-
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 -
Cell Reports Dec 2021Specific classes of GABAergic neurons play specific roles in regulating information processing in the brain. In the hippocampus, two major classes,...
Specific classes of GABAergic neurons play specific roles in regulating information processing in the brain. In the hippocampus, two major classes, parvalbumin-expressing (PV) and somatostatin-expressing (SST), differentially regulate endogenous firing patterns and target subcellular compartments of principal cells. How these classes regulate the flow of information throughout the hippocampus is poorly understood. We hypothesize that PV and SST interneurons in the dentate gyrus (DG) and CA3 differentially modulate CA3 patterns of output, thereby altering the influence of CA3 on CA1. We find that while suppressing either interneuron class increases DG and CA3 output, the effects on CA1 were very different. Suppressing PV interneurons increases local field potential signatures of coupling from CA3 to CA1 and decreases signatures of coupling from entorhinal cortex to CA1; suppressing SST interneurons has the opposite effect. Thus, DG and CA3 PV and SST interneurons bidirectionally modulate the flow of information through the hippocampal circuit.
Topics: Action Potentials; Animals; CA1 Region, Hippocampal; CA3 Region, Hippocampal; Dentate Gyrus; Entorhinal Cortex; Female; GABAergic Neurons; Interneurons; Male; Mice; Mice, Inbred C57BL; Somatostatin
PubMed: 34965435
DOI: 10.1016/j.celrep.2021.110159 -
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 -
Neurobiology of Disease Feb 2020Pten, a gene associated with autism spectrum disorder, is an upstream regulator of receptor tyrosine kinase intracellular signaling pathways that mediate extracellular...
Pten, a gene associated with autism spectrum disorder, is an upstream regulator of receptor tyrosine kinase intracellular signaling pathways that mediate extracellular cues to inform cellular development and activity-dependent plasticity. We therefore hypothesized that Pten loss would interfere with activity dependent dendritic growth. We investigated the effects of this interaction on the maturation of retrovirally labeled postnatally generated wild-type and Pten knockout granule neurons in male and female mouse dentate gyrus while using chemogenetics to manipulate the activity of the perforant path afferents. We find that enhancing network activity accelerates the dendritic outgrowth of wild-type, but not Pten knockout, neurons. This was specific to immature neurons during an early developmental window. We also examined synaptic connectivity and physiological measures of neuron maturation. The input resistance, membrane capacitance, dendritic spine morphology, and frequency of spontaneous synaptic events were not differentially altered by activity in wild-type versus Pten knockout neurons. Therefore, Pten and its downstream signaling pathways regulate the activity-dependent sculpting of the dendritic arbor during neuronal maturation.
Topics: Action Potentials; Animals; Dendritic Spines; Dentate Gyrus; Female; Male; Mice, Transgenic; PTEN Phosphohydrolase; Synapses
PubMed: 31838155
DOI: 10.1016/j.nbd.2019.104703 -
Molecular Psychiatry Apr 2024Astrocytes, a major glial cell type in the brain, are indispensable for the integration, maintenance and survival of neurons during development and adulthood. Both life... (Review)
Review
Astrocytes, a major glial cell type in the brain, are indispensable for the integration, maintenance and survival of neurons during development and adulthood. Both life phases make specific demands on the molecular and physiological properties of astrocytes, and most research projects traditionally focus on either developmental or adult astrocyte functions. In most brain regions, the generation of brain cells and the establishment of neural circuits ends with postnatal development. However, few neurogenic niches exist in the adult brain in which new neurons and glial cells are produced lifelong, and the integration of new cells into functional circuits represent a very special form of plasticity. Consequently, in the neurogenic niche, the astrocytes must be equipped to execute both mature and developmental tasks in order to integrate newborn neurons into the circuit and yet maintain overall homeostasis without affecting the preexisting neurons. In this review, we focus on astrocytes of the hippocampal dentate gyrus (DG), and discuss specific features of the astrocytic compartment that may allow the execution of both tasks. Firstly, astrocytes of the adult DG are molecularly, morphologically and functionally diverse, and the distinct astrocytes subtypes are characterized by their localization to DG layers. This spatial separation may lead to a functional specification of astrocytes subtypes according to the neuronal structures they are embedded in, hence a division of labor. Secondly, the astrocytic compartment is not static, but steadily increasing in numbers due to lifelong astrogenesis. Interestingly, astrogenesis can adapt to environmental and behavioral stimuli, revealing an unexpected astrocyte dynamic that allows the niche to adopt to changing demands. The diversity and dynamic of astrocytes in the adult DG implicate a vital contribution to hippocampal plasticity and represent an interesting model to uncover mechanisms how astrocytes simultaneously fulfill developmental and adult tasks.
Topics: Astrocytes; Dentate Gyrus; Humans; Animals; Neurogenesis; Neurons; Adult; Neuronal Plasticity
PubMed: 38177351
DOI: 10.1038/s41380-023-02386-4 -
ENeuro May 2023Exercise may prevent or delay aging-related memory loss and neurodegeneration. In rodents, running increases the number of adult-born neurons in the dentate gyrus (DG)...
Exercise may prevent or delay aging-related memory loss and neurodegeneration. In rodents, running increases the number of adult-born neurons in the dentate gyrus (DG) of the hippocampus, in association with improved synaptic plasticity and memory function. However, it is unclear whether adult-born neurons remain fully integrated into the hippocampal network during aging and whether long-term running affects their connectivity. To address this issue, we labeled proliferating DG neural progenitor cells with retrovirus expressing the avian TVA receptor in two-month-old sedentary and running male C57Bl/6 mice. More than six months later, we injected EnvA-pseudotyped rabies virus into the DG as a monosynaptic retrograde tracer, to selectively infect TVA expressing "old" new neurons. We identified and quantified the direct afferent inputs to these adult-born neurons within the hippocampus and (sub)cortical areas. Here, we show that long-term running substantially modifies the network of the neurons generated in young adult mice, upon middle-age. Exercise increases input from hippocampal interneurons onto "old" adult-born neurons, which may play a role in reducing aging-related hippocampal hyperexcitability. In addition, running prevents the loss of adult-born neuron innervation from perirhinal cortex, and increases input from subiculum and entorhinal cortex, brain areas that are essential for contextual and spatial memory. Thus, long-term running maintains the wiring of "old" new neurons, born during early adulthood, within a network that is important for memory function during aging.
Topics: Mice; Male; Animals; Neurogenesis; Neurons; Hippocampus; Spatial Memory; Running; Dentate Gyrus
PubMed: 37188520
DOI: 10.1523/ENEURO.0084-23.2023 -
Science Immunology Jan 2021Senescent neuroblasts activate NK cells in the dentate gyrus of the aged brain, leading to neuronal destruction that impairs cognition.
Senescent neuroblasts activate NK cells in the dentate gyrus of the aged brain, leading to neuronal destruction that impairs cognition.
Topics: Brain; Dentate Gyrus; Killer Cells, Natural; Neurons
PubMed: 33419793
DOI: 10.1126/sciimmunol.abg3186 -
Development (Cambridge, England) Nov 2022The dentate gyrus, a gateway for input to the hippocampal formation, arises from progenitors in the medial telencephalic neuroepithelium adjacent to the cortical hem....
The dentate gyrus, a gateway for input to the hippocampal formation, arises from progenitors in the medial telencephalic neuroepithelium adjacent to the cortical hem. Dentate progenitors navigate a complex migratory path guided by two cell populations that arise from the hem, the fimbrial glia and Cajal-Retzius (CR) cells. As the hem expresses multiple Wnt genes, we examined whether β-catenin, which mediates canonical Wnt signaling and also participates in cell adhesion, is necessary for the development of hem-derived lineages. We report that, in mice, the fimbrial glial scaffold is disorganized and CR cells are mispositioned upon hem-specific disruption of β-catenin. Consequently, the dentate migratory stream is severely affected, and the dentate gyrus fails to form. Using selective Cre drivers, we further determined that β-catenin function is required in the fimbrial glial scaffold, but not in the CR cells, for guiding the dentate migration. Our findings highlight a primary requirement for β-catenin for the organization of the fimbrial scaffold and a secondary role for this factor in dentate gyrus morphogenesis.
Topics: Animals; Mice; beta Catenin; Dentate Gyrus; Hippocampus; Morphogenesis; Neuroglia; Neurons
PubMed: 36196585
DOI: 10.1242/dev.200953 -
Nature Communications Aug 2020New neurons are generated in adult mammals. Adult hippocampal neurogenesis is considered to play an important role in cognition and mental health. The number and... (Review)
Review
New neurons are generated in adult mammals. Adult hippocampal neurogenesis is considered to play an important role in cognition and mental health. The number and properties of newly born neurons are regulatable by a broad range of physiological and pathological conditions. To begin to understand the underlying cellular mechanisms and functional relevance of adult neurogenesis, many studies rely on quantification of adult-born neurons. However, lack of standardized methods to quantify new neurons is impeding research reproducibility across laboratories. Here, we review the importance of stereology, and propose why and how it should be applied to the study of adult neurogenesis.
Topics: Adult; Adult Stem Cells; Animals; Brain; Dentate Gyrus; Humans; Models, Neurological; Neural Stem Cells; Neurogenesis; Neuronal Plasticity
PubMed: 32848155
DOI: 10.1038/s41467-020-18046-y -
Bipolar Disorders Jun 2021As a common model for adverse early experience and depression, maternal separation (MS) is always used to investigate the psychological disease. Despite extensive and...
OBJECTIVES
As a common model for adverse early experience and depression, maternal separation (MS) is always used to investigate the psychological disease. Despite extensive and strong evidence verified the depression-like state induced by MS, little is known about the specific mechanism of MS. Therefore, the present study aimed to investigate the neurobiology mechanism of the MS-induced depression-like state.
METHODS
To verify the depression-like behaviors of offspring induced by MS, a series of behavioral tests were performed. Then, in vivo electroporation and three-dimensional reconstruction, combining with immunohistochemistry and BrdU labeling, were mainly used to explore the neurogenesis and synaptogenesis in postnatal dentate gyrus.
RESULTS
Prolonged MS indeed induced the depression-like behaviors of offspring in adulthood. Surprisingly, learning and memory were enhanced by prolonged MS. Further investigation indicated that prolonged MS inhibited the proliferation of neural stem cells, impaired the survival, and altered the fate decision of newborn cells, whereas the total length and terminal tips of dendrite, and the spine density, especially thin spine, were significantly increased in prolonged MS mice.
CONCLUSIONS
Our results elucidated that prolonged MS induced the depression-like state by impairing postnatal neurogenesis of dentate gyrus. Importantly, our results emphasized that prolonged MS increased the spine density, especially thin spine, by increasing the total length and number of terminal tips of dendrite, thereby enhancing learning and memory.
Topics: Animals; Bipolar Disorder; Dentate Gyrus; Maternal Deprivation; Mice; Neurogenesis
PubMed: 32805776
DOI: 10.1111/bdi.12986