Cognitive Inflexibility after Prefrontal Serotonin Depletion Is Behaviorally and Neurochemically Specific

Abstract

We have previously demonstrated that prefrontal serotonin depletion impairs orbitofrontal cortex (OFC)-mediated serial discrimination reversal (SDR) learning but not lateral prefrontal cortex (PFC)-mediated attentional set shifting. To address the neurochemical specificity of this reversal deficit, Experiment 1 compared the effects of selective serotonin and selective dopamine depletions of the OFC on performance of the SDR task. Whereas serotonin depletions markedly impaired performance, OFC dopamine depletions were without effect. The behavioral specificity of this reversal impairment was investigated in Experiment 2 by examining the effect of OFC serotonin depletion on performance of a modified SDR task designed to distinguish between 3 possible causes of the impairment. The results showed that the reversal deficit induced by prefrontal serotonin depletion was not due to a failure to approach a previously unrewarded stimulus (enhanced learned avoidance) or reduced proactive interference. Instead, it was due specifically to a failure to inhibit responding to the previously rewarded stimulus. The neurochemical and behavioral specificity of this particular form of cognitive inflexibility is of particular relevance to our understanding of the aetiology and treatment of inflexible behavior apparent in many neuropsychiatric and neurodegenerative disorders involving the PFC.

Chronic intermittent cold stress and serotonin depletion induce deficits of reversal learning in an attentional set-shifting test in rats

“…In agreement with previous studies which have established a role of the 5-HT system in reversal learning (Clarke et al 2004;Clarke et al 2005;Clarke et al 2007), impairment in the first reversal task was also seen in the present study following depletion of central serotonin by PCPA, comparable to that induced by chronic cold stress, suggesting a possible involvement of the serotonergic system in the CIC stress-induced reversal deficit. Further evidence for involvement of 5-HT in the stress-induced impairment of reversal learning was seen in Experiment 3, in which acute treatment with the 5-HT reuptake inhibitor citalopram attenuated the detrimental effect of CIC stress on the reversal task.…”

“…In previous studies, 5-HT depletion similarly impaired the ability to switch responding between stimuli on reversal trials in a visual discrimination task (Clarke et al 2004;Clarke et al 2007), but left cognitive set-shifting ability intact (Clarke et al 2005). Further, PCPA treatment did not affect spatial navigation in a water maze or passive avoidance learning (Riekkinen et al 1992), arguing against a general decline in cognitive capability.…”

“…For instance, in a previous study, we have shown that increases in noradrenergic neurotransmission in mPFC selectively facilitated ED set shifting Lapiz and Morilak 2006). By contrast, others have suggested that reversal learning may be modulated in OFC specifically by serotonergic neurotransmission (Clarke et al 2004;Clarke et al 2005;Clarke et al 2007). …”

“…Reversal learning has been studied as a measure of cognitive flexibility in humans (Fellows and Farah 2003;Murphy et al 2002;Rogers et al 2000;Rolls et al 1994), nonhuman primates (Clarke et al 2004;Clarke et al 2005;Clarke et al 2007;Dias et al 1996;Lee et al 2007), and rats (Birrell and Brown 2000;Boulougouris et al 2007a;Boulougouris et al 2007b;Idris et al 2005;McAlonan and Brown 2003;van der Meulen et al 2007). Effective reversal learning involves a number of specific and distinct operations, including: 1) detection of the shift in contingency (i.e., "error detection"); 2) inhibition of the prepotent, previously learned positive response; 3) overcoming learned avoidance of the previously negative stimulus; and 4) acquisition of the new association.…”

Neuronal and morphological bases of cognitive decline in aged rhesus monkeys

“…In marmosets, 5-HT depletion within the orbitofrontal cortex produces increased perseverative responding in a serial discrimination RL paradigm (Clarke et al 2004(Clarke et al , 2007, while leaving set-shifting abilities intact (Clarke et al 2005). In contrast to the marked effect of dopamine, 5-HT depletion in area 46 has no effect on working memory in monkeys (Brozoski et al 1979).…”