Lesions of the Medial Striatum in Monkeys Produce Perseverative Impairments during Reversal Learning Similar to Those Produced by Lesions of the Orbitofrontal Cortex

Abstract

The ability to switch responding between two visual stimuli based on their changing relationship with reward is dependent on the orbitofrontal cortex (OFC). OFC lesions in humans, monkeys, and rats disrupt performance on a common test of this ability, the visual serial discrimination reversal task. This finding is of particular significance to our understanding of psychiatric disorders such as obsessive-compulsive disorder (OCD) and schizophrenia, in which behavioral inflexibility is a prominent symptom. Although OFC dysfunction can occur in these disorders, there is considerable evidence for more widespread dysfunction within frontostriatal and frontoamygdalar circuitry. Because the contribution of these subcortical structures to behavioral flexibility is poorly understood, the present study compared the effects of excitotoxic lesions of the medial striatum (MS), amygdala, and OFC in the marmoset monkey on performance of the serial reversal task.All monkeys were able to learn a novel stimulus-reward association but, compared with both control and amygdala-lesioned monkeys, those with MS or OFC lesions showed a perseverative impairment in their ability to reverse this association. However, whereas both MS and OFC groups showed insensitivity to negative feedback, only OFC-lesioned monkeys showed insensitivity to positive feedback. These findings suggest that, for different reasons, both the MS and OFC support behavioral flexibility after changes in reward contingencies, and are consistent with the hypothesis that striatal and OFC dysfunction can contribute to pathological perseveration.

Selective Remediation of Reversal Learning Deficits in the Neurodevelopmental MAM Model of Schizophrenia by a Novel mGlu5 Positive Allosteric Modulator

“…Reversal learning is known to be controlled by a neural network including several regions of importance in schizophrenia, such as the hippocampus, amygdala, medial mGlu5 PAM remediates MAM reversal learning deficits F Gastambide et al striatum, orbitofrontal (OFC) and medial prefrontal cortex (mPFC). This network has been defined through lesion and electrophysiological studies in rats and monkeys (Becker et al, 1981;Dias et al, 1996;Murray et al, 1998;Chudasama and Robbins, 2003;Stalnaker et al, 2007;Clarke et al, 2008;Kimchi and Laubach, 2009), and there is also some functional neuroimaging data in humans consistent with this anatomical organization of reversal learning (eg Hampshire and Owen, 2006). Impaired reversal learning has recently been highlighted to occur reliably in schizophrenia.…”

The Role of Frontal Cortical and Medial-Temporal Lobe Brain Areas in Learning a Bayesian Prior Belief on Reversals

“…Inconsistent with this is the fact that this group has the strongest win-stay performance. Consistent with this, however, is the finding that monkeys with AMG lesions extinguish responding more quickly than controls in instrumental (Izquierdo and Murray, 2005;Clarke et al, 2008; and conditioned reinforcement (Parkinson et al, 2001) paradigms. In several settings, AMG damage has been shown to disrupt Pavlovian stimulus-outcome associations (Everitt et al, 2003;Balleine and Killcross, 2006).…”

Serotonin and Dopamine: Unifying Affective, Activational, and Decision Functions

“…Thus, as is the case for DA, 5-HT might have distinct effects in the ventral striatum, the amygdala, and the OFC (Clarke et al, 2008;Boulougouris and Robbins, 2010), or on functions associated with ventral versus dorsal frontostriatal circuitry (Tanaka et al, 2007). Crucial insights will also derive from an understanding of the neural mechanisms that control the activity of 5-HT neurons, such as the medial prefrontal cortex (Amat et al, 2005) and/or lateral habenula Hikosaka, 2010).…”