scholarly journals Defective memory engram reactivation underlies impaired fear memory recall in Fragile X syndrome

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Jie Li ◽  
Rena Y Jiang ◽  
Kristin L Arendt ◽  
Yu-Tien Hsu ◽  
Sophia R Zhai ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Cognitive Deficits ◽  
Fragile X ◽  
Fear Memory ◽  
Enriched Environment ◽  
Memory Recall ◽  
Behavioral Learning ◽  
Functional Deficits ◽  
Network Activation ◽  
Memory Engram

Fragile X syndrome (FXS) is an X chromosome-linked disease associated with severe intellectual disabilities. Previous studies using the Fmr1 knockout (KO) mouse, an FXS mouse model, have attributed behavioral deficits to synaptic dysfunctions. However, how functional deficits at neural network level lead to abnormal behavioral learning remains unexplored. Here, we show that the efficacy of hippocampal engram reactivation is reduced in Fmr1 KO mice performing contextual fear memory recall. Experiencing an enriched environment (EE) prior to learning improved the engram reactivation efficacy and rescued memory recall in the Fmr1 KO mice. In addition, chemogenetically inhibiting EE-engaged neurons in CA1 reverses the rescue effect of EE on memory recall. Thus, our results suggest that inappropriate engram reactivation underlies cognitive deficits in FXS, and enriched environment may rescue cognitive deficits by improving network activation accuracy.

scholarly journals Author response: Defective memory engram reactivation underlies impaired fear memory recall in Fragile X syndrome

2020 ◽  
Author(s):  
Jie Li ◽  
Rena Y Jiang ◽  
Kristin L Arendt ◽  
Yu-Tien Hsu ◽  
Sophia R Zhai ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Fragile X ◽  
Fear Memory ◽  
Author Response ◽  
Memory Recall ◽  
Memory Engram

scholarly journals 116.1 GABA-B Agonist Baclofen Normalizes Auditory-Evoked Neural Oscillations and Some Cognitive Deficits in a Fragile X Syndrome Mouse Model

2017 ◽  
Vol 43 (suppl_1) ◽  
pp. S62-S62
Author(s):  
Steven Siegel ◽  
Dunan Sinclair ◽  
Mitsuyuki Matsumoto ◽  
Robert Featherstone ◽  
Olya Melnechenko ◽  
...  
Keyword(s):  
Mouse Model ◽  
Fragile X Syndrome ◽  
Cognitive Deficits ◽  
Fragile X ◽  
Neural Oscillations

scholarly journals Sustained correction of hippocampal neurogenic and cognitive deficits after a brief treatment by Nutlin-3 in a mouse model of Fragile X Syndrome

2022 ◽  
Author(s):  
Sahar Javadi ◽  
Yue Li ◽  
Jie Shen ◽  
Lucy Zhao ◽  
Yao Fu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Young Adult ◽  
Neural Stem Cells ◽  
Fragile X Syndrome ◽  
Cognitive Deficits ◽  
Fragile X ◽  
Therapeutic Effects ◽  
Mature Adult ◽  
Mature Adults ◽  
Deficient Mice

Background: Fragile X syndrome (FXS), the most prevalent inherited intellectual disability and one of the most common monogenic form of autism, is caused by a loss of FMRP translational regulator 1 (FMR1). We have previously shown that FMR1 represses the levels and activities of ubiquitin ligase MDM2 in young adult FMR1-deficient mice and treatment by a MDM2 inhibitor Nutlin-3 rescues both hippocampal neurogenic and cognitive deficits in FMR1-deficient mice when analyzed shortly after the administration. However, it is unknown whether Nutlin-3 treatment can have long-lasting therapeutic effects. Methods: We treated 2-month-old young adult FMR1-deficient mice with Nutlin-3 for 10 days and then assessed the persistent effect of Nutlin-3 on both cognitive functions and adult neurogenesis when mice were 6-month-old mature adults. To investigate the mechanisms underlying persistent effects of Nutlin-3, we analyzed proliferation and differentiation of neural stem cells isolated from these mice and assessed the transcriptome of the hippocampal tissues of treated mice. Results: We found that transient treatment with Nutlin-3 of 2-month-old young adult FMR1-deficient mice prevents the emergence of neurogenic and cognitive deficits in mature adult FXS mice at 6-month of age. We further found that the long-lasting restoration of neurogenesis and cognitive function might not be mediated by changing intrinsic properties of adult neural stem cells. Transcriptomic analysis of the hippocampal tissue demonstrated that transient Nultin-3 treatment leads to significant expression changes in genes related to extracellular matrix, secreted factors, and cell membrane proteins in FMR1-deficient hippocampus.

scholarly journals Control of recollection by slow gamma dominating mid-frequency gamma in hippocampus CA1

2017 ◽  
Author(s):  
Dino Dvorak ◽  
Basma Radwan ◽  
Fraser T. Sparks ◽  
Zoe Nicole Talbot ◽  
André A. Fenton
Keyword(s):  
Fragile X Syndrome ◽  
Cognitive Deficits ◽  
Pyramidal Cell ◽  
Fragile X ◽  
Avoidance Task ◽  
Cognitive Variables ◽  
Wild Type ◽  
Cognitive Inflexibility ◽  
Place Avoidance ◽  
Shock Zone

ABSTRACTBehavior is used to assess memory and cognitive deficits in animals like Fmrl-null mice that model Fragile X Syndrome, but behavior is a proxy for unknown neural events that define cognitive variables like recollection. We identified an electrophysiological signature of recollection in mouse dorsal CA1 hippocampus. During a shocked-place avoidance task, slow gamma (SG: 30-50 Hz) dominates mid-frequency gamma (MG: 70-90 Hz) oscillations 2-3 seconds before successful avoidance, but not failures. Wild-type but not Fmrl-null mice rapidly adapt to relocating the shock; concurrently, SG/MG maxima (SGdominance) decrease in wild-type but not in cognitively inflexible Fmrl-null mice. During SGdominance, putative pyramidal cell ensembles represent distant locations; during place avoidance, these are avoided places. During shock relocation, wild-type ensembles represent distant locations near the currently-correct shock zone but Fmrl-null ensembles represent the formerly-correct zone. These findings indicate that recollection occurs when CA1 slow gamma dominates mid-frequency gamma, and that accurate recollection of inappropriate memories explains Fmrl-null cognitive inflexibility.

scholarly journals Brain-wide mapping of contextual fear memory engram ensembles supports the dispersed engram complex hypothesis

2019 ◽  
Author(s):  
Dheeraj S Roy ◽  
Young-Gyun Park ◽  
Sachie K Ogawa ◽  
Jae H Cho ◽  
Heejin Choi ◽  
...  
Keyword(s):  
High Probability ◽  
Fear Memory ◽  
Brain Regions ◽  
Memory Recall ◽  
Contextual Fear ◽  
Contextual Fear Memory ◽  
Neuronal Ensembles ◽  
Specific Memory ◽  
Complex Hypothesis ◽  
Memory Engram

Neuronal ensembles that hold specific memory (memory engrams) have been identified in the hippocampus, amygdala, and cortex. It has been hypothesized that engrams for a specific memory are distributed among multiple brain regions that are functionally connected. Here, we report the hitherto most extensive engram map for contextual fear memory by characterizing activity-tagged neurons in 409 regions using SHIELD-based tissue phenotyping. The mapping was aided by a novel engram index, which identified cFos+ brain regions holding engrams with a high probability. Optogenetic manipulations confirmed previously known engrams and revealed new engrams. Many of these engram holding-regions were functionally connected to the CA1 or amygdala engrams. Simultaneous chemogenetic reactivation of multiple engrams, which mimics natural memory recall, conferred a greater level of memory recall than reactivation of a single engram ensemble. Overall, our study supports the hypothesis that a memory is stored in functionally connected engrams distributed across multiple brain regions.

Metformin for Treatment of Fragile X Syndrome and Other Neurological Disorders

2019 ◽  
Vol 70 (1) ◽  
pp. 167-181 ◽  
Author(s):  
Ilse Gantois ◽  
Jelena Popic ◽  
Arkady Khoutorsky ◽  
Nahum Sonenberg
Keyword(s):  
Fragile X Syndrome ◽  
Cognitive Deficits ◽  
Neurological Disorders ◽  
Fragile X ◽  
Autism Spectrum ◽  
Cellular Models ◽  
The Us ◽  
Mental Retardation Protein ◽  
Drug Treatments ◽  
Core Symptoms

Fragile X syndrome (FXS) is the most frequent inherited form of intellectual disability and autism spectrum disorder. Loss of the fragile X mental retardation protein, FMRP, engenders molecular, behavioral, and cognitive deficits in FXS patients. Experiments using different animal models advanced our knowledge of the pathophysiology of FXS and led to the discovery of many targets for drug treatments. In this review, we discuss the potential of metformin, an antidiabetic drug approved by the US Food and Drug Administration, to correct core symptoms of FXS and other neurological disorders in humans. We summarize its mechanisms of action in different animal and cellular models and human diseases.

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