Domain-related differentiation of working memory in the Japanese macaque (Macaca fuscata) frontal cortex: a positron emission tomography study T. Kojima, 1 H. Onoe, 1,2 K. Hikosaka, 1 K. Tsutsui, 3 H. Tsukada 4 and M. Watanabe 1 1 Department of Psychology, Tokyo Metropolitan Institute for Neuroscience, Musashidai 2–6, Fuchu, Tokyo, 183–8526, Japan 2 Functional Probe Research Laboratory, Molecular Imaging Research Program, RIKEN Frontier System, 2–1, Hirosawa, Wako, Saitama, Japan 3 Division of Systems Neuroscience, Tohoku University Graduate School of Life Sciences, Sendai, Miyagi, Japan 4 Central Research Laboratory, Hamamatsu Photonics K.K., Hiraguchi 5000, Hamamatsu, Shizuoka, Japan Keywords: dorsolateral, non-spatial, prefrontal, spatial, ventrolateral Abstract The lateral prefrontal cortex (LPFC) is important for working memory (WM) task performance. Neuropsychological and neurophysiological studies in monkeys suggest that the lateral prefrontal cortex is functionally segregated based on the working memory domain (spatial vs. non-spatial). However, this is not supported by most human neuroimaging studies, and the discrepancy might be due to differences in methods and ⁄ or species (monkey neuropsychology ⁄ physiology vs. human neuroimaging). We used positron emission topography to examine the functional segregation of the lateral prefrontal cortex of Japanese macaques (Macaca fuscata) that showed near 100% accuracy on spatial and non-spatial working memory tasks. Compared with activity during the non- working memory control tasks, the dorsolateral prefrontal cortex (DLPFC) was more active during the non-spatial, but not during the spatial, working memory task, although a muscimol microinjection into the dorsolateral prefrontal cortex significantly impaired the performance of both working memory tasks. A direct comparison of the brain activity between the two working memory tasks revealed no differences within the lateral prefrontal cortex, whereas the premotor area was more active during the spatial working memory task. Comparing the delay-specific activity, which did not include task-associated stimulus ⁄ response-related activity, revealed more spatial working memory-related activity in the posterior parietal and premotor areas, and more non-spatial working memory-related activity in the dorsolateral prefrontal cortex and hippocampus. These results suggest that working memory in the monkey brain is segregated based on domain, not within the lateral prefrontal cortex but rather between the posterior parietal- premotor areas and the dorsolateral prefrontal-hippocampus areas. Introduction The prefrontal cortex (PFC) is important for working memory (WM) task performance (Goldman-Rakic, 1996). Based on monkey ablation (Gross & Weiskranz, 1962; Passingham, 1975; Mishkin & Manning, 1978) and neurophysiological (Wilson et al., 1993) studies, Goldman- Rakic proposed the ‘domain-specific differentiation’ model of the lateral PFC (LPFC), suggesting that the dorsolateral (DL) and ventrolateral (VL) PFC are involved in spatial and object WM, respectively (Goldman-Rakic, 1996). However, this idea has not been supported by subsequent ablation (Petrides, 1996) and neurophysio- logical (Rao et al., 1997) studies on monkeys. Furthermore, most human neuroimaging studies have not found domain-specific differ- entiation of the LPFC in relation to WM (Owen et al., 1998; Postle & D’Esposito, 1999). Nevertheless, a recent monkey ablation study demonstrated a functional dissociation between the DLPFC and the dorsomedial (DM) PFC with respect to WM processes (Levy & Goldman-Rakic, 1999). A neuromaging study indicated domain-specific differentiation of the human PFC in relation to WM between the VLPFC and superior frontal sulcus (Courtney et al., 1998). A human transcranial magnetic stimulation (TMS) study suggested that the DMPFC and VLPFC are concerned with spatial and object WM, respectively, with the DLPFC being involved in both spatial and object WM (Mottaghy et al., 2002). It is still unclear whether there is domain-specific differentiation of the PFC in relation to WM. Unfortunately, this hypothesis has been investigated only in ablation and neuronal recording studies in monkeys, whereas it has been examined predominantly by neuroi- maging studies in humans. Although 2-deoxyglucose (Friedman & Goldman-Rakic, 1994) and positron emission tomography (PET; Inoue et al., 2004) studies in monkeys have revealed LPFC activity in relation to WM task performance, neuroimaging methods have not been used to examine domain-specific differentiation in the monkey PFC. Inter-species differences might exist (Ungerleider et al., 1998). To settle this matter, we conducted a PET study in monkeys, aiming to determine whether there is differential activity within the LPFC in relation to spatial vs. non-spatial WM. We used a spatial delayed response task and a delayed conditional visuomotor association task as the spatial and non-spatial WM tasks, respectively, in which spatial and pictorial instructions indicated the Correspondence: Dr Masataka Watanabe, as above. E-mail: masataka@tmin.ac.jp Received 3 September 2006, revised 26 February 2007, accepted 28 February 2007 European Journal of Neuroscience, Vol. 25, pp. 2523–2535, 2007 doi:10.1111/j.1460-9568.2007.05504.x ª The Authors (2007). Journal Compilation ª Federation of European Neuroscience Societies and Blackwell Publishing Ltd