Schoenbaum G, Nugen SL, Saddoris ML, Setlow B. Orbitofrontal lesions in rats impair reversal but not acquisition of go, no-go odor discriminations. Neuroreport 13: 885-890

Department of Psychological and Brain Sciences, Johns Hopkins University, 3400 North Charles Street, 25 Ames Hall, Baltimore, MD 21218, USA.
Neuroreport (Impact Factor: 1.52). 06/2002; 13(6):885-90. DOI: 10.1097/00001756-200205070-00030
Source: PubMed


Recent evidence suggests that orbitofrontal cortex lesions cause an inability to withhold inappropriate responses particularly when learned behavior must be modified to reflect changes in the likely outcome or consequence of responding. By this account, orbitofrontal cortex should not be necessary for acquisition of simple discrimination problems, but should be critical for acquiring reversals of those problems. However, previous work in rats has shown orbitofrontal cortex to be critical for withholding responses even in a simple go, no-go discrimination task. Here we have reexamined the contribution of rat orbitofrontal cortex to acquisition and reversal of go, no-go odor discrimination problems. Contrary to prior reports, we found that rats with lesions of the orbitofrontal cortex acquired novel discrimination problems at the same rate as controls. Impairments were evident in lesioned rats when the response contingencies of the odors in the discrimination problem were reversed. These findings suggest that orbitofrontal cortex is not necessary for inhibiting responses unless responses must be altered to reflect changing relationships between cues and outcomes.

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    • "Studies investigating the contribution of the orbitofrontal cortex to behavioral flexibility have yielded results that suggest that this prefrontal cortex subregion makes different contributions than the prelimbic cortex. Experiments involving orbitofrontal cortex inactivation or lesions found that these manipulations do not affect acquisition of different discrimination learning tests, for example, olfactory or visuospatial discrimination , but do impair reversal learning (Boulougouris et al. 2007; Churchwell et al. 2009; Ghods-Sharifi et al. 2008; Kim and Ragozzino 2005; McAlonan and Brown 2003; Riceberg and Shapiro 2012; Schoenbaum et al. 2002). This occurred in reversal-learning tests that involved the flexible use of odor, "
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    ABSTRACT: The Kesner neurobiologically based attribute model of memory is a multiple memory systems model proposing that different brain systems support specific memory representations based on attribute information. The model has served as a useful framework to test hypotheses about the nature of memory representations in the brain. The model has expanded beyond the neurobiology of memory to investigate how separate prefrontal cortex subregions support behavioral flexibility based on how attribute information must be used in different ways to allow adaptive behavior. Behavioral flexibility refers to the ability to adapt strategies or choice patterns when changes in external or internal conditions signal a behavioral strategy switch. The chapter first describes how different prefrontal cortex subregions support the flexible use of attribute information based on the behavioral operation required to adapt. Under conditions in which a change in outcomes signals that a behavioral switch should occur, accumulating evidence supports the idea that the prelimbic cortex enables a switch in strategies that allows the flexible use of different attribute information, that is, set-shifting. The orbitofrontal cortex enables behavioral flexibility when conditions require a new choice pattern using the same attribute information, that is, reversal learning. The chapter additionally considers a role for the dorsomedial striatum, which receives input from multiple prefrontal areas, in both set-shifting and reversal learning. Based on examination of the error patterns in these different tests, the prefrontal cortex enables behavioral flexibility by initially inhibiting a previous choice pattern and/or generating a new choice pattern while the dorsomedial striatum facilitates the reliable execution of a new choice pattern. It also describes recent findings indicating that the prelimbic cortex along with the subthalamic nucleus and dorsomedial striatum acts in a cooperative manner to enable behavioral flexibility when cues, as opposed to outcomes, guide a proactive behavioral switch. Specifically, the prelimbic cortex and subthalamic nucleus enable the rapid inhibition of an ongoing choice pattern while concomitantly a neural system that includes the prelimbic cortex and dorsomedial striatum enables selection of an alternative choice pattern and maintenance of that selection. Taken together, the Kesner neurobiological model of memory has served as a framework to build substantial support for the idea that prefrontal cortex and basal ganglia structures are crucial to allow rapid and repeated adaptations under changing environmental demands.
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    • "This conclusion is also supported by the fact that atomoxetine does not affect probabilistic learning in humans (Chamberlain et al. 2006). Additionally, reversals, which isolate the use of outcomes to change behavior while keeping stimuli constant, depend on different PFC sub-regions in comparison to attentional set shifting and depends upon PFC serotonin neurotransmission rather than NE and DA (Dias et al. 1996; Birrell and Brown 2000; Schoenbaum et al. 2002). Therefore, it is unlikely that atomoxetine affected processing of outcomes. "
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    ABSTRACT: Shifting to a new rule is a form of behavioral flexibility that is impaired in numerous psychiatric and neurological illnesses. Animal studies have revealed that this form of flexibility depends upon norepinephrine (NE) neurotransmission. Atomoxetine, a NE reuptake inhibitor, improves performance of humans in set shifting tasks. Our objective was to validate its effects in a rodent set shifting task. We tested the drug effect using an operant task that required a shift from a visual cue-guided behavior to a novel location-guided rule. A 1.0-mg/kg dose significantly accelerated rule shifting without affecting learning strategies, such as win-stay or lose-shift. Fitting behavioral performance with a learning function provided a measure of learning rate. This novel analysis revealed that atomoxetine accelerated shifting to the new rule without affecting learning rate.
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    • "Reversal learning as measured in the reversal phases of the CANTAB ID/ED-task of executive functioning is sensitive to deficits in patients with schizophrenia, independently of generalised intelligence (Leeson et al. 2009). These reversal learning deficits likely represent underlying abnormalities in fronto-striatal circuits, as these structures have been linked to reversal learning through imaging studies in humans (O'Doherty et al. 2003) as well as through excitotoxic and neurotransmitter-selective lesion studies in experimental animals (Bussey et al. 1997a, b; Schoenbaum et al. 2002; McAlonan and Brown 2003; Chudasama and Robbins 2003; Kim and Ragozzino 2005; Bissonette et al. 2008; Ghods- Sharifi et al. 2008; Burke et al. 2009; Graybeal et al. 2011). Specifically, intact 5-HT signalling in the orbitofrontal cortex (OFC) and dopamine signalling in the caudate nucleus (primates) or dorsomedial striatum (rodents) is critical for successful reversal learning (Clarke et al. 2004, 2011; O'Neill and Brown 2007; Boulougouris and Robbins 2010; Groman et al. 2013). "
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    ABSTRACT: The NEWMEDS initiative (Novel Methods leading to New Medications in Depression and Schizophrenia, ) is a large industrial-academic collaborative project aimed at developing new methods for drug discovery for schizophrenia. As part of this project, Work package 2 (WP02) has developed and validated a comprehensive battery of novel touchscreen tasks for rats and mice for assessing cognitive domains relevant to schizophrenia. This article provides a review of the touchscreen battery of tasks for rats and mice for assessing cognitive domains relevant to schizophrenia and highlights validation data presented in several primary articles in this issue and elsewhere. The battery consists of the five-choice serial reaction time task and a novel rodent continuous performance task for measuring attention, a three-stimulus visual reversal and the serial visual reversal task for measuring cognitive flexibility, novel non-matching to sample-based tasks for measuring spatial working memory and paired-associates learning for measuring long-term memory. The rodent (i.e. both rats and mice) touchscreen operant chamber and battery has high translational value across species due to its emphasis on construct as well as face validity. In addition, it offers cognitive profiling of models of diseases with cognitive symptoms (not limited to schizophrenia) through a battery approach, whereby multiple cognitive constructs can be measured using the same apparatus, enabling comparisons of performance across tasks. This battery of tests constitutes an extensive tool package for both model characterisation and pre-clinical drug discovery.
    No preview · Article · Jul 2015 · Psychopharmacology
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