Transient Prepubertal Mifepristone Treatment Normalizes Deficits in Contextual Memory and Neuronal Activity of Adult Male Rats Exposed to Maternal Deprivation

Manila Loi, Ratna Angela Sarabdjitsingh, Andromachi Tsouli, Stephanie Trinh, Marit Arp, Harmen J. Krugers, Henk Karst, Ruud van den Bos, Marian Joels

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    Abstract

    Early life adversity is a well-known risk factor for behavioral dysfunction later in life, including the formation of contextual memory; it is also (transiently) accompanied by hyperactivity of the stress system. We tested whether mifepristone (MIF) treatment, which among other things blocks glucocorticoid receptors (GRs), during the prepubertal period [ postnatal days (PND) 26-PND28] normalizes memory deficits in adult male rats exposed to 24-h maternal deprivation (MD) at PND3. MD reduced body weight gain and increased basal corticosterone (CORT) levels during the PND26, but not in adulthood. In adulthood, contextual memory formation of MD compared to noMD (i.e., control) male rats was significantly impaired. This impairment was fully prevented by MIF treatment at PND26-PND28, whereas MIF by itself did not affect behavior. A second behavioral test, a rodent version of the Iowa Gambling Task (rIGT), revealed that flexible spatial learning rather than reward-based aspects of performance was impaired by MD; the deficit was prevented by MIF. Neuronal activity as tested by c-Fos staining in the latter task revealed changes in the right hippocampal-dorsomedial striatal pathway, but not in prefrontal areas involved in reward learning. Follow-up electrophysiological recordings measuring spontaneous glutamate transmission showed reduced frequency of miniature postsynaptic excitatory currents in adult CA1 dorsal hippocampal and enhanced frequency in dorsomedial striatal neurons from MD versus noMD rats, which was not seen in MIF-treated rats. We conclude that transient prepubertal MIF treatment normalizes hippocampus-striatal-dependent contextual memory/spatial learning deficits in male rats exposed to early life adversity, possibly by normalizing glutamatergic transmission.

    Original languageEnglish
    Article numberUNSP e0253-17.2017
    Number of pages17
    JournalEneuro
    Volume4
    Issue number5
    DOIs
    Publication statusPublished - 26-Oct-2017

    Keywords

    • early life stress
    • glutamate transmission
    • mifepristone
    • reward-based decision making
    • Rodent Iowa Gambling Task
    • spatial memory
    • EARLY-LIFE STRESS
    • HIPPOCAMPAL GLUCOCORTICOID-RECEPTORS
    • IOWA GAMBLING TASK
    • DECISION-MAKING
    • SYNAPTIC PLASTICITY
    • SPINY NEURONS
    • RODENT MODEL
    • IN-VIVO
    • CARE
    • CORTICOSTERONE

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