Frontal lesions altered animals' emotional responses and social behaviour; the patterns of changes after ACC or OFC lesions were distinct. OFC lesions were associated with altered emotional responsiveness in hyponeophagia and a small, but statistically significant increase in aggressive behaviour in the adult social interaction test. By contrast, ACC lesions reduced social behaviour in the social interaction test and impaired the utilization of social information in the social memory test. This dissociation suggests that distinct mechanisms, dependent on ACC and OFC, may mediate social interaction and emotional responses, respectively. Deficits in emotional responsiveness were correlated with changes in performance on a delay-based decision-making task (Rudebeck et al., 2006b), suggesting that OFC-dependent emotional changes may be related to increased impulsive choice. Whether ACC lesion-related changes in the valuation of social information are related to aspects of impaired action valuation and decision-making, however, is not clear.
OFC and emotional responsiveness
A number of reports have linked the OFC with emotional responsiveness in animals (Kolb, 1974; de Bruin et al., 1983; Izquierdo et al., 2005; Machado & Bachevalier, 2006), but two issues have remained unclear; whether the same lesions also affect social interaction and whether other frontal lesions cause similar effects. In the present study, OFC lesion animals valued the opportunity to acquire social information about other individuals as much as controls. OFC lesion and control animals engaged in similar amounts of social behaviours, such as sniffing and close following, on encountering an unfamiliar adult (Fig. 4) or juvenile (Fig. 2). Moreover, OFC animals exhibited normal patterns of social memory. In the social memory test rats had the opportunity to interact with juvenile rats on two occasions; sometimes the same juvenile twice, but on other tests a different juvenile on each occasion. Control and OFC groups showed less interest when the same juvenile was presented again, either immediately after the first encounter (Fig. 2C) or after delay (Fig. 2A), but they continued to engage in a high rate of socially orientated investigative behaviours when the identity of the juvenile was changed (Fig. 2B).
Although OFC lesions did not diminish animals' social engagement, they led to a small but significant increase in aggression (Fig. 4), and decreased fear in response to unconditioned stimuli on the hyponeophagia test (Fig. 7). It is important to note that the overall levels of aggression were low, and amounted to only 2% of the test duration, and thus some caution is required in interpreting these data. Furthermore, the significant main effect of replication observed for this test may also indicate that the prior history of the animals may have had an influence on the outcome. Importantly, however, there was no group by replication interaction, and there is no a priori reason for expecting that different histories on the T-maze would necessarily influence aggression levels. Indeed, closer inspection of the data reveals that the same pattern of results was observed across the three groups of rats, for both social and aggressive behaviours, in both replications of the study (i.e. irrespective of the nature of the prior maze testing; see Table 1).
Table 1. The effect of replication on the amount of time animals spent engaged in aggressive and social behaviours during the 300-s social interactions test
|Group and replications||Social interaction|
| 1||5.86 ± 1.68||41.33 ± 3.33|
| 2||16.255 ± 5.01||42.84 ± 3.05|
| 1||2.12 ± 0.82||34.63 ± 2.57|
| 2||8.75 ± 1.51||27.16 ± 1.17|
| 1||0.875 ± 0.47||44.1 ± 2.48|
| 2||8.77 ± 1.70||37.91 ± 2.39|
Furthermore, previous lesion studies have also implicated the rat OFC in aggression (Kolb, 1974; de Bruin et al., 1983). There is also a striking similarity in the changes in emotional responsivity following OFC lesions in rats and macaques. A small increase in aggression and a decrease in fear for unconditioned but ethologically significant stimuli is prominent when OFC lesions are made in the macaque (Izquierdo et al., 2005; Machado & Bachevalier, 2006; Rudebeck et al., 2006a). Following OFC lesions, macaques more readily take food from the top of a Perspex box containing fearful objects and, in other situations, they were more aggressive to unfamiliar humans (Izquierdo et al., 2005). As in the current experiment the effect is specific to OFC; ACC lesions did not significantly alter fear or aggression in macaques. Furthermore, because the lesions in the current study were made by excitotoxin, in contrast to the non-fibre sparing approaches adopted in earlier studies, including the studies in primates (Kolb, 1974; de Bruin et al., 1983; Izquierdo et al., 2005; Rudebeck et al., 2006a), it is unlikely that OFC lesion-induced changes in emotional responsiveness are the result of inadvertent damage to the underlying white matter.
These findings in macaques were interpreted as the consequence of an impairment in response selection, driven by the inability to represent expected outcomes (Izquierdo et al., 2005). The propensity for OFC-lesioned rats to eat novel foods more quickly may similarly reflect a failure to properly integrate the anxiogenic nature of the novel environment with the potentially rewarding properties of the food leading to the production of an inappropriate or impulsive response of eating. All animals took a similar amount of time to make contact with the novel food item, but only the OFC lesion group had shorter latencies to begin eating, suggesting that they failed to integrate the potential cost associated with the novel environment and the potential value of the reward before acting.
The present study may thus provide further insight into why changes in emotional responsiveness are seen after OFC lesions. Importantly, it rules out the possibility that such changes are contingent on a general change in anxiety because none was observed in the adult social interaction or successive alleys tests. Instead, the present data may provide further support for the hypothesis that alterations in fear and aggression after OFC lesions may be related to an inability to generate outcome expectancies, as suggested by Izquierdo et al. (2005). A growing body of evidence suggests that the OFC is critical for representing the value of goals or outcomes (Baxter et al., 2000; Bechara et al., 2000; Izquierdo et al., 2004; Roesch & Olson, 2004; Roesch et al., 2006). We have argued previously that an inability to represent the expected value of outcomes may explain why rats chose impulsively in the delay-based decision-making task (Mobini et al., 2002; Rudebeck et al., 2006b). Some animals in the present study also performed the delay-based decision-making task. The same OFC lesion affected performance on this task as well as both fear and aggression levels, suggesting that they may share a common neuroanatomical basis.
Therefore, the OFC-related increase in aggression in the social interaction test, although small, may similarly be construed as the selection of inappropriate or impulsive choices when confronted by a novel stimulus, in this case another adult rat. The correlation analyses conducted (Fig. 5A) showed that the amount of aggressive behaviour exhibited by the animals in replication 1 was inversely correlated with their impulsive performance on a delay-based decision-making task, a task that is thought to require the ability to generate outcome expectations. Higher scores on the delay-based decision-making task (less impulsivity) are associated with lower levels of aggression, while a low score on the decision-making task (high impulsivity) was associated with heightened levels of aggression. However, further experiments are needed to clarify the relationship between outcome expectations and aggressive behaviour.
In a recent study, Ross and colleagues showed that rats with cholinergic depletions of the OFC were impaired in acquiring social transmission of food preference (STFP; Ross et al., 2005). STFP describes the process whereby rats are more inclined to eat a novel foodstuff if they have previously engaged in social interaction with a conspecific that has just recently ingested that same foodstuff (Galef, 1986). It is thought that STFP might lessen the risk of eating novel (potentially toxic) foods, because a food recently eaten by a healthy animal is apparently safe. The observation from the present study that OFC lesions do not affect the amount of social behaviour, or the utilization of social information, suggests that the deficit in STFP with OFC lesions is not due to the social context of the experiment. Rather, the impairment in STFP is most likely due to an inability to associate a particular stimulus with a specific outcome, and thus reflects a deficit in generating an accurate outcome expectancy.
The ACC and the utilization of social information
Although ACC lesions did not alter fear or aggression, they did disrupt the utilization of social information (Figs 2 and 4). The lowered valuation of social information after ACC lesions is strikingly similar to that seen when lesions of the ACC (Hadland et al., 2003), and specifically the ACC gyrus (Rudebeck et al., 2006a), are made in macaques. Normal male macaques value the opportunity to gain more information about a high status male or a female macaque, but this is not the case after ACC gyrus lesions. Like the rats with ACC lesions in the present experiment, macaques with ACC lesions spend less time in proximity with one another, but there is no consistent change in fear or aggression. The current results show that the absence of a change in fear and aggression reported after ACC lesions in these macaques was not simply a consequence of low statistical power.
The role of the ACC in social behaviour may also extend to humans. Neuroimaging studies have reported ACC activation when people perform tasks that require cooperation, such as the prisoner's dilemma game (Rilling et al., 2002, 2004) and the trust game (King-Casas et al., 2005; Tomlin et al., 2006). Cooperation in such tasks is more stable when participants have the opportunity to find out about each other (Fehr & Fischbacher, 2003). The current results suggest that the ACC activation that occurs when participants make and monitor choices in cooperation games reflects the acquisition and retrieval of information about the other player. Other studies have reported ACC activation during social evaluation and theory of mind tasks that require consideration of other individuals (Amodio & Frith, 2006). Furthermore, lesions that include parts of the ACC and OFC are associated with social and emotional changes in patients (Cummings, 1993; Hornak et al., 2003).
The present results underline the causal importance of the ACC for normal social engagement and for the utilization of social information. Successive alleys and hyponeophagia tests demonstrated that changes in social behaviour following ACC lesions are not the consequence of changes in anxiety (Figs 6 and 7). Moreover, unlike OFC lesions, the representation of expected outcomes in the delay-based decision-making task was not affected by ACC lesions (Rudebeck et al., 2006b).
Anatomical studies and stimulation experiments have demonstrated that some regions of the ACC are important in autonomic control (Burns & Wyss, 1985; Floyd et al., 2000; Gabbott et al., 2005). It is difficult, however, to attribute the present finding of altered retention of social information after the ACC lesion to a general change in arousal. An account of the ACC lesion deficit couched in terms of a general decrease in arousal would also have predicted changes in behaviour on the successive alleys and hyponeophagia anxiety tests. On the contrary, however, ACC lesion animals showed intact anxiety and fear responses on these two tests, suggesting that aspects of arousal were unchanged. One explanation is that the ACC is important for regulating arousal specifically during social interactions. However, it is worth pointing out that whereas normal animals habituated to repeated presentations of the same individual in the social memory test, the poor performance of ACC animals actually involved maintaining higher levels of responding to repeated presentations of the same individual.
The deficit in social recognition memory is likely to reflect a specific deficit in the processing of social information rather than a general memory impairment. For example, previous studies have shown that lesions including the ACC do not affect object recognition memory (Ennaceur et al., 1997; Yee, 2000). In the spontaneous object recognition memory task animals are commonly presented with two identical objects and then after a delay period are presented with a third identical object and a novel object. Object recognition memory manifests itself as an increase in investigation time of the novel, as opposed to the familiar, object. Animals with lesions of the ACC are unaffected on the spontaneous object recognition task and perform similarly to control animals (Ennaceur et al., 1997; Yee, 2000). Both groups show a significant and equivalent preference for the novel object. Therefore, the deficit with ACC lesions appears to be specific to social situations and cannot simply be attributed to a disruption in mnemonic processing per se.
An alternative explanation is that altered social behaviour may be related to a different type of decision-making deficit. Although animals with ACC lesions are unimpaired on delay-based decision-making tasks, the ACC is critical for evaluation of how much effort it is worth investing to obtain a larger reward in rats (Walton et al., 2003; Rudebeck et al., 2006b). Studies in macaques have shown that ACC neurons represent an animals' progression through a work schedule (Shidara & Richmond, 2002), suggesting that the ACC may have a similar role in the primate brain. While such tasks may not assess the representation of future reinforcement or outcome expectations, they may instead probe a representation of the intrinsic value of actions that comprises both the action's costs and benefits. It is possible that there is a shared basis for the changes in action valuation and the changes in social valuation that are seen after ACC lesions. However, the correlation analyses performed as part of the present study, examining a potential relationship between performance on an effort-based decision-making task and the amount of time spent socially interacting, failed to fully support this hypothesis (Fig. 5B).
Indeed, evidence from macaques and humans suggests that deficits in decision-making and social behaviour following ACC lesions may not in fact share the same neural substrates. In macaques deficits in decision-making and social valuation are most closely associated with the ACC sulcus and gyrus, respectively (Kennerley et al., 2006; Rudebeck et al., 2006a). Similarly, human imaging studies have shown that dorsal ACC is activated following expectancy violations, whereas ventral ACC is more active during social feedback and memory retrieval (Mitchell et al., 2004; Somerville et al., 2006). This functional correspondence within the ACC between different species suggests that a region of the ACC specialized for social behaviour may be common to all mammals, including rats.