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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 -
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 -
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 -
Biochimica Et Biophysica Acta.... Sep 2022Mossy cells (MCs) are glutamatergic cells of the dentate gyrus with an important role in temporal lobe epilepsy. Under physiological conditions MCs can control both... (Review)
Review
Mossy cells (MCs) are glutamatergic cells of the dentate gyrus with an important role in temporal lobe epilepsy. Under physiological conditions MCs can control both network excitations via direct synapses to granule cells and inhibition via connections to GABAergic interneurons innervating granule cells. In temporal lobe epilepsy mossy cell loss is one of the major hallmarks, but whether the surviving MCs drive or inhibit seizure initiation and generalization is still a debate. The aim of the present review is to summarize the latest findings on the role of mossy cells in healthy and overexcited hippocampus.
Topics: Epilepsy; Epilepsy, Temporal Lobe; Hippocampus; Humans; Mossy Fibers, Hippocampal; Seizures
PubMed: 35526721
DOI: 10.1016/j.bbamcr.2022.119279 -
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 -
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 -
Nature Communications Oct 2022The dentate gyrus (DG) output plays a key role in the emergence of spatial and contextual map representation within the hippocampus during learning. Differences in...
The dentate gyrus (DG) output plays a key role in the emergence of spatial and contextual map representation within the hippocampus during learning. Differences in neuronal network activity have been observed between left and right CA1-3 areas, implying lateralization in spatial coding properties. Whether bilateral differences of DG granule cell (GC) assemblies encoding spatial and contextual information exist remains largely unexplored. Here, we employed two-photon calcium imaging of the left or the right DG to record the activity of GC populations over five consecutive days in head-fixed mice navigating through familiar and novel virtual environments. Imaging revealed similar mean GC activity on both sides. However, spatial tuning, context-selectivity and run-to-run place field reliability was markedly higher for DG place cells in the left than the right hemisphere. Moreover, the proportion of GCs reconfiguring their place fields between contexts was greater in the left DG. Thus, our data suggest that contextual information is differentially processed by GC populations depending on the hemisphere, with higher context discrimination in the left but a bias towards generalization in the right DG.
Topics: Mice; Animals; Dentate Gyrus; Calcium; Reproducibility of Results; Hippocampus; Place Cells
PubMed: 36266288
DOI: 10.1038/s41467-022-34039-5 -
Translational Psychiatry Dec 2022Post-traumatic stress disorder (PTSD) is a psychiatric disorder vulnerable individuals can develop following a traumatic event, whereas others are resilient. Enhanced...
Post-traumatic stress disorder (PTSD) is a psychiatric disorder vulnerable individuals can develop following a traumatic event, whereas others are resilient. Enhanced insight into the mechanistic underpinnings contributing to these inter-individual differences in trauma susceptibility is key to improved treatment and prevention. Aberrant function of the hippocampal dentate gyrus (DG) may contribute to its psychopathology, with the dorsal DG potentially encoding trauma memory generalization and the ventral DG anxiety. Using a mouse model, we hypothesized that susceptibility to develop PTSD-like symptoms following trauma will be underpinned by aberrant DG structure and function. Mice were exposed to a traumatic event (unpredictable, inescapable foot shocks) and tested for PTSD-like symptomatology following recovery. In four independent experiments, DG neuronal morphology, synaptic protein gene and protein expression, and neuronal activity during trauma encoding and recall were assessed. Behaviorally, trauma-susceptible animals displayed increased anxiety-like behavior already prior to trauma, increased novelty-induced freezing, but no clear differences in remote trauma memory recall. Comparison of the ventral DG of trauma susceptible vs resilient mice revealed lower spine density, reduced expression of the postsynaptic protein homer1b/c gene and protein, a larger population of neurons active during trauma encoding, and a greater presence of somatostatin neurons. In contrast, the dorsal DG of trauma-susceptible animals did not differ in terms of spine density or gene expression but displayed more active neurons during trauma encoding and a lower amount of somatostatin neurons. Collectively, we here report on specific structural and functional changes in the ventral DG in trauma susceptible male mice.
Topics: Male; Animals; Somatostatin; Dentate Gyrus
PubMed: 36473832
DOI: 10.1038/s41398-022-02264-7 -
ELife Mar 2021The hippocampal dentate gyrus is an important relay conveying sensory information from the entorhinal cortex to the hippocampus proper. During exploration, the dentate...
The hippocampal dentate gyrus is an important relay conveying sensory information from the entorhinal cortex to the hippocampus proper. During exploration, the dentate gyrus has been proposed to act as a pattern separator. However, the dentate gyrus also shows structured activity during immobility and sleep. The properties of these activity patterns at cellular resolution, and their role in hippocampal-dependent memory processes have remained unclear. Using dual-color in vivo two-photon Ca imaging, we show that in immobile mice dentate granule cells generate sparse, synchronized activity patterns associated with entorhinal cortex activation. These population events are structured and modified by changes in the environment; and they incorporate place- and speed cells. Importantly, they are more similar than expected by chance to population patterns evoked during self-motion. Using optogenetic inhibition, we show that granule cell activity is not only required during exploration, but also during immobility in order to form dentate gyrus-dependent spatial memories.
Topics: Animals; Dentate Gyrus; Female; Immobilization; Male; Mice; Neuroimaging; Neurons; Optogenetics
PubMed: 33709911
DOI: 10.7554/eLife.65786