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Translational Psychiatry Oct 2021Lithium is a first-line treatment for bipolar disorder, where it acts as a mood-stabilizing agent. Although its precise mechanism remains unclear, neuroimaging studies...
Lithium is a first-line treatment for bipolar disorder, where it acts as a mood-stabilizing agent. Although its precise mechanism remains unclear, neuroimaging studies have shown that lithium accumulates in the hippocampus and that chronic use amongst bipolar disorder patients is associated with larger hippocampal volumes. Here, we tested the chronic effects of low (0.75 mM) and high (2.25 mM) doses of lithium on human hippocampal progenitor cells and used immunocytochemistry to investigate the effects of lithium on cell parameters implicated in neurogenesis. Corresponding RNA-sequencing and gene-set enrichment analyses were used to evaluate whether genes affected by lithium in our model overlap with those regulating the volume of specific layers of the dentate gyrus. We observed that high-dose lithium treatment in human hippocampal progenitors increased the generation of neuroblasts (P ≤ 0.01), neurons (P ≤ 0.01), and glia (P ≤ 0.001), alongside the expression of genes, which regulate the volume of the molecular layer of the dentate gyrus. This study provides empirical support that adult hippocampal neurogenesis and gliogenesis are mechanisms that could contribute to the effects of lithium on human hippocampal volume.
Topics: Dentate Gyrus; Hippocampus; Humans; Lithium; Lithium Compounds; Neurogenesis; Neurons
PubMed: 34718328
DOI: 10.1038/s41398-021-01695-y -
Journal of Neuroinflammation Jun 2023Neuroinflammation and microglia play critical roles in the development of depression. Cluster of differentiation 200 (CD200) is an anti-inflammatory glycoprotein that is...
BACKGROUND
Neuroinflammation and microglia play critical roles in the development of depression. Cluster of differentiation 200 (CD200) is an anti-inflammatory glycoprotein that is mainly expressed in neurons, and its receptor CD200R1 is primarily in microglia. Although the CD200-CD200R1 pathway is necessary for microglial activation, its role in the pathophysiology of depression remains unknown.
METHODS
The chronic social defeat stress (CSDS) with behavioral tests were performed to investigate the effect of CD200 on the depressive-like behaviors. Viral vectors were used to overexpress or knockdown of CD200. The levels of CD200 and inflammatory cytokines were tested with molecular biological techniques. The status of microglia, the expression of BDNF and neurogenesis were detected with immunofluorescence imaging.
RESULTS
We found that the expression of CD200 was decreased in the dentate gyrus (DG) region of mice experienced CSDS. Overexpression of CD200 alleviated the depressive-like behaviors of stressed mice and inhibition of CD200 facilitated the susceptibility to stress. When CD200R1 receptors on microglia were knocked down, CD200 was unable to exert its role in alleviating depressive-like behavior. Microglia in the DG brain region were morphologically activated after exposure to CSDS. In contrast, exogenous administration of CD200 inhibited microglia hyperactivation, alleviated neuroinflammatory response in hippocampus, and increased the expression of BDNF, which in turn ameliorated adult hippocampal neurogenesis impairment in the DG induced by CSDS.
CONCLUSIONS
Taken together, these results suggest that CD200-mediated alleviation of microglia hyperactivation contributes to the antidepressant effect of neurogenesis in dentate gyrus in mice.
Topics: Animals; Mice; Brain-Derived Neurotrophic Factor; Microglia; Hippocampus; Neurogenesis; Dentate Gyrus
PubMed: 37391731
DOI: 10.1186/s12974-023-02836-4 -
International Journal of Molecular... Apr 2022The dentate gyrus (DG), an important part of the hippocampus, plays a significant role in learning, memory, and emotional behavior. Factors potentially influencing... (Review)
Review
The dentate gyrus (DG), an important part of the hippocampus, plays a significant role in learning, memory, and emotional behavior. Factors potentially influencing normal development of neurons and glial cells in the DG during its maturation can exert long-lasting effects on brain functions. Early life stress may modify maturation of the DG and induce lifelong alterations in its structure and functioning, underlying brain pathologies in adults. In this paper, maturation of neurons and glial cells (microglia and astrocytes) and the effects of early life events on maturation processes in the DG have been comprehensively reviewed. Early postnatal interventions affecting the DG eventually result in an altered number of granule neurons in the DG, ectopic location of neurons and changes in adult neurogenesis. Adverse events in early life provoke proinflammatory changes in hippocampal glia at cellular and molecular levels immediately after stress exposure. Later, the cellular changes may disappear, though alterations in gene expression pattern persist. Additional stressful events later in life contribute to manifestation of glial changes and behavioral deficits. Alterations in the maturation of neuronal and glial cells induced by early life stress are interdependent and influence the development of neural nets, thus predisposing the brain to the development of cognitive and psychiatric disorders.
Topics: Dentate Gyrus; Hippocampus; Humans; Neurogenesis; Neuroglia; Neurons
PubMed: 35457079
DOI: 10.3390/ijms23084261 -
Biological Psychiatry Jun 2023The dentate gyrus, a "gate" that controls the flow of information into the hippocampus, is critical for learning, memory, spatial navigation, and mood regulation.... (Review)
Review
The dentate gyrus, a "gate" that controls the flow of information into the hippocampus, is critical for learning, memory, spatial navigation, and mood regulation. Several lines of evidence have demonstrated that deficits in dentate granule cells (DGCs) (e.g., loss of DGCs or genetic mutations in DGCs) contribute to the development of various psychiatric disorders, such as depression and anxiety disorders. Whereas ventral DGCs are believed to be critical for mood regulation, the functions of dorsal DGCs in this regard remain elusive. Here, we review the role of DGCs, in particular the dorsal DGCs, in the regulation of mood, their functional relationships with DGC development, and the contributions of dysfunctional DGCs to mental disorders.
Topics: Humans; Dentate Gyrus; Neurons; Hippocampus; Learning; Mental Disorders; Neurogenesis
PubMed: 36894487
DOI: 10.1016/j.biopsych.2023.01.005 -
The Journal of Neuroscience : the... Sep 2022Post-traumatic epilepsy (PTE) and behavioral comorbidities frequently develop after traumatic brain injury (TBI). Aberrant neurogenesis of dentate granule cells (DGCs)...
Post-traumatic epilepsy (PTE) and behavioral comorbidities frequently develop after traumatic brain injury (TBI). Aberrant neurogenesis of dentate granule cells (DGCs) after TBI may contribute to the synaptic reorganization that occurs in PTE, but how neurogenesis at different times relative to the injury contributes to feedback inhibition and recurrent excitation in the dentate gyrus is unknown. Thus, we examined whether DGCs born at different postnatal ages differentially participate in feedback inhibition and recurrent excitation in the dentate gyrus using the controlled cortical impact (CCI) model of TBI. Both sexes of transgenic mice expressing channelrhodopsin2 (ChR2) in postnatally born DGCs were used for optogenetic activation of three DGC cohorts: postnatally early born DGCs, or those born just before or after CCI. We performed whole-cell patch-clamp recordings from ChR2-negative, mature DGCs and parvalbumin-expressing basket cells (PVBCs) in hippocampal slices to determine whether optogenetic activation of postnatally born DGCs increases feedback inhibition and/or recurrent excitation in mice 8-10 weeks after CCI and whether PVBCs are targets of ChR2-positive DGCs. In the dentate gyrus ipsilateral to CCI, activation of ChR2-expressing DGCs born before CCI produced increased feedback inhibition in ChR2-negative DGCs and increased excitation in PVBCs compared with those from sham controls. This upregulated feedback inhibition was less prominent in DGCs born early in life or after CCI. Surprisingly, ChR2-positive DGC activation rarely evoked recurrent excitation in mature DGCs from any cohort. These results support that DGC birth date-related increased feedback inhibition in of DGCs may contribute to altered excitability after TBI. Dentate granule cells (DGCs) control excitability of the dentate gyrus through synaptic interactions with inhibitory GABAergic interneurons. Persistent changes in DGC synaptic connectivity develop after traumatic brain injury, contributing to hyperexcitability in post-traumatic epilepsy (PTE). However, the impact of DGC neurogenesis on synaptic reorganization, especially on inhibitory circuits, after brain injury is not adequately described. Here, upregulation of feedback inhibition in mature DGCs from male and female mice was associated with increased excitation of parvalbumin-expressing basket cells by postnatally born DGCs, providing novel insights into underlying mechanisms of altered excitability after brain injury. A better understanding of these inhibitory circuit changes can help formulate hypotheses for development of novel, evidence-based treatments for post-traumatic epilepsy by targeting birth date-specific subsets of DGCs.
Topics: Animals; Brain Injuries; Brain Injuries, Traumatic; Dentate Gyrus; Disease Models, Animal; Epilepsy, Post-Traumatic; Feedback; Female; Humans; Male; Mice; Mice, Transgenic; Parvalbumins; Up-Regulation
PubMed: 36002261
DOI: 10.1523/JNEUROSCI.2263-21.2022 -
Cerebral Cortex (New York, N.Y. : 1991) Aug 2021Human AUTS2 mutations are linked to a syndrome of intellectual disability, autistic features, epilepsy, and other neurological and somatic disorders. Although it is...
Human AUTS2 mutations are linked to a syndrome of intellectual disability, autistic features, epilepsy, and other neurological and somatic disorders. Although it is known that this unique gene is highly expressed in developing cerebral cortex, the molecular and developmental functions of AUTS2 protein remain unclear. Using proteomics methods to identify AUTS2 binding partners in neonatal mouse cerebral cortex, we found that AUTS2 associates with multiple proteins that regulate RNA transcription, splicing, localization, and stability. Furthermore, AUTS2-containing protein complexes isolated from cortical tissue bound specific RNA transcripts in RNA immunoprecipitation and sequencing assays. Deletion of all major functional isoforms of AUTS2 (full-length and C-terminal) by conditional excision of exon 15 caused breathing abnormalities and neonatal lethality when Auts2 was inactivated throughout the developing brain. Mice with limited inactivation of Auts2 in cerebral cortex survived but displayed abnormalities of cerebral cortex structure and function, including dentate gyrus hypoplasia with agenesis of hilar mossy neurons, and abnormal spiking activity on EEG. Also, RNA transcripts that normally associate with AUTS2 were dysregulated in mutant mice. Together, these findings indicate that AUTS2 regulates RNA metabolism and is essential for development of cerebral cortex, as well as subcortical breathing centers.
Topics: Animals; Animals, Newborn; Cerebral Cortex; Cytoskeletal Proteins; Dentate Gyrus; Electroencephalography; Exons; Gene Deletion; Gene Expression Regulation; Intellectual Disability; Mice; Mice, Inbred C57BL; RNA; RNA-Seq; Respiration; Transcription Factors
PubMed: 34013328
DOI: 10.1093/cercor/bhab124 -
Neuroscience Letters Aug 2021The subgranular zone of the dentate gyrus provides a local microenvironment (niche) for neural stem cells. In the adult brain, it has been established that the vascular... (Review)
Review
The subgranular zone of the dentate gyrus provides a local microenvironment (niche) for neural stem cells. In the adult brain, it has been established that the vascular compartment of such niches has a significant role in regulating adult hippocampal neurogenesis. More recently, evidence showed that neurovascular coupling, the relationship between blood flow and neuronal activity, also regulates hippocampal neurogenesis. Here, we review the most recent articles on addressing the intricate relationship between neurovasculature and adult hippocampal neurogenesis and a novel pathway where functional hyperemia enhances hippocampal neurogenesis. In the end, we have further reviewed recent research showing that impaired neurovascular coupling may cause declined neurogenesis and contribute to brain damage in neurodegenerative diseases.
Topics: Adult; Alzheimer Disease; Animals; Dentate Gyrus; Disease Models, Animal; Humans; Interneurons; Neovascularization, Physiologic; Neural Stem Cells; Neurogenesis; Nitric Oxide Synthase Type I; Parvalbumins; Vascular Endothelial Growth Factor A
PubMed: 34147540
DOI: 10.1016/j.neulet.2021.136071 -
Glia Aug 2022The entorhinal cortex-dentate gyrus circuit is centrally involved in memory processing conveying to the hippocampus spatial and nonspatial context information via,... (Review)
Review
The entorhinal cortex-dentate gyrus circuit is centrally involved in memory processing conveying to the hippocampus spatial and nonspatial context information via, respectively, medial and lateral perforant path (MPP and LPP) excitatory projections onto dentate granule cells (GCs). Here, we review work of several years from our group showing that astrocytes sense local synaptic transmission and exert in turn a presynaptic control at PP-GC synapses. Modulation of neurotransmitter release probability by astrocytes sets basal synaptic strength and dynamic range for long-term potentiation of PP-GC synapses. Intriguingly, this astrocyte control is circuit-specific, being present only at MPP-GC (not LPP-GC) synapses, which selectively express atypical presynaptic N-methyl-D-aspartate receptors (NMDAR) suitable to activation by astrocyte-released glutamate. Moreover, the astrocytic control is peculiarly dependent on the cytokine TNFα, which at constitutive levels acts as a gating factor for the astrocyte signaling. During inflammation/infection processes, increased levels of TNFα lead to uncontrolled astrocyte glutamate release, altered PP-GC circuit processing and, ultimately, impaired contextual memory performance. The TNFα-dependent pathological switch of the synaptic control from astrocytes and its deleterious consequences are observed in animal models of HIV brain infection and multiple sclerosis, conditions both known to cause cognitive disturbances in up to 50% of patients. The review also discusses open issues related to the identified astrocytic pathway: its role in contextual memory processing, potential damaging role in Alzheimer's disease, the existence of vesicular glutamate release from DG astrocytes, and the possible synaptic-like connectivity between astrocytic output sites and PP receptive sites.
Topics: Animals; Astrocytes; Cognition; Dentate Gyrus; Entorhinal Cortex; Glutamic Acid; Humans; Synapses; Tumor Necrosis Factor-alpha
PubMed: 34904753
DOI: 10.1002/glia.24128 -
Cell Reports Feb 2023The central circadian regulator within the suprachiasmatic nucleus transmits time of day information by a diurnal spiking rhythm driven by molecular clock genes...
The central circadian regulator within the suprachiasmatic nucleus transmits time of day information by a diurnal spiking rhythm driven by molecular clock genes controlling membrane excitability. Most brain regions, including the hippocampus, harbor similar intrinsic circadian transcriptional machinery, but whether these molecular programs generate oscillations of membrane properties is unclear. Here, we show that intrinsic excitability of mouse dentate granule neurons exhibits a 24-h oscillation that controls spiking probability. Diurnal changes in excitability are mediated by antiphase G-protein regulation of potassium and sodium currents that reduce excitability during the Light phase. Disruption of the circadian transcriptional machinery by conditional deletion of Bmal1 enhances excitability selectively during the Light phase by removing G-protein regulation. These results reveal that circadian transcriptional machinery regulates intrinsic excitability by coordinated regulation of ion channels by G-protein signaling, highlighting a potential novel mechanism of cell-autonomous oscillations.
Topics: Mice; Animals; Circadian Rhythm; Neurons; Suprachiasmatic Nucleus; GTP-Binding Proteins; Dentate Gyrus; Circadian Clocks
PubMed: 36749664
DOI: 10.1016/j.celrep.2023.112039 -
Cell Reports Mar 2024Engrams, or the physical substrate of memory, recruit heterogeneous cell types. Targeted reactivation of neurons processing discrete memories drives the behavioral...
Engrams, or the physical substrate of memory, recruit heterogeneous cell types. Targeted reactivation of neurons processing discrete memories drives the behavioral expression of memory, though the underlying landscape of recruited cells and their real-time responses remain elusive. To understand how artificial stimulation of fear affects intra-hippocampal neuron-astrocyte dynamics as well as their behavioral consequences, we express channelrhodopsin-2 in an activity-dependent manner within dentate gyrus neurons while recording both cell types with fiber photometry in hippocampal ventral CA1 across learning and memory. Both cell types exhibit shock responsiveness, with astrocytic calcium events uniquely modulated by fear conditioning. Optogenetic stimulation of a hippocampus-mediated engram recapitulates coordinated calcium signatures time locked to freezing, mirroring those observed during natural fear memory recall. Our findings reveal cell-type-specific dynamics in the hippocampus during freezing behavior, emphasizing neuronal-astrocytic coupling as a shared mechanism enabling both natural and artificially induced memory retrieval and the behavioral expression of fear.
Topics: Dentate Gyrus; Calcium; Memory; Hippocampus; Fear
PubMed: 38401120
DOI: 10.1016/j.celrep.2024.113850