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Nature Reviews. Neuroscience Aug 2023There has been considerable speculation regarding the function of the dentate gyrus (DG) - a subregion of the mammalian hippocampus - in learning and memory. In this... (Review)
Review
There has been considerable speculation regarding the function of the dentate gyrus (DG) - a subregion of the mammalian hippocampus - in learning and memory. In this Perspective article, we compare leading theories of DG function. We note that these theories all critically rely on the generation of distinct patterns of activity in the region to signal differences between experiences and to reduce interference between memories. However, these theories are divided by the roles they attribute to the DG during learning and recall and by the contributions they ascribe to specific inputs or cell types within the DG. These differences influence the information that the DG is thought to impart to downstream structures. We work towards a holistic view of the role of DG in learning and memory by first developing three critical questions to foster a dialogue between the leading theories. We then evaluate the extent to which previous studies address our questions, highlight remaining areas of conflict, and suggest future experiments to bridge these theories.
Topics: Animals; Humans; Dentate Gyrus; Hippocampus; Mental Recall; Learning; Mammals
PubMed: 37316588
DOI: 10.1038/s41583-023-00710-z -
Journal of Neuroinflammation Nov 2023As one of most common and severe mental disorders, major depressive disorder (MDD) significantly increases the risks of premature death and other medical conditions for... (Review)
Review
As one of most common and severe mental disorders, major depressive disorder (MDD) significantly increases the risks of premature death and other medical conditions for patients. Neuroinflammation is the abnormal immune response in the brain, and its correlation with MDD is receiving increasing attention. Neuroinflammation has been reported to be involved in MDD through distinct neurobiological mechanisms, among which the dysregulation of neurogenesis in the dentate gyrus (DG) of the hippocampus (HPC) is receiving increasing attention. The DG of the hippocampus is one of two niches for neurogenesis in the adult mammalian brain, and neurotrophic factors are fundamental regulators of this neurogenesis process. The reported cell types involved in mediating neuroinflammation include microglia, astrocytes, oligodendrocytes, meningeal leukocytes, and peripheral immune cells which selectively penetrate the blood-brain barrier and infiltrate into inflammatory regions. This review summarizes the functions of the hippocampus affected by neuroinflammation during MDD progression and the corresponding influences on the memory of MDD patients and model animals.
Topics: Adult; Animals; Humans; Depressive Disorder, Major; Depression; Neuroinflammatory Diseases; Hippocampus; Neurogenesis; Mammals
PubMed: 38012702
DOI: 10.1186/s12974-023-02964-x -
Frontiers in Immunology 2023Adult hippocampal neurogenesis generates functional neurons from neural progenitor cells in the hippocampal dentate gyrus (DG) to complement and repair neurons and... (Review)
Review
Adult hippocampal neurogenesis generates functional neurons from neural progenitor cells in the hippocampal dentate gyrus (DG) to complement and repair neurons and neural circuits, thus benefiting the treatment of depression. Increasing evidence has shown that aberrant microglial activity can disrupt the appropriate formation and development of functional properties of neurogenesis, which will play a crucial role in the occurrence and development of depression. However, the mechanisms of the crosstalk between microglia and adult hippocampal neurogenesis in depression are not yet fully understood. Therefore, in this review, we first introduce recent discoveries regarding the roles of microglia and adult hippocampal neurogenesis in the etiology of depression. Then, we systematically discuss the possible mechanisms of how microglia regulate adult hippocampal neurogenesis in depression according to recent studies, which involve toll-like receptors, microglial polarization, fractalkine-C-X3-C motif chemokine receptor 1, hypothalamic-pituitary-adrenal axis, cytokines, brain-derived neurotrophic factor, and the microbiota-gut-brain axis, etc. In addition, we summarize the promising drugs that could improve the adult hippocampal neurogenesis by regulating the microglia. These findings will help us understand the complicated pathological mechanisms of depression and shed light on the development of new treatment strategies for this disease.
Topics: Depression; Microglia; Hypothalamo-Hypophyseal System; Pituitary-Adrenal System; Hippocampus; Neurogenesis
PubMed: 37881439
DOI: 10.3389/fimmu.2023.1193053 -
Current Opinion in Neurobiology Aug 2023Cerebellins (Cbln1-4) are secreted adaptor proteins that connect presynaptic neurexins (Nrxn1-3) to postsynaptic ligands (GluD1/2 for Cbln1-3 vs. DCC and Neogenin-1 for... (Review)
Review
Cerebellins (Cbln1-4) are secreted adaptor proteins that connect presynaptic neurexins (Nrxn1-3) to postsynaptic ligands (GluD1/2 for Cbln1-3 vs. DCC and Neogenin-1 for Cbln4). Classical studies demonstrated that neurexin-Cbln1-GluD2 complexes organize cerebellar parallel-fiber synapses, but the role of cerebellins outside of the cerebellum has only recently been clarified. In synapses of the hippocampal subiculum and prefrontal cortex, Nrxn1-Cbln2-GluD1 complexes strikingly upregulate postsynaptic NMDA-receptors, whereas Nrxn3-Cbln2-GluD1 complexes conversely downregulate postsynaptic AMPA-receptors. At perforant-path synapses in the dentate gyrus, in contrast, neurexin/Cbln4/Neogenin-1 complexes are essential for LTP without affecting basal synaptic transmission or NMDA- or AMPA-receptors. None of these signaling pathways are required for synapse formation. Thus, outside of the cerebellum neurexin/cerebellin complexes regulate synapse properties by activating specific downstream receptors.
Topics: N-Methylaspartate; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Nerve Tissue Proteins; Synapses; Receptors, AMPA
PubMed: 37209532
DOI: 10.1016/j.conb.2023.102727 -
Neuron Dec 2023Investigations of memory mechanisms have been, thus far, neuron centric, despite the brain comprising diverse cell types. Using rats and mice, we assessed the...
Investigations of memory mechanisms have been, thus far, neuron centric, despite the brain comprising diverse cell types. Using rats and mice, we assessed the cell-type-specific contribution of hippocampal insulin-like growth factor 2 (IGF2), a polypeptide regulated by learning and required for long-term memory formation. The highest level of hippocampal IGF2 was detected in pericytes, the multi-functional mural cells of the microvessels that regulate blood flow, vessel formation, the blood-brain barrier, and immune cell entry into the central nervous system. Learning significantly increased pericytic Igf2 expression in the hippocampus, particularly in the highly vascularized stratum lacunosum moleculare and stratum moleculare layers of the dentate gyrus. Igf2 increases required neuronal activity. Regulated hippocampal Igf2 knockout in pericytes, but not in fibroblasts or neurons, impaired long-term memories and blunted the learning-dependent increase of neuronal immediate early genes (IEGs). Thus, neuronal activity-driven signaling from pericytes to neurons via IGF2 is essential for long-term memory.
Topics: Animals; Mice; Rats; Hippocampus; Memory, Long-Term; Neurons; Pericytes; Signal Transduction
PubMed: 37788670
DOI: 10.1016/j.neuron.2023.08.030 -
Autophagy Apr 2024Macroautophagy/autophagy is the intracellular degradation process of cytoplasmic content and damaged organelles. Autophagy is strongly associated with the progression of...
Macroautophagy/autophagy is the intracellular degradation process of cytoplasmic content and damaged organelles. Autophagy is strongly associated with the progression of Alzheimer disease (AD). Microglia are brain-resident macrophages, and recent studies indicate that autophagy in microglia protects neurons from neurodegeneration. Postnatal neurogenesis, the generation of new neurons from adult neural stem cells (NSCs), is impaired in AD patients as well as in AD animal models. However, the extent to which microglial autophagy influences adult NSCs and neurogenesis in AD animal models has not been studied. Here, we showed that conditional knock out (cKO) of (autophagy related 5) in microglia inhibited postnatal neurogenesis in the dentate gyrus (DG) of the hippocampus, but not in the subventricular zone (SVZ) of a 5×FAD mouse model. Interestingly, the protection of neurogenesis by in microglia was only observed in female AD mice. To confirm the roles of autophagy in microglia for postnatal hippocampal neurogenesis, we generated additional cKO mice to delete autophagy essential genes or in microglia. However, these cKO and cKO mice did not exhibit neurogenesis defects in the context of a female AD mouse model. Last, we used the CSF1R antagonist to deplete ATG5-deficient microglia and this intervention restored neurogenesis in the hippocampus of 5×FAD mice. These results indicate that microglial ATG5 is essential to maintain postnatal hippocampal neurogenesis in a mouse model of AD. Our findings further support the notion that ATG5 in microglia supports NSC health and may prevent neurodegeneration. 5×FAD: familial Alzheimer disease; Aβ: β-amyloid; AD: Alzheimer disease; AIF1: allograft inflammatory factor 1; ATG: autophagy related; BrdU: 5-bromo-2'-deoxyuridine; CA: Cornu Ammonis; cKO: conditional knock out; CSF1R: colony stimulating factor 1 receptor; Ctrl: control; DCX: doublecortin; DG: dentate gyrus; GFAP: glial fibrillary acidic protein; GZ: granular zone; H&E: hematoxylin and eosin; IF: immunofluorescence; LD: lipid droplet; LDAM: lipid droplets accumulated microglia; LPS: lipopolysaccharides; MAP1LC3B/LC3: microtubule-associated protein 1 light chain 3 beta; NSCs: neural stem cells; RB1CC1: RB1-inducible coiled-coil 1; SOX2: SRY (sex determining region Y)-box 2; SGZ: subgranular zone; SVZ: subventricular zone; WT: wild type.
Topics: Animals; Neurogenesis; Microglia; Autophagy-Related Protein 5; Alzheimer Disease; Hippocampus; Autophagy; Mice, Knockout; Female; Mice; Neural Stem Cells; Dentate Gyrus; Male; Disease Models, Animal; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; Doublecortin Protein; Autophagy-Related Proteins
PubMed: 37915255
DOI: 10.1080/15548627.2023.2277634 -
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