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Cells Jul 2023Neural progenitor cells (NPCs) are multipotent neural stem cells (NSCs) capable of self-renewing and differentiating into neurons, astrocytes and oligodendrocytes. In... (Review)
Review
Neural progenitor cells (NPCs) are multipotent neural stem cells (NSCs) capable of self-renewing and differentiating into neurons, astrocytes and oligodendrocytes. In the postnatal/adult brain, NPCs are primarily located in the subventricular zone (SVZ) of the lateral ventricles (LVs) and subgranular zone (SGZ) of the hippocampal dentate gyrus (DG). There is evidence that NPCs are also present in the postnatal/adult hypothalamus, a highly conserved brain region involved in the regulation of core homeostatic processes, such as feeding, metabolism, reproduction, neuroendocrine integration and autonomic output. In the rodent postnatal/adult hypothalamus, NPCs mainly comprise different subtypes of tanycytes lining the wall of the 3 ventricle. In the postnatal/adult human hypothalamus, the neurogenic niche is constituted by tanycytes at the floor of the 3 ventricle, ependymal cells and ribbon cells (showing a gap-and-ribbon organization similar to that in the SVZ), as well as suprachiasmatic cells. We speculate that in the postnatal/adult human hypothalamus, neurogenesis occurs in a highly complex, exquisitely sophisticated neurogenic niche consisting of at least four subniches; this structure has a key role in the regulation of extrahypothalamic neurogenesis, and hypothalamic and extrahypothalamic neural circuits, partly through the release of neurotransmitters, neuropeptides, extracellular vesicles (EVs) and non-coding RNAs (ncRNAs).
Topics: Adult; Humans; Neural Stem Cells; Neurons; Hypothalamus; Brain; Lateral Ventricles
PubMed: 37508487
DOI: 10.3390/cells12141822 -
Advanced Science (Weinheim,... Aug 2023Hippocampal circuitry stimulation is sufficient to regulate adult hippocampal neurogenesis and ameliorate depressive-like behavior, but its underlying mechanism remains...
Hippocampal circuitry stimulation is sufficient to regulate adult hippocampal neurogenesis and ameliorate depressive-like behavior, but its underlying mechanism remains unclear. Here, it is shown that inhibition of medial septum (MS)-dentate gyrus (DG) circuit reverses the chronic social defeat stress (CSDS)-induced depression-like behavior. Further analysis exhibits that inhibition of gamma-aminobutyric acidergic neurons in MS projecting to the DG (MS -DG) increases the expression of platelet-derived growth factor-BB (PDGF-BB) in somatostatin (SOM) positive interneurons of DG, which contributes to the antidepressant-like effects. Overexpression of the PDGF-BB or exogenous administration of PDGF-BB in DG rescues the effect of chronic stress on the inhibition of neural stem cells (NSCs) proliferation and dendritic growth of adult-born hippocampal neurons, as well as on depressive-like behaviors. Conversely, knockdown of PDGF-BB facilitates CSDS-induced deficit of hippocampal neurogenesis and promotes the susceptibility to chronic stress in mice. Finally, conditional knockdown platelet-derived growth factor receptor beta (PDGFRβ) in NSCs blocks an increase in NSCs proliferation and the antidepressant effects of PDGF-BB. These results delineate a previously unidentified PDGF-BB/PDGFRβ signaling in regulating depressive-like behaviors and identify a novel mechanism by which the MS -DG pathway regulates the expression of PDGF-BB in SOM-positive interneurons.
Topics: Mice; Animals; Becaplermin; Neurogenesis; gamma-Aminobutyric Acid; Antidepressive Agents; Dentate Gyrus
PubMed: 37325895
DOI: 10.1002/advs.202301110 -
Frontiers in Neuroscience 2023
PubMed: 38249580
DOI: 10.3389/fnins.2023.1307844 -
Brain, Behavior, and Immunity Oct 2023Microglia have an innate immunity memory (IIM) with divergent functions in different animal models of neurodegenerative diseases, including Alzheimer's disease (AD). AD...
Microglia have an innate immunity memory (IIM) with divergent functions in different animal models of neurodegenerative diseases, including Alzheimer's disease (AD). AD is characterized by chronic neuroinflammation, neurodegeneration, tau tangles and β-amyloid (Aβ) deposition. Systemic inflammation has been implicated in contributing to the progression of AD. Multiple reports have demonstrated unique microglial signatures in AD mouse models and patients. However, the proteomic profiles of microglia modified by IIM have not been well-documented in an AD model. Therefore, in the present study, we investigate whether lipopolysaccharide (LPS)-induced IIM in the pre-clinical stage of AD alters the microglial responses and shapes the neuropathology. We accomplished this by priming 5xFAD and wild-type (WT) mice with an LPS injection at 6 weeks (before the robust development of plaques). 140 days later, we evaluated microglial morphology, activation, the microglial barrier around Aβ, and Aβ deposition in both 5xFAD primed and unprimed mice. Priming induced decreased soma size of microglia and reduced colocalization of PSD95 and Synaptophysin in the retrosplenial cortex. Priming appeared to increase phagocytosis of Aβ, resulting in fewer Thioflavin S Aβ fibrils in the dentate gyrus. RIPA-soluble Aβ 40 and 42 were significantly reduced in Primed-5xFAD mice leading to a smaller size of MOAB2 Aβ plaques in the prefrontal cortex. We also found that Aβ-associated microglia in the Primed-5xFAD mice were less activated and fewer in number. After priming, we also observed improved memory performance in 5xFAD. To further elucidate the molecular mechanism underlying these changes, we performed quantitative proteomic analysis of microglia and bone marrow monocytes. A specific pattern in the microglial proteome was revealed in primed 5xFAD mice. These results suggest that the imprint signatures of primed microglia display a distinctive phenotype and highlight the potential for a beneficial adaption of microglia when intervention occurs in the pre-clinical stage of AD.
Topics: Mice; Animals; Alzheimer Disease; Lipopolysaccharides; Microglia; Mice, Transgenic; Proteomics; Amyloid beta-Peptides; Disease Models, Animal
PubMed: 37437821
DOI: 10.1016/j.bbi.2023.07.006 -
Scientific Reports May 2024Reduced hippocampal volume occurs in major depressive disorder (MDD), potentially due to elevated glucocorticoids from an overactivated hypothalamus-pituitary-adrenal... (Randomized Controlled Trial)
Randomized Controlled Trial
Reduced hippocampal volume occurs in major depressive disorder (MDD), potentially due to elevated glucocorticoids from an overactivated hypothalamus-pituitary-adrenal (HPA) axis. To examine this in humans, hippocampal volume and hypothalamus (HPA axis) metabolism was quantified in participants with MDD before and after antidepressant treatment. 65 participants (n = 24 males, n = 41 females) with MDD were treated in a double-blind, randomized clinical trial of escitalopram. Participants received simultaneous positron emission tomography (PET)/magnetic resonance imaging (MRI) before and after treatment. Linear mixed models examined the relationship between hippocampus/dentate gyrus volume and hypothalamus metabolism. Chi-squared tests and multivariable logistic regression examined the association between hippocampus/dentate gyrus volume change direction and hypothalamus activity change direction with treatment. Multiple linear regression compared these changes between remitter and non-remitter groups. Covariates included age, sex, and treatment type. No significant linear association was found between hippocampus/dentate gyrus volume and hypothalamus metabolism. 62% (38 of 61) of participants experienced a decrease in hypothalamus metabolism, 43% (27 of 63) of participants demonstrated an increase in hippocampus size (51% [32 of 63] for the dentate gyrus) following treatment. No significant association was found between change in hypothalamus activity and change in hippocampus/dentate gyrus volume, and this association did not vary by sex, medication, or remission status. As this multimodal study, in a cohort of participants on standardized treatment, did not find an association between hypothalamus metabolism and hippocampal volume, it supports a more complex pathway between hippocampus neurogenesis and hypothalamus metabolism changes in response to treatment.
Topics: Humans; Depressive Disorder, Major; Male; Female; Hypothalamus; Adult; Hippocampus; Magnetic Resonance Imaging; Middle Aged; Double-Blind Method; Positron-Emission Tomography; Dentate Gyrus; Citalopram; Hypothalamo-Hypophyseal System; Organ Size
PubMed: 38724691
DOI: 10.1038/s41598-024-61519-z -
Neuron Oct 2023Heterozygous mutations in the dual-specificity tyrosine phosphorylation-regulated kinase 1a (Dyrk1a) gene define a syndromic form of autism spectrum disorder. The...
Heterozygous mutations in the dual-specificity tyrosine phosphorylation-regulated kinase 1a (Dyrk1a) gene define a syndromic form of autism spectrum disorder. The synaptic and circuit mechanisms mediating DYRK1A functions in social cognition are unclear. Here, we identify a social experience-sensitive mechanism in hippocampal mossy fiber-parvalbumin interneuron (PV IN) synapses by which DYRK1A recruits feedforward inhibition of CA3 and CA2 to promote social recognition. We employ genetic epistasis logic to identify a cytoskeletal protein, ABLIM3, as a synaptic substrate of DYRK1A. We demonstrate that Ablim3 downregulation in dentate granule cells of adult heterozygous Dyrk1a mice is sufficient to restore PV IN-mediated inhibition of CA3 and CA2 and social recognition. Acute chemogenetic activation of PV INs in CA3/CA2 of adult heterozygous Dyrk1a mice also rescued social recognition. Together, these findings illustrate how targeting DYRK1A synaptic and circuit substrates as "enhancers of DYRK1A function" harbors the potential to reverse Dyrk1a haploinsufficiency-associated circuit and cognition impairments.
Topics: Animals; Mice; Autism Spectrum Disorder; Brain; Mossy Fibers, Hippocampal; Parvalbumins; Recognition, Psychology; Synapses; Dyrk Kinases
PubMed: 37797581
DOI: 10.1016/j.neuron.2023.09.009 -
Nature Communications Oct 2023The hippocampus plays major roles in learning and memory, and its formation requires precise coordination of patterning, cell proliferation, differentiation, and...
The hippocampus plays major roles in learning and memory, and its formation requires precise coordination of patterning, cell proliferation, differentiation, and migration. Here we removed the chromatin-association capability of KDM2B in the progenitors of developing dorsal telencephalon (Kdm2b) to discover that Kdm2b hippocampus, particularly the dentate gyrus, became drastically smaller with disorganized cellular components and structure. Kdm2b mice display prominent defects in spatial memory, motor learning and fear conditioning, resembling patients with KDM2B mutations. The migration and differentiation of neural progenitor cells is greatly impeded in the developing Kdm2b hippocampus. Mechanism studies reveal that Wnt signaling genes in developing Kdm2b hippocampi are de-repressed due to reduced enrichment of repressive histone marks by polycomb repressive complexes. Activating the Wnt signaling disturbs hippocampal neurogenesis, recapitulating the effect of KDM2B loss. Together, we unveil a previously unappreciated gene repressive program mediated by KDM2B that controls progressive fate specifications and cell migration, hence morphogenesis of the hippocampus.
Topics: Animals; Humans; Mice; Cell Differentiation; Hippocampus; Neurogenesis; Polycomb-Group Proteins; Wnt Signaling Pathway
PubMed: 37838801
DOI: 10.1038/s41467-023-42322-2 -
Cell Reports Aug 2023Long-term memories are stored as configurations of neuronal ensembles, termed engrams. Although investigation of engram cell properties and functionality in memory...
Long-term memories are stored as configurations of neuronal ensembles, termed engrams. Although investigation of engram cell properties and functionality in memory recall has been extensive, less is known about how engram cells are affected by forgetting. We describe a form of interference-based forgetting using an object memory behavioral paradigm. By using activity-dependent cell labeling, we show that although retroactive interference results in decreased engram cell reactivation during recall trials, optogenetic stimulation of the labeled engram cells is sufficient to induce memory retrieval. Forgotten engrams may be reinstated via the presentation of similar or related environmental information. Furthermore, we demonstrate that engram activity is necessary for interference to occur. Taken together, these findings indicate that retroactive interference modules engram expression in a manner that is both reversible and updatable. Inference may constitute a form of adaptive forgetting where, in everyday life, new perceptual and environmental inputs modulate the natural forgetting process.
Topics: Memory; Memory, Long-Term; Mental Recall; Optogenetics
PubMed: 37590145
DOI: 10.1016/j.celrep.2023.112999 -
Developmental Neurobiology 2023Social memories formed in early life, like those for family and unrelated peers, are known to contribute to healthy social interactions throughout life, although how the... (Review)
Review
Social memories formed in early life, like those for family and unrelated peers, are known to contribute to healthy social interactions throughout life, although how the developing brain supports social memory remains relatively unexplored. The CA2 subregion of the hippocampus is involved in social memory function, but most literature on this subject is restricted to studies of adult rodents. Here, we review the current literature on the embryonic and postnatal development of hippocampal subregion CA2 in mammals, with a focus on the emergence of its unusual molecular and cellular characteristics, including its notably high expression of plasticity-suppressing molecules. We also consider the connectivity of the CA2 with other brain areas, including intrahippocampal regions, such as the dentate gyrus, CA3, and CA1 regions, and extrahippocampal regions, such as the hypothalamus, ventral tegmental area, basal forebrain, raphe nuclei, and the entorhinal cortex. We review developmental milestones of CA2 molecular, cellular, and circuit-level features that may contribute to emerging social recognition abilities for kin and unrelated conspecifics in early life. Lastly, we consider genetic mouse models related to neurodevelopmental disorders in humans in order to survey evidence about whether atypical formation of the CA2 may contribute to social memory dysfunction.
Topics: Humans; Mice; Animals; CA2 Region, Hippocampal; Hippocampus; Recognition, Psychology; Entorhinal Cortex; CA1 Region, Hippocampal; Mammals
PubMed: 37326250
DOI: 10.1002/dneu.22919 -
Journal of Neuroinflammation Nov 2023Previously we reported that inhibition of GPR17 prevents amyloid β 1-42 (Aβ)-induced cognitive impairment in mice. However, the role of GPR17 on cognition is still...
BACKGROUND
Previously we reported that inhibition of GPR17 prevents amyloid β 1-42 (Aβ)-induced cognitive impairment in mice. However, the role of GPR17 on cognition is still largely unknown.
METHODS
Herein, we used a mouse model of cognitive impairment induced by lipopolysaccharide (LPS) to further investigate the role of GPR17 in cognition and its potential mechanism. The mice were pretreated with GPR17 shRNA lentivirus and cangrelor by microinjection into the dentate gyrus (DG) region of the hippocampus. After 21 days, LPS (0.25 mg/kg, i.p.) was administered for 7 days. Animal behavioral tests as well as pathological and biochemical assays were performed to evaluate the cognitive function in mice.
RESULTS
LPS exposure resulted in a significant increase in GPR17 expression at both protein and mRNA levels in the hippocampus. Gene reduction and pharmacological blockade of GPR17 improved cognitive impairment in both the Morris water maze and novel object recognition tests. Knockdown and inhibition of GPR17 inhibited Aβ production, decreased the expression of NF-κB p65, increased CREB phosphorylation and elevated BDNF expression, suppressed the accumulation of pro-inflammatory cytokines, inhibited Glial cells (microglia and astrocytes) activation, and increased Bcl-2, PSD-95, and SYN expression, reduced Bax expression as well as decreased caspase-3 activity and TUNEL-positive cells in the hippocampus of LPS-treated mice. Notably, knockdown and inhibition of GPR17 not only provided protective effects against cholinergic dysfunction but also facilitated the regulation of oxidative stress. In addition, cangrelor pretreatment can effectively inhibit the expression of inflammatory cytokines by suppressing NF-κB/CREB/BDNF signaling in BV-2 cells stimulated by LPS. However, activation of hippocampal GPR17 with MDL-29951 induced cognitive impairment in normal mice.
CONCLUSIONS
These observations indicate that GPR17 may possess a neuroprotective effect against LPS-induced cognition deficits, and neuroinflammation by modulation of NF-κB/CREB/BDNF signaling in mice, indicating that GPR17 may be a promising new target for the prevention and treatment of AD.
Topics: Mice; Animals; Lipopolysaccharides; NF-kappa B; Brain-Derived Neurotrophic Factor; Amyloid beta-Peptides; Cognitive Dysfunction; Cytokines; Microglia; Hippocampus; Nerve Tissue Proteins; Receptors, G-Protein-Coupled
PubMed: 37990234
DOI: 10.1186/s12974-023-02958-9