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Science (New York, N.Y.) Jan 2020In 1904, Richard Semon introduced the term "engram" to describe the neural substrate for storing memories. An experience, Semon proposed, activates a subset of cells... (Review)
Review
In 1904, Richard Semon introduced the term "engram" to describe the neural substrate for storing memories. An experience, Semon proposed, activates a subset of cells that undergo off-line, persistent chemical and/or physical changes to become an engram. Subsequent reactivation of this engram induces memory retrieval. Although Semon's contributions were largely ignored in his lifetime, new technologies that allow researchers to image and manipulate the brain at the level of individual neurons has reinvigorated engram research. We review recent progress in studying engrams, including an evaluation of evidence for the existence of engrams, the importance of intrinsic excitability and synaptic plasticity in engrams, and the lifetime of an engram. Together, these findings are beginning to define an engram as the basic unit of memory.
Topics: Animals; Brain; Brain Chemistry; Humans; Memory Disorders; Mental Recall; Neurons
PubMed: 31896692
DOI: 10.1126/science.aaw4325 -
Cell Death and Differentiation May 2021Iron homeostasis disturbance has been implicated in Alzheimer's disease (AD), and excess iron exacerbates oxidative damage and cognitive defects. Ferroptosis is a...
Iron homeostasis disturbance has been implicated in Alzheimer's disease (AD), and excess iron exacerbates oxidative damage and cognitive defects. Ferroptosis is a nonapoptotic form of cell death dependent upon intracellular iron. However, the involvement of ferroptosis in the pathogenesis of AD remains elusive. Here, we report that ferroportin1 (Fpn), the only identified mammalian nonheme iron exporter, was downregulated in the brains of APPswe/PS1dE9 mice as an Alzheimer's mouse model and Alzheimer's patients. Genetic deletion of Fpn in principal neurons of the neocortex and hippocampus by breeding Fpn mice with NEX-Cre mice led to AD-like hippocampal atrophy and memory deficits. Interestingly, the canonical morphological and molecular characteristics of ferroptosis were observed in both Fpn and AD mice. Gene set enrichment analysis (GSEA) of ferroptosis-related RNA-seq data showed that the differentially expressed genes were highly enriched in gene sets associated with AD. Furthermore, administration of specific inhibitors of ferroptosis effectively reduced the neuronal death and memory impairments induced by Aβ aggregation in vitro and in vivo. In addition, restoring Fpn ameliorated ferroptosis and memory impairment in APPswe/PS1dE9 mice. Our study demonstrates the critical role of Fpn and ferroptosis in the progression of AD, thus provides promising therapeutic approaches for this disease.
Topics: Alzheimer Disease; Animals; Disease Models, Animal; Ferroptosis; Humans; Memory Disorders; Mice
PubMed: 33398092
DOI: 10.1038/s41418-020-00685-9 -
International Journal of Environmental... Aug 2021This research involved the participation of 3036 Chinese students in the first and second years of senior high school. The adolescents were active users of TikTok. The...
This research involved the participation of 3036 Chinese students in the first and second years of senior high school. The adolescents were active users of TikTok. The mediating effect of depression, anxiety, and stress between TikTok use disorder and memory loss was investigated. A forward and backward digit span test was applied to measure memory loss. Structural equation modeling (SEM) was established, and SPSS Amos was used for analysis. The results show a partial mediation effect of depression and anxiety between TikTok use disorder and forward digit span. A partial mediation effect of depression, anxiety, and stress between TikTok use disorder and backward digit span is also shown. These results also show gender differences. Attention should be given to male students, who have more depression, anxiety, and stress than female students; they also have more memory loss.
Topics: Adolescent; Anxiety; Anxiety Disorders; Depression; Female; Humans; Male; Memory Disorders; Social Media
PubMed: 34444569
DOI: 10.3390/ijerph18168820 -
The Lancet. Psychiatry Feb 2020Cognitive symptoms are common, and yet many who seek help for cognitive symptoms neither have, nor go on to develop, dementia. A proportion of these people are likely to...
Cognitive symptoms are common, and yet many who seek help for cognitive symptoms neither have, nor go on to develop, dementia. A proportion of these people are likely to have functional cognitive disorders, a subtype of functional neurological disorders, in which cognitive symptoms are present, associated with distress or disability, but caused by functional alterations rather than degenerative brain disease or another structural lesion. In this Review, we have systematically examined the prevalence and clinical associations of functional cognitive disorders, and related phenotypes, within the wider cognitive disorder literature. Around a quarter of patients presenting to memory clinics received diagnoses that might indicate the presence of functional cognitive disorders, which were associated with affective symptoms, negative self-evaluation, negative illness perceptions, non-progressive symptom trajectories, and linguistic and behavioural differences during clinical interactions. Those with functional cognitive disorder phenotypes are at risk of iatrogenic harm because of misdiagnosis or inaccurate prediction of future decline. Further research is imperative to improve diagnosis and identify effective treatments for functional cognitive disorders, and better understanding these phenotypes will also improve the specificity of diagnoses of prodromal degenerative brain disease.
Topics: Affective Symptoms; Attitude to Health; Cognition Disorders; Humans; Medically Unexplained Symptoms; Memory Disorders
PubMed: 31732482
DOI: 10.1016/S2215-0366(19)30405-5 -
Nature Communications Mar 2021Aberrant regulation of microRNAs (miRNAs) has been implicated in the pathogenesis of Alzheimer's disease (AD), but most abnormally expressed miRNAs found in AD are not...
Aberrant regulation of microRNAs (miRNAs) has been implicated in the pathogenesis of Alzheimer's disease (AD), but most abnormally expressed miRNAs found in AD are not regulated by synaptic activity. Here we report that dysfunction of miR-135a-5p/Rock2/Add1 results in memory/synaptic disorder in a mouse model of AD. miR-135a-5p levels are significantly reduced in excitatory hippocampal neurons of AD model mice. This decrease is tau dependent and mediated by Foxd3. Inhibition of miR-135a-5p leads to synaptic disorder and memory impairments. Furthermore, excess Rock2 levels caused by loss of miR-135a-5p plays an important role in the synaptic disorder of AD via phosphorylation of Ser726 on adducin 1 (Add1). Blocking the phosphorylation of Ser726 on Add1 with a membrane-permeable peptide effectively rescues the memory impairments in AD mice. Taken together, these findings demonstrate that synaptic-related miR-135a-5p mediates synaptic/memory deficits in AD via the Rock2/Add1 signaling pathway, illuminating a potential therapeutic strategy for AD.
Topics: Alzheimer Disease; Animals; Cells, Cultured; Cytoskeletal Proteins; Disease Models, Animal; Hippocampus; Male; Maze Learning; Memory Disorders; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; MicroRNAs; Neurons; Phosphorylation; Signal Transduction; Synapses; rho-Associated Kinases; tau Proteins; Mice
PubMed: 33771994
DOI: 10.1038/s41467-021-22196-y -
Cell Stem Cell Oct 2021Neural stem cells residing in the hippocampal neurogenic niche sustain lifelong neurogenesis in the adult brain. Adult hippocampal neurogenesis (AHN) is functionally...
Neural stem cells residing in the hippocampal neurogenic niche sustain lifelong neurogenesis in the adult brain. Adult hippocampal neurogenesis (AHN) is functionally linked to mnemonic and cognitive plasticity in humans and rodents. In Alzheimer's disease (AD), the process of generating new neurons at the hippocampal neurogenic niche is impeded, yet the mechanisms involved are unknown. Here we identify miR-132, one of the most consistently downregulated microRNAs in AD, as a potent regulator of AHN, exerting cell-autonomous proneurogenic effects in adult neural stem cells and their progeny. Using distinct AD mouse models, cultured human primary and established neural stem cells, and human patient material, we demonstrate that AHN is directly affected by AD pathology. miR-132 replacement in adult mouse AD hippocampus restores AHN and relevant memory deficits. Our findings corroborate the significance of AHN in mouse models of AD and reveal the possible therapeutic potential of targeting miR-132 in neurodegeneration.
Topics: Alzheimer Disease; Animals; Disease Models, Animal; Hippocampus; Humans; Memory Disorders; Mice; MicroRNAs; Neurogenesis
PubMed: 34033742
DOI: 10.1016/j.stem.2021.05.001 -
Nature Neuroscience Apr 2020Cognitive decline remains an unaddressed problem for the elderly. We show that myelination is highly active in young mice and greatly inhibited in aged mice, coinciding...
Cognitive decline remains an unaddressed problem for the elderly. We show that myelination is highly active in young mice and greatly inhibited in aged mice, coinciding with spatial memory deficits. Inhibiting myelination by deletion of Olig2 in oligodendrocyte precursor cells impairs spatial memory in young mice, while enhancing myelination by deleting the muscarinic acetylcholine receptor 1 in oligodendrocyte precursor cells, or promoting oligodendroglial differentiation and myelination via clemastine treatment, rescues spatial memory decline during aging.
Topics: Aging; Animals; Demyelinating Diseases; Memory Disorders; Mice; Mice, Transgenic; Myelin Basic Protein; Myelin Sheath; Oligodendrocyte Precursor Cells; Oligodendrocyte Transcription Factor 2; Oligodendroglia
PubMed: 32042174
DOI: 10.1038/s41593-020-0588-8 -
Science Advances Apr 2023Transactivating response region DNA binding protein 43 (TDP-43) pathology is prevalent in dementia, but the cell type-specific effects of TDP-43 pathology are not clear,...
Transactivating response region DNA binding protein 43 (TDP-43) pathology is prevalent in dementia, but the cell type-specific effects of TDP-43 pathology are not clear, and therapeutic strategies to alleviate TDP-43-linked cognitive decline are lacking. We found that patients with Alzheimer's disease or frontotemporal dementia have aberrant TDP-43 accumulation in hippocampal astrocytes. In mouse models, induction of widespread or hippocampus-targeted accumulation in astrocytic TDP-43 caused progressive memory loss and localized changes in antiviral gene expression. These changes were cell-autonomous and correlated with impaired astrocytic defense against infectious viruses. Among the changes, astrocytes had elevated levels of interferon-inducible chemokines, and neurons had elevated levels of the corresponding chemokine receptor CXCR3 in presynaptic terminals. CXCR3 stimulation altered presynaptic function and promoted neuronal hyperexcitability, akin to the effects of astrocytic TDP-43 dysregulation, and blockade of CXCR3 reduced this activity. Ablation of CXCR3 also prevented TDP-43-linked memory loss. Thus, astrocytic TDP-43 dysfunction contributes to cognitive impairment through aberrant chemokine-mediated astrocytic-neuronal interactions.
Topics: Mice; Animals; Interferons; Antiviral Agents; Astrocytes; DNA-Binding Proteins; Memory Disorders
PubMed: 37075107
DOI: 10.1126/sciadv.ade1282 -
NeuroImage. Clinical 2022Children with Attention Deficit Hyperactivity Disorder (ADHD) face deficits in working memory capacity that often persist into adulthood. In healthy peers, exercise... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Children with Attention Deficit Hyperactivity Disorder (ADHD) face deficits in working memory capacity that often persist into adulthood. In healthy peers, exercise targeting motor skill acquisition benefits visuospatial working memory, but its potential to reduce ADHD-related deficits remains unclear. We investigated the effect of a judo training program targeting motor skills on behavioral and neurocognitive indices of working memory capacity in children with ADHD.
METHODS
Children with ADHD aged 8 to 12 years (N = 57) were randomly allocated to a judo training group and a wait-list control group. The training program encompassed 120 min of judo per week over three months. Before and after the intervention period, participants completed a bilateral Change Detection task with low and high memory load conditions and the Movement Assessment Battery for Children-2 (MABC-2). The contralateral delay activity (CDA) elicited by the cognitive task was recorded using electroencephalography.
RESULTS
Compared to the control group, the judo training group showed a higher K-score on the Change Detection task and an increased negativity of the CDA on the high load condition following the intervention, when pretest scores (and confounders) were accounted for. In contrast, no group differences were found for MABC-2 score.
CONCLUSION
In children with ADHD, judo training may complement the pharmacological treatment by increasing the effectiveness of working memory maintenance processes. On a behavioral level, this improvement is accompanied with an increased capacity to store visuospatial information.
Topics: Child; Humans; Adult; Memory, Short-Term; Attention Deficit Disorder with Hyperactivity; Motor Skills; Memory Disorders; Electroencephalography; Executive Function
PubMed: 35988343
DOI: 10.1016/j.nicl.2022.103156 -
PloS One 2020The GluD1 gene is associated with susceptibility for schizophrenia, autism, depression, and bipolar disorder. However, the function of GluD1 and how it is involved in...
The GluD1 gene is associated with susceptibility for schizophrenia, autism, depression, and bipolar disorder. However, the function of GluD1 and how it is involved in these conditions remain elusive. In this study, we generated a Grid1 gene-knockout (GluD1-KO) mouse line with a pure C57BL/6N genetic background and performed several behavioral analyses. Compared to a control group, GluD1-KO mice showed no significant anxiety-related behavioral differences, evaluated using behavior in an open field, elevated plus maze, a light-dark transition test, the resident-intruder test of aggression and sensorimotor gating evaluated by the prepulse inhibition test. However, GluD1-KO mice showed (1) higher locomotor activity in the open field, (2) decreased sociability and social novelty preference in the three-chambered social interaction test, (3) impaired memory in contextual, but not cued fear conditioning tests, and (4) enhanced depressive-like behavior in a forced swim test. Pharmacological studies revealed that enhanced depressive-like behavior in GluD1-KO mice was restored by the serotonin reuptake inhibitors imipramine and fluoxetine, but not the norepinephrine transporter inhibitor desipramine. In addition, biochemical analysis revealed no significant difference in protein expression levels, such as other glutamate receptors in the synaptosome and postsynaptic densities prepared from the frontal cortex and the hippocampus. These results suggest that GluD1 plays critical roles in fear memory, sociability, and depressive-like behavior.
Topics: Animals; Anxiety; Behavior, Animal; Depression; Fear; Glutamate Dehydrogenase; Interpersonal Relations; Male; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Social Behavior Disorders
PubMed: 32078638
DOI: 10.1371/journal.pone.0229288