Dopamine Development in the Mouse Orbital Prefrontal Cortex Is Protracted and Sensitive to Amphetamine in Adolescence

Abstract

The prefrontal cortex (PFC) is divided into subregions, including the medial and orbital prefrontal cortices. Dopamine connectivity in the medial PFC (mPFC) continues to be established throughout adolescence as the result of the continuous growth of axons that innervated the nucleus accumbens (NAcc) 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 PFC (oPFC) is critical for some of the most complex functions of the PFC 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 oPFC and its vulnerability to amphetamine in adolescence. We find that dopamine innervation to the oPFC 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 oPFC 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 fibers, and the PFC in general, particularly vulnerable to environmental risk factors during adolescence, such as recreational drug use.

Adolescence and “Late Blooming” Synapses of the Prefrontal Cortex

“…Histological studies have also shown striking late growth of dopaminergic terminals into the primate and rodent PFC extending from the juvenile period well into the young adult period (Kalsbeek et al 1988;Benes et al 2000;Naneix et al 2012;Willing et al 2017;Hoops et al 2018). In mice, dopaminergic boutons in the PFC show greater activity-dependent plasticity in mid adolescence compared to adulthood (Mastwal et al 2014).…”

Adolescents exhibit reduced Pavlovian biases on instrumental learning

“…The dopaminergic system exhibits substantial reorganization across adolescence 75,76 , including nonlinear changes in dopamine receptor and transporter density [77][78][79][80][81] . Moreover, dopaminergic projections from the striatum to the prefrontal cortex continue to develop in adolescence 82,83 . Such nonlinear changes in the dopaminergic system and corticostriatal connectivity might contribute to the adolescent-specific attenuation of the Pavlovian bias.…”

Dopamine Axon Targeting in the Nucleus Accumbens in Adolescence Requires Netrin-1

“…The developmental trajectory of the PFC in adolescence is demarcated by the gradual increase in dopamine innervation ( Rosenberg and Lewis, 1995 ; Weickert et al, 2007 ; Rothmond et al, 2012 ; Gulley and Juraska, 2013 ; Hoops and Flores, 2017 ), is highly responsive to genetic and environmental factors, and determines vulnerability or resilience to psychiatric disease ( Lee et al, 2014 ; Fuhrmann et al, 2015 ). The density of the mesocortical dopamine input continues to increase across adolescence due to the ongoing growth of dopamine axons toward the PFC ( Hoops et al, 2018 ; Reynolds et al, 2018 ). This contrasts with the anatomically and functionally distinct mesolimbic dopamine pathway, which achieves adult-like density levels soon after postnatal development ( Antonopoulos et al, 2002 ; Brummelte and Teuchert-Noodt, 2006 ).…”