Dorsolateral Striatal proBDNF Improves Reversal Learning by Enhancing Coordination of Neural Activity in Rats

Behavioral flexibility allows individuals to adapt to situations in which rewards and goals change. The dorsolateral striatum (DLS) is part of corticostriatal circuits that is involved in flexible behavior. Pro-brain-derived neurotrophic factor (proBDNF) can enhance fear memory extinction and weaken synaptic transmission, which may enable flexible adaptations. However, the role of proBDNF in cognitive flexibility is unclear. Here, through infusion of cleavage-resistant proBDNF or its antibody into the DLS of rats, we sought evidence for the influences by employing behavioral tests, immunoblotting, immunocytochemistry, and electrophysiological recoding. Infusion of proBDNF significantly facilitated reversal learning while inhibiting DLS proBDNF by anti-proBDNF antibody impaired the behavioral performance. Furthermore, elevation of DLS proBDNF facilitated neural correlate with reversal performance while blocking proBDNF expression decayed the spike-field coupling during the correct turning. Reversal learning induced increases in endogenous neuronal proBDNF, with a strong correlation between DLS and infralimbic cortex (IL), but not prelimbic cortex (PL) or sensory-motor cortex (SM). Importantly, blockade of IL proBDNF disrupted the DLS-mediated reversal learning enhancement, implying the involvement of both IL and DLS regions in reversal habitual behavior. Taken together, our findings provide first evidence for the essential role of the DLS proBDNF in cognitive flexibility and suggest that proBDNF-mediated neural function could be the mechanism.