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The Journal of Neuroscience, May 6, 2009, 29(18):6033-6041; doi:10.1523/JNEUROSCI.0312-09.2009

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Behavioral/Systems/Cognitive
Response Disengagement on a Spatial Self-Ordered Sequencing Task: Effects of Regionally Selective Excitotoxic Lesions and Serotonin Depletion within the Prefrontal Cortex

Susannah C. Walker,^1,2 Trevor W. Robbins,^1,2 and Angela C. Roberts^2,3

¹Department of Experimental Psychology and ²Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge CB2 3EB, United Kingdom, and ³Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, United Kingdom

Correspondence should be addressed to Dr. Angela C. Roberts, Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3DY, UK. Email: acr4{at}cam.ac.uk

Prefrontal cortex (PFC) is critical for self-ordered response sequencing. Patients with frontal lobe damage are impaired on response sequencing tasks, and increased blood flow has been reported in ventrolateral and dorsolateral PFC in subjects performing such tasks. Previously, we have shown that large excitotoxic lesions of the lateral PFC (LPFC) and orbitofrontal cortex FC (OFC), but not global prefrontal dopamine depletion, markedly impaired marmoset performance on a spatial self-ordered sequencing task (SSOST). To determine whether LPFC or OFC was responsible for the previously observed impairments and whether the underlying neural mechanism was modulated by serotonin, the present study compared the effects of selective LPFC and OFC excitotoxic lesions and 5,7-DHT-induced PFC serotonin depletions in marmosets on SSOST performance. Severe and long-lasting impairments in SSOST performance, including robust perseverative responding, followed LPFC but not OFC lesions. The deficit was ameliorated by task manipulations that precluded perseveration. Depletions of serotonin within LPFC and OFC had no effect, despite impairing performance on a visual discrimination reversal task, thus providing further evidence for differential monaminergic regulation of prefrontal function. In the light of the proposed attentional control functions of ventrolateral PFC and the failure of LPFC-lesioned animals to disengage from the immediately preceding response, it is proposed that this deficit may be due to a failure to attend to and register that a response has been made and thus should not be repeated. However, 5-HT does not appear to be implicated in this response inhibitory capacity.

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Received Jan. 20, 2009; revised March 27, 2009; accepted March 27, 2009.

Correspondence should be addressed to Dr. Angela C. Roberts, Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3DY, UK. Email: acr4{at}cam.ac.uk

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