Brief neonatal maternal separation alters extinction of conditioned fear and corticolimbic glucocorticoid and NMDA receptor expression in adult rats

Abstract

Neonatal maternal separation alters adult HPA axis responsiveness to stress, adult emotionality, and glucocorticoid receptor (GR) concentrations in forebrain regions such as hippocampus. To investigate effects of neonatal maternal separation on emotion regulation and its neural substrates, we assessed acquisition and extinction of conditioned fear in adult rats that underwent neonatal maternal separation. Corticolimbic structures including basolateral amygdala and medial prefrontal cortex are critical for acquisition and extinction of conditioned fear, and such learning is N-methyl-D-aspartic acid (NMDA) receptor-dependent. Thus, we used immunohistochemistry to assess expression of the GR and the NR1 subunit of the NMDA receptor in basolateral amygdala and medial prefrontal cortex. On postnatal days 2-14, pups underwent control rearing or maternal separation for 15 min per day. Fear conditioning and extinction in adulthood were then assessed in male rats. Rats received five tone-alone habituation trials, then seven tone/footshock pairings. After 1 h, rats received tone-alone extinction trials to criterion, and 15 recall of extinction trials the next day. Brains were processed for immunohistochemical labeling of GR and NR1, and staining was quantified. Brief maternal separation did not alter acquisition or initial extinction, but impaired extinction recall. Brief maternal separation did not alter GR or NR1 expression in basolateral amygdala. However, brief maternal separation increased GR and decreased NR1 expression specifically in the infralimbic region of medial prefrontal cortex, consistent with work implicating this area in extinction recall. Thus, brief maternal separation impaired extinction recall and altered GR and NR1 expression in its neural substrate in adults.