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

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.

The stressed brain of humans and rodents

“…Using this approach, it was shown that impaired contextual/spatial memory seen in (adult) rats that were exposed to 24-h maternal deprivation at P3 can be fully prevented by only 3 days of treatment with a GRantagonist, between P26 and P28 ( Figure 6C). 35 The impairment was very specific for areas involved in spatial memory and was not seen in areas involved in reward learning. In both studies, glutamate transmission in single hippocampal cells was suppressed by early life adversity per se, but fully restored in the MR-overexpressing group or animals temporarily treated with the GR-antagonist.…”

“…Changes in MR relative to GR activation can also be achieved by treating animals with a GR‐antagonist; the timing of this pharmacological approach is very precise (with fewer compensatory effects than genetic modification) but, of course, peripheral administration affects many more organs than just the brain. Using this approach, it was shown that impaired contextual/spatial memory seen in (adult) rats that were exposed to 24‐h maternal deprivation at P3 can be fully prevented by only 3 days of treatment with a GR‐antagonist, between P26 and P28 (Figure C) . The impairment was very specific for areas involved in spatial memory and was not seen in areas involved in reward learning.…”

Top‐down and bottom‐up control of stress‐coping

“…The new data on prevention and/or reversal of stress-induced programming effects add to a growing body of evidence demonstrating that blockade of the GR can reset stress response patterns imposed by (early life) trauma and chronic stress. 144,145 Presently, there are two hypotheses to explain later life consequences of early experience. First, dysregulation and increased vulnerability can occur when later life experience does not match the early-life conditions: the match-mismatch hypothesis.…”

Corticosteroids and the brain

“…Examples illustrate that basal glutamate transmission in the hippocampus is altered when animals have a history of early life adversity (e.g. Loi et al 2017). Also, many neuronal properties are influenced by chronic stress in adulthood (reviewed in Joëls et al 2012).…”