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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 -
Cell Stem Cell Apr 2018Adult hippocampal neurogenesis declines in aging rodents and primates. Aging humans are thought to exhibit waning neurogenesis and exercise-induced angiogenesis, with a...
Adult hippocampal neurogenesis declines in aging rodents and primates. Aging humans are thought to exhibit waning neurogenesis and exercise-induced angiogenesis, with a resulting volumetric decrease in the neurogenic hippocampal dentate gyrus (DG) region, although concurrent changes in these parameters are not well studied. Here we assessed whole autopsy hippocampi from healthy human individuals ranging from 14 to 79 years of age. We found similar numbers of intermediate neural progenitors and thousands of immature neurons in the DG, comparable numbers of glia and mature granule neurons, and equivalent DG volume across ages. Nevertheless, older individuals have less angiogenesis and neuroplasticity and a smaller quiescent progenitor pool in anterior-mid DG, with no changes in posterior DG. Thus, healthy older subjects without cognitive impairment, neuropsychiatric disease, or treatment display preserved neurogenesis. It is possible that ongoing hippocampal neurogenesis sustains human-specific cognitive function throughout life and that declines may be linked to compromised cognitive-emotional resilience.
Topics: Adolescent; Adult; Aged; Aging; Dentate Gyrus; Hippocampus; Humans; Middle Aged; Neurogenesis; Neurons; Young Adult
PubMed: 29625071
DOI: 10.1016/j.stem.2018.03.015 -
Nature Mar 2018New neurons continue to be generated in the subgranular zone of the dentate gyrus of the adult mammalian hippocampus. This process has been linked to learning and...
New neurons continue to be generated in the subgranular zone of the dentate gyrus of the adult mammalian hippocampus. This process has been linked to learning and memory, stress and exercise, and is thought to be altered in neurological disease. In humans, some studies have suggested that hundreds of new neurons are added to the adult dentate gyrus every day, whereas other studies find many fewer putative new neurons. Despite these discrepancies, it is generally believed that the adult human hippocampus continues to generate new neurons. Here we show that a defined population of progenitor cells does not coalesce in the subgranular zone during human fetal or postnatal development. We also find that the number of proliferating progenitors and young neurons in the dentate gyrus declines sharply during the first year of life and only a few isolated young neurons are observed by 7 and 13 years of age. In adult patients with epilepsy and healthy adults (18-77 years; n = 17 post-mortem samples from controls; n = 12 surgical resection samples from patients with epilepsy), young neurons were not detected in the dentate gyrus. In the monkey (Macaca mulatta) hippocampus, proliferation of neurons in the subgranular zone was found in early postnatal life, but this diminished during juvenile development as neurogenesis decreased. We conclude that recruitment of young neurons to the primate hippocampus decreases rapidly during the first years of life, and that neurogenesis in the dentate gyrus does not continue, or is extremely rare, in adult humans. The early decline in hippocampal neurogenesis raises questions about how the function of the dentate gyrus differs between humans and other species in which adult hippocampal neurogenesis is preserved.
Topics: Adolescent; Adult; Aged; Animals; Animals, Newborn; Cell Count; Cell Proliferation; Child; Child, Preschool; Dentate Gyrus; Epilepsy; Female; Fetal Development; Healthy Volunteers; Hippocampus; Humans; Infant; Macaca mulatta; Male; Middle Aged; Neural Stem Cells; Neurogenesis; Neurons; Young Adult
PubMed: 29513649
DOI: 10.1038/nature25975 -
Molecular Psychiatry Jan 2019Adult neurogenesis in the dentate gyrus of the hippocampus is highly regulated by a number of environmental and cell-intrinsic factors to adapt to environmental changes.... (Review)
Review
Adult neurogenesis in the dentate gyrus of the hippocampus is highly regulated by a number of environmental and cell-intrinsic factors to adapt to environmental changes. Accumulating evidence suggests that adult-born neurons may play distinct physiological roles in hippocampus-dependent functions, such as memory encoding and mood regulation. In addition, several brain diseases, such as neurological diseases and mood disorders, have deleterious effects on adult hippocampal neurogenesis, and some symptoms of those diseases can be partially explained by the dysregulation of adult hippocampal neurogenesis. Here we review a possible link between the physiological functions of adult-born neurons and their roles in pathological conditions.
Topics: Adult; Affect; Brain; Brain Diseases; Dentate Gyrus; Hippocampus; Humans; Memory; Neurogenesis; Neuronal Plasticity; Neurons; Temporal Lobe
PubMed: 29679070
DOI: 10.1038/s41380-018-0036-2 -
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 Jul 2018Adult neurogenesis in the dentate gyrus of the hippocampus is highly regulated by environmental influences, and functionally implicated in behavioural responses to...
Adult neurogenesis in the dentate gyrus of the hippocampus is highly regulated by environmental influences, and functionally implicated in behavioural responses to stress and antidepressants. However, how adult-born neurons regulate dentate gyrus information processing to protect from stress-induced anxiety-like behaviour is unknown. Here we show in mice that neurogenesis confers resilience to chronic stress by inhibiting the activity of mature granule cells in the ventral dentate gyrus (vDG), a subregion that is implicated in mood regulation. We found that chemogenetic inhibition of adult-born neurons in the vDG promotes susceptibility to social defeat stress, whereas increasing neurogenesis confers resilience to chronic stress. By using in vivo calcium imaging to record neuronal activity from large cell populations in the vDG, we show that increased neurogenesis results in a decrease in the activity of stress-responsive cells that are active preferentially during attacks or while mice explore anxiogenic environments. These effects on dentate gyrus activity are necessary and sufficient for stress resilience, as direct silencing of the vDG confers resilience whereas excitation promotes susceptibility. Our results suggest that the activity of the vDG may be a key factor in determining individual levels of vulnerability to stress and related psychiatric disorders.
Topics: Affect; Animals; Calcium; Chronic Disease; Dentate Gyrus; Male; Mice; Neurogenesis; Resilience, Psychological; Stress, Psychological
PubMed: 29950730
DOI: 10.1038/s41586-018-0262-4 -
Nature Mar 2016Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive memory decline and subsequent loss of broader cognitive functions. Memory decline...
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive memory decline and subsequent loss of broader cognitive functions. Memory decline in the early stages of AD is mostly limited to episodic memory, for which the hippocampus has a crucial role. However, it has been uncertain whether the observed amnesia in the early stages of AD is due to disrupted encoding and consolidation of episodic information, or an impairment in the retrieval of stored memory information. Here we show that in transgenic mouse models of early AD, direct optogenetic activation of hippocampal memory engram cells results in memory retrieval despite the fact that these mice are amnesic in long-term memory tests when natural recall cues are used, revealing a retrieval, rather than a storage impairment. Before amyloid plaque deposition, the amnesia in these mice is age-dependent, which correlates with a progressive reduction in spine density of hippocampal dentate gyrus engram cells. We show that optogenetic induction of long-term potentiation at perforant path synapses of dentate gyrus engram cells restores both spine density and long-term memory. We also demonstrate that an ablation of dentate gyrus engram cells containing restored spine density prevents the rescue of long-term memory. Thus, selective rescue of spine density in engram cells may lead to an effective strategy for treating memory loss in the early stages of AD.
Topics: Aging; Alzheimer Disease; Amnesia; Amyloid beta-Protein Precursor; Animals; Dendritic Spines; Dentate Gyrus; Disease Models, Animal; Early Medical Intervention; Humans; Long-Term Potentiation; Male; Memory, Episodic; Memory, Long-Term; Mice; Mice, Transgenic; Optogenetics; Plaque, Amyloid; Presenilin-1; Synapses; Transgenes; tau Proteins
PubMed: 26982728
DOI: 10.1038/nature17172 -
Science (New York, N.Y.) May 2015Memory consolidation is the process by which a newly formed and unstable memory transforms into a stable long-term memory. It is unknown whether the process of memory...
Memory consolidation is the process by which a newly formed and unstable memory transforms into a stable long-term memory. It is unknown whether the process of memory consolidation occurs exclusively through the stabilization of memory engrams. By using learning-dependent cell labeling, we identified an increase of synaptic strength and dendritic spine density specifically in consolidated memory engram cells. Although these properties are lacking in engram cells under protein synthesis inhibitor-induced amnesia, direct optogenetic activation of these cells results in memory retrieval, and this correlates with retained engram cell-specific connectivity. We propose that a specific pattern of connectivity of engram cells may be crucial for memory information storage and that strengthened synapses in these cells critically contribute to the memory retrieval process.
Topics: Amnesia, Retrograde; Amygdala; Animals; Conditioning, Classical; Dendrites; Dentate Gyrus; Fluorescent Dyes; Luminescent Proteins; Memory, Long-Term; Mice; Neuronal Plasticity; Protein Synthesis Inhibitors; Staining and Labeling; Synapses; Red Fluorescent Protein
PubMed: 26023136
DOI: 10.1126/science.aaa5542 -
Nature Nov 2015Bipolar disorder is a complex neuropsychiatric disorder that is characterized by intermittent episodes of mania and depression; without treatment, 15% of patients commit...
Bipolar disorder is a complex neuropsychiatric disorder that is characterized by intermittent episodes of mania and depression; without treatment, 15% of patients commit suicide. Hence, it has been ranked by the World Health Organization as a top disorder of morbidity and lost productivity. Previous neuropathological studies have revealed a series of alterations in the brains of patients with bipolar disorder or animal models, such as reduced glial cell number in the prefrontal cortex of patients, upregulated activities of the protein kinase A and C pathways and changes in neurotransmission. However, the roles and causation of these changes in bipolar disorder have been too complex to exactly determine the pathology of the disease. Furthermore, although some patients show remarkable improvement with lithium treatment for yet unknown reasons, others are refractory to lithium treatment. Therefore, developing an accurate and powerful biological model for bipolar disorder has been a challenge. The introduction of induced pluripotent stem-cell (iPSC) technology has provided a new approach. Here we have developed an iPSC model for human bipolar disorder and investigated the cellular phenotypes of hippocampal dentate gyrus-like neurons derived from iPSCs of patients with bipolar disorder. Guided by RNA sequencing expression profiling, we have detected mitochondrial abnormalities in young neurons from patients with bipolar disorder by using mitochondrial assays; in addition, using both patch-clamp recording and somatic Ca(2+) imaging, we have observed hyperactive action-potential firing. This hyperexcitability phenotype of young neurons in bipolar disorder was selectively reversed by lithium treatment only in neurons derived from patients who also responded to lithium treatment. Therefore, hyperexcitability is one early endophenotype of bipolar disorder, and our model of iPSCs in this disease might be useful in developing new therapies and drugs aimed at its clinical treatment.
Topics: Action Potentials; Antipsychotic Agents; Bipolar Disorder; Calcium Signaling; Dentate Gyrus; Endophenotypes; Humans; Induced Pluripotent Stem Cells; Lithium Compounds; Male; Mitochondria; Neurons; Patch-Clamp Techniques
PubMed: 26524527
DOI: 10.1038/nature15526 -
Frontiers in Neural Circuits 2014
Topics: Animals; Dentate Gyrus; Humans; Models, Neurological; Nerve Net; Neuronal Plasticity
PubMed: 25309334
DOI: 10.3389/fncir.2014.00107