Activation of a novel p70 S6 kinase 1-dependent intracellular cascade in the basolateral nucleus of the amygdala is required for the acquisition of extinction memory.

Repeated presentations of a previously conditioned stimulus lead to a new form of learning known as extinction, which temporarily alters the response to the original stimulus. Previous studies have shown that the consolidation of extinction memory requires de novo protein synthesis. However, the role of specific nodes of translational control in extinction is unknown. Using auditory threat conditioning in mice, we investigated the role of mechanistic target of rapamycin complex 1 (mTORC1) and its effector p70 S6 kinase 1 (S6K1) in the extinction of auditory threat conditioning. We found that rapamycin attenuated the consolidation of extinction memory. In contrast, genetic deletion and pharmacological inhibition of S6K1, a downstream effector of mTORC1, blocked within-session extinction, indicating a role for S6K1 independent of protein synthesis. Indeed, the activation of S6K1 during extinction required extracellular signal-regulated kinase (ERK) activation in the basolateral nucleus of the amygdala (BLA) and was necessary for increased phosphorylation of the GluA1 (Thr840) subunit of the AMPA receptor following extinction training. Mice exposed to brief uncontrollable stress showed impaired within-session extinction as well as a downregulation of ERK and S6K1 signaling in the amygdala. Finally, using fiber photometry we were able to record calcium signals in vivo, and we found that inhibition of S6K1 reduces extinction-induced changes in neuronal activity of the BLA. These results implicate a novel ERK-S6K1-GluA1 signaling cascade critically involved in extinction.

The effect of physical abuse on children's social and affective status: a model of cognitive and behavioral processes explaining the association.

This study proposes a model explaining the association between physical abuse of children and children's social and affective status as one in which children's social expectations and behavior, developed within the context of abusive parenting, mediate current functioning in these two outcome domains. Subjects included one hundred 9 to 12-year-old physically abused children recruited from consecutive entries onto the New York State Register for Child Abuse for New York City and 100 case-matched classmate nonabused comparison children. Sociometric assessments were carried out in classrooms, interviews were conducted with the children and their parents, and teachers, parents, and classmates rated the children's behavior. Path analysis was utilized to test the conceptually derived models. Children's social expectations regarding peers, and two social behaviors--aggressive behavior and prosocial behavior--were found to mediate between abuse and positive and negative social status, as well as between abuse and positive and negative reciprocity. Social expectations and withdrawn behavior mediated between abuse and positive social status, but only where withdrawn behavior was a function of social expectations. Social expectations were generally found to mediate between abuse and internalizing problems. Negative social status (peer rejection) added to social expectations in producing internalizing problems. Identification of these mediating pathways can serve to guide secondary preventive intervention efforts so that they best address the problems abused children face in the absence of adequate parental and peer support as the children enter adolescence.