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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 -
Neuroscience Letters Aug 2023Within the hippocampus, the CA1 and dentate gyrus (DG) regions are considered the most and the least susceptible to damage by cerebral ischemia, respectively. In...
Intranasal erythropoietin protects granular cells and reduces astrogliosis in the dentate gyrus after ischemic damage, an effect associated with molecular changes in erythropoietin and its receptor.
Within the hippocampus, the CA1 and dentate gyrus (DG) regions are considered the most and the least susceptible to damage by cerebral ischemia, respectively. In addition, it has been tested that rHuEPO exhibits neuroprotective properties. This work investigates the effect of different intranasal doses of rHuEPO, applied in different ischemic post-damage times in the DG, and the effect of the rHuEPO on astroglial reactivity after cerebral ischemia. Additionally, an effective dose for neuroprotection and an administration time was used to evaluate gene and protein expression changes of EPO and EPOR in the DG region. We observed a considerable loss of cells on the granular layer and an increased number of GFAP immunoreactive cells in this region only 72 h after the onset of ischemia/damage. When rHuEPO was administered, the number of morphologically abnormal cells and immunoreactivity decreased. In the analysis of protein and gene expression, there is no correlation between expression level of these molecules, although the rHuEPO amplifies the response to ischemia of EPO and EPOR gene for each evaluated time; in the case of the protein only at 2 h this effect was observed. We demonstrated the susceptibility of the DG to ischemia; so granular cells damage was observed, moreover of the astrocytic response, which is accompanied by molecular changes in signaling mediated by rHuEPO intranasal administration.
Topics: Humans; Administration, Intranasal; Gliosis; Erythropoietin; Brain Ischemia; Cerebral Infarction; Dentate Gyrus
PubMed: 37393008
DOI: 10.1016/j.neulet.2023.137366 -
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 -
Behavioural Brain Research Mar 2022Nitric oxide (NO)-dependent pathways may play a significant role in the decline of synaptic and cognitive functions in Alzheimer's disease (AD). However, whether NO in...
Nitric oxide impairs spatial learning and memory in a rat model of Alzheimer's disease via disturbance of glutamate response in the hippocampal dentate gyrus during spatial learning.
Nitric oxide (NO)-dependent pathways may play a significant role in the decline of synaptic and cognitive functions in Alzheimer's disease (AD). However, whether NO in the hippocampal dentate gyrus (DG) is involved in the spatial learning and memory impairments of AD by affecting the glutamate (Glu) response during these processes is not well-understood. Here, we prepared an AD rat model by long-term i.p. of D-galactose into ovariectomized rats, and then the effects of L-NMMA (a NO synthase inhibitor) on Glu concentration and amplitude of field excitatory postsynaptic potential (fEPSP) were measured in the DG region during the Morris water maze (MWM) test in freely-moving rats. During the MWM test, compared with the sham group, the escape latency was increased in the place navigation trial, and the percentage of time spent in target quadrant and the number of platform crossings were decreased in the spatial probe trial, in addition, the increase of fEPSP amplitude in the DG was significantly attenuated in AD group rats. L-NMMA significantly attenuated the spatial learning and memory impairment in AD rats, and reversed the inhibitory effect of AD on increase of fEPSP amplitude in the DG during the MWM test. In sham group rats, the Glu level in the DG increased significantly during the MWM test, and this response was markedly enhanced in AD rats. Furthermore, the response of Glu in the DG during spatial learning was recovered by microinjection of L-NMMA into the DG. Our results suggest that NO in the DG impairs spatial learning and memory and related synaptic plasticity in AD rats, by disturbing the Glu response during spatial learning.
Topics: Alzheimer Disease; Animals; Behavior, Animal; Dentate Gyrus; Disease Models, Animal; Enzyme Inhibitors; Excitatory Postsynaptic Potentials; Female; Glutamic Acid; Maze Learning; Nitric Oxide; Nitric Oxide Synthase; Ovariectomy; Rats; Rats, Sprague-Dawley; omega-N-Methylarginine
PubMed: 35033612
DOI: 10.1016/j.bbr.2022.113750 -
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 -
The Journal of Physiology Oct 2021The activation of α7 nicotinic acetylcholine receptors (nAChRs) has been shown to improve hippocampus-dependent learning and memory. α7 nAChRs are densely expressed...
The activation of α7 nicotinic acetylcholine receptors (nAChRs) has been shown to improve hippocampus-dependent learning and memory. α7 nAChRs are densely expressed among several different cell types in the hippocampus, with high Ca permeability, although it is unclear if α7 nAChRs mobilize differential signalling mechanisms among distinct neuronal populations. To address this question, we compared α7 nAChR agonist-induced responses (i.e. calcium and cAMP changes) between granule cells and GABAergic neurons in the hippocampal dentate gyrus both in vitro and in vivo. In cultured organotypic hippocampal slices, we observed robust intracellular calcium and cAMP increases in dentate granule cells upon activation of α7 nAChRs. In contrast, GABAergic interneurons displayed little change in either calcium or cAMP concentration after α7 nAChR activation, even though they displayed much larger α7 nAChR current responses than those of dentate granule cells. We found that this was due to smaller α7 nAChR-induced Ca rises in GABAergic interneurons. Thus, the regulation of the Ca transients in different cell types resulted in differential subsequent intracellular signalling cascades and likely the ultimate outcome of α7 nAChR activation. Furthermore, we monitored neuronal activities of dentate granule cells and GABAergic interneurons in vivo via optic fibre photometry. We observed enhancement of neuronal activities after nicotine administration in dentate granule cells, but not in GABAergic neurons, which was absent in α7 nAChR-deficient granule cells. In summary, we reveal a mechanism for α7 nAChR-mediated increase of neuronal activity via cell type-specific intracellular signalling pathways. KEY POINTS: α7 nicotinic acetylcholine receptors (nAChRs) are widely distributed throughout the central nervous system and regulate a variety of brain functions including learning and memory. Understanding the cellular signalling mechanisms of their activations among different neuronal populations is important for delineating their actions in cognitive function, and developing effective treatment strategies for cognitive deficits. We report that α7 nAChR activation leads to Ca and cAMP increases in granule cells (but not in GABAergic interneurons) in hippocampal dentate gyrus in vitro, a key region for pattern separation during learning. We also found that nicotine enhanced granule cell (but not in GABAergic interneurons) activity in an α7 nAChR-dependent manner via in vivo fibre photometry recording. Based on our findings, we propose that differential responses to α7 nAChR activation between granule cells and GABAergic interneurons is responsible for the increase of excitation by α7 nAChR agonists in hippocampal circuits synergistically.
Topics: Dentate Gyrus; GABAergic Neurons; Hippocampus; Receptors, Nicotinic; alpha7 Nicotinic Acetylcholine Receptor
PubMed: 34487349
DOI: 10.1113/JP280505 -
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 -
International Journal of Molecular... Mar 2023Studies indicating the influence of masticatory dysfunction, due to a soft diet or lack of molars, on impairing spatial memory and learning have led to research about...
The Masticatory Activity Interference in Quantitative Estimation of CA1, CA3 and Dentate Gyrus Hippocampal Astrocytes of Aged Murine Models and under Environmental Stimulation.
Studies indicating the influence of masticatory dysfunction, due to a soft diet or lack of molars, on impairing spatial memory and learning have led to research about neuronal connections between areas and cell populations possibly affected. In this sense, with scarce detailed data on the subfields of hippocampus in dementia neurodegeneration, there is no information about astrocytic responses in its different layers. Thus, considering this context, the present study evaluated the effects of deprivation and rehabilitation of masticatory activity, aging, and environmental enrichment on the stereological quantification of hippocampal astrocytes from layers CA1, CA3, and DG. For this purpose, we examined mature (6-month-old; 6M), and aged (18-month-old; 18M) mice, subjected to distinct masticatory regimens and environments. Three different regimens of masticatory activity were applied: continuous normal mastication with hard pellets (HD); normal mastication followed by deprived mastication with equal periods of pellets followed by soft powder (HD/SD); or rehabilitated masticatory activity with equal periods of HD, followed by powder, followed by pellets (HD/SD/HD). Under each specific regimen, half of the animals were raised in standard cages (impoverished environment (IE)) and the other half in enriched cages (enriched environment (EE)), mimicking sedentary or active lifestyles. Microscopic stereological, systematic, and random sampling approaches with an optical dissector of GFAP-immunolabeled astrocytes were done, allowing for an astrocyte numerical estimate. Stratum moleculare and hilus, from the dentate gyrus (DG) and Strata Lacunosum-Moleculare, Oriens, and Radiatum, similarly to the dentate gyrus, showed no significant change in any of the investigated variables (age, diet, or environment) in these layers. However, in Stratum radiatum, it was possible to observe significant differences associated with diet regimens and age. Therefore, diet-related differences were found when the HD 18M IE group was compared to the HD/SD/HD 18-month-old group in the same environment (IE) ( = 0.007). In the present study, we present modulatory factors (masticatory function, environmental enrichment, and aging) for the differentiated quantitative laminar response in the hippocampal regions, suggesting other studies to read the plasticity and responsiveness of astrocytes, including the molecular background.
Topics: Mice; Animals; Astrocytes; Disease Models, Animal; Powders; Hippocampus; Dentate Gyrus
PubMed: 37047502
DOI: 10.3390/ijms24076529