Exogenous BDNF facilitates strategy set-shifting by modulating glutamate dynamics in the dorsal striatum Drew E. D’Amore, Brittany A. Tracy, Vinay Parikh * Department of Psychology and Neuroscience Program, Temple University,1701 N.13th Street, Weiss Hall, Philadelphia, PA 19122, USA article info Article history: Received 26 June 2013 Received in revised form 29 July 2013 Accepted 30 July 2013 Keywords: BDNF Cognitive flexibility Dorsal striatum Glutamate abstract 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 (1e100 ng/hemisphere) in mice per- forming 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 doseeresponse 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 doseere- sponse 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. Published by Elsevier Ltd. 1. Introduction Brain-derived neurotrophic factor (BDNF) plays an important role in activity-dependent regulation of synaptic function, long- term potentiation, learning, and memory (Huang and Reichardt, 2001; Lu et al., 2008). Substantial evidence suggests that BDNF exerts neuromodulatory effects on synaptic activity via activation of the tropomyosin-related kinase B (trkB) receptors (Carvalho et al., 2008). Alterations in BDNF-trkB signaling produce a multi- tude of behavioral effects. TrkB antagonism in the hippocampus impairs acquisition and retention of spatial memory (Minichiello et al., 1999). Blockade of BDNF signaling in basolateral amygdala impaired both the acquisition and consolidation of fear condition and fear extinction (Minichiello, 2009; Rattiner et al., 2004). BDNF infusion in the central nucleus of amygdala enhanced conditioned taste aversion memory (Ma et al., 2011). Lower BDNF expression in the hippocampus produced depression-like behavior (Autry and Monteggia, 2012; Monteggia et al., 2004). On the other hand, BDNF signaling enhanced conditioned reward to cocaine, and higher BDNF expression in mesolimbic structures during cocaine withdrawal was linked to relapse (Graham et al., 2009; Lobo et al., 2010; Lu et al., 2010). Taken together, these studies suggested that the behavioral effects of BDNF are region/circuit specific. Although, the role of BDNF in the regulation of mnemonic and affective/ motivational processes is well studied, whether this neurotrophin could also regulate higher cognitive functions such as cognitive control and decision-making is not known. Adaptive cognitive control is necessary to act flexibly in changing environments and to maintain cognitive operations in accordance with ongoing task demands. The integrity of corti- costriatal circuits is critical for cognitive flexibility (Floresco et al., 2006; Ragozzino, 2007) and disruption in these circuits are linked to deficits in executive functions associated with schizophrenia (Floresco et al., 2009), major depression (Austin et al., 2001; Gotlib and Joormann, 2010) and drug addiction (Kalivas and Volkow, 2005). Furthermore, BDNF signaling is proposed to be compro- mised in these psychiatric disorders (Autry and Monteggia, 2012; * Corresponding author. Tel.: þ1 215 204 1572. E-mail address: vinay.parikh@temple.edu (V. Parikh). Contents lists available at ScienceDirect Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm 0028-3908/$ e see front matter Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.neuropharm.2013.07.033 Neuropharmacology 75 (2013) 312e323