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Cell Reports Apr 2023Hippocampal place cells exhibit spatially modulated firing, or place fields, which can remap to encode changes in the environment or other variables. Unique among...
Hippocampal place cells exhibit spatially modulated firing, or place fields, which can remap to encode changes in the environment or other variables. Unique among hippocampal subregions, the dentate gyrus (DG) has two excitatory populations of place cells, granule cells and mossy cells, which are among the least and most active spatially modulated cells in the hippocampus, respectively. Previous studies of remapping in the DG have drawn different conclusions about whether granule cells exhibit global remapping and contribute to the encoding of context specificity. By recording granule cells and mossy cells as mice foraged in different environments, we found that by most measures, both granule cells and mossy cells remapped robustly but through different mechanisms that are consistent with firing properties of each cell type. Our results resolve the ambiguity surrounding remapping in the DG and suggest that most spatially modulated granule cells contribute to orthogonal representations of distinct spatial contexts.
Topics: Mice; Animals; Mossy Fibers, Hippocampal; Dentate Gyrus; Hippocampus; Place Cells
PubMed: 37043350
DOI: 10.1016/j.celrep.2023.112334 -
Philosophical Transactions of the Royal... Jul 2024Commentaries about long-term potentiation (LTP) generally proceed with an implicit assumption that largely the same physiological effect is sampled across different... (Review)
Review
Commentaries about long-term potentiation (LTP) generally proceed with an implicit assumption that largely the same physiological effect is sampled across different experiments. However, this is clearly not the case. We illustrate the point by comparing LTP in the CA3 projections to CA1 with the different forms of potentiation in the dentate gyrus. These studies lead to the hypothesis that specialized properties of CA1-LTP are adaptations for encoding unsupervised learning and episodic memory, whereas the dentate gyrus variants subserve learning that requires multiple trials and separation of overlapping bodies of information. Recent work has added sex as a second and somewhat surprising dimension along which LTP is also differentiated. Triggering events for CA1-LTP differ between the sexes and the adult induction threshold is significantly higher in females; these findings help explain why males have an advantage in spatial learning. Remarkably, the converse is true before puberty: Females have the lower LTP threshold and are better at spatial memory problems. A mechanism has been identified for the loss-of-function in females but not for the gain-of-function in males. We propose that the many and disparate demands of natural environments, with different processing requirements across ages and between sexes, led to the emergence of multiple LTPs. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.
Topics: Animals; Female; Humans; Male; CA1 Region, Hippocampal; CA3 Region, Hippocampal; Dentate Gyrus; Long-Term Potentiation; Memory; Sex Factors
PubMed: 38853551
DOI: 10.1098/rstb.2023.0223 -
The Journal of Neuroscience : the... Nov 2019The complementary processes of pattern completion and pattern separation are thought to be essential for successful memory storage and recall. The dentate gyrus (DG) and...
The complementary processes of pattern completion and pattern separation are thought to be essential for successful memory storage and recall. The dentate gyrus (DG) and proximal CA3 (pCA3) regions have been implicated in pattern separation, in part through extracellular recording studies of these areas. However, the DG contains two types of excitatory cells: granule cells of the granule layer and mossy cells of the hilus. Little is known about the firing properties of mossy cells in freely moving animals, and it is unclear how their activity may contribute to the mnemonic functions of the hippocampus. Furthermore, tetrodes in the dentate granule layer and pCA3 pyramidal layer can also record mossy cells, thus introducing ambiguity into the identification of cell types recorded. Using a random forests classifier, we classified cells recorded in DG (Neunuebel and Knierim, 2014) and pCA3 (Lee et al., 2015) of 16 male rats and separately examined the responses of granule cells, mossy cells, and pCA3 pyramidal cells in a local/global cue mismatch task. All three cell types displayed low correlations between the population representations of the rat's position in the standard and cue-mismatch sessions. These results suggest that all three excitatory cell types within the DG/pCA3 circuit may act as a single functional unit to support pattern separation. Mossy cells in the dentate gyrus (DG) are an integral component of the DG/pCA3 circuit. While the role of granule cells in the circuitry and computations of the hippocampus has been a focus of study for decades, the contributions of mossy cells have been largely overlooked. Recent studies have revealed the spatial firing properties of mossy cells in awake behaving animals, but how the activity of these highly active cells contributes to the mnemonic functions of the DG is uncertain. We separately analyzed mossy cells, granule cells, and pCA3 cells and found that all three cell types respond similarly to a local/global cue mismatch, suggesting that they form a single functional unit supporting pattern separation.
Topics: Animals; CA3 Region, Hippocampal; Dentate Gyrus; Male; Mossy Fibers, Hippocampal; Pyramidal Cells; Random Allocation; Rats; Rats, Long-Evans
PubMed: 31641051
DOI: 10.1523/JNEUROSCI.0940-19.2019 -
Experimental Neurology Dec 2022Memory extinction and renewal are major factors that limits the efficacy of exposure therapy. The dorsal dentate gyrus (dDG) plays a crucial role in spatial memory, and...
Memory extinction and renewal are major factors that limits the efficacy of exposure therapy. The dorsal dentate gyrus (dDG) plays a crucial role in spatial memory, and epigenetic modifications in the dDG play an important role in fear memory renewal. However, whether dDG activity regulates fear memory extinction and renewal remains unclear. In this study, we showed that an extinction procedure that prevents fear memory renewal (extinction within the reconsolidation window) leads to increased c-fos expression in the dDG. Chemicogenetic activation of dDG excitatory neurons during extinction training elevated fear memory extinction and prevented renewal, whereas inhibition of dDG excitatory neurons inhibited fear memory extinction. We also demonstrated that inhibiting fear engram cells (neurons active during fear acquisition) during extinction training inhibits fear memory extinction. Therefore, dDG activity during fear extinction plays an important role in fear memory extinction and renewal.
Topics: Dentate Gyrus; Extinction, Psychological; Fear; Memory; Neurons
PubMed: 36089058
DOI: 10.1016/j.expneurol.2022.114224 -
Cells Oct 2022Hippocampus-related cognitive deficits in working and verbal memory are frequent in schizophrenia, and hippocampal volume loss, particularly in the cornu ammonis (CA)...
Hippocampus-related cognitive deficits in working and verbal memory are frequent in schizophrenia, and hippocampal volume loss, particularly in the cornu ammonis (CA) subregions, was shown by magnetic resonance imaging studies. However, the underlying cellular alterations remain elusive. By using unbiased design-based stereology, we reported a reduction in oligodendrocyte number in CA4 in schizophrenia and of granular neurons in the dentate gyrus (DG). Here, we aimed to replicate these findings in an independent sample. We used a stereological approach to investigate the numbers and densities of neurons, oligodendrocytes, and astrocytes in CA4 and of granular neurons in the DG of left and right hemispheres in 11 brains from men with schizophrenia and 11 brains from age- and sex-matched healthy controls. In schizophrenia, a decreased number and density of oligodendrocytes was detected in the left and right CA4, whereas mean volumes of CA4 and the DG and the numbers and density of neurons, astrocytes, and granular neurons were not different in patients and controls, even after adjustment of variables because of positive correlations with postmortem interval and age. Our results replicate the previously described decrease in oligodendrocytes bilaterally in CA4 in schizophrenia and point to a deficit in oligodendrocyte maturation or a loss of mature oligodendrocytes. These changes result in impaired myelination and neuronal decoupling, both of which are linked to altered functional connectivity and subsequent cognitive dysfunction in schizophrenia.
Topics: Humans; Astrocytes; Neurons; Oligodendroglia; Schizophrenia; Dentate Gyrus
PubMed: 36291109
DOI: 10.3390/cells11203242 -
Molecular and Cellular Biochemistry Mar 2022Neural stem cells (NSCs) are responsible for maintaining the nervous system and repairing damages. Utility of NSCs could provide a novel solution to treat...
Neural stem cells (NSCs) are responsible for maintaining the nervous system and repairing damages. Utility of NSCs could provide a novel solution to treat neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. However, we have no idea the exact phenotypic and functional characteristics of NSCs and their precise role in geriatric neurological and aging-related diseases. In this study, C57BL/6 mice were used to isolate and identify CD133GFAPCD117Sca1 cells in the hippocampal dentate gyrus region of the mouse brain as a novel neural stem cell population, in terms of cell phenotype, self-renewal capacity, and differentiation capability. With increasing in aging, the function, total cell number, and self-renewal capacity of CD133GFAPCD117Sca1 cells decreased, and the activity of differentiated cells also decreased. Meanwhile, we investigated differentially expressed genes in order to further classify their gene signature and pathways associated with their functional changes. Taken together, these findings demonstrate the existence of a rare population of NSCs in the hippocampal dentate gyrus region. Identification of specific NSCs offers ample opportunities for alleviating neural diseases.
Topics: AC133 Antigen; Animals; Cell Differentiation; Dentate Gyrus; Glial Fibrillary Acidic Protein; Mice; Neural Stem Cells; Proto-Oncogene Proteins c-kit
PubMed: 35079926
DOI: 10.1007/s11010-021-04339-3 -
Neurobiology of Disease Aug 2023Embryonic and early postnatal deletion of the gene phosphatase and tensin homolog (PTEN) results in neuronal hypertrophy, formation of aberrant neural networks and...
Vector-mediated PTEN deletion in the adult dentate gyrus initiates new growth of granule cell bodies and dendrites and expansion of mossy fiber terminal fields that continues for months.
Embryonic and early postnatal deletion of the gene phosphatase and tensin homolog (PTEN) results in neuronal hypertrophy, formation of aberrant neural networks and spontaneous seizures. Our previous studies document that deletion of PTEN in mature neurons also causes growth of cortical neuron cell bodies and dendrites, but it is unknown how this growth alters connectivity in mature circuits. Here, we explore consequences of deleting PTEN in a focal area of the dentate gyrus in adult male and female mice. PTEN deletion was accomplished by injecting AAV-Cre unilaterally into the dentate gyrus of double transgenic mice with lox-P sites flanking exon 5 of the PTEN gene and stop/flox tdTomato in the Rosa locus (PTEN/Rosa). Focal deletion led to progressive increases in the size of the dentate gyrus at the injection site, enlargement of granule cell bodies, and increases in dendritic length and caliber. Quantitative analysis of dendrites by Golgi staining revealed dramatic increases in spine numbers throughout the proximo-distal extent of the dendritic tree, suggesting that dendritic growth is sufficient to induce new synapse formation by input neurons with intact PTEN expression. Tract tracing of input pathways to the dentate gyrus from the ipsilateral entorhinal cortex and commissural/associational system revealed that laminar specificity of termination of inputs is maintained. Mossy fiber axons from PTEN-deleted granule cells expanded their terminal field in CA3 where PTEN expression was intact and supra-granular mossy fibers developed in some mice. These findings document that persistent activation of mTOR via PTEN deletion in fully mature neurons re-initiates a state of robust cell-intrinsic growth, upending connectional homeostasis in fully mature hippocampal circuits.
Topics: Mice; Animals; Mossy Fibers, Hippocampal; Cell Body; Hippocampus; Mice, Transgenic; Dendrites; Dentate Gyrus
PubMed: 37290578
DOI: 10.1016/j.nbd.2023.106190 -
Molecular Neurobiology Apr 2020On the basis of the evidence that rapid intracellular Zn dysregulation by amyloid β (Aβ) in the normal hippocampus transiently induces cognitive decline, here we...
On the basis of the evidence that rapid intracellular Zn dysregulation by amyloid β (Aβ) in the normal hippocampus transiently induces cognitive decline, here we report preferential neurodegeneration in the dentate gyrus by Aβ-induced intracellular Zn dysregulation and its defense strategy. Neurodegeneration was preferentially observed in the dentate granule cell layer in the hippocampus after a single Aβ injection into the lateral ventricle but not in the CA1 and CA3 pyramidal cell layers, while intracellular Zn dysregulation was extensively observed in the hippocampus in addition to the dentate gyrus. Neurodegeneration in the dentate granule cell layer was rescued after co-injection of extracellular and intracellular Zn chelators, i.e., CaEDTA and ZnAF-2DA, respectively. Aβ-induced cognitive impairment was also rescued by co-injection of CaEDTA and ZnAF-2DA. Pretreatment with dexamethasone, an inducer of metalothioneins, Zn-binding proteins rescued neurodegeneration in the dentate granule cell layer and cognitive impairment via blocking the intracellular Zn dysregulation induced by Aβ. The present study indicates that intracellular Zn dysregulation induced by Aβ preferentially causes neurodegeneration in the dentate gyrus, resulting in hippocampus-dependent cognitive decline. It is likely that controlling intracellular Zn dysregulation, which is induced by the rapid uptake of Zn-Aβ complexes, is a defense strategy for Alzheimer's disease pathogenesis.
Topics: Amyloid beta-Peptides; Animals; Cognitive Dysfunction; Dentate Gyrus; Dexamethasone; Humans; Injections, Intraventricular; Intracellular Space; Male; Mice; Nerve Degeneration; Zinc
PubMed: 31865526
DOI: 10.1007/s12035-019-01853-w -
Molecular Neurobiology Sep 2022Neuroadaptations in neurocircuitry of reward memories govern the persistent and compulsive behaviors. The study of the role of hippocampus in processing of reward memory...
Neuroadaptations in neurocircuitry of reward memories govern the persistent and compulsive behaviors. The study of the role of hippocampus in processing of reward memory and its retrieval is critical to our understanding of addiction and relapse. The aim of this study is to probe the epigenetic mechanisms underlying reward memory in the frame of dentate gyrus (DG). To that end, the rats conditioned to the food baited arm of a Y-maze and subjected to memory probe trial. The hippocampus of conditioned rats displayed higher mRNA levels of Ten-eleven translocase 1 (Tet1) and brain-derived neurotrophic factor (Bdnf) after memory probe trial. The DNA hydroxymethylation and TET1 occupancy at the Bdnf promoters showed concomitant increase. Stereotactic administration of Tet1 siRNA in the DG before and after conditioning inhibited reward memory formation and recall, respectively. Administration of Tet1 siRNA impaired the reward memory recall that was reinstated following administration of exogenous BDNF peptide or after wash-off period of 8 days. Infusion of a MEK/ERK inhibitor, U0126 in the DG inhibited reward memory retrieval. The TET1-induced DNA demethylation at the Bdnf promoters raised BDNF levels in the hippocampus, thereby setting the stage for reward memory retrieval. The study underscores the causative role of TET1 in the DG for reward memory formation and recall.
Topics: Animals; Brain-Derived Neurotrophic Factor; DNA Demethylation; Dentate Gyrus; Dioxygenases; Hippocampus; RNA, Small Interfering; Rats; Reward
PubMed: 35705787
DOI: 10.1007/s12035-022-02917-0 -
Neurobiology of Disease Oct 2023Interictal spikes (IIS) are a common type of abnormal electrical activity in Alzheimer's disease (AD) and preclinical models. The brain regions where IIS are largest are...
Interictal spikes (IIS) are a common type of abnormal electrical activity in Alzheimer's disease (AD) and preclinical models. The brain regions where IIS are largest are not known but are important because such data would suggest sites that contribute to IIS generation. Because hippocampus and cortex exhibit altered excitability in AD models, we asked which areas dominate the activity during IIS along the cortical-CA1-dentate gyrus (DG) dorso-ventral axis. Because medial septal (MS) cholinergic neurons are overactive when IIS typically occur, we also tested the novel hypothesis that silencing the MS cholinergic neurons selectively would reduce IIS. We used mice that simulate aspects of AD: Tg2576 mice, presenilin 2 (PS2) knockout mice and Ts65Dn mice. To selectively silence MS cholinergic neurons, Tg2576 mice were bred with choline-acetyltransferase (ChAT)-Cre mice and offspring were injected in the MS with AAV encoding inhibitory designer receptors exclusively activated by designer drugs (DREADDs). We recorded local field potentials along the cortical-CA1-DG axis using silicon probes during wakefulness, slow-wave sleep (SWS) and rapid eye movement (REM) sleep. We detected IIS in all transgenic or knockout mice but not age-matched controls. IIS were detectable throughout the cortical-CA1-DG axis and occurred primarily during REM sleep. In all 3 mouse lines, IIS amplitudes were significantly greater in the DG granule cell layer vs. CA1 pyramidal layer or overlying cortex. Current source density analysis showed robust and early current sources in the DG, and additional sources in CA1 and the cortex also. Selective chemogenetic silencing of MS cholinergic neurons significantly reduced IIS rate during REM sleep without affecting the overall duration, number of REM bouts, latency to REM sleep, or theta power during REM. Notably, two control interventions showed no effects. Consistent maximal amplitude and strong current sources of IIS in the DG suggest that the DG is remarkably active during IIS. In addition, selectively reducing MS cholinergic tone, at times when MS is hyperactive, could be a new strategy to reduce IIS in AD.
Topics: Mice; Animals; Alzheimer Disease; Cholinergic Neurons; Dentate Gyrus; Cholinergic Agents; Mice, Knockout
PubMed: 37714307
DOI: 10.1016/j.nbd.2023.106294