Cognitive Inflexibility After Prefrontal Serotonin Depletion

Abstract

Serotonergic dysregulation within the prefrontal cortex (PFC) is implicated in many neuropsychiatric disorders, but the precise role of serotonin within the PFC is poorly understood. Using a serial discrimination reversal paradigm, we showed that upon reversal, selective serotonin depletion of the marmoset PFC produced perseverative responding to the previously rewarded stimulus without any significant effects on either retention of a discrimination learned preoperatively or acquisition of a novel discrimination postoperatively. These results highlight the importance of prefrontal serotonin in behavioral flexibility and are highly relevant to obsessive-compulsive disorder, schizophrenia, and the cognitive sequelae of drug abuse in which perseveration is prominent.

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). …”

“…By contrast, reversal learning may depend specifically on function of the orbitofrontal cortex, as suggested in humans (Hornak et al 2004;Rolls et al 1994), non-human primates (Clarke et al 2004;Dias et al 1996), and more recently in rats (McAlonan and Brown 2003). Thus, it appears that different types of chronic stress may have different effects on cognitive flexibility, dependent upon distinct subregions of prefrontal cortex, and potentially involving dysregulation of different monoaminergic systems.…”

“…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.…”