Figure 1.

Graphical representation of TBI-induced disruption of the neurovascular unit (NVU) within reward pathway nuclei and subsequent cellular and behavioral consequences linked to increased risk of substance use disorders. A: Under normal conditions, endothelial cells (red) lining the vasculature and expressing tight junction proteins (TJP) (grey) remain intact, with no indications of blood-brain-barrier (BBB) permeability, or immune cell infiltration (Yellow: Ly6C low/patrolling monocytes; Orange: Ly6C intermediate/pro-inflammatory monocytes; Red: Ly6C high/classical monocytes). Astrocytes (green) and microglia (blue) remain quiescently surveilling the environment, with some microglia involved in adolescent synaptic pruning of neuronal proteins (engulfed purple circles). Magnification shows the synapse of interneurons/medium spiny neurons residing in the NAc. Dopamine (pink) release mediates reward-motivated behaviors that underlie substance use disorders. B. Following early-life TBI, neuropathology includes endothelial activation, disruption of TJP, BBB hyperpermeability, and infiltration of immune cells with persistent Ly6C pro-inflammatory monocytes reported in adolescent brain injury. Activated microglia phagocytose neuronal proteins resulting in adverse changes to medium spiny neuron morphology and spine density. Magnification shows adolescent TBI-induced hypodopaminergic state and changes to spine length. Long thin spines are unstable and associated with dynamic changes and increased excitability. C. Proposed behavioral consequences seen in preclinical research models of early-life TBI and cocaine conditioned place preference. Adolescent animals show increased sensitivity to subthreshold doses of cocaine (green) compared to adults (blue). TBI during adulthood (blue, striped) augments the magnitude of CPP shift to high cocaine doses, which is further exacerbated in adolescent TBI (green, striped).