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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 -
Progress in Neuro-psychopharmacology &... Jun 2024Multiple lines of evidence suggest that the trace amine-associated receptor 1 (TAAR1) holds promise as a potential target for stress-related disorders, such as treating...
Multiple lines of evidence suggest that the trace amine-associated receptor 1 (TAAR1) holds promise as a potential target for stress-related disorders, such as treating major depressive disorder (MDD). The role of TAAR1 in the regulation of adult neurogenesis is recently supported by transcriptomic data. However, it remains unknown whether TAAR1 in dentate gyrus (DG) mediate chronic stress-induced negative effects on hippocampal plasticity and related behavior in mice. The present study consisted of a series of experiments using RNAscope, genetic approaches, behavioral tests, immunohistochemical staining, Golgi-Cox technique to unravel the effects of TAAR1 on alterations of dentate neuronal plasticity and cognitive function in the chronic social defeat stress model. The mice subjected to chronic defeat stress exhibited a noteworthy decrease in the mRNA level of TAAR1 in DG. Additionally, they exhibited compromised social memory and spatial object recognition memory, as well as impaired proliferation and maturation of adult-born dentate granule cells. Moreover, the selective knockout TAAR1 in DG mostly mimicked the cognitive function deficits and neurogenesis impairment induced by chronic stress. Importantly, the administration of the selective TAAR1 partial agonist RO5263397 during stress exposure attenuated the adverse effects of chronic stress on cognitive function, adult neurogenesis, dendritic arborization, and the synapse number of dentate neurons in DG. In summary, our findings suggest that TAAR1 plays a crucial role in mediating the detrimental effects of chronic stress on hippocampal plasticity and cognition. TAAR1 agonists exhibit therapeutic potential for individuals suffering from cognitive impairments associated with MDD.
Topics: Animals; Mice; Dentate Gyrus; Depressive Disorder, Major; Hippocampus; Cognition; Neuronal Plasticity; Neurogenesis; Receptors, G-Protein-Coupled
PubMed: 38514038
DOI: 10.1016/j.pnpbp.2024.110995 -
Behavioural Brain Research Feb 2020Hypotheses about the functional properties of the dentate gyrus and adult dentate neurogenesis have been shaped by early observations of the anatomy of this region,... (Review)
Review
Hypotheses about the functional properties of the dentate gyrus and adult dentate neurogenesis have been shaped by early observations of the anatomy of this region, mostly in rodents. This has led to the development of a few core propositions that have guided research over the past several years, including the predicted role of this region in pattern separation and the local transformation of inputs from the entorhinal cortex. We now have the opportunity to review these predictions and update these anatomical observations based on recently developed techniques that reveal the complex structure, connectivity, and dynamic properties of distinct cell populations in the dentate gyrus at a higher resolution. Cumulative evidence suggests that the dentate gyrus and adult-born granule cells play a role in some forms of behavioral discriminations, but there are still many unanswered questions about how the dentate gyrus processes information to support the disambiguation of stimuli.
Topics: Animals; Dentate Gyrus; Discrimination, Psychological; Neurogenesis; Neuronal Plasticity
PubMed: 31722241
DOI: 10.1016/j.bbr.2019.112346 -
Neuron Jul 2021Dysregulation in contextual processing is believed to affect several forms of psychopathology, such as post-traumatic stress disorder (PTSD). The dentate gyrus (DG), a...
Dysregulation in contextual processing is believed to affect several forms of psychopathology, such as post-traumatic stress disorder (PTSD). The dentate gyrus (DG), a subregion of the hippocampus, is thought to be an important brain region for disambiguating new experiences from prior experiences. Noradrenergic (NE) neurons in the locus coeruleus (LC) are more tonically active during stressful events and send dense projections to the DG, yet an understanding of their function in DG-dependent contextual discrimination has not been established. Here, we isolate a key function of the LC-NE-DG circuit in contextual aversive generalization using selective manipulations and in vivo single-cell calcium imaging. We report that activation of LC-NE neurons and terminal activity results in contextual generalization. We found that these effects required β-adrenergic-mediated modulation of hilar interneurons to ultimately promote aversive generalization, suggesting that disruption of noradrenergic tone may serve as an important avenue for treating stress-induced disorders.
Topics: Adrenergic Neurons; Animals; Conditioning, Classical; Dentate Gyrus; Fear; Female; Generalization, Psychological; Locus Coeruleus; Male; Mice, Inbred C57BL; Mice
PubMed: 34081911
DOI: 10.1016/j.neuron.2021.05.006 -
Current Opinion in Neurobiology Oct 2020The hippocampus performs two complementary processes, pattern separation and pattern completion, to minimize interference and maximize the storage capacity of memories.... (Review)
Review
The hippocampus performs two complementary processes, pattern separation and pattern completion, to minimize interference and maximize the storage capacity of memories. Classic computational models have suggested that the dentate gyrus (DG) supports pattern separation and the putative attractor circuitry in CA3 supports pattern completion. However, recent evidence of functional heterogeneity along the CA3 transverse axis of the hippocampus suggests that the DG and proximal CA3 work as a functional unit for pattern separation, while distal CA3 forms an autoassociative network for pattern completion. We propose that the outputs of these functional circuits, combined with direct projections from entorhinal cortex to CA1, form interconnected, parallel processing circuits to support accurate memory storage and retrieval.
Topics: Dentate Gyrus; Entorhinal Cortex; Hippocampus; Memory
PubMed: 32502734
DOI: 10.1016/j.conb.2020.03.004 -
Behavioural Brain Research Nov 2019Anatomical observations, theoretical work and lesion experiments have led to the idea that an important function of the dentate gyrus of the mammalian hippocampus is... (Review)
Review
Anatomical observations, theoretical work and lesion experiments have led to the idea that an important function of the dentate gyrus of the mammalian hippocampus is pattern separation, a neural computation that ensures new memories are encoded without interference from previously stored memories that share similar features. The dentate gyrus also exhibits a unique form of neural plasticity that results from the continuous integration of newly born excitatory granule cells, termed adult hippocampal neurogenesis. However, the manner in which adult neurogenesis contributes to dentate gyrus network activity and computations is incompletely understood. Here, we first describe the prevailing models for the role of adult neurogenesis in dentate gyrus network function and then re-evaluate these models in the light of recent findings regarding the in vivo activity of the dentate gyrus and synaptic interactions of adult born granule cells with local circuit components, as well as, inputs, and outputs of the dentate gyrus. We propose that adult neurogenesis provides flexibility for the dentate gyrus to rapidly generate a context specific, distributed representation of important sensory stimuli such as spatial cues, which ultimately gives rise to behavioral discrimination.
Topics: Adult; Animals; Cues; Dentate Gyrus; Hippocampus; Humans; Memory; Nerve Net; Neurogenesis; Neuronal Plasticity; Neurons
PubMed: 31377252
DOI: 10.1016/j.bbr.2019.112112 -
F1000Research 2019The dentate gyrus continually produces new neurons throughout life. Behavioral studies in rodents and network models show that new neurons contribute to normal dentate... (Review)
Review
The dentate gyrus continually produces new neurons throughout life. Behavioral studies in rodents and network models show that new neurons contribute to normal dentate functions, but there are many unanswered questions about how the relatively small population of new neurons alters network activity. Here we discuss experimental evidence that supports multiple cellular mechanisms by which adult-born neurons contribute to circuit function. Whereas past work focused on the unique intrinsic properties of young neurons, more recent studies also suggest that adult-born neurons alter the excitability of the mature neuronal population via unexpected circuit interactions.
Topics: Adult; Dentate Gyrus; Humans; Neurogenesis; Neurons
PubMed: 31824650
DOI: 10.12688/f1000research.20642.1 -
Cells Sep 2022In mammals, neurogenesis occurs during both embryonic and postnatal development. In eutherians, most brain structures develop embryonically; conversely, in marsupials, a... (Review)
Review
In mammals, neurogenesis occurs during both embryonic and postnatal development. In eutherians, most brain structures develop embryonically; conversely, in marsupials, a number of brain structures develop after birth. The exception is the generation of granule cells in the dentate gyrus, olfactory bulb, and cerebellum of eutherian species. The formation of these structures starts during embryogenesis and continues postnatally. In both eutherians and marsupials, neurogenesis continues in the subventricular zone of the lateral ventricle (SVZ) and the dentate gyrus of the hippocampal formation throughout life. The majority of proliferated cells from the SVZ migrate to the olfactory bulb, whereas, in the dentate gyrus, cells reside within this structure after division and differentiation into neurons. A key aim of this review is to evaluate advances in understanding developmental neurogenesis that occurs postnatally in both marsupials and eutherians, with a particular emphasis on the generation of granule cells during the formation of the olfactory bulb, dentate gyrus, and cerebellum. We debate the significance of immature neurons in the piriform cortex of young mammals. We also synthesize the knowledge of adult neurogenesis in the olfactory bulb and the dentate gyrus of marsupials by considering whether adult-born neurons are essential for the functioning of a given area.
Topics: Animals; Dentate Gyrus; Eutheria; Mammals; Marsupialia; Neurogenesis
PubMed: 36078144
DOI: 10.3390/cells11172735 -
Biological Psychiatry Jun 2023The dentate gyrus, a "gate" that controls the flow of information into the hippocampus, is critical for learning, memory, spatial navigation, and mood regulation.... (Review)
Review
The dentate gyrus, a "gate" that controls the flow of information into the hippocampus, is critical for learning, memory, spatial navigation, and mood regulation. Several lines of evidence have demonstrated that deficits in dentate granule cells (DGCs) (e.g., loss of DGCs or genetic mutations in DGCs) contribute to the development of various psychiatric disorders, such as depression and anxiety disorders. Whereas ventral DGCs are believed to be critical for mood regulation, the functions of dorsal DGCs in this regard remain elusive. Here, we review the role of DGCs, in particular the dorsal DGCs, in the regulation of mood, their functional relationships with DGC development, and the contributions of dysfunctional DGCs to mental disorders.
Topics: Humans; Dentate Gyrus; Neurons; Hippocampus; Learning; Mental Disorders; Neurogenesis
PubMed: 36894487
DOI: 10.1016/j.biopsych.2023.01.005 -
International Journal of Molecular... Apr 2022The dentate gyrus (DG), an important part of the hippocampus, plays a significant role in learning, memory, and emotional behavior. Factors potentially influencing... (Review)
Review
The dentate gyrus (DG), an important part of the hippocampus, plays a significant role in learning, memory, and emotional behavior. Factors potentially influencing normal development of neurons and glial cells in the DG during its maturation can exert long-lasting effects on brain functions. Early life stress may modify maturation of the DG and induce lifelong alterations in its structure and functioning, underlying brain pathologies in adults. In this paper, maturation of neurons and glial cells (microglia and astrocytes) and the effects of early life events on maturation processes in the DG have been comprehensively reviewed. Early postnatal interventions affecting the DG eventually result in an altered number of granule neurons in the DG, ectopic location of neurons and changes in adult neurogenesis. Adverse events in early life provoke proinflammatory changes in hippocampal glia at cellular and molecular levels immediately after stress exposure. Later, the cellular changes may disappear, though alterations in gene expression pattern persist. Additional stressful events later in life contribute to manifestation of glial changes and behavioral deficits. Alterations in the maturation of neuronal and glial cells induced by early life stress are interdependent and influence the development of neural nets, thus predisposing the brain to the development of cognitive and psychiatric disorders.
Topics: Dentate Gyrus; Hippocampus; Humans; Neurogenesis; Neuroglia; Neurons
PubMed: 35457079
DOI: 10.3390/ijms23084261