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Physiological Reviews Oct 2014Adult neurogenesis in the hippocampus is a notable process due not only to its uniqueness and potential impact on cognition but also to its localized vertical... (Review)
Review
Adult neurogenesis in the hippocampus is a notable process due not only to its uniqueness and potential impact on cognition but also to its localized vertical integration of different scales of neuroscience, ranging from molecular and cellular biology to behavior. This review summarizes the recent research regarding the process of adult neurogenesis from these different perspectives, with particular emphasis on the differentiation and development of new neurons, the regulation of the process by extrinsic and intrinsic factors, and their ultimate function in the hippocampus circuit. Arising from a local neural stem cell population, new neurons progress through several stages of maturation, ultimately integrating into the adult dentate gyrus network. The increased appreciation of the full neurogenesis process, from genes and cells to behavior and cognition, makes neurogenesis both a unique case study for how scales in neuroscience can link together and suggests neurogenesis as a potential target for therapeutic intervention for a number of disorders.
Topics: Animals; Brain; Dentate Gyrus; Gene Expression Regulation; Humans; Neural Stem Cells; Neurogenesis
PubMed: 25287858
DOI: 10.1152/physrev.00004.2014 -
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 -
Journal of Pharmacological Sciences Dec 2020The hippocampus is a brain region well-known to exhibit structural and functional changes in temporal lobe epilepsy. Studies analyzing the brains of patients with... (Review)
Review
The hippocampus is a brain region well-known to exhibit structural and functional changes in temporal lobe epilepsy. Studies analyzing the brains of patients with epilepsy and those from animal models of epilepsy have revealed that microglia are excessively activated, especially in the hippocampus. These findings suggest that microglia may contribute to the onset and aggravation of epilepsy; however, direct evidence for microglial involvement or the underlying mechanisms by which this occurs remain to be fully discovered. To date, neuron-microglia interactions have been vigorously studied in adult epilepsy models; such studies have clarified microglial responses to excessive synchronous firing of neurons. In contrast, the role of microglia in the postnatal brain of patients with epileptic seizures remain largely unclear. Some early-life seizures, such as complex febrile seizures, have been shown to cause structural and functional changes in the brain, which is a risk factor for future development of epilepsy. Because brain structure and function are actively modulated by microglia in both health and disease, it is essential to clarify the role of microglia in early-life seizures and its impact on epileptogenesis.
Topics: Age Factors; Age of Onset; Animals; Cell Communication; Dentate Gyrus; Disease Models, Animal; Epilepsy, Temporal Lobe; Hippocampus; Humans; Mice; Microglia; Neurons; Rats; Risk Factors; Seizures, Febrile; Synapses
PubMed: 33070840
DOI: 10.1016/j.jphs.2020.09.003 -
Brain Structure & Function Jun 2018Abstinence from unregulated methamphetamine self-administration increases hippocampal dependent, context-driven reinstatement of methamphetamine seeking. The current...
Abstinence from unregulated methamphetamine self-administration increases hippocampal dependent, context-driven reinstatement of methamphetamine seeking. The current study tested the hypothesis that alterations in the functional properties of granule cell neurons (GCNs) in the dentate gyrus (DG) of the hippocampus in concert with altered expression of synaptic plasticity-related proteins and ultrastructural changes in the DG are associated with enhanced context-driven methamphetamine-seeking behavior. Whole-cell patch-clamp recordings were performed in acute brain slices from methamphetamine naïve (controls) and methamphetamine experienced animals (during acute withdrawal, during abstinence, after extinction and after reinstatement). Spontaneous excitatory postsynaptic currents (sEPSCs) and intrinsic excitability were recorded from GCNs. Reinstatement of methamphetamine seeking increased sEPSC frequency and produced larger amplitude responses in GCNs compared to controls and all other groups. Reinstatement of methamphetamine seeking reduced spiking capability in GCNs compared to controls, and all other groups, as indicated by reduced intrinsic spiking elicited by increasing current injections, membrane resistance and fast after hyperpolarization. In rats that reinstated methamphetamine seeking, these altered electrophysiological properties of GCNs were associated with enhanced expression of Fos, GluN2A subunits and PSD95 and reduced expression of GABA subunits in the DG and enhanced expression of synaptic PSD in the molecular layer. The alterations in functional properties of GCNs and plasticity related proteins in the DG paralleled with no changes in structure of microglial cells in the DG. Taken together, our results demonstrate that enhanced reinstatement of methamphetamine seeking results in alterations in intrinsic spiking and spontaneous glutamatergic synaptic transmission in the GCNs and concomitant increases in neuronal activation of GCNs, and expression of GluNs and decreases in GABA subunits that may contribute to the altered synaptic connectivity-neuronal circuitry-and activity in the hippocampus, and enhance propensity for relapse.
Topics: Animals; Calcium-Binding Proteins; Central Nervous System Stimulants; Conditioning, Operant; Cues; Dentate Gyrus; Drug-Seeking Behavior; Excitatory Postsynaptic Potentials; Extinction, Psychological; Gene Expression Regulation; Glutamic Acid; Male; Methamphetamine; Microfilament Proteins; Microglia; Neurons; Oncogene Proteins v-fos; Rats; Rats, Wistar; Receptors, GABA-A; Self Administration
PubMed: 29441405
DOI: 10.1007/s00429-018-1615-3 -
Nature Neuroscience Nov 2022The dentate gyrus (DG) gates neocortical information flow to the hippocampus. Intriguingly, the DG also produces adult-born dentate granule cells (abDGCs) throughout the...
The dentate gyrus (DG) gates neocortical information flow to the hippocampus. Intriguingly, the DG also produces adult-born dentate granule cells (abDGCs) throughout the lifespan, but their contribution to downstream firing dynamics remains unclear. Here, we show that abDGCs promote sparser hippocampal population spiking during mnemonic processing of novel stimuli. By combining triple-(DG-CA3-CA1) ensemble recordings and optogenetic interventions in behaving mice, we show that abDGCs constitute a subset of high-firing-rate neurons with enhanced activity responses to novelty and strong modulation by theta oscillations. Selectively activating abDGCs in their 4-7-week post-birth period increases sparsity of hippocampal population patterns, whereas suppressing abDGCs reduces this sparsity, increases principal cell firing rates and impairs novel object recognition with reduced dimensionality of the network firing structure, without affecting single-neuron spatial representations. We propose that adult-born granule cells transiently support sparser hippocampal population activity structure for higher-dimensional responses relevant to effective mnemonic information processing.
Topics: Animals; Mice; Dentate Gyrus; Hippocampus; Neurons; Memory
PubMed: 36216999
DOI: 10.1038/s41593-022-01176-5 -
Proceedings of the National Academy of... Nov 2022New neurons are continuously generated in the subgranular zone of the dentate gyrus throughout adulthood. These new neurons gradually integrate into hippocampal...
New neurons are continuously generated in the subgranular zone of the dentate gyrus throughout adulthood. These new neurons gradually integrate into hippocampal circuits, forming new naive synapses. Viewed from this perspective, these new neurons may represent a significant source of "wiring" noise in hippocampal networks. In machine learning, such noise injection is commonly used as a regularization technique. Regularization techniques help prevent overfitting training data and allow models to generalize learning to new, unseen data. Using a computational modeling approach, here we ask whether a neurogenesis-like process similarly acts as a regularizer, facilitating generalization in a category learning task. In a convolutional neural network (CNN) trained on the CIFAR-10 object recognition dataset, we modeled neurogenesis as a replacement/turnover mechanism, where weights for a randomly chosen small subset of hidden layer neurons were reinitialized to new values as the model learned to categorize 10 different classes of objects. We found that neurogenesis enhanced generalization on unseen test data compared to networks with no neurogenesis. Moreover, neurogenic networks either outperformed or performed similarly to networks with conventional noise injection (i.e., dropout, weight decay, and neural noise). These results suggest that neurogenesis can enhance generalization in hippocampal learning through noise injection, expanding on the roles that neurogenesis may have in cognition.
Topics: Memory; Neurogenesis; Hippocampus; Neurons; Synapses; Dentate Gyrus
PubMed: 36322739
DOI: 10.1073/pnas.2206704119 -
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 -
Scientific Reports Dec 2019Understanding the sequence of events from undifferentiated stem cells to neuron is not only important for the basic knowledge of stem cell biology, but also for...
Understanding the sequence of events from undifferentiated stem cells to neuron is not only important for the basic knowledge of stem cell biology, but also for therapeutic applications. In this study we examined the sequence of biological events during neural differentiation of human periodontal ligament stem cells (hPDLSCs). Here, we show that hPDLSCs-derived neural-like cells display a sequence of morphologic development highly similar to those reported before in primary neuronal cultures derived from rodent brains. We observed that cell proliferation is not present through neurogenesis from hPDLSCs. Futhermore, we may have discovered micronuclei movement and transient cell nuclei lobulation coincident to in vitro neurogenesis. Morphological analysis also reveals that neurogenic niches in the adult mouse brain contain cells with nuclear shapes highly similar to those observed during in vitro neurogenesis from hPDLSCs. Our results provide additional evidence that it is possible to differentiate hPDLSCs to neuron-like cells and suggest the possibility that the sequence of events from stem cell to neuron does not necessarily requires cell division from stem cell.
Topics: Animals; Cell Differentiation; Cell Nucleus; Cell Proliferation; Dentate Gyrus; Humans; Lateral Ventricles; Mice; Microscopy, Electron, Transmission; Neurogenesis; Neurons; Periodontal Ligament; Primary Cell Culture; Spheroids, Cellular; Stem Cell Niche; Stem Cells
PubMed: 31792338
DOI: 10.1038/s41598-019-54745-3 -
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 -
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