Prefrontal Serotonin Depletion Affects Reversal Learning But Not Attentional Set Shifting

Abstract

Recently, we have shown that serotonin (5-HT) depletion from the prefrontal cortex (PFC) of the marmoset monkey impairs performance on a serial discrimination reversal (SDR) task, resulting in perseverative responding to the previously correct stimulus (Clarke et al., 2004). This pattern of impairment is just one example of inflexible responding seen after damage to the PFC, with performance on the SDR task being dependent on the integrity of the orbitofrontal cortex. However, the contribution of 5-HT to other forms of flexible responding, such as attentional set shifting, an ability dependent on lateral PFC (Dias et al., 1996a), is unknown. The present study addresses this issue by examining the effects of 5,7-dihydroxytryptamine-induced PFC 5-HT depletions on the ability to shift attention between two perceptual dimensions of a compound visual stimulus (extradimensional shift).Monkeys with selective PFC 5-HT lesions, despite being impaired in their ability to reverse a stimulus-reward association, were unimpaired in their ability to make an extradimensional shift when compared with sham-operated controls. These findings suggest that 5-HT is critical for flexible responding at the level of changing stimulus-reward contingencies but is not essential for the higher-order shifting of attentional set. Thus, psychological functions dependent on different loci within the PFC are differentially sensitive to serotonergic modulation, a finding of relevance to our understanding of cognitive inflexibility apparent in disorders such as obsessivecompulsive disorder and schizophrenia.

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

“…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.…”

Chronic Unpredictable Stress Induces a Cognitive Deficit and Anxiety-Like Behavior in Rats that is Prevented by Chronic Antidepressant Drug Treatment

“…Destruction of cortical serotonergic projections or depletion of 5-HT produced deficits in reversal learning, rather than cognitive set shifting (Clarke et al, 2005(Clarke et al, , 2007Nomura, 1992). Reversal learning appears to be related more to the function of orbitofrontal cortex rather than medial prefrontal cortex (Clarke et al, 2007;McAlonan and Brown, 2003).…”

Acute Tryptophan Depletion in Healthy Volunteers Enhances Punishment Prediction but Does not Affect Reward Prediction

“…This manipulation dramatically impairs the ability to inhibit responding to the previously rewarded stimulus, while not affecting the initial acquisition of a discrimination (Clarke et al, 2004(Clarke et al, , 2005(Clarke et al, , 2007. To explain this discrepancy, we must take into account three factors: (1) the method of depletion, (2) the extent to which the task depends on inhibitory control, and (3) the neural site of action of 5-HT.…”

“…Finally, neuroimaging studies with human volunteers have shown particularly pronounced effects of ATD on the (dorso)medial PFC during cognitive performance (Cools et al, 2005a;Evers et al, 2005Evers et al, , 2006aTalbot and Cooper, 2006;Van der Veen et al, 2007). Conversely, the disinhibitory effects resulted from selective 5-HT depletion in the OFC (Clarke et al, 2004(Clarke et al, , 2005(Clarke et al, , 2007. Thus, 5-HT depletion may have different functional consequences depending on the extent of depletion, task demands and on the neural site of action (medial PFC vs OFC).…”