Behavioural Brain Research 245 (2013) 7–12 Contents lists available at SciVerse ScienceDirect Behavioural Brain Research j ourna l ho mepage: www.elsevier.com/locate/bbr Research report Deep brain stimulation in the lateral orbitofrontal cortex impairs spatial reversal learning Marianne Klanker a,b,∗ , Ger Post a , Ruud Joosten a , Matthijs Feenstra a,b , Damiaan Denys a,b a Netherlands Institute for Neuroscience, Institute of the Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands b Department of Psychiatry, Academic Medical Center, University of Amsterdam, Postbus 22660, 1100 DD Amsterdam, The Netherlands h i g h l i g h t s ◮ Deep brain stimulation in the orbitofrontal cortex impaired spatial reversal learning. ◮ Stimulated rats kept responding on the lever that was rewarded before the reversal. ◮ Deficit was only observed during the first reversal presented. ◮ Acquisition of spatial discrimination learning was not affected by OFC stimulation. ◮ OFC stimulation results in perseverative behavior or an inability to adapt behavior to altered response-reward contingencies. a r t i c l e i n f o Article history: Received 24 April 2012 Received in revised form 8 January 2013 Accepted 15 January 2013 Available online 8 February 2013 Keywords: Cognitive flexibility High frequency stimulation Orbitofrontal cortex Perseverative responding Spatial reversal learning a b s t r a c t Deep Brain Stimulation (DBS) is a successful novel treatment for treatment-resistant obsessive- compulsive disorder and is currently under investigation for addiction and eating disorders. Clinical and preclinical studies have shown functional changes in the orbitofrontal cortex (OFC) following DBS in the ventral capsule/ventral striatum. These findings suggest that DBS can affect neural activity in distant regions that are connected to the site of electrode implantation. However, the behavioral consequences of direct OFC stimulation are not known. Here, we studied the effects of direct stimulation in the lateral OFC on spatial discrimination and reversal learning in rats. Rats were implanted with stimulating elec- trodes and were trained on a spatial discrimination and reversal learning task. DBS in the OFC did not affect acquisition of a spatial discrimination. Stimulated animals made more incorrect responses during the first reversal. Acquisition of the second reversal was not affected. These results suggest that DBS may inhibit activity in the OFC, or may disrupt output of the OFC to other cortical or subcortical areas, resulting in perseverative behavior or an inability to adapt behavior to altered response-reward contingencies. © 2013 Elsevier B.V. All rights reserved. 1. Introduction Deep Brain Stimulation (DBS) is a novel treatment for treatment- resistant obsessive-compulsive disorder (OCD) [1–3] and is under investigation for intractable addiction and eating disorders [4]. Despite the apparent success of DBS in reducing clinical symptoms, the mechanism by which DBS reduces symptoms remains elusive. In addition, it is not clear which target area can best be stimulated to result in optimal clinical effects. Preclinical animal studies have been initiated to answer these questions. For example, preclinical ∗ Corresponding author at: Netherlands Institute for Neuroscience, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands. Tel.: +31 20 5665489; fax: +31 20 5666121. E-mail addresses: marianneklanker@yahoo.com, m.klanker@nin.knaw.nl (M. Klanker). studies have shown that DBS in several target regions can influence behavioral processes that are altered in OCD and other compulsive disorders. Compulsive behavior is reduced by DBS in the subthala- mic nucleus [5,6], nucleus accumbens core and shell [7,8], globus pallidus and entopeduncular nucleus [9]. In addition, DBS in the ventral striatum influences anxiety [10], impulsivity [11] and drug taking behavior [12] and can evoke changes in cognitive function- ing [13]. Effects of DBS on cognition are important to study; not only because DBS in psychiatry intends to induce changes in cog- nitive functioning that may be impaired in the disorder, but also to investigate possible cognitive side effects of stimulation. A possible mechanisms through which DBS in commonly used targets for compulsivity disorders could be successful, is by modu- lation of activity in the frontostriatal circuit, a network connecting prefrontal regions with the thalamus and striatum. Modulation of activity in the orbitofrontal cortex (OFC) could be particularly important. OCD patients show hyperactivity of the OFC in rest 0166-4328/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.bbr.2013.01.043