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 emotion-ality, and glucocorticoid receptor (GR) concentrations in forebrain regions such as hippocampus. To investi-gate effects of neonatal maternal separation on emotion regulation and its neural substrates, we assessed acquisi-tion 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 extinc-tion 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 baso-lateral amygdala and medial prefrontal cortex. On post-natal days 2–14, pups underwent control rearing or maternal separation for 15 min per day. Fear condition-ing and extinction in adulthood were then assessed in male rats. Rats received five tone-alone habituation tri-als, 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 proc-essed for immunohistochemical labeling of GR and NR1, and staining was quantified. Brief maternal sepa-ration did not alter acquisition or initial extinction, but impaired extinction recall. Brief maternal separation did not alter GR or NR1 expression in basolateral amyg-dala. However, brief maternal separation increased GR and decreased NR1 expression specifically in the infra-limbic 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 neura