Dopamine development in the mouse orbital prefrontal cortex is protracted and sensitive to amphetamine in adolescence

Abstract

The prefrontal cortex is divided into subregions including the medial and orbital prefrontal cortices. Dopamine connectivity in the medial prefrontal cortex continues to be established throughout adolescence as the result of the continuous growth of axons that innervated the nucleus accumbens prior to adolescence. During this period, dopamine axons remain vulnerable to environmental influences, such as drugs used recreationally by humans. The developmental trajectory of the orbital prefrontal dopamine innervation remains almost completely unstudied. Nonetheless, the orbital prefrontal cortex is critical for some of the most complex functions of the prefrontal cortex and is disrupted by drugs of abuse, both in adolescent humans and rodents. Here, we use quantitative neuroanatomy, axon-initiated viral-vector recombination, and pharmacology in mice to determine the spatiotemporal development of the dopamine innervation to the orbital prefrontal cortex and its vulnerability to amphetamine in adolescence. We find that dopamine innervation to the orbital prefrontal cortex also continues to increase during adolescence and that this increase is due to the growth of new dopamine axons to this region. Furthermore, amphetamine in adolescence dramatically reduces the number of presynaptic sites on orbital prefrontal cortex dopamine axons. In contrast, dopamine innervation to the piriform cortex is not protracted across adolescence and is not impacted by amphetamine exposure during adolescence, indicating that dopamine development during adolescence is a uniquely prefrontal phenomenon. This renders these fibres, and the prefrontal cortex in general, particularly vulnerable to environmental risk factors during adolescence, such as recreational drug use.

Significance Dopamine function in the orbital prefrontal cortex underlies many complex cognitive tasks and is disrupted by drugs of abuse. However, the developmental trajectory of the dopamine innervation to this portion of the prefrontal cortex remains almost completely unstudied. We show that dopamine axons continue to innervate the orbital prefrontal cortex during adolescence. This renders these axons particularly vulnerable to environmental influences. Exposure to amphetamine, at doses equivalent to those used recreationally by adolescent people, reduces the number of dopamine connections in the orbital prefrontal cortex. This effect is selective; it also occurs in the medial prefrontal cortex but not in the piriform cortex. The impact of amphetamine on cortical dopamine development in adolescence appears to be a uniquely prefrontal phenomenon.