Adolescent isolation disrupts medial amygdala and ventral tegmental area maturation and sex-specifically dysregulates transcriptional responses to cocaine and stress.

Adolescence is a sensitive developmental period marked by immense social and neural changes during which stressful experiences are associated with susceptibility to neuropsychiatric disorders. The medial amygdala (meA) is especially sensitive to the persistent transcriptional effects of adolescent social isolation. Although critical for social reward, the meA is generally considered to be outside the canonical reward circuitry; however, tracing studies reveal extensive connectivity of the meA with reward circuitry. Here, we show that cocaine-responsive transcriptional concordance is disrupted between the meA and ventral tegmental area (VTA) but not other regions of the mesocorticolimbic reward circuitry by adolescent isolation. This loss of concordance is driven by sex-specific differences in stimulus- and cocaine-responsive gene transcription within and between meA-VTA. We use retrograde tracing techniques to show that these effects are not due to differences in meA-VTA connectivity, nor are they due to differences in dopamine neuronal firing rate in the VTA. Finally, we find that adolescent isolation induced sex-specific disruption of maturational profiles of glutamatergic signaling genes in the meA and VTA. In the meA, isolation increased gene expression of glutamatergic markers Camk2b and Slc17a7 in females, but decreased expression of Camk2a and Camk2b in males. In the VTA, isolation increases expression of NMDA receptor subunits Grin1 and Grin2b in females, while reducing Grin1 and increasing dopamine receptor Drd2 expression in males. These findings establish an integral role of a meA-VTA circuit in the etiology and expression of features of adolescent-onset neuropsychiatric disruptions.