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Seizure Apr 2015Granule cells pathology in dentate gyrus, have received considerable attention in terms of understanding the pathophysiology of temporal lobe epilepsy with hippocampal...
PURPOSE
Granule cells pathology in dentate gyrus, have received considerable attention in terms of understanding the pathophysiology of temporal lobe epilepsy with hippocampal sclerosis. The aim of this study was to determine the nestin (an intermediate filament protein expressed by newly formed cells), immunoreactivity (IR) in granular cells layers of hippocampal tissue extirpated during epilepsy surgical procedure, in patients with drug-resistant epilepsy.
METHODS
Hippocampal sections of 16 patients with hippocampal sclerosis and drug-resistant temporal lobe epilepsy were processed using immunoperoxidase with antibody to nestin. Archival material from 8 normal post-mortem hippocampus, were simultaneously processed. Reactive area for nestin-IR, the total number of positive nestin cells per field (20×), and the MGV (mean gray value) was determined by computerized image analysis (ImageJ), and compared between groups. Student's t test was used for statistical analysis.
RESULTS
Nestin-IR cells were found in granule cells layers of both controls and patients. Larger reactive somas (p < 0.01) were found in epileptic's sections but a significant reduction in the total number of nestin-IR cells per field and in the MGV was found in granular cells layers of patients with hippocampal sclerosis (p < 0.01).
CONCLUSION
Reduced expression of nestin-IR in granular cells layers of epileptic's dentate gyrus may reflect changes in dentate gyrus neuroplasticity associated to chronic temporal epilepsy with hippocampal sclerosis. Further studies are required to determine the clinical implications on memory an emotional alterations such as depression.
Topics: Adult; Dentate Gyrus; Diagnosis; Drug Resistant Epilepsy; Electroencephalography; Epilepsy, Temporal Lobe; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Nestin; Neuropsychological Tests; Sclerosis; Young Adult
PubMed: 25891932
DOI: 10.1016/j.seizure.2015.02.008 -
The Journal of Neuroscience : the... Sep 2020The hippocampus plays an essential role in learning. Each of the three major hippocampal subfields, dentate gyrus (DG), CA3, and CA1, has a unique function in memory...
The hippocampus plays an essential role in learning. Each of the three major hippocampal subfields, dentate gyrus (DG), CA3, and CA1, has a unique function in memory formation and consolidation, and also exhibit distinct local field potential (LFP) signatures during memory consolidation processes in non-rapid eye movement (NREM) sleep. The classic LFP events of the CA1 region, sharp-wave ripples (SWRs), are induced by CA3 activity and considered to be an electrophysiological biomarker for episodic memory. In LFP recordings along the dorsal CA1-DG axis from sleeping male mice, we detected and classified two types of LFP events in the DG: high-amplitude dentate spikes (DSs), and a novel event type whose current source density (CSD) signature resembled that seen during CA1 SWR, but which, most often, occurred independently of them. Because we hypothesize that this event type is similarly induced by CA3 activity, we refer to it as dentate sharp wave (DSW). We show that both DSWs and DSs differentially modulate the electrophysiological properties of SWR and multiunit activity (MUA). Following two hippocampus-dependent memory tasks, DSW occurrence rates, ripple frequencies, and ripple and sharp wave (SW) amplitudes were increased in both, while SWR occurrence rates in dorsal CA1 increased only after the spatial task. Our results suggest that DSWs, like SWRs, are induced by CA3 activity and that DSWs complement SWRs as a hippocampal LFP biomarker of memory consolidation. Awake experience is consolidated into long-term memories during sleep. Memory consolidation crucially depends on sharp-wave ripples (SWRs), which are local field potential (LFP) patterns in hippocampal CA1 that increase after learning. The dentate gyrus (DG) plays a central role in the process of memory formation, prompting us to cluster sharp waves (SWs) in the DG [dentate SWs (DSWs)] during sleep. We show that both DSW coupling to CA1 SWRs, and their occurrence rates, robustly increase after learning trials. Our results suggest that the DG is directly affected by memory consolidation processes. DSWs may thus complement SWRs as a sensitive electrophysiological biomarker of memory consolidation in mice.
Topics: Animals; Brain Waves; Dentate Gyrus; Male; Memory; Mice; Mice, Inbred C57BL; Sleep, REM; Wakefulness
PubMed: 32817247
DOI: 10.1523/JNEUROSCI.2275-19.2020 -
Frontiers in Neural Circuits 2013Over the past four decades, a "standard framework" has emerged to explain the neural mechanisms of episodic memory storage. This framework has been instrumental in... (Review)
Review
Over the past four decades, a "standard framework" has emerged to explain the neural mechanisms of episodic memory storage. This framework has been instrumental in driving hippocampal research forward and now dominates the design and interpretation of experimental and theoretical studies. It postulates that cortical inputs drive plasticity in the recurrent cornu ammonis 3 (CA3) synapses to rapidly imprint memories as attractor states in CA3. Here we review a range of experimental studies and argue that the evidence against the standard framework is mounting, notwithstanding the considerable evidence in its support. We propose CRISP as an alternative theory to the standard framework. CRISP is based on Context Reset by dentate gyrus (DG), Intrinsic Sequences in CA3, and Pattern completion in cornu ammonis 1 (CA1). Compared to previous models, CRISP uses a radically different mechanism for storing episodic memories in the hippocampus. Neural sequences are intrinsic to CA3, and inputs are mapped onto these intrinsic sequences through synaptic plasticity in the feedforward projections of the hippocampus. Hence, CRISP does not require plasticity in the recurrent CA3 synapses during the storage process. Like in other theories DG and CA1 play supporting roles, however, their function in CRISP have distinct implications. For instance, CA1 performs pattern completion in the absence of CA3 and DG contributes to episodic memory retrieval, increasing the speed, precision, and robustness of retrieval. We propose the conceptual theory, discuss its implications for experimental results and suggest testable predictions. It appears that CRISP not only accounts for those experimental results that are consistent with the standard framework, but also for results that are at odds with the standard framework. We therefore suggest that CRISP is a viable, and perhaps superior, theory for the hippocampal function in episodic memory.
Topics: Animals; Dentate Gyrus; Hippocampus; Humans; Memory, Episodic; Models, Neurological; Neuronal Plasticity
PubMed: 23653597
DOI: 10.3389/fncir.2013.00088 -
The Journal of Neuroscience : the... Jul 2018Sparse neural activity in the dentate gyrus is enforced by powerful networks of inhibitory GABAergic interneurons in combination with low intrinsic excitability of the...
Sparse neural activity in the dentate gyrus is enforced by powerful networks of inhibitory GABAergic interneurons in combination with low intrinsic excitability of the principal neurons, the dentate granule cells (GCs). Although the cellular and circuit properties that dictate synaptic inhibition are well studied, less is known about mechanisms that confer low GC intrinsic excitability. Here we demonstrate that intact G protein-mediated signaling contributes to the characteristic low resting membrane potential that differentiates mature dentate GCs from CA1 pyramidal cells and developing adult-born GCs. In mature GCs from male and female mice, intact G protein signaling robustly reduces intrinsic excitability, whereas deletion of G protein-activated inwardly rectifying potassium channel 2 (GIRK2) increases excitability and blocks the effects of G protein signaling on intrinsic properties. Similarly, pharmacological manipulation of GABA receptors (GABARs) or GIRK channels alters intrinsic excitability and GC spiking behavior. However, adult-born new GCs lack functional GIRK activity, with phasic and constitutive GABAR-mediated GIRK signaling appearing after several weeks of maturation. Phasic activation is interneuron specific, arising primarily from nNOS-expressing interneurons rather than parvalbumin- or somatostatin-expressing interneurons. Together, these results demonstrate that G protein signaling contributes to the intrinsic excitability that differentiates mature and developing dentate GCs and further suggest that late maturation of GIRK channel activity is poised to convert early developmental functions of GABA receptor signaling into GABAR-mediated inhibition. The dentate gyrus exhibits sparse neural activity that is essential for the computational function of pattern separation. Sparse activity is ascribed to strong local inhibitory circuits in combination with low intrinsic excitability of the principal neurons, the granule cells. Here we show that constitutive activity of G protein-coupled inwardly rectifying potassium channels (GIRKs) underlies to the hallmark low resting membrane potential and input resistance of mature dentate neurons. Adult-born neurons initially lack functional GIRK channels, with constitutive and phasic GABA receptor-mediated GIRK inhibition developing in tandem after several weeks of maturation. Our results reveal that GABA/GIRK activity is an important determinant of low excitability of mature dentate granule cells that may contribute to sparse DG activity .
Topics: Animals; Cell Differentiation; Dentate Gyrus; Female; G Protein-Coupled Inwardly-Rectifying Potassium Channels; Male; Mice; Mice, Inbred C57BL; Neurons
PubMed: 29915136
DOI: 10.1523/JNEUROSCI.0674-18.2018 -
Proceedings of the National Academy of... Sep 1997Neuronal apoptosis was observed in the rat dentate gyrus in two experimental models of human limbic epilepsy. Five hours after one hippocampal kindling stimulation, a...
Neuronal apoptosis was observed in the rat dentate gyrus in two experimental models of human limbic epilepsy. Five hours after one hippocampal kindling stimulation, a marked increase of in situ terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling (TUNEL) of fragmented DNA was observed in nuclei located within and on the hilar border of the granule cell layer and in the polymorphic region. Forty kindling stimulations with 5-min interval produced higher numbers of labeled nuclei compared with one stimulation. The increase of TUNEL-positive nuclei was prevented by the protein synthesis inhibitor cycloheximide but not affected by the N-methyl-D-aspartate receptor antagonist MK-801. Kainic acid-induced seizures lead to a pattern of labeling in the hippocampal formation identical to that evoked by kindling. A large proportion of cells displaying TUNEL-positive nuclei was double-labeled by the neuron-specific antigen NeuN, demonstrating the neuronal identity of apoptotic cells. Either 1 or 40 kindling stimulations also gave rise to a marked increase of the number of cells double-labeled with the mitotic marker bromodeoxyuridine and NeuN in the subgranular zone and on the hilar border of the dentate granule cell layer. The present data show that single and intermittent, brief seizures induce both apoptotic death and proliferation of dentate gyrus neurons. We hypothesize that these processes, occurring early during epileptogenesis, are primary events in the development of hippocampal pathology in animals and possibly also in patients suffering from temporal lobe epilepsy.
Topics: Animals; Apoptosis; Cell Division; Dentate Gyrus; Epilepsy; Limbic System; Male; Neurons; Rats; Rats, Sprague-Dawley
PubMed: 9294228
DOI: 10.1073/pnas.94.19.10432 -
ELife Jun 2021In adult dentate gyrus neurogenesis, the link between maturation of newborn neurons and their function, such as behavioral pattern separation, has remained puzzling. By...
In adult dentate gyrus neurogenesis, the link between maturation of newborn neurons and their function, such as behavioral pattern separation, has remained puzzling. By analyzing a theoretical model, we show that the switch from excitation to inhibition of the GABAergic input onto maturing newborn cells is crucial for their proper functional integration. When the GABAergic input is excitatory, cooperativity drives the growth of synapses such that newborn cells become sensitive to stimuli similar to those that activate mature cells. When GABAergic input switches to inhibitory, competition pushes the configuration of synapses onto newborn cells toward stimuli that are different from previously stored ones. This enables the maturing newborn cells to code for concepts that are novel, yet similar to familiar ones. Our theory of newborn cell maturation explains both how adult-born dentate granule cells integrate into the preexisting network and why they promote separation of similar but not distinct patterns.
Topics: Animals; Animals, Newborn; Dentate Gyrus; GABAergic Neurons; Interneurons; Models, Neurological; Nerve Net; Neurogenesis; Rodentia; Synapses
PubMed: 34137370
DOI: 10.7554/eLife.66463 -
Progress in Brain Research 2007The hippocampus is typically described in the context of the trisynaptic circuit, a pathway that relays information from the perforant path to the dentate gyrus, dentate... (Review)
Review
The hippocampus is typically described in the context of the trisynaptic circuit, a pathway that relays information from the perforant path to the dentate gyrus, dentate to area CA3, and CA3 to area CA1. Associated with this concept is the assumption that most hippocampal information processing occurs along the trisynaptic circuit. However, the entorhinal cortex may not be the only major extrinsic input to consider, and the trisynaptic circuit may not be the only way information is processed in hippocampus. Area CA3 receives input from a variety of sources, and may be as much of an "entry point" to hippocampus as the dentate gyrus. The axon of CA3 pyramidal cells targets diverse cell types, and has commissural projections, which together make it able to send information to much more of the hippocampus than granule cells. Therefore, CA3 pyramidal cells seem better designed to spread information through hippocampus than the granule cells. From this perspective, CA3 may be a point of entry that receives information which needs to be "broadcasted," whereas the dentate gyrus may be a point of entry that receives information with more selective needs for hippocampal processing. One aspect of the argument that CA3 pyramidal cells have a widespread projection is based on a part of its axonal arbor that has received relatively little attention, the collaterals that project in the opposite direction to the trisynaptic circuit, "back" to the dentate gyrus. The evidence for this "backprojection" to the dentate gyrus is strong, particularly in area CA3c, the region closest to the dentate gyrus, and in temporal hippocampus. The influence on granule cells is indirect, through hilar mossy cells and GABAergic neurons of the dentate gyrus, and appears to include direct projections in the case of CA3c pyramidal cells of ventral hippocampus. Physiological studies suggest that normally area CA3 does not have a robust excitatory influence on granule cells, but serves instead to inhibit it by activating dentate gyrus GABAergic neurons. Thus, GABAergic inhibition normally controls the backprojection to dentate granule cells, analogous to the way GABAergic inhibition appears to control the perforant path input to granule cells. From this perspective, the dentate gyrus has two robust glutamatergic inputs, entorhinal cortex and CA3, and two "gates," or inhibitory filters that reduce the efficacy of both inputs, keeping granule cells relatively quiescent. When GABAergic inhibition is reduced experimentally, or under pathological conditions, CA3 pyramidal cells activate granule cells reliably, and do so primarily by disynaptic excitation that is mediated by mossy cells. We suggest that the backprojection has important functions normally that are dynamically regulated by nonprincipal cells of the dentate gyrus. Slightly reduced GABAergic input would lead to increased polysynaptic associative processing between CA3 and the dentate gyrus. Under pathological conditions associated with loss of GABAergic interneurons, the backprojection may support reverberatory excitatory activity between CA3, mossy cells, and granule cells, possibly enhanced by mossy fiber sprouting. In this case, the backprojection could be important to seizure activity originating in hippocampus, and help explain the seizure susceptibility of ventral hippocampus.
Topics: Animals; Dentate Gyrus; Neural Pathways; Pyramidal Cells; Synaptic Transmission
PubMed: 17765742
DOI: 10.1016/S0079-6123(07)63034-9 -
Nature Communications Jan 2018Early life experience influences stress reactivity and mental health through effects on cognitive-emotional functions that are, in part, linked to gene expression in the...
Early life experience influences stress reactivity and mental health through effects on cognitive-emotional functions that are, in part, linked to gene expression in the dorsal and ventral hippocampus. The hippocampal dentate gyrus (DG) is a major site for experience-dependent plasticity associated with sustained transcriptional alterations, potentially mediated by epigenetic modifications. Here, we report comprehensive DNA methylome, hydroxymethylome and transcriptome data sets from mouse dorsal and ventral DG. We find genome-wide transcriptional and methylation differences between dorsal and ventral DG, including at key developmental transcriptional factors. Peripubertal environmental enrichment increases hippocampal volume and enhances dorsal DG-specific differences in gene expression. Enrichment also enhances dorsal-ventral differences in DNA methylation, including at binding sites of the transcription factor NeuroD1, a regulator of adult neurogenesis. These results indicate a dorsal-ventral asymmetry in transcription and methylation that parallels well-known functional and anatomical differences, and that may be enhanced by environmental enrichment.
Topics: Animals; Animals, Newborn; Basic Helix-Loop-Helix Transcription Factors; Binding Sites; Conditioning, Psychological; DNA; DNA Methylation; Dentate Gyrus; Epigenesis, Genetic; Gene Expression Regulation, Developmental; Gene-Environment Interaction; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins; Neurogenesis; Neuronal Plasticity; Neurons; Protein Binding; Transcriptome
PubMed: 29352183
DOI: 10.1038/s41467-017-02748-x -
Hippocampus Apr 2022Information processing in cortical circuits, including the hippocampus, relies on the dynamic control of neuronal activity by GABAergic interneurons (INs). INs form a...
Information processing in cortical circuits, including the hippocampus, relies on the dynamic control of neuronal activity by GABAergic interneurons (INs). INs form a heterogenous population with defined types displaying distinct morphological, molecular, and physiological characteristics. In the major input region of the hippocampus, the dentate gyrus (DG), a number of IN types have been described which provide synaptic inhibition to distinct compartments of excitatory principal cells (PrCs) and other INs. In this study, we perform an unbiased classification of GABAergic INs in the DG by combining in vitro whole-cell patch-clamp recordings, intracellular labeling, morphological analysis, and unsupervised cluster analysis to better define IN type diversity in this region. This analysis reveals that DG INs divide into at least 13 distinct morpho-physiological types which reflect the complexity of the local IN network and serve as a basis for further network analyses.
Topics: Animals; Dentate Gyrus; Hippocampus; Interneurons; Neurons; Patch-Clamp Techniques; Rats
PubMed: 35171512
DOI: 10.1002/hipo.23408 -
Hippocampus Nov 2021The dentate gyrus not only gates the flow of information into the hippocampus, it also integrates and processes this information. Mossy cells (MCs) are a major type of...
The dentate gyrus not only gates the flow of information into the hippocampus, it also integrates and processes this information. Mossy cells (MCs) are a major type of excitatory neuron strategically located in the hilus of the dentate gyrus where they can contribute to this processing through networks of synapses with inhibitory neurons and dentate granule cells. Some prior work has suggested that MCs can form excitatory synapses with other MCs, but the role of these synapses in the network activity of the dentate gyrus has received little attention. Here, we investigated synaptic inputs to MCs in mouse hippocampal slices using a genetically encoded hybrid voltage sensor (hVOS) targeted to MCs by Cre-lox technology. This enabled optical recording of voltage changes from multiple MCs simultaneously. Stimulating granule cells and CA3 pyramidal cells activated well-established inputs to MCs and elicited synaptic responses as expected. However, the weak blockade of MC responses to granule cell layer stimulation by DCG-IV raised the possibility of another source of excitation. To evaluate synapses between MCs as this source, single MCs were stimulated focally. Stimulation of one MC above its action potential threshold evoked depolarizing responses in neighboring MCs that depended on glutamate receptors. Short latency responses of MCs to other MCs did not depend on release from granule cell axons. However, granule cells did contribute to the longer latency responses of MCs to stimulation of other MCs. Thus, MCs transmit their activity to other MCs both through direct synaptic coupling and through polysynaptic coupling with dentate granule cells. MC-MC synapses can redistribute information entering the dentate gyrus and thus shape and modulate the electrical activity underlying hippocampal functions such as navigation and memory, as well as excessive excitation during seizures.
Topics: Animals; Dentate Gyrus; Hippocampus; Mice; Mossy Fibers, Hippocampal; Rats; Rats, Sprague-Dawley; Synapses
PubMed: 34478219
DOI: 10.1002/hipo.23386