No abstract

Central to many emotional responses is the accompanying peripheral somatic and autonomic arousal, feedback from which has been hypothesized to enhance emotional memory and to contribute to appraisal processes and decision making, and dysfunction of which may contribute to antisocial behaviour. Whilst peripheral arousal may accompany both positive and negative emotional contexts, its relationship with the former is poorly understood, as are the neural mechanisms underlying such a relationship. The purpose of the present study was to determine the autonomic correlates of anticipation, as well as consumption, of high incentive food, in the freely moving common marmoset and to investigate the contribution of the amygdala to such effects. Blood pressure (BP) and heart rate (HR) were measured remotely by a telemetric device implanted into the descending aorta and behavioural responses were monitored whilst marmosets viewed preferred or non-preferred foods and were then allowed access to eat those foods. A marked rise in blood pressure in unrestrained marmosets was observed in response both to the sight of highly preferred foods (anticipatory period) as well as during the actual consumption of those foods (consummatory period). Excitotoxic lesions of the amygdala abolished the autonomic arousal in the anticipatory period, but spared both the behavioural arousal in the anticipatory period and the autonomic arousal in the consummatory period. Together these data serve as an important step towards understanding the role of autonomic arousal in emotion and its neural underpinnings.

Successful adaptation to changes in an animal's emotional and motivational environment depends on behavioral flexibility accompanied by changes in bodily responses, e.g., autonomic and endocrine, which support the change in behavior. Here, we identify the orbitofrontal cortex (OFC) as pivotal in the flexible regulation and coordination of behavioral and autonomic responses during adaptation. Using an appetitive Pavlovian task, we demonstrate that OFC lesions in the marmoset (i) impair an animal's ability to rapidly suppress its appetitive cardiovascular arousal upon termination of a conditioned stimulus and (ii) cause an uncoupling of the behavioral and autonomic components of the adaptive response after reversal of the reward contingencies. These findings highlight the role of the OFC in emotional regulation and are highly relevant to our understanding of disorders such as schizophrenia and autism in which uncoupling of emotional responses may contribute to the experiential distress and disadvantageous behavior associated with these disorders.behavioral inhibition ͉ emotion ͉ reversal learning T he orbitofrontal cortex (OFC) has long been implicated in behavioral f lexibility as measured by tests of discrimination reversal learning and extinction (1, 2). In reversal learning, an animal is first taught to respond to one of two visual stimuli to receive food reward, a response to the other being unrewarded. Lesions of the OFC do not affect initial acquisition of the visual discrimination, but the ability to alter responding when the association between the stimuli and reward is reversed is markedly impaired across a range of species (3-9). Similarly, animals with OFC lesions display prolonged responding during extinction when the response no longer results in the receipt of food reward (1, 10, 11). However, an alteration in behavioral output is just one component of the overall adaptive response of an animal to changes in its environment. It is important to recognize that behavioral adaptation is accompanied by alterations in the bodily state, including autonomic and endocrine activity, appropriate to the motivational and emotional context. Thus, Pavlov showed that dogs stopped salivating to a buzzer when it no longer predicted reward (12), and, had the behavioral response also been measured, it would have presumably shown that they stopped approaching the buzzer too. Indeed, if, despite inhibiting their salivation during extinction, Pavlov's dogs found themselves still approaching the buzzer, or vice versa, such incongruency between the somatic and autonomic feedback might be expected to produce emotional ambiguity, an issue that will be considered in more detail in Discussion.Currently, we have very little understanding of the neural circuitry underlying the coordination of behavioral and bodily responses in adaptive responding. Although the OFC is critical for behavioral adaptation, its role in the overall coordination of the adaptive response is unknown. Indeed, few studies have investigated the role of the O...

High trait anxiety is a risk factor for the development of anxiety disorders. Like the disorders themselves high trait anxiety has marked phenotypic variation at the level of symptomatology and neural circuits, suggesting that there may be different symptoms and distinct neural circuits associated with risk for these disorders. To address these issues, it is essential to develop reliable animal models of trait anxiety in a non-human primate whose brain bears structural and functional similarity to humans. The present study investigated individual variation in responsivity to fearful and anxiety provoking stimuli in the common marmoset monkey. Seven out of 27 animals failed to display discriminative, conditioned cardiovascular and behavioral responses on an auditory fear discrimination task, similar to that seen in high anxious humans and rodents. Their heightened emotionality to a rubber snake was consistent with the hypothesis that they were high in trait-like anxiety. Evidence for phenotypic variation in the high anxiety group was provided by the finding that discrimination failure was predicted early in conditioning by either hyper-vigilant scanning to the cues or a reduction in blood pressure to the context, i.e., test apparatus. Given that high trait anxiety in humans can be associated with altered prefrontal cognitive functioning and previously we implicated the marmoset anterior orbitofrontal (antOFC) and ventrolateral prefrontal cortex (vlPFC) in negative emotion regulation, we also tested the marmosets on two tests of cognitive flexibility differentially dependent on these two regions. While the high anxious group did not differ overall in their perseverative performance, the two distinct phenotypes were differentially correlated with reduced perseverative responding on the OFC- and vlPFC-dependent flexibility tests. Together, this study provides a new model of trait anxiety in marmosets amenable to analysis of phenotypic variation and neural circuitry.

Avoidance and alerting behaviors and accompanying physiological responses, including changes in heart rate (HR), are core components of negative emotion. Investigations into the neural mechanisms underlying the regulation and integration of these responses require animal models that simultaneously measure both the physiological and behavioral components of emotion. A primate model is of particular importance in view of the well developed prefrontal cortex of primates, and this region's critical role in emotion regulation and the etiology of affective disorders. Therefore, we have developed a simple aversive conditioning paradigm to assess, simultaneously, cardiovascular and behavioral responses in the marmoset (Callithrix jacchus). Validation of the paradigm was achieved by (1) comparing conditioned responses to a predictive cue with pseudoconditioned responses to a nonpredictive cue; (2) assessing the acquisition of conditioning following lesions of the amygdala, a region essential for associative learning in humans and rats; and (3) determining the contributions of the sympathetic and parasympathetic nervous system to the conditioned autonomic responses. Marmosets acquired conditioned HR and behavioral responses in the conditioned, but not the pseudoconditioned or amygdala lesioned groups. Conditioned HR accelerations were reduced by both parasympathetic and sympathetic blockade. Thus, a model of associative learning of mild negative emotion in the marmoset has been validated by psychological, neurological, and pharmacological investigation. Future studies will determine the role of the prefrontal cortex in the regulation of these negative emotional responses, to provide insights into the neuropathology of affective disorders.

Trait anxiety is a risk factor for the development and maintenance of affective disorders, and insights into the underlying brain mechanisms are vital for improving treatment and prevention strategies. Translational studies in non-human primates, where targeted neurochemical and genetic manipulations can be made, are critical in view of their close neuroanatomical similarity to humans in brain regions implicated in trait anxiety. Thus, we characterised the serotonergic and regional brain volume correlates of trait-like anxiety in the marmoset monkey. Low- and high-anxious animals were identified by behavioral responses to a human intruder (HI) that are known to be sensitive to anxiolytic drug treatment. Extracellular serotonin levels within the amygdala were measured with in vivo microdialysis, at baseline and in response to challenge with the selective serotonin reuptake inhibitor, citalopram. Regional brain volume was assessed by structural magnetic resonance imaging. Anxious individuals showed persistent, long-term fearful responses to both a HI and a model snake, alongside sustained attention (vigilance) to novel cues in a context associated with unpredictable threat. Neurally, high-anxious marmosets showed reduced amygdala serotonin levels, and smaller volumes in a closely connected prefrontal region, the dorsal anterior cingulate cortex. These findings highlight behavioral and neural similarities between trait-like anxiety in marmosets and humans, and set the stage for further investigation of the processes contributing to vulnerability and resilience to affective disorders.

This paper will review two avenues of our research in marmosets that have focused on the role of the orbitofrontal cortex (OFC) in amygdala-dependent appetitive behavior. The first demonstrates the important contribution of both the OFC and the amygdala to conditioned reinforcement (CRF). The second reveals the regulatory effects of the OFC on amygdala-dependent autonomic and behavioral arousal in appetitive conditioning. The process of CRF is one way in which an environmental cue can guide emotional behavior. As a consequence of its previous relationship with reward, a cue can take on affective value and reinforce behavior. Lesion studies in marmosets are described that show that CRF is dependent upon both the amygdala and OFC. The synergistic interactions between these structures that have been shown to underlie other aspects of reward processing are then considered with respect to CRF. The results are contrasted with those that show the importance of the OFC in suppressing positive affective responses elicited by the amygdala in response to a conditioned stimulus (CS). Specifically, it will be shown that the OFC is involved in the rapid suppression of conditioned autonomic arousal upon CS withdrawal and in the co-ordination of conditioned autonomic and behavioral responses when adapting to changing reward contingencies. It will be argued that, overall, the OFC plays a critical role in the context-dependent regulation of positive affective responding governed by external cues, in keeping with a role in executive control.

Impaired top-down regulation of the amygdala, and its modulation by serotonin (5-HT), is strongly implicated in the dysregulation of negative emotion that characterizes a number of affective disorders. However, the contribution of these mechanisms to the regulation of positive emotion is not well understood. This study investigated the role of 5-HT within the amygdala and the orbitofrontal cortex (OFC), on the expression of appetitive Pavlovian conditioned emotional responses and their reversal in a primate, the common marmoset. Its effects were compared to those of the amygdala itself. Having developed conditioned autonomic and behavioural responses to an appetitive cue prior to surgery, marmosets with excitotoxic amygdala lesions failed to display such conditioned autonomic arousal at retention, but still displayed intact cue-directed conditioned behaviours. In contrast, 5,7-DHT infusions into the amygdala, reducing extracellular 5-HT levels, selectively enhanced the expression of appetitive conditioned behaviour at retention. Similar infusions into the OFC, producing marked reductions in post-mortem 5-HT tissue levels, had no overall effect on autonomic or behavioural responses, either at retention or during reversal learning, but caused an uncoupling of these responses, thereby fractionating emotional output. These data demonstrate the critical role of the amygdala in the expression of appetitive autonomic conditioning, and the region-selective contribution of 5-HT in the amygdala and OFC, respectively, to the expression of conditioned behaviour and the overall coordination of the emotional response. They provide insight into the neurochemical mechanisms underlying the regulation of positive emotional responses, advancing our understanding of the neural basis of pathologically dysregulated emotion.