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Science Advances Jan 2024Adult neurogenesis confers the hippocampus with unparalleled neural plasticity, essential for intricate cognitive functions. The specific influence of sparse newborn...
Adult neurogenesis confers the hippocampus with unparalleled neural plasticity, essential for intricate cognitive functions. The specific influence of sparse newborn neurons (NBNs) in modulating neural activities and subsequently steering behavior, however, remains obscure. Using an engineered NBN-tetanus toxin mouse model (NBN-TeTX), we noninvasively silenced NBNs, elucidating their crucial role in impulse inhibition and cognitive flexibility as evidenced through Morris water maze reversal learning and Go/Nogo task in operant learning. Task-based functional MRI (tb-fMRI) paired with operant learning revealed dorsal hippocampal hyperactivation during the Nogo task in male NBN-TeTX mice, suggesting that hippocampal hyperexcitability might underlie the observed behavioral deficits. Additionally, resting-state fMRI (rs-fMRI) exhibited enhanced functional connectivity between the dorsal and ventral dentate gyrus following NBN silencing. Further investigations into the activities of PV interneurons and mossy cells highlighted the indispensability of NBNs in maintaining the hippocampal excitation/inhibition balance. Our findings emphasize that the neural plasticity driven by NBNs extensively modulates the hippocampus, sculpting inhibitory control and cognitive flexibility.
Topics: Male; Animals; Mice; Neurons; Cognition; Learning; Interneurons; Synaptic Transmission
PubMed: 38198539
DOI: 10.1126/sciadv.adk4741 -
CNS Neuroscience & Therapeutics Nov 2023Neuronal abnormalities are closely associated with major depressive disorder (MDD). Available evidence suggests a role for microRNAs (miRNAs) in regulating the...
BACKGROUND
Neuronal abnormalities are closely associated with major depressive disorder (MDD). Available evidence suggests a role for microRNAs (miRNAs) in regulating the expression of genes involved in MDD. Hence, miRNAs that can be potential therapeutic targets need to be identified.
METHODS
A mouse model of chronic unpredictable stress (CUS) was used to evaluate the function of miRNAs in MDD. miR-144-5p was screened from the hippocampi of CUS mice based on sequencing results. Adenovirus-associated vectors were used to overexpress or knockdown miR-144-5p in mice. BpV(pic) and LY294002 were used to determine the relationship between miR-144-5p target genes PTEN and TLR4 in neuronal impairment caused by miR-144-5p deficiency. Western blotting, immunofluorescence, ELISA immunosorbent assay, and Golgi staining were used to detect neuronal abnormalities. Serum samples from healthy individuals and patients with MDD were used to detect miR-144-5p levels in the serum and serum exosomes using qRT-PCR.
RESULTS
miR-144-5p expression was significantly decreased within the hippocampal dentate gyrus (DG) of CUS mice. Upregulation of miR-144-5p in the DG ameliorated depression-like behavior in CUS mice and attenuated neuronal abnormalities by directly targeting PTEN and TLR4 expression. Furthermore, miR-144-5p knockdown in normal mice led to depression-like behavior via inducing neuronal abnormalities, including abnormal neurogenesis, neuronal apoptosis, altered synaptic plasticity, and neuroinflammation. miR-144-5p deficiency-mediated neuronal impairment was mediated by PI3K/Akt/FoxO1 signaling. Furthermore, miR-144-5p levels were downregulated in the sera of patients with MDD and associated with depressive symptoms. Consistently, serum exosome-derived miR-144-5p levels were decreased in patients with MDD.
CONCLUSION
miR-144-5p plays a vital role in regulating neuronal abnormalities in depression. Our findings provide translational evidence that miR-144-5p is a new potential therapeutic target for MDD.
Topics: Humans; Animals; Mice; Depressive Disorder, Major; Phosphatidylinositol 3-Kinases; Toll-Like Receptor 4; MicroRNAs; Signal Transduction
PubMed: 37308778
DOI: 10.1111/cns.14291 -
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 -
Advanced Science (Weinheim,... Oct 2023Lysine demethylase KDM7A removes histone modifications H3K9me1/2 and H3K27me1/2. KDM7A plays critical roles in gene expression and contribute to biological processes...
Lysine demethylase KDM7A removes histone modifications H3K9me1/2 and H3K27me1/2. KDM7A plays critical roles in gene expression and contribute to biological processes including tumorigenesis, metabolism, and embryonic development. However, the functions of KDM7A in mammalian nervous system are still poorly explored. In this study, functional roles of KDM7A are comprehensively investigated in neuronal cells by applying CUT&Tag-seq, RNA-seq and mice models. Knockdown of Kdm7a in N2A cells result in the alteration of histone modifications near transcription start sites (TSSs) and the expression changes of a large number of genes. In particular, the expression of immediate early genes (IEGs), a series of genes maintaining the function of the nervous system and associating with neurological disorders, are significantly decreased upon Kdm7a knockdown. Furthermore, in vivo knockdown of Kdm7a in dentate gyrus (DG) neuron of mice hippocampus, via Adeno-associated virus (AAV)-based stereotaxic microinjection, led to a significant decrease of the expression of c-Fos, a marker of neuron activity. Behavior assays in mice further revealed that Kdm7a knockdown in hippocampus repress neuron activity, which leading to impairment of emotion and memory. Collectively, the study reveals that KDM7A affects neuron functions by regulating IEGs, which may provide new clues for understanding epigenetic mechanisms in neurological disorders.
Topics: Mice; Animals; Jumonji Domain-Containing Histone Demethylases; Lysine; Genes, Immediate-Early; Neurons; Nervous System Diseases; Mammals
PubMed: 37565374
DOI: 10.1002/advs.202301367 -
Neurobiology of Disease Nov 2023Sprouting of mossy fibers, one of the most consistent findings in tissue from patients with mesial temporal lobe epilepsy, exhibits several uncommon axonal growth...
Sprouting of mossy fibers, one of the most consistent findings in tissue from patients with mesial temporal lobe epilepsy, exhibits several uncommon axonal growth features and has been considered a paradigmatic example of circuit plasticity that occurs in the adult brain. Clarifying the mechanisms responsible may provide new insight into epileptogenesis as well as axon misguidance in the central nervous system. Methyl-CpG-binding protein 2 (MeCP2) binds to methylated genomic DNA to regulate a range of physiological functions implicated in neuronal development and adult synaptic plasticity. However, exploring the potential role of MeCP2 in the documented misguidance of axons in the dentate gyrus has not yet been attempted. In this study, a status epilepticus-induced decrease of neuronal MeCP2 was observed in the dentate gyrus (DG). An essential regulatory role of MeCP2 in the development of functional mossy fiber sprouting (MFS) was confirmed through stereotaxic injection of a recombinant adeno-associated virus (AAV) to up- or down-regulate MeCP2 in the dentate neurons. Chromatin immunoprecipitation sequencing (ChIP-seq) was performed to identify the binding profile of native MeCP2 using micro-dissected dentate tissues. In both dentate tissues and HT22 cell lines, we demonstrated that MeCP2 could act as a transcription repressor on miR-682 with the involvement of the DNA methylation mechanism. Further, we found that miR-682 could bind to mRNA of phosphatase and tensin homolog (PTEN) in a sequence specific manner, thus leading to the suppression of PTEN and excessive activation of mTOR. This study therefore presents a novel epigenetic mechanism by identifying MeCP2/miR-682/PTEN/mTOR as an essential signal pathway in regulating the formation of MFS in the temporal lobe epileptic (TLE) mice. SIGNIFICANCE STATEMENT: Understanding the mechanisms that regulate axon guidance is important for a better comprehension of neural disorders. Sprouting of mossy fibers, one of the most consistent findings in patients with mesial temporal lobe epilepsy, has been considered a paradigmatic example of circuit plasticity in the adult brain. Although abnormal regulation of DNA methylation has been observed in both experimental rodents and humans with epilepsy, the potential role of DNA methylation in this well-documented example of sprouting of dentate axon remains elusive. This study demonstrates an essential role of methyl-CpG-binding protein 2 in the formation of mossy fiber sprouting. The underlying signal pathway has been also identified. The data hence provide new insight into epileptogenesis as well as axon misguidance in the central nervous system.
Topics: Animals; Humans; Mice; Dentate Gyrus; Epilepsy; Epilepsy, Temporal Lobe; Methyl-CpG-Binding Protein 2; MicroRNAs; Mossy Fibers, Hippocampal; TOR Serine-Threonine Kinases
PubMed: 37931884
DOI: 10.1016/j.nbd.2023.106346 -
Frontiers in Neuroscience 2023Aging is associated with impairments in learning, memory, and cognitive flexibility, as well as a gradual decline in hippocampal neurogenesis. We investigated the...
Aging is associated with impairments in learning, memory, and cognitive flexibility, as well as a gradual decline in hippocampal neurogenesis. We investigated the performance of 6-and 14-month-old mice (considered mature adult and late middle age, respectively) in learning and memory tasks based on the Morris water maze (MWM) and determined their levels of preceding and current neurogenesis. While both age groups successfully performed in the spatial version of MWM (sMWM), the older mice were less efficient compared to the younger mice when presented with modified versions of the MWM that required a reassessment of the previously acquired experience. This was detected in the reversal version of MWM (rMWM) and was particularly evident in the context discrimination MWM (cdMWM), a novel task that required integrating various distal cues, local cues, and altered contexts and adjusting previously used search strategies. Older mice were impaired in several metrics that characterize rMWM and cdMWM, however, they showed improvement and narrowed the performance gap with the younger mice after additional training. Furthermore, we analyzed the adult-born mature and immature neurons in the hippocampal dentate gyrus and found a significant correlation between neurogenesis levels in individual mice and their performance in the tasks demanding cognitive flexibility. These results provide a detailed description of the age-related changes in learning and memory and underscore the importance of hippocampal neurogenesis in supporting cognitive flexibility.
PubMed: 37645372
DOI: 10.3389/fnins.2023.1232670 -
Cell Reports Oct 2023CDKL5 deficiency disorder (CDD) is a severe epileptic encephalopathy resulting from pathological mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene....
CDKL5 deficiency disorder (CDD) is a severe epileptic encephalopathy resulting from pathological mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene. Despite significant progress in understanding the neuronal function of CDKL5, the molecular mechanisms underlying CDD-associated epileptogenesis are unknown. Here, we report that acute ablation of CDKL5 from adult forebrain glutamatergic neurons leads to elevated neural network activity in the dentate gyrus and the occurrence of early-onset spontaneous seizures via tropomyosin-related kinase B (TrkB) signaling. We observe increased expression of brain-derived neurotrophic factor (BDNF) and enhanced activation of its receptor TrkB in the hippocampus of Cdkl5-deficient mice prior to the onset of behavioral seizures. Moreover, reducing TrkB signaling in these mice rescues the altered synaptic activity and suppresses recurrent seizures. These results suggest that TrkB signaling mediates epileptogenesis in a mouse model of CDD and that targeting this pathway might be effective for treating epilepsy in patients affected by CDKL5 mutations.
Topics: Humans; Adult; Animals; Mice; Spasms, Infantile; Epileptic Syndromes; Seizures; Neurons; Mice, Knockout; Protein Serine-Threonine Kinases
PubMed: 37777961
DOI: 10.1016/j.celrep.2023.113202 -
The EMBO Journal Nov 2023For decades, the mammalian hippocampus has been the focus of cellular, anatomical, behavioral, and computational studies aimed at understanding the fundamental... (Review)
Review
For decades, the mammalian hippocampus has been the focus of cellular, anatomical, behavioral, and computational studies aimed at understanding the fundamental mechanisms underlying cognition. Long recognized as the brain's seat for learning and memory, a wealth of knowledge has been accumulated on how the hippocampus processes sensory input, builds complex associations between objects, events, and space, and stores this information in the form of memories to be retrieved later in life. However, despite major efforts, our understanding of hippocampal cognitive function remains fragmentary, and models trying to explain it are continually revisited. Here, we review the literature across all above-mentioned domains and offer a new perspective by bringing attention to the most distinctive, and generally neglected, feature of the mammalian hippocampal formation, namely, the structural separability of the two blades of the dentate gyrus into "supra-pyramidal" and "infra-pyramidal". Next, we discuss recent reports supporting differential effects of adult neurogenesis in the regulation of mature granule cell activity in these two blades. We propose a model for how differences in connectivity and adult neurogenesis in the two blades can potentially provide a substrate for subtly different cognitive functions.
Topics: Animals; Dentate Gyrus; Hippocampus; Neurons; Learning; Memory; Neurogenesis; Mammals
PubMed: 37743770
DOI: 10.15252/embj.2023113524 -
Proceedings of the National Academy of... Dec 2023Somatostatin-expressing interneurons (SOMIs) in the mouse dentate gyrus (DG) receive feedforward excitation from granule cell (GC) mossy fiber (MF) synapses and provide...
Somatostatin-expressing interneurons (SOMIs) in the mouse dentate gyrus (DG) receive feedforward excitation from granule cell (GC) mossy fiber (MF) synapses and provide feedback lateral inhibition onto GC dendrites to support environment representation in the DG network. Although this microcircuitry has been implicated in memory formation, little is known about activity-dependent plastic changes at MF-SOMI synapses and their influence on behavior. Here, we report that the metabotropic glutamate receptor 1α (mGluR1α) is required for the induction of associative long-term potentiation (LTP) at MF-SOMI synapses. Pharmacological block of mGluR1α, but not mGluR5, prevented synaptic weight changes. LTP at MF-SOMI synapses was postsynaptically induced, required increased intracellular Ca, involved G-protein-mediated and Ca-dependent (extracellular signal-regulated kinase) ERK1/2 pathways, and the activation of NMDA receptors. Specific knockdown of mGluR1α in DG-SOMIs by small hairpin RNA expression prevented MF-SOMI LTP, reduced SOMI recruitment, and impaired object location memory. Thus, postsynaptic mGluR1α-mediated MF-plasticity at SOMI input synapses critically supports DG-dependent mnemonic functions.
Topics: Mice; Animals; Mossy Fibers, Hippocampal; Neuronal Plasticity; Interneurons; Long-Term Potentiation; Synapses; Somatostatin; Dentate Gyrus; Synaptic Transmission
PubMed: 38091292
DOI: 10.1073/pnas.2312752120 -
NeuroImage Nov 2023The connectivity of the hippocampus is essential to its functions. To gain a whole system view of intrahippocampal connectivity, ex vivo mesoscale (100 μm isotropic...
The connectivity of the hippocampus is essential to its functions. To gain a whole system view of intrahippocampal connectivity, ex vivo mesoscale (100 μm isotropic resolution) multi-shell diffusion MRI (11.7T) and tractography were performed on entire post-mortem human right hippocampi. Volumetric measurements indicated that the head region was largest followed by the body and tail regions. A unique anatomical organization in the head region reflected a complex organization of the granule cell layer (GCL) of the dentate gyrus. Tractography revealed the volumetric distribution of the perforant path, including both the tri-synaptic and temporoammonic pathways, as well as other well-established canonical connections, such as Schaffer collaterals. Visualization of the perforant path provided a means to verify the borders between the pro-subiculum and CA1, as well as between CA1/CA2. A specific angularity of different layers of fibers in the alveus was evident across the whole sample and allowed a separation of afferent and efferent connections based on their origin (i.e. entorhinal cortex) or destination (i.e. fimbria) using a cluster analysis of streamlines. Non-canonical translamellar connections running along the anterior-posterior axis were also discerned in the hilus. In line with "dentations" of the GCL, mossy fibers were bunching together in the sagittal plane revealing a unique lamellar organization and connections between these. In the head region, mossy fibers projected to the origin of the fimbria, which was distinct from the body and tail region. Mesoscale tractography provides an unprecedented systems view of intrahippocampal connections that underpin cognitive and emotional processing.
Topics: Humans; Hippocampus; Perforant Pathway; Entorhinal Cortex; Brain; Diffusion Magnetic Resonance Imaging
PubMed: 37827206
DOI: 10.1016/j.neuroimage.2023.120406