Neuropsychological investigations of the prefrontal cortex have shown a clear role for both PFo and PFm in reward-guided behavior and emotion (Izquierdo and Murray 2004;Izquierdo et al., 2005). Damage in either area leads to altered emotion and social behavior as well as disrupted autonomic responses to valued foods. Building on this work, neurophysiologists have found a role for both PFo and PFm in the recording and prediction of feedback consisting of rewards and punishments. Although PFo and PFm damage is associated with difficulty adjusting behavior to changes in feedback, there is little understanding of how neurons in PFo and PFm adapt to changes in feedback. In particular, no one understands the brain mechanisms that allow us to alter our choices based on changes in feedback. Because reward and punishment feedback is processed in the amygdala, PFo and PFm, we need to understand how the amygdala interacts with these cortical areas to process feedback and change maladaptive choices. Autonomic responses provide an objective measure of emotional responses to feedback. The amygdala, PFo and PFm are key sites for processing reward information and generating autonomic responses. All three areas are reciprocally interconnected and neuropsychological studies have revealed both cooperative and contrasting functions of the amygdala and prefrontal cortex in feedback-guided behavior. In addition, neurophysiology studies have shown that the activity of single neurons in amygdala, PFo and PFm correlates with the value of expected reward feedback. However, little is known about the physiological interactions of these areas with each other or how these interactions produce autonomic and other emotional responses. To address these issues the present project examined the contribution of the amygdala to autonomic responses and to neuronal activity in PFo and PFm. Two subjects performed a reward-guided task. The subjects had previously learned that stimuli were associated with different magnitudes of reward feedback. Given the choice between two stimuli, they needed to choose the one that produced the most reward. We recorded the activity of single neurons in PFo and PFm, as well as autonomic and behavioral responses, both before and after lesions of the amygdala. Subjects with an intact amygdala chose the stimulus associated with highest amount of reward on nearly every trial. Neuronal activity in PFo and PFm, as well as response latencies and autonomic responses, were all significantly modulated by the amount of reward a particular decision would produce. Amygdala damage did not affect the ability to select the stimulus associated with largest reward, but it did affect both response latency and pupil diameter (a measure of autonomic responding). Both measures of emotion showed a weaker relation to reward quantity after amygdala damage. Because the hippocampus is important for emotional behavior, as well as for flexible responding in the face of changing reward feedback, we will also examine the role of the hippocampus in producing emotional responses in anticipation of and in reaction to reward feedback from decisions. This work will examine hippocampal-frontal interactions, thereby complementing the study on amygdalo-frontal interactions mentioned above. Subjects are being trained to make choices of stimuli based on the probability of reward. When they have learned, we will record neuronal activity from PFo and PFm before and after hippocampal lesions. PFm is anatomically connected to nuclei that regulate autonomic functioning, such as portions of the hypothalamus, amygdala and periacqueductal grey. The infralimbic cortex (IL) is part of PFm, and is thought to be critical for extinction learning. This form of learning involves acquiring the knowledge that that a previously learned association has been rescinded. One of the characteristics of certain mental health disorders, such as MDD, is that patients respond persistently to stimuli that predict emotional events even when these stimuli cease to do so. If IL cortex underlies extinction learning, lesions of IL should lead to spontaneous recovery of an extinguished response. We tested this hypothesis in a Pavlovian conditioning task. As in the amygdala study described above, changes in pupil diameter were used to monitor emotional responses. After reward delivery, pupil diameter changed as part of an innate emotional reflex response to positive events. It is well known that this change in pupil diameter results from an autonomic response. With experience, the same autonomic response came to follow an initially neutral stimulus that was associated with reward. After this learning had occurred, we could test our hypothesis about IL function by breaking the association between the stimulus and the occurrence of reward. This extinction procedure has proven successful in a control group of subjects, and results from subjects with IL damage will be available in the near future. If our hypothesis is confirmed, it should provide important insights in the failure of some patients to adapt to improved life situations with more adaptive emotional responses.

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