Abstract
Early life experiences program lifelong responses to stress. In agreement, resilience and vulnerability to psychopathologies, such as posttraumatic stress disorder (PTSD), have been suggested to depend on the early background. New therapies have targeted memory reconsolidation as a strategy to modify the emotional valence of traumatic memories. Here, we used animal models to study the molecular mechanism through which early experiences may later affect aversive memory reconsolidation. Handling (H)—separation of pups from dams for 10 min—or maternal separation (MS) — 3-h separation—were performed from PDN1–10, using non-handled (NH) litters as controls. Adult males were trained in a contextual fear conditioning (CFC) task; 24 h later, a short reactivation session was conducted in the conditioned or in a novel context, followed by administration of midazolam 3 mg/kg i.p. (mdz), known to disturb reconsolidation, or vehicle; a test session was performed 24 h after. The immunocontent of relevant proteins was studied 15 and 60 min after memory reactivation in the dorsal hippocampus (dHc) and basolateral amygdala complex (BLA). Mdz-treated controls (NH) showed decreased freezing to the conditioned context, consistent with reconsolidation impairment, but H and MS were resistant to labilization. Additionally, MS males showed increased freezing to the novel context, suggesting fear generalization; H rats showed lower freezing than the other groups, in accordance with previous suggestions of reduced emotionality facing adversities. Increased levels of Zif268, GluN2B, β-actin and polyubiquitination found in the BLA of all groups suggest that memory reconsolidation was triggered. In the dHc, only NH showed increased Zif268 levels after memory retrieval; also, a delay in ERK1/2 activation was found in H and MS animals. We showed here that reconsolidation of a contextual fear memory is insensitive to interference by a GABAergic drug in adult male rats exposed to different neonatal experiences; surprisingly, we found no differences in the reconsolidation process in the BLA, but the dHc appears to suffer temporal desynchronization in the engagement of reconsolidation. Our results support a hippocampal-dependent mechanism for reconsolidation resistance in models of early experiences, which aligns with current hypotheses for the etiology of PTSD.
Highlights
Life experiences modify the development of neural circuits, impacting the individuals on cognitive and emotional levels (Bolton et al, 2017) and may program the development of vulnerability or resilience to psychopathologies later in life (Franklin et al, 2012; Singh-Taylor et al, 2015; Di Segni et al, 2018)
Post hoc analysis revealed that Non-handled group (NH) animals that were administered mdz 3 mg/kg after React had freezing levels significantly lower than NH rats that received sal (p = 0.040, Tukey post hoc test), showing that mdz administered during the reconsolidation window successfully disrupted memory in NH rats and providing evidence that the experimental conditions employed here successfully induced memory reconsolidation in control animals (Figure 1C)
Neonatal interventions appeared to affect this process; there were no differences in freezing between sal or mdz-treated H and maternal separation (MS) rats (p = 1.000 and p = 0.937, respectively; Tukey post hoc test), suggesting that fear memory in these animals was resistant to interference by a GABAAR positive allosteric modulator
Summary
Life experiences modify the development of neural circuits, impacting the individuals on cognitive and emotional levels (Bolton et al, 2017) and may program the development of vulnerability or resilience to psychopathologies later in life (Franklin et al, 2012; Singh-Taylor et al, 2015; Di Segni et al, 2018). The rodent neonatal period corresponds to early childhood in humans (Eiland and Romeo, 2013), an important period of the development that has been viewed as extremely relevant for the development of vulnerability or resilience to psychopathologies (Singh-Taylor et al, 2015); external interventions in this period, such as handling (H) or maternal separation (MS) modify the dynamics of dam-pup interaction in rats (Couto-Pereira et al, 2016), resulting in useful models to study the effects of early experiences on traumatic memories (Diehl et al, 2012, 2014)
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