-
Cell Apr 2020Memories are believed to be encoded by sparse ensembles of neurons in the brain. However, it remains unclear whether there is functional heterogeneity within individual...
Memories are believed to be encoded by sparse ensembles of neurons in the brain. However, it remains unclear whether there is functional heterogeneity within individual memory engrams, i.e., if separate neuronal subpopulations encode distinct aspects of the memory and drive memory expression differently. Here, we show that contextual fear memory engrams in the mouse dentate gyrus contain functionally distinct neuronal ensembles, genetically defined by the Fos- or Npas4-dependent transcriptional pathways. The Fos-dependent ensemble promotes memory generalization and receives enhanced excitatory synaptic inputs from the medial entorhinal cortex, which we find itself also mediates generalization. The Npas4-dependent ensemble promotes memory discrimination and receives enhanced inhibitory drive from local cholecystokinin-expressing interneurons, the activity of which is required for discrimination. Our study provides causal evidence for functional heterogeneity within the memory engram and reveals synaptic and circuit mechanisms used by each ensemble to regulate the memory discrimination-generalization balance.
Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Brain; Dentate Gyrus; Fear; Interneurons; Male; Memory; Mice; Mice, Inbred C57BL; Neurons; Proto-Oncogene Proteins c-fos
PubMed: 32187527
DOI: 10.1016/j.cell.2020.02.055 -
Nature Reviews. Neuroscience Mar 2020The dentate gyrus (DG) has a key role in hippocampal memory formation. Intriguingly, DG lesions impair many, but not all, hippocampus-dependent mnemonic functions,... (Review)
Review
The dentate gyrus (DG) has a key role in hippocampal memory formation. Intriguingly, DG lesions impair many, but not all, hippocampus-dependent mnemonic functions, indicating that the rest of the hippocampus (CA1-CA3) can operate autonomously under certain conditions. An extensive body of theoretical work has proposed how the architectural elements and various cell types of the DG may underlie its function in cognition. Recent studies recorded and manipulated the activity of different neuron types in the DG during memory tasks and have provided exciting new insights into the mechanisms of DG computational processes, particularly for the encoding, retrieval and discrimination of similar memories. Here, we review these DG-dependent mnemonic functions in light of the new findings and explore mechanistic links between the cellular and network properties of, and the computations performed by, the DG.
Topics: Animals; Dentate Gyrus; Discrimination Learning; Entorhinal Cortex; Humans; Memory Consolidation; Memory, Episodic; Mental Recall; Models, Neurological; Neurons
PubMed: 32042144
DOI: 10.1038/s41583-019-0260-z -
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 -
Nature Jul 2022Immature dentate granule cells (imGCs) arising from adult hippocampal neurogenesis contribute to plasticity and unique brain functions in rodents and are dysregulated in...
Immature dentate granule cells (imGCs) arising from adult hippocampal neurogenesis contribute to plasticity and unique brain functions in rodents and are dysregulated in multiple human neurological disorders. Little is known about the molecular characteristics of adult human hippocampal imGCs, and even their existence is under debate. Here we performed single-nucleus RNA sequencing aided by a validated machine learning-based analytic approach to identify imGCs and quantify their abundance in the human hippocampus at different stages across the lifespan. We identified common molecular hallmarks of human imGCs across the lifespan and observed age-dependent transcriptional dynamics in human imGCs that suggest changes in cellular functionality, niche interactions and disease relevance, that differ from those in mice. We also found a decreased number of imGCs with altered gene expression in Alzheimer's disease. Finally, we demonstrated the capacity for neurogenesis in the adult human hippocampus with the presence of rare dentate granule cell fate-specific proliferating neural progenitors and with cultured surgical specimens. Together, our findings suggest the presence of a substantial number of imGCs in the adult human hippocampus via low-frequency de novo generation and protracted maturation, and our study reveals their molecular properties across the lifespan and in Alzheimer's disease.
Topics: Adult; Aging; Alzheimer Disease; Animals; Cell Proliferation; Dentate Gyrus; Gene Expression Profiling; Hippocampus; Humans; Longevity; Machine Learning; Mice; Neural Stem Cells; Neurogenesis; Neurons; Reproducibility of Results; Sequence Analysis, RNA; Single-Cell Analysis; Transcription, Genetic
PubMed: 35794479
DOI: 10.1038/s41586-022-04912-w -
Science (New York, N.Y.) Nov 2021Disrupted hippocampal performance underlies psychiatric comorbidities and cognitive impairments in patients with neurodegenerative disorders. To understand the...
Disrupted hippocampal performance underlies psychiatric comorbidities and cognitive impairments in patients with neurodegenerative disorders. To understand the contribution of adult hippocampal neurogenesis (AHN) to amyotrophic lateral sclerosis, Huntington’s disease, Parkinson’s disease, dementia with Lewy bodies, and frontotemporal dementia, we studied postmortem human samples. We found that adult-born dentate granule cells showed abnormal morphological development and changes in the expression of differentiation markers. The ratio of quiescent to proliferating hippocampal neural stem cells shifted, and the homeostasis of the neurogenic niche was altered. Aging and neurodegenerative diseases reduced the phagocytic capacity of microglia, triggered astrogliosis, and altered the microvasculature of the dentate gyrus. Thus, enhanced vulnerability of AHN to neurodegeneration might underlie hippocampal dysfunction during physiological and pathological aging in humans.
Topics: Adult; Aged; Aged, 80 and over; Aging; Amyotrophic Lateral Sclerosis; Cell Proliferation; Dentate Gyrus; Female; Frontotemporal Dementia; Hippocampus; Humans; Huntington Disease; Lewy Body Disease; Male; Microglia; Middle Aged; Neural Stem Cells; Neurodegenerative Diseases; Neurogenesis; Parkinson Disease; Phagocytosis
PubMed: 34672693
DOI: 10.1126/science.abl5163 -
Nature Communications Aug 2019The etiology of major depressive disorder (MDD), the leading cause of worldwide disability, is unknown. The neurogenic hypothesis proposes that MDD is linked to...
The etiology of major depressive disorder (MDD), the leading cause of worldwide disability, is unknown. The neurogenic hypothesis proposes that MDD is linked to impairments of adult neurogenesis in the hippocampal dentate gyrus (DG), while the effects of antidepressants are mediated by increased neurogenesis. However, alterations in neurogenesis and endophenotypes are not always causally linked, and the relationship between increased neurogenesis and altered behavior is controversial. To address causality, we used chemogenetics in transgenic mice to selectively manipulate activity of newborn DG neurons. Suppressing excitability of newborn neurons without altering neurogenesis abolish the antidepressant effects of fluoxetine. Remarkably, activating these neurons is sufficient to alleviate depression-like behavior and reverse the adverse effects of unpredictable chronic mild stress. Our results demonstrate a direct causal relationship between newborn neuronal activity and affective behavior. Thus, strategies that target not only neurogenesis but also activity of newborn neurons may lead to more effective antidepressants.
Topics: Animals; Antidepressive Agents; Anxiety; Behavior, Animal; Dentate Gyrus; Depression; Depressive Disorder, Major; Disease Models, Animal; Female; Fluoxetine; Hippocampus; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurogenesis; Neurons
PubMed: 31434877
DOI: 10.1038/s41467-019-11641-8 -
The Journal of Clinical Investigation Aug 2021Depression is a neuropsychiatric disease associated with neuronal anomalies within specific brain regions. In the present study, we screened microRNA (miRNA) expression...
Depression is a neuropsychiatric disease associated with neuronal anomalies within specific brain regions. In the present study, we screened microRNA (miRNA) expression profiles in the dentate gyrus (DG) of the hippocampus and found that miR-26a-3p was markedly downregulated in a rat model of depression, whereas upregulation of miR-26a-3p within DG regions rescued the neuronal deterioration and depression-like phenotypes resulting from stress exposure, effects that appear to be mediated by the PTEN pathway. The knockdown of miR-26a-3p in DG regions of normal control rats induced depression-like behaviors, effects that were accompanied by activation of the PTEN/PI3K/Akt signaling pathway and neuronal deterioration via suppression of autophagy, impairments in synaptic plasticity, and promotion of neuronal apoptosis. In conclusion, these results suggest that miR-26a-3p deficits within the hippocampal DG mediated the neuronal anomalies contributing to the display of depression-like behaviors. This miRNA may serve as a potential therapeutic target for the treatment of depression.
Topics: Animals; Apoptosis; Autophagy; Dentate Gyrus; Depression; Disease Models, Animal; Gene Knockdown Techniques; Hippocampus; Male; MicroRNAs; Neuronal Plasticity; Neurons; PTEN Phosphohydrolase; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Signal Transduction; Synaptic Transmission; Transcriptome
PubMed: 34228643
DOI: 10.1172/JCI148853 -
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 -
Biomolecules Feb 2020It is now well established that neurogenesis occurs throughout adulthood in select brain regions, but the functional significance of adult neurogenesis remains unclear.... (Review)
Review
It is now well established that neurogenesis occurs throughout adulthood in select brain regions, but the functional significance of adult neurogenesis remains unclear. There is considerable evidence that steroid hormones modulate various stages of adult neurogenesis, and this review provides a focused summary of the effects of testosterone on adult neurogenesis. Initial evidence came from field studies with birds and wild rodent populations. Subsequent experiments with laboratory rodents have tested the effects of testosterone and its steroid metabolites upon adult neurogenesis, as well as the functional consequences of induced changes in neurogenesis. These experiments have provided clear evidence that testosterone increases adult neurogenesis within the dentate gyrus region of the hippocampus through an androgen-dependent pathway. Most evidence indicates that androgens selectively enhance the survival of newly generated neurons, while having little effect on cell proliferation. Whether this is a result of androgens acting directly on receptors of new neurons remains unclear, and indirect routes involving brain-derived neurotrophic factor (BDNF) and glucocorticoids may be involved. In vitro experiments suggest that testosterone has broad-ranging neuroprotective effects, which will be briefly reviewed. A better understanding of the effects of testosterone upon adult neurogenesis could shed light on neurological diseases that show sex differences.
Topics: Androgens; Animals; Brain; Brain-Derived Neurotrophic Factor; Cell Proliferation; Cell Survival; Dentate Gyrus; Female; Glucocorticoids; Hippocampus; Humans; Male; Neurogenesis; Neurons; Neuroprotective Agents; Olfactory Bulb; Testosterone
PubMed: 32028656
DOI: 10.3390/biom10020225 -
Nature Dec 2021Could learning that uses cognitive control to judiciously use relevant information while ignoring distractions generally improve brain function, beyond forming explicit...
Could learning that uses cognitive control to judiciously use relevant information while ignoring distractions generally improve brain function, beyond forming explicit memories? According to a neuroplasticity hypothesis for how some cognitive behavioural therapies are effective, cognitive control training (CCT) changes neural circuit information processing. Here we investigated whether CCT persistently alters hippocampal neural circuit function. We show that mice learned and remembered a conditioned place avoidance during CCT that required ignoring irrelevant locations of shock. CCT facilitated learning new tasks in novel environments for several weeks, relative to unconditioned controls and control mice that avoided the same place during reduced distraction. CCT rapidly changes entorhinal cortex-to-dentate gyrus synaptic circuit function, resulting in an excitatory-inhibitory subcircuit change that persists for months. CCT increases inhibition that attenuates the dentate response to medial entorhinal cortical input, and through disinhibition, potentiates the response to strong inputs, pointing to overall signal-to-noise enhancement. These neurobiological findings support the neuroplasticity hypothesis that, as well as storing item-event associations, CCT persistently optimizes neural circuit information processing.
Topics: Animals; Avoidance Learning; CA1 Region, Hippocampal; Cognition; Cognitive Behavioral Therapy; Conditioning, Operant; Dentate Gyrus; Entorhinal Cortex; Female; GABAergic Neurons; Hippocampus; Long-Term Potentiation; Male; Memory; Mice; Mice, Inbred C57BL; Models, Neurological; Neural Inhibition; Neural Pathways; Neuronal Plasticity; Spatial Processing; Synapses
PubMed: 34759316
DOI: 10.1038/s41586-021-04070-5