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Suppressing unwanted memories reduces their unconscious influence via targeted cortical inhibition.

ABSTRACT: Suppressing retrieval of unwanted memories reduces their later conscious recall. It is widely believed, however, that suppressed memories can continue to exert strong unconscious effects that may compromise mental health. Here we show that excluding memories from awareness not only modulates medial temporal lobe regions involved in explicit retention, but also neocortical areas underlying unconscious expressions of memory. Using repetition priming in visual perception as a model task, we found that excluding memories of visual objects from consciousness reduced their later indirect influence on perception, literally making the content of suppressed memories harder for participants to see. Critically, effective connectivity and pattern similarity analysis revealed that suppression mechanisms mediated by the right middle frontal gyrus reduced activity in neocortical areas involved in perceiving objects and targeted the neural populations most activated by reminders. The degree of inhibitory modulation of the visual cortex while people were suppressing visual memories predicted, in a later perception test, the disruption in the neural markers of sensory memory. These findings suggest a neurobiological model of how motivated forgetting affects the unconscious expression of memory that may be generalized to other types of memory content. More generally, they suggest that the century-old assumption that suppression leaves unconscious memories intact should be reconsidered.

SUBMITTER: Gagnepain P

PROVIDER: S-EPMC3977236 | biostudies-other | 2014 Apr

REPOSITORIES: biostudies-other

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Suppressing unwanted memories reduces their unconscious influence via targeted cortical inhibition.

Gagnepain Pierre P Henson Richard N RN Anderson Michael C MC

Proceedings of the National Academy of Sciences of the United States of America 20140317 13

Suppressing retrieval of unwanted memories reduces their later conscious recall. It is widely believed, however, that suppressed memories can continue to exert strong unconscious effects that may compromise mental health. Here we show that excluding memories from awareness not only modulates medial temporal lobe regions involved in explicit retention, but also neocortical areas underlying unconscious expressions of memory. Using repetition priming in visual perception as a model task, we found t ...[more]

PMID: 24639546

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Project description:Tumor-specific metabolic rewiring, acquired to confer a proliferative and survival advantage over nontransformed cells, represents a renewed focus in cancer therapy development. Hepatocellular carcinoma (HCC), a malignancy that has hitherto been resistant to compounds targeting oncogenic signaling pathways, represents a candidate cancer to investigate the efficacy of selectively antagonizing such adaptive metabolic reprogramming. To this end, we sought to characterize metabolic changes in HCC necessary for tumorigenesis. We analyzed gene expression profiles in three independent large-scale patient cohorts who had HCC. We identified a commonly deregulated purine metabolic signature in tumors with the extent of purine biosynthetic enzyme up-regulation correlated with tumor grade and a predictor of clinical outcome. The functional significance of enhanced purine metabolism as a hallmark in human HCC was then validated using a combination of HCC cell lines, patient-derived xenograft (PDX) organoids, and mouse models. Targeted ablation of purine biosynthesis by knockdown of the rate-limiting enzyme inosine-5'-monophosphate dehydrogenase (IMPDH) or using the drug mycophenolate mofetil (MMF) reduced HCC proliferation in vitro and decreased the tumor burden in vivo. In comparing the sensitivities of PDX tumor organoids to MMF therapy, we found that HCC tumors defined by high levels of IMPDH and guanosine nucleosides were most susceptible to treatment. Mechanistically, a phosphoinositide 3-kinase (PI3K)-E2F transcription factor 1 (E2F1) axis coordinated purine biosynthetic enzyme expression, deregulation of which altered the activity of mitogen-activated protein kinase/RAS signaling. Simultaneously abolishing PI3K signaling and IMPDH activity with clinically approved inhibitors resulted in greatest efficacy in reducing tumor growth in a PDX mouse model. Conclusion: Enhanced purine metabolic activity regulated by PI3K pathway-dependent activation of E2F1 promotes HCC carcinogenesis, suggesting the potential for targeting purine metabolic reprogramming as a precision therapeutic strategy for patients with HCC.

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Suppressing unwanted memories reduces their unconscious influence via targeted cortical inhibition.

Publications

Suppressing unwanted memories reduces their unconscious influence via targeted cortical inhibition.

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