Flexible behavior depends on the ability to shift an internal cognitive set as soon as external demand changes. According to neuropsychological studies in human and nonhuman primates, selective lesion to the PFC impairs flexible behavioral shifting. Our previous fMRI study demonstrated that the prefrontal regions showed transient activation related to set shifting in humans and monkeys. To investigate the underlying neural processing, we recorded single-unit activities while monkeys performed a cognitive-set-shifting task, which required shifting between shape-matching and color-matching behaviors. We identified a group of neurons in the inferior arcuate region that exhibited selective activity when the monkeys were required to shift their cognitive set. These shift-related neurons were localized in the focal area along the posterior bank of the inferior arcuate sulcus. Reversible inactivation of this area ipsilateral to the response hand with a small volume of muscimol (even with 0.5 μl) selectively impaired the performance of behavioral shifting. Moreover, this selective behavioral impairment strongly correlated with the dose of muscimol. These results demonstrated localized neural processing for cognitive set shifting and its causal role for behavioral flexibility in primates.

Cognitive flexibility arises from our ability to shift behaviors depending on demand changes. Behavioral shifting recruits both a preparatory process for an upcoming behavior and an execution process for the actual behavior. Although neuroimaging studies have shown that several brain regions, including posterior parietal cortex (PPC) participated in each component process, it remains unresolved how such processes are implemented at the single-cell level or even whether these processes are distinctively carried out across microstructures in such regions. By recording single-unit activity from PPC of two monkeys performing an analog of the Wisconsin Card Sorting Test, we found that, in the execution process, two types of neurons exhibited activity modulation depending on whether shift was (shift trial) or was not required (nonshift trial): one type showing larger activity and the other showing smaller activity in the shift trial than in the nonshift trial. In the preparatory process, in contrast, the population activity of both types became larger in the shift trial than in the nonshift trial. The majority of both types exhibited shift-related activity modulation in both processes, whereas the remaining was specialized in the execution process. The former and the latter neurons were spatially intermingled within PPC. Significantly, when the animals performed set shifting spontaneously in prospect of a demand change, the shift-related activity modulation still emerged in both processes. We suggest that both execution and preparation signals are represented within PPC, and that these signals reflect behavioral shifting mechanisms that can be driven by either internal or external triggers.