Forgetting at biologically realistic levels of neurogenesis in a large-scale hippocampal model

Tran, Lina M.; Josselyn, Sheena A.; Richards, Blake A.; Frankland, Paul W.

doi:10.1016/j.bbr.2019.112180

Cited by 22 publications

(15 citation statements)

References 64 publications

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“…These findings support a potential stage-dependent contribution of dysregulated newborn neurons with unique physiological properties in regulating the output connectivity of brain-wide functional network for spatial memory. Recent computational modeling has shown that adding a small number of active newborn neurons (~0.2% of dentate neuron population) to the DG network can have a profound effect on memory function (Tran et al, 2019), further supporting that small changes in hippocampal neurogenesis are sufficient to profoundly impact cognitive functions.…”

Section: Discussionmentioning

confidence: 93%

“…Having identified altered MDTH and IC activity resulted from dysregulated newborn neurons, we wondered whether local hippocampal regions could serve as intermediates to couple aberrant activity from dysregulated newborn neurons to these distal brain regions, including the MDTH and IC. Adult-born new neurons reside in a tri-synaptic circuit, and it was thought that these new neurons are capable of impacting the activity of their downstream hippocampal regions, such as CA3 and CA1 (Bao and Song, 2018;Christian et al, 2014;Tran et al, 2019). Therefore, we asked whether hippocampal CA3 or CA1 is a direct input region to MDTH (Fig.3 A).…”

Section: Dysregulated Adult-born Immature Neurons Disrupt Local Hippomentioning

confidence: 99%

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Dysregulation of hippocampal adult-born immature neurons disrupts a brain-wide network for spatial memory

Bao

Hu²,

Lee

et al. 2020

Preprint

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SummaryMounting evidence suggests that cognitive deficits associated with various neurological disorders may arise in part from a small population of dysregulated adult-born neurons in the dentate gyrus (DG). How these dysregulated adult-born neurons contribute to brain-wide network maladaptation and subsequent cognitive deficits remains unknown. Using an established mouse model with a small number of time-stamped dysregulated adult-born immature neurons and spatial memory deficits, we performed resting state functional magnetic resonance imaging and found that approximately 500 deficient immature neurons (<0.1% of total DG granule neurons) are sufficient to induce a significant decrease in the functional connectivity between DG and insular cortex (IC), two brain regions without direct anatomical connections. Furthermore, using a combination of rabies-based retrograde tracing and in vivo fiber photometry recording, we demonstrated that dysregulated adult-born neurons induce aberrant activity and synchrony in local hippocampal CA3 and CA1 regions, as well as distal medial-dorsal thalamus and IC regions during a spatial memory process. These results suggest that a few hundred dysregulated adult-born immature neurons can impact brain-wide network dynamics across several anatomically discrete regions and collectively contribute to impaired cognitive functions.

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Section: Discussionmentioning

confidence: 93%

Section: Dysregulated Adult-born Immature Neurons Disrupt Local Hippomentioning

confidence: 99%

Dysregulation of hippocampal adult-born immature neurons disrupts a brain-wide network for spatial memory

Bao

Hu²,

Lee

et al. 2020

Preprint

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“…This hypothesis argues that newly generated neurons integrate into existing networks (Gonçalves, Schafer, & Gage, 2016) and, in doing so, disrupt some pre‐existing connections (Adlaf et al., 2017)—causing the loss of information held therein. Both experimental (Akers et al., 2014; Epp et al., 2016; Frankland, Köhler, & Josselyn, 2013; Guskjolen et al., 2018; Kitamura et al., 2009) and modeled data (Tran, Josselyn, Richards, & Frankland, 2019; Weisz & Argibay, 2012) support the idea that neurogenesis (and the rate of neurogenesis) can regulate forgetting in certain brain structures (e.g., the hippocampus).…”

Section: Theories Of Forgettingmentioning

confidence: 85%

Molecular mechanisms of forgetting

Moreno

2020

Eur J of Neuroscience

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While every culture has attributed different meanings to forgetting throughout history (Eliade, 1963), it was not until the late nineteenth century that it started to attract the attention of the scientific community (e.g., Ebbinghaus, 1885). It still remains one of the least studied phenomena within the field of learning and memory. However, during the last years, an increasing number of publications have addressed the study of forgetting from different perspectives-ranging from genetic manipulations of fruit flies to in vivo electrophysiological studies in rodents. A number of these publications have proposed an actively modulated forgetting network with dedicated machinery as the primary molecular mechanism for forgetting. This review considers the molecules allegedly involved in forgetting and memory decay and integrates them into a common framework. Despite there being excellent reviews on the topic of forgetting (Bauer

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“…From a mechanistic point of view, although our data do not directly demonstrate the involvement of adult neurogenesis in the behavioral deficits exhibited by Vangl2 deficient mice, they are consistent with the putative role of adult-born neurons in relational memory, flexibility, and forgetting. Indeed, we and others have previously uncovered the specific role of adult-born neurons in supporting behavioral flexibility (Dupret et al, 2008 ; Garthe et al, 2009 ; Burghardt et al, 2012 ), and several recent studies strongly support their involvement in the balance between forgetting previously-acquired memories and learning new information that conflicts with these previously acquired memories, a process also known as active forgetting (Akers et al, 2014 ; Epp et al, 2016 ; Tran et al, 2019 ). In particular, computational and experimental models taken together indicate that decreasing neurogenesis stabilizes existing memories, thereby enhancing interference for the encoding of new memories, particularly when existing and new memories overlap in content, as is the case with goal reversal in the water maze (Aimone et al, 2009 ; Epp et al, 2016 ).…”

Section: Discussionmentioning

confidence: 97%

Vangl2, a Core Component of the WNT/PCP Pathway, Regulates Adult Hippocampal Neurogenesis and Age-Related Decline in Cognitive Flexibility

Koehl

Ladevèze

Montcouquiol

et al. 2022

Front. Aging Neurosci.

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Decline in episodic memory is one of the hallmarks of aging and represents one of the most important health problems facing Western societies. A key structure in episodic memory is the hippocampal formation and the dentate gyrus in particular, as the continuous production of new dentate granule neurons in this brain region was found to play a crucial role in memory and age-related decline in memory. As such, understanding the molecular processes that regulate the relationship between adult neurogenesis and aging of memory function holds great therapeutic potential. Recently, we found that Vang-Gogh like 2 (Vangl2), a core component of the Planar Cell Polarity (PCP) signaling pathway, is enriched in the dentate gyrus of adult mice. In this context, we sought to evaluate the involvement of this member of the Wnt/PCP pathway in both adult neurogenesis and memory abilities in adult and middle-aged mice. Using a heterozygous mouse model carrying a dominant-negative mutation in the Vangl2 gene, called Looptail (Vangl2Lp), we show that alteration in Vangl2 expression decreases the survival of adult-born granule cells and advances the onset of a decrease in cognitive flexibility. The inability of mutant mice to erase old irrelevant information to the benefit of new relevant ones highlights a key role of Vangl2 in interference-based forgetting. Taken together, our findings show that Vangl2 activity may constitute an interesting target to prevent age-related decline in hippocampal plasticity and memory.

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Forgetting at biologically realistic levels of neurogenesis in a large-scale hippocampal model

Cited by 22 publications

References 64 publications

Dysregulation of hippocampal adult-born immature neurons disrupts a brain-wide network for spatial memory

Dysregulation of hippocampal adult-born immature neurons disrupts a brain-wide network for spatial memory

Molecular mechanisms of forgetting

Vangl2, a Core Component of the WNT/PCP Pathway, Regulates Adult Hippocampal Neurogenesis and Age-Related Decline in Cognitive Flexibility

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