Abstract
The fine arrangement of neuronal connectivity during development involves the coordinated action of guidance cues and their receptors. In adolescence, the dopamine circuitry is still developing, with mesolimbic dopamine axons undergoing target-recognition events in the nucleus accumbens (NAcc), while mesocortical projections continue to grow toward the prefrontal cortex (PFC) until adulthood. This segregation of mesolimbic versus mesocortical dopamine pathways is mediated by the guidance cue receptor DCC, which signals dopamine axons intended to innervate the NAcc to recognize this region as their final target. Whether DCC-dependent mesolimbic dopamine axon targeting in adolescence requires the action of its ligand, Netrin-1, is unknown. Here we combined shRNA strategies, quantitative analysis of pre- and post-synaptic markers of neuronal connectivity, and pharmacological manipulations to address this question. Similar to DCC levels in the ventral tegmental area, Netrin-1 expression in the NAcc is dynamic across postnatal life, transitioning from high to low expression across adolescence. Silencing Netrin-1 in the NAcc in adolescence results in an increase in the expanse of the dopamine input to the PFC in adulthood, with a corresponding increase in the number of presynaptic dopamine sites. This manipulation also results in altered dendritic spine density and morphology of medium spiny neurons in the NAcc in adulthood and in reduced sensitivity to the behavioral activating effects of the stimulant drug of abuse, amphetamine. These cellular and behavioral effects mirror those induced by Dcc haploinsufficiency within dopamine neurons in adolescence. Dopamine targeting in adolescence requires the complementary interaction between DCC receptors in mesolimbic dopamine axons and Netrin-1 in the NAcc. Factors regulating either DCC or Netrin-1 in adolescence can disrupt mesocorticolimbic dopamine development, rendering vulnerability or protection to phenotypes associated with psychiatric disorders.
Highlights
Adolescence is a critical developmental period characterized by dramatic neurological and behavioral changes, with neurocircuitry in the prefrontal cortex (PFC), a brain region essential for cognitive and reward functions, being established during this time (Gogtay et al, 2004; Sowell et al, 2004; Petanjek et al, 2011)
We have shown previously that Dcc mRNA and protein expression in the ventral tegmental area (VTA) decreases from adolescence to adulthood (Manitt et al, 2010; Cuesta et al, 2018)
We measured Netrin-1 expression in the nucleus accumbens (NAcc) of mice at PND21±1, PND35±1, and PND75±15 (Figure 1B) and found that the levels are high in early adolescence, but diminish significantly by adulthood (Figure 1C; oneway ANOVA: F(2,23) = 5.20, p = 0.014; the expression at PND21 is significantly higher than PND75; post hoc Bonferroni, p < 0.05)
Summary
Adolescence is a critical developmental period characterized by dramatic neurological and behavioral changes, with neurocircuitry in the prefrontal cortex (PFC), a brain region essential for cognitive and reward functions, being established during this time (Gogtay et al, 2004; Sowell et al, 2004; Petanjek et al, 2011). 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). Both pathways extend from the ventral tegmental area (VTA) along the medial forebrain bundle, but segregate at the level of the striatum in a process mediated by the guidance cue receptor DCC (Figure 1A). Mesocortical dopamine axons, lack or only rarely express DCC receptors and instead of recognizing the NAcc as their final target, they continue to grow to the PFC across adolescence (Manitt et al, 2011; Reynolds et al, 2018)
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