Irreversible neonatal dopamine depletion produces functional and structural corticostriatal disconnection and setting-dependent alterations of exploration / exploitation balance.

BRAZ B; GALIÑANES G; TARAVINI I; BELFORTE J; MURER MG

Washington, DC

Congreso; 2014 Annual meeting of the Society for Neuroscience; 2014

Society for Neuroscience

Neurodevelopmental psychiatric disorders as attention deficit hyperactivity disorder (ADHD) might stem from alterations of dopamine regulation of the corticostriatal system. Neonatal dopamine (DA) depletion induced with 6-hydroxydopamine (proposed as an ADHD mouse model) produces juvenile hyperactivity that wanes in adults as compensatory mechanisms are called into play. However, symptoms and neurobiological correlates can persist in adulthood and patients have a higher risk of suffering obsessive-compulsive disorder and other neuropsychiatric conditions as adults. To assess the enduring behavioral consequences of early dopamine depletion, we subjected neonatally DA depleted mice to a battery of behavioral tests after reaching adulthood. DA depleted mice exhibited normal levels of horizontal activity and grooming but showed changes in exploratory behavior favoring local over global exploration of the environment across different settings. Enhanced local exploration was seen as increased vertical activity in small arenas, reduced traveled distance with enhanced local activity in large arenas, longer time spent in the initial visited arm of a maze, longer latency to visit all arms of a maze and reduced number of visits to maze arms. Enhanced local exploration is not specifically directed to salient environmental stimuli or to exploitation of environmental resources, since they showed a decrease in social approach behavior, no interest in burying marbles, diminished food hoarding and deficient nest building. To determine if neonatal DA depletion induces persistent changes in corticostriatal connectivity, we performed electrophysiological and morphological studies of striatal projection neurons. To study corticostriatal connectivity, we recorded evoked striatal field responses to prefrontal cortex stimulation at different current intensities. Striatal evoked responses were diminished in DA depleted mice, suggesting that corticostriatal connectivity is reduced. Finally, we used D1R-TOM / D2R-EGFP double transgenic mice to determine whether these functional changes have a morphological correlate in the direct and indirect pathways. We found a reduction in length and complexity of the dendritic tree in both D1R- and D2R-expressing striatal projection neurons but no differences in spine density in DA depleted mice. We propose that decreased dopamine levels during development causes a functional and structural corticostriatal disconnection which underlies an altered exploration / exploitation balance in our mouse model. Furthermore, the core behavioral alterations of neonatally DA depleted mice may differ or resemble only partially those of ADHD.