Chronic fluoxetine prevents fear memory generalization and enhances subsequent extinction by remodeling hippocampal dendritic spines and slowing down systems consolidation View Full Text


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Article Info

DATE

2019-01-31

AUTHORS

Lizeth K. Pedraza, Rodrigo O. Sierra, Marcelo Giachero, Walquiria Nunes-Souza, Fernanda N. Lotz, Lucas de Oliveira Alvares

ABSTRACT

Fear memory overgeneralization contributes to the genesis and persistence of anxiety disorders and is a central hallmark in the pathophysiology of post-traumatic stress disorder (PTSD). Recent findings suggest that fear generalization is closely related to hippocampal dependency during retrieval. The selective serotonin reuptake inhibitor (SSRI) fluoxetine has been used as a first-line treatment for PTSD; however, how it exerts its therapeutic effect remains a matter of debate. Here, using contextual fear conditioning in rats, we show that chronic fluoxetine treatment prevents fear generalization and enhances subsequent extinction. Moreover, fluoxetine treatment after extinction prevents spontaneous recovery. The mechanism through which fluoxetine affects generalization and extinction seems to be through the postponement of systems consolidation, thereby maintaining hippocampal involvement during retrieval. Such an effect relies on a remodeling of dendritic spines in the hippocampus, as well as the number of mature, mushroom-type spines promoted by fluoxetine treatment. In order to further investigate whether fear generalization is a potential predictor of extinction effectiveness, we categorized a large naive population according to their generalization rate. We found that discriminator rats showed a better extinction profile compared to generalizers, suggesting that the generalization rate predicts extinction effectiveness. Hence, we propose that the therapeutic strategy of choice should take into account the extension of memory generalization, in which therapies based on extinction could induce a better outcome in patients who present less fear overgeneralization. These results open new avenues for the development of interventions that prevent fear generalization by maintaining memory dependency of the hippocampus. More... »

PAGES

53

References to SciGraph publications

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  • 2007-04-01. Memory consolidation or transformation: context manipulation and hippocampal representations of memory in NATURE NEUROSCIENCE
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    http://scigraph.springernature.com/pub.10.1038/s41398-019-0371-3

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    34 schema:description Fear memory overgeneralization contributes to the genesis and persistence of anxiety disorders and is a central hallmark in the pathophysiology of post-traumatic stress disorder (PTSD). Recent findings suggest that fear generalization is closely related to hippocampal dependency during retrieval. The selective serotonin reuptake inhibitor (SSRI) fluoxetine has been used as a first-line treatment for PTSD; however, how it exerts its therapeutic effect remains a matter of debate. Here, using contextual fear conditioning in rats, we show that chronic fluoxetine treatment prevents fear generalization and enhances subsequent extinction. Moreover, fluoxetine treatment after extinction prevents spontaneous recovery. The mechanism through which fluoxetine affects generalization and extinction seems to be through the postponement of systems consolidation, thereby maintaining hippocampal involvement during retrieval. Such an effect relies on a remodeling of dendritic spines in the hippocampus, as well as the number of mature, mushroom-type spines promoted by fluoxetine treatment. In order to further investigate whether fear generalization is a potential predictor of extinction effectiveness, we categorized a large naive population according to their generalization rate. We found that discriminator rats showed a better extinction profile compared to generalizers, suggesting that the generalization rate predicts extinction effectiveness. Hence, we propose that the therapeutic strategy of choice should take into account the extension of memory generalization, in which therapies based on extinction could induce a better outcome in patients who present less fear overgeneralization. These results open new avenues for the development of interventions that prevent fear generalization by maintaining memory dependency of the hippocampus.
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    42 account
    43 affects generalization
    44 anxiety disorders
    45 avenues
    46 better extinction profile
    47 better outcomes
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    50 chronic fluoxetine treatment prevents
    51 conditioning
    52 consolidation
    53 contextual fear conditioning
    54 debate
    55 dendritic spines
    56 dependency
    57 development
    58 development of interventions
    59 discriminator rats
    60 disorders
    61 effect
    62 effectiveness
    63 extension
    64 extinction
    65 extinction effectiveness
    66 extinction profiles
    67 fear conditioning
    68 fear generalization
    69 fear overgeneralization
    70 findings
    71 first-line treatment
    72 fluoxetine
    73 fluoxetine affects generalization
    74 fluoxetine prevents
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    76 fluoxetine treatment prevents
    77 generalization
    78 generalization rate
    79 generalizers
    80 genesis
    81 hallmark
    82 hippocampal dendritic spines
    83 hippocampal dependency
    84 hippocampal involvement
    85 hippocampus
    86 inhibitor (SSRI) fluoxetine
    87 intervention
    88 involvement
    89 large naive populations
    90 less fear overgeneralization
    91 matter
    92 matter of debate
    93 mechanism
    94 memory dependencies
    95 memory generalization
    96 memory overgeneralization
    97 mushroom-type spines
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    104 pathophysiology
    105 patients
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    110 potential predictors
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