges also had significantly higher pyknotic cell densities in the entire GCL + SGZ and in the dorsal GCL + SGZ. These results support the hypothesis that cell proliferation and cell death within the hippocampus are involved with spatial memory formation. However, a marker of neurogenesis (DCX+) was not correlated with range size, suggesting that there may be selective cellular turnover in the dentate gyrus when a vole is ranging through its environment.
Topics: Animals; Male; Rats; Mice; Dentate Gyrus; Homing Behavior; Ki-67 Antigen; Cell Proliferation; Cell Death; Neurogenesis; Arvicolinae
PubMed: 37245693
DOI: 10.1016/j.neuroscience.2023.05.018 -
Nature Communications Oct 2022The dentate gyrus (DG) output plays a key role in the emergence of spatial and contextual map representation within the hippocampus during learning. Differences in...
The dentate gyrus (DG) output plays a key role in the emergence of spatial and contextual map representation within the hippocampus during learning. Differences in neuronal network activity have been observed between left and right CA1-3 areas, implying lateralization in spatial coding properties. Whether bilateral differences of DG granule cell (GC) assemblies encoding spatial and contextual information exist remains largely unexplored. Here, we employed two-photon calcium imaging of the left or the right DG to record the activity of GC populations over five consecutive days in head-fixed mice navigating through familiar and novel virtual environments. Imaging revealed similar mean GC activity on both sides. However, spatial tuning, context-selectivity and run-to-run place field reliability was markedly higher for DG place cells in the left than the right hemisphere. Moreover, the proportion of GCs reconfiguring their place fields between contexts was greater in the left DG. Thus, our data suggest that contextual information is differentially processed by GC populations depending on the hemisphere, with higher context discrimination in the left but a bias towards generalization in the right DG.
Topics: Mice; Animals; Dentate Gyrus; Calcium; Reproducibility of Results; Hippocampus; Place Cells
PubMed: 36266288
DOI: 10.1038/s41467-022-34039-5 -
ELife Mar 2021The hippocampal dentate gyrus is an important relay conveying sensory information from the entorhinal cortex to the hippocampus proper. During exploration, the dentate...
The hippocampal dentate gyrus is an important relay conveying sensory information from the entorhinal cortex to the hippocampus proper. During exploration, the dentate gyrus has been proposed to act as a pattern separator. However, the dentate gyrus also shows structured activity during immobility and sleep. The properties of these activity patterns at cellular resolution, and their role in hippocampal-dependent memory processes have remained unclear. Using dual-color in vivo two-photon Ca imaging, we show that in immobile mice dentate granule cells generate sparse, synchronized activity patterns associated with entorhinal cortex activation. These population events are structured and modified by changes in the environment; and they incorporate place- and speed cells. Importantly, they are more similar than expected by chance to population patterns evoked during self-motion. Using optogenetic inhibition, we show that granule cell activity is not only required during exploration, but also during immobility in order to form dentate gyrus-dependent spatial memories.
Topics: Animals; Dentate Gyrus; Female; Immobilization; Male; Mice; Neuroimaging; Neurons; Optogenetics
PubMed: 33709911
DOI: 10.7554/eLife.65786 -
Cell Reports Aug 2021Mouse hippocampus CA1 place-cell discharge typically encodes current location, but during slow gamma dominance (SG), when SG oscillations (30-50 Hz) dominate...
Mouse hippocampus CA1 place-cell discharge typically encodes current location, but during slow gamma dominance (SG), when SG oscillations (30-50 Hz) dominate mid-frequency gamma oscillations (70-90 Hz) in CA1 local field potentials, CA1 discharge switches to represent distant recollected locations. We report that dentate spike type 2 (DS) events initiated by medial entorhinal cortex II (MECII)→ dentate gyrus (DG) inputs promote SG and change excitation-inhibition coordinated discharge in DG, CA3, and CA1, whereas type 1 (DS) events initiated by lateral entorhinal cortex II (LECII)→DG inputs do not. Just before SG, LECII-originating SG oscillations in DG and CA3-originating SG oscillations in CA1 phase and frequency synchronize at the DS peak when discharge within DG and CA3 increases to promote excitation-inhibition cofiring within and across the DG→CA3→CA1 pathway. This optimizes discharge for the 5-10 ms DG-to-CA1 neuro-transmission that SG initiates. DS properties identify extrahippocampal control of SG and a cortico-hippocampal mechanism that switches between memory-related modes of information processing.
Topics: Action Potentials; Animals; Behavior, Animal; Biomarkers; CA1 Region, Hippocampal; CA3 Region, Hippocampal; Dentate Gyrus; Gamma Rhythm; Hippocampus; Memory; Mice, Inbred C57BL; Perforant Pathway; Signal Transduction; Mice
PubMed: 34348165
DOI: 10.1016/j.celrep.2021.109497 -
The Journal of Neuroscience : the... Feb 2021Mossy cells (MCs) of the dentate gyrus (DG) are a major group of excitatory hilar neurons that are important for regulating activity of dentate granule cells. MCs are...
Mossy cells (MCs) of the dentate gyrus (DG) are a major group of excitatory hilar neurons that are important for regulating activity of dentate granule cells. MCs are particularly intriguing because of their extensive longitudinal connections within the DG. It has generally been assumed that MCs in the dorsal and ventral DG have similar patterns of termination in the inner one-third of the dentate molecular layer. Here, we demonstrate that axonal projections of MCs in these two regions are considerably different. MCs in dorsal and ventral regions were labeled selectively with Cre-dependent eYFP or mCherry, using two transgenic mouse lines (including both sexes) that express Cre-recombinase in MCs. At four to six weeks following unilateral labeling of MCs in the ventral DG, a dense band of fibers was present in the inner one-fourth of the molecular layer and extended bilaterally throughout the rostral-caudal extent of the DG, replicating the expected distribution of MC axons. In contrast, following labeling of MCs in the dorsal DG, the projections were more diffusely distributed. At the level of transfection, fibers were present in the inner molecular layer, but they progressively expanded into the middle molecular layer and, most ventrally, formed a distinct band in this region. Optical stimulation of these caudal fibers expressing ChR2 demonstrated robust EPSCs in ipsilateral granule cells and enhanced the effects of perforant path stimulation in the ventral DG. These findings suggest that MCs in the dorsal and ventral DG differ in the distribution of their axonal projections and possibly their function. Mossy cells (MCs), a major cell type in the hilus of the dentate gyrus (DG), are unique in providing extensive longitudinal and commissural projections throughout the DG. Although it has been assumed that all MCs have similar patterns of termination in the inner molecular layer of the DG, we discovered that the axonal projections of dorsal and ventral MCs differ. While ventral MC projections exhibit the classical pattern, with dense innervation in the inner molecular layer, dorsal MCs have a more diffuse distribution and expand into the middle molecular layer where they overlap and interact with innervation from the perforant path. These distinct locations and patterns of axonal projections suggest that dorsal and ventral MCs may have different functional roles.
Topics: Animals; Axons; Dentate Gyrus; Excitatory Postsynaptic Potentials; Female; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mossy Fibers, Hippocampal; Optogenetics
PubMed: 33268544
DOI: 10.1523/JNEUROSCI.2455-20.2020 -
International Journal of Molecular... Jun 2022As aging and cognitive decline progresses, the impact of a sedentary lifestyle on the appearance of environment-dependent cellular morphologies in the brain becomes more... (Review)
Review
As aging and cognitive decline progresses, the impact of a sedentary lifestyle on the appearance of environment-dependent cellular morphologies in the brain becomes more apparent. Sedentary living is also associated with poor oral health, which is known to correlate with the rate of cognitive decline. Here, we will review the evidence for the interplay between mastication and environmental enrichment and assess the impact of each on the structure of the brain. In previous studies, we explored the relationship between behavior and the morphological features of dentate gyrus glial fibrillary acidic protein (GFAP)-positive astrocytes during aging in contrasting environments and in the context of induced masticatory dysfunction. Hierarchical cluster and discriminant analysis of GFAP-positive astrocytes from the dentate gyrus molecular layer revealed that the proportion of AST1 (astrocyte arbors with greater complexity phenotype) and AST2 (lower complexity) are differentially affected by environment, aging and masticatory dysfunction, but the relationship is not straightforward. Here we re-evaluated our previous reconstructions by comparing dorsal and ventral astrocyte morphologies in the dentate gyrus, and we found that morphological complexity was the variable that contributed most to cluster formation across the experimental groups. In general, reducing masticatory activity increases astrocyte morphological complexity, and the effect is most marked in the ventral dentate gyrus, whereas the effect of environment was more marked in the dorsal dentate gyrus. All morphotypes retained their basic structural organization in intact tissue, suggesting that they are subtypes with a non-proliferative astrocyte profile. In summary, the increased complexity of astrocytes in situations where neuronal loss and behavioral deficits are present is counterintuitive, but highlights the need to better understand the role of the astrocyte in these conditions.
Topics: Aging; Astrocytes; Cognitive Dysfunction; Dentate Gyrus; Glial Fibrillary Acidic Protein; Hippocampus; Humans; Sedentary Behavior
PubMed: 35683023
DOI: 10.3390/ijms23116342 -
Current Biology : CB Mar 2022The hippocampus is involved in the formation of memories that require associations among stimuli to construct representations of space and the items and events within...
The hippocampus is involved in the formation of memories that require associations among stimuli to construct representations of space and the items and events within that space. Neurons in the dentate gyrus (DG), an initial input region of the hippocampus, have robust spatial tuning, but it is unclear how nonspatial information may be integrated with spatial activity in this region. We recorded from the DG of 21 adult mice as they foraged for food in an environment that contained discrete objects. We found DG cells with multiple firing fields at a fixed distance and direction from objects (landmark vector cells) and cells that exhibited localized changes in spatial firing when objects in the environment were manipulated. By classifying recorded DG cells into putative dentate granule cells and mossy cells, we examined how the addition or displacement of objects affected the spatial firing of these DG cell types. Object-related activity was detected in a significant proportion of mossy cells. Although few granule cells with responses to object manipulations were recorded, likely because of the sparse nature of granule cell firing, there was generally no significant difference in the proportion of granule cells and mossy cells with object responses. When mice explored a second environment with the same objects, DG spatial maps completely reorganized, and a different subset of cells responded to object manipulations. Together, these data reveal the capacity of DG cells to detect small changes in the environment while preserving a stable spatial representation of the overall context.
Topics: Animals; Dentate Gyrus; Hippocampus; Mice; Neurons
PubMed: 35108522
DOI: 10.1016/j.cub.2022.01.023