Exogenous BDNF facilitates strategy set-shifting by modulating glutamate dynamics in the dorsal striatum.

Brain-derived neurotrophic factor (BDNF) signaling via tropomyosin-related kinase B (trkB) receptors exerts modulatory effects on glutamatergic transmission, learning, memory and reward processing. Although the role of BDNF in the regulation of mnemonic and affective/motivational processes is well studied, whether this neurotrophin could also regulate executive functions is not known. In the present study, we assessed the effects of intrastriatal infusions on BDNF (1-100 ng/hemisphere) in mice performing an operant strategy set-shifting task that required the animals to eliminate a visual cue-based strategy and adopt a new egocentric spatial response strategy to achieve rewards. Exogenous BDNF administration facilitated the acquisition of strategy shifting by minimizing response perseveration to the previously acquired strategy and this effect resemble an inverted-U shaped dose-response pattern. Faster acquisition of strategy switching in BDNF-infused animals was dependent upon the activation of striatal trkB receptors. Moreover, activation of mGluR2/3 receptors by the selective group II metabotropic receptor agonist LY379268 abolished BDNF-induced cognitive enhancement suggesting the involvement of presynaptic glutamatergic activity. Assessment of striatal glutamate dynamics using electrochemical recordings indicated that local application of BDNF directly induces glutamate release by activating presynaptic trkB receptors on glutamatergic terminals, and this effect followed a bell-shaped dose-response pattern similar to strategy shifting performance. These data suggest that activation of BDNF-trkB signaling in the dorsal striatum improves strategy switching by effectively minimizing response conflicts, and this effect primarily involves facilitation of glutamatergic transmission.