-
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 Jan 2020The hippocampus is an important part of the limbic system in the human brain that has essential roles in spatial navigation and the consolidation of information from...
The hippocampus is an important part of the limbic system in the human brain that has essential roles in spatial navigation and the consolidation of information from short-term memory to long-term memory. Here we use single-cell RNA sequencing and assay for transposase-accessible chromatin using sequencing (ATAC-seq) analysis to illustrate the cell types, cell linage, molecular features and transcriptional regulation of the developing human hippocampus. Using the transcriptomes of 30,416 cells from the human hippocampus at gestational weeks 16-27, we identify 47 cell subtypes and their developmental trajectories. We also identify the migrating paths and cell lineages of PAX6 and HOPX hippocampal progenitors, and regional markers of CA1, CA3 and dentate gyrus neurons. Multiomic data have uncovered transcriptional regulatory networks of the dentate gyrus marker PROX1. We also illustrate spatially specific gene expression in the developing human prefrontal cortex and hippocampus. The molecular features of the human hippocampus at gestational weeks 16-20 are similar to those of the mouse at postnatal days 0-5 and reveal gene expression differences between the two species. Transient expression of the primate-specific gene NBPF1 leads to a marked increase in PROX1 cells in the mouse hippocampus. These data provides a blueprint for understanding human hippocampal development and a tool for investigating related diseases.
Topics: Animals; Carrier Proteins; Cell Lineage; Dentate Gyrus; Evolution, Molecular; Female; Gene Expression Regulation, Developmental; Hippocampus; Homeodomain Proteins; Humans; Male; Mice; Neural Stem Cells; Neurogenesis; Neurons; PAX6 Transcription Factor; Prefrontal Cortex; Species Specificity; Transcriptome; Tumor Suppressor Proteins
PubMed: 31942070
DOI: 10.1038/s41586-019-1917-5 -
Nature Oct 2020The ability to recognize information that is incongruous with previous experience is critical for survival. Novelty signals have therefore evolved in the mammalian brain...
The ability to recognize information that is incongruous with previous experience is critical for survival. Novelty signals have therefore evolved in the mammalian brain to enhance attention, perception and memory. Although the importance of regions such as the ventral tegmental area and locus coeruleus in broadly signalling novelty is well-established, these diffuse monoaminergic transmitters have yet to be shown to convey specific information on the type of stimuli that drive them. Whether distinct types of novelty, such as contextual and social novelty, are differently processed and routed in the brain is unknown. Here we identify the supramammillary nucleus (SuM) as a novelty hub in the hypothalamus. The SuM region is unique in that it not only responds broadly to novel stimuli, but also segregates and selectively routes different types of information to discrete cortical targets-the dentate gyrus and CA2 fields of the hippocampus-for the modulation of mnemonic processing. Using a new transgenic mouse line, SuM-Cre, we found that SuM neurons that project to the dentate gyrus are activated by contextual novelty, whereas the SuM-CA2 circuit is preferentially activated by novel social encounters. Circuit-based manipulation showed that divergent novelty channelling in these projections modifies hippocampal contextual or social memory. This content-specific routing of novelty signals represents a previously unknown mechanism that enables the hypothalamus to flexibly modulate select components of cognition.
Topics: Animals; CA2 Region, Hippocampal; Cognition; Dentate Gyrus; Female; Hippocampus; Hypothalamus, Posterior; Male; Memory; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neural Pathways; Neurons; Social Interaction
PubMed: 32999460
DOI: 10.1038/s41586-020-2771-1 -
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 -
Biological Psychiatry Dec 2022In the neurogenic niches of the adult hippocampus, new functional neurons are continuously generated throughout life, and generation of these neurons has been implicated...
BACKGROUND
In the neurogenic niches of the adult hippocampus, new functional neurons are continuously generated throughout life, and generation of these neurons has been implicated in learning and memory. Astrocytes, as components of the neurogenic niches, are critical in the regulation of adult hippocampal neurogenesis (AHN). However, little is known about how astrocytes receive and respond to extrinsic cues to regulate AHN.
METHODS
By using a transgenic strategy to conditionally delete astrocytic CRHM1 in mice and AAV (adeno-associated virus)-mediated overexpression of astrocytic CHRM1 specifically in the hippocampal dentate gyrus, we systematically investigated the role of astrocytic CHRM1 in the regulation of AHN and the underlying mechanisms using the combined approaches of immunohistochemistry, retrovirus labeling, electrophysiology, primary astrocyte cultures, immunoblotting, and behavioral assays.
RESULTS
We report that genetic ablation of CHRM1 in astrocytes led to defects in neural stem cell survival, neuronal differentiation, and maturation and integration of newborn neurons in the dentate gyrus. Astrocytic CHRM1-mediated modulation of AHN was mediated by BDNF (brain-derived neurotrophic factor) signaling. Furthermore, CHRM1 ablation in astrocytes impaired contextual fear memory. These impairments in both AHN and memory were rescued by overexpression of astrocytic CHRM1 in the dentate gyrus.
CONCLUSIONS
Our findings reveal a critical role for astrocytes in mediating cholinergic regulation of AHN and memory through CHRM1.
Topics: Mice; Animals; Astrocytes; Neurogenesis; Hippocampus; Receptors, Muscarinic; Cholinergic Agents; Dentate Gyrus
PubMed: 35787318
DOI: 10.1016/j.biopsych.2022.04.019 -
The European Journal of Neuroscience Jan 2021Extensive preclinical research has been conducted in recent years to reveal the cell types, neuronal circuits and molecular and morphological changes implicated in the... (Review)
Review
Extensive preclinical research has been conducted in recent years to reveal the cell types, neuronal circuits and molecular and morphological changes implicated in the function of the dentate gyrus in depression. This was profoundly facilitated by the emergence of methods such as gene targeting, neuronal cell activity manipulation, including optogenetics and chemogenetics, and the development of novel RNA sequencing technology and powerful MRI imagers that were used in clinical studies. These advancements provided researchers with the precise skills needed to evaluate the changes in the dentate gyrus structure and cell function in rodent models as well as in brains of depressed and medicated patients. Here, we review these latest findings and discuss the existing gaps in our knowledge of the role of the dentate gyrus in depression and in mediating the response to antidepressant therapies.
Topics: Brain; Dentate Gyrus; Depression; Humans; Neurons; Optogenetics
PubMed: 31811730
DOI: 10.1111/ejn.14640 -
Nature Neuroscience Jan 2021Normal aging is accompanied by escalating systemic inflammation. Yet the potential impact of immune homeostasis on neurogenesis and cognitive decline during brain aging...
Normal aging is accompanied by escalating systemic inflammation. Yet the potential impact of immune homeostasis on neurogenesis and cognitive decline during brain aging have not been previously addressed. Here we report that natural killer (NK) cells of the innate immune system reside in the dentate gyrus neurogenic niche of aged brains in humans and mice. In situ expansion of these cells contributes to their abundance, which dramatically exceeds that of other immune subsets. Neuroblasts within the aged dentate gyrus display a senescence-associated secretory phenotype and reinforce NK cell activities and surveillance functions, which result in NK cell elimination of aged neuroblasts. Genetic or antibody-mediated depletion of NK cells leads to sustained improvements in neurogenesis and cognitive function during normal aging. These results demonstrate that NK cell accumulation in the aging brain impairs neurogenesis, which may serve as a therapeutic target to improve cognition in the aged population.
Topics: Adult; Aged; Aging; Animals; Cellular Senescence; Cognitive Dysfunction; Cytotoxicity, Immunologic; Dentate Gyrus; Female; Humans; Immunity, Innate; Interleukin-27; Killer Cells, Natural; Male; Mice; Mice, Inbred C57BL; Neural Stem Cells; Neurogenesis; Sequence Analysis, RNA; Single-Cell Analysis
PubMed: 33257875
DOI: 10.1038/s41593-020-00745-w -
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 -
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