Damage within the OFC, MFC or amygdala leads to altered emotion and social behavior as well as disrupted autonomic responses to highly valued foods. The amygdala, the OFC and the MFC are key sites for processing reward information and for 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, neurophysiological studies have shown that the activity of single neurons in amygdala, the OFC and the MFC correlates with the value of expected rewarding or aversive events. However, little is known about the physiological interactions among these areas or how these interactions produce autonomic and emotional responses. To address these issues, this project has examined the contribution of the amygdala to autonomic responses and to neuronal activity in both the OFC and MFC. To examine the influence of the amygdala on the OFC and MFC, we recorded the activity of single neurons in both cortical areas while subjects performed a reward-guided task. Recording was carried out both before and after lesions of the amygdala. The subjects had previously learned that visual stimuli were associated with different magnitudes of reward. Preoperatively, the firing rates of many neurons in both the OFC and the MFC were modulated by the amount of reward associated with the visual stimuli presented on each trial. This stimulus-reward encoding was, however, more prevalent in the OFC than in the MFC. The firing rate of a large proportion of single neurons in both areas was not only correlated with the amount of reward that the subject expected to receive, but also with the amount that was received after successful choices. There were exceptions, however, and the encoding of expected reward, but not received reward, was more prevalent in the OFC than in the MFC. Bilateral lesions of the amygdala abolished the differences in stimulus-reward encoding between the OFC and MFC. In addition, the proportion of neurons that encoded the quantity of expected reward, but not received reward, was also decreased relative to preoperative levels. This decrease occurred mainly in the OFC, with the result that amygdala lesions also abolished this preoperative difference between the OFC and MFC. These data indicate that input from the amygdala is more important for encoding of expected reward values in the OFC than in the MFC. To examine the amygdala influence on autonomic responses, we recorded heart rate (HR) and pupil diameter (PD) in the same two subjects. After reward delivery, PD changed as part of an innate emotional reflex response to positive events. It is well known that this change in PD results from an autonomic response. We developed and validated methods to select and analyze heart rate variability (HRV) during brief (5 s) trials. HRV and PD were highly correlated with reward size. The high temporal resolution of the PD response allowed us to identify different response patterns during reward anticipation and consumption within a single trial. These responses were consistent across both subjects preoperatively. After amygdala lesions, the ability of both subjects to choose the stimulus associated with the highest amount of reward was not altered. Amygdala lesions increased the mean response latencies, but this measure was still modulated by expected reward. Lesions increased mean HR and abolished reward-dependent PD responses in the reward-anticipation period, but they only had this effect for a brief period after the amygdala lesions. The reward-predictive PD response returned in subsequent testing. The lesion had no effect on PD during the consumption period in any testing period. Although amygdala damage transiently disrupted PD responses in anticipation of rewards, our results show that in the long term the amygdala is not essential for the generation of appropriate autonomic or instrumental responses to expected reward quantity. The MFC is anatomically connected to nuclei that regulate autonomic functioning, such as portions of the hypothalamus, amygdala and periaqueductal gray. One of the characteristics of certain mental health disorders, such as major depressive disorder, is that patients respond persistently to stimuli that predict emotional events even when these stimuli cease to do so. Thus, a part of the MFC, called the infralimbic cortex (IL), is implicated in the acquisition and extinction of learning for emotional events. To investigate the role of the IL cortex in conditioned autonomic responding, subjects with bilateral lesions of IL were trained using a Pavlovian conditioning task, which was subsequently carried out under extinction conditions. During the initial training, presentation of one picture (the CS+) preceded delivery of a reward, whereas presentation of a different picture (the CS-) did not. As in the amygdala study described above, changes in PD were used to monitor emotional responses. Our preliminary results show that, as predicted, all subjects initially showed PD changes to the reward delivery. These responses transferred to the CS+ but not the CS- over a number of sessions. Although subjects with lesions of the IL cortex acquired conditioned autonomic responses, they exhibited a different time course of PD responses compared to controls. In particular, these subjects showed a smaller PD response in the trace period between CS+ offset and reward delivery. These findings show that a key part of the MFC, the IL cortex, plays a role in anticipatory autonomic responses in the absence of a currently available stimulus, a finding of relevance to major depressive disorder.

Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
U.S. National Institute of Mental Health
Zip Code
Mitz, Andrew R; Philyaw, Travis J; Boccuto, Luigi et al. (2018) Identification of 22q13 genes most likely to contribute to Phelan McDermid syndrome. Eur J Hum Genet 26:293-302
Rudebeck, Peter H; Ripple, Joshua A; Mitz, Andrew R et al. (2017) Amygdala Contributions to Stimulus-Reward Encoding in the Macaque Medial and Orbital Frontal Cortex during Learning. J Neurosci 37:2186-2202
Mitz, Andrew R; Chacko, Ravi V; Putnam, Philip T et al. (2017) Using pupil size and heart rate to infer affective states during behavioral neurophysiology and neuropsychology experiments. J Neurosci Methods 279:1-12
Kaskan, P M; Costa, V D; Eaton, H P et al. (2016) Learned Value Shapes Responses to Objects in Frontal and Ventral Stream Networks in Macaque Monkeys. Cereb Cortex :
Rudebeck, Peter H; Murray, Elisabeth A (2014) The orbitofrontal oracle: cortical mechanisms for the prediction and evaluation of specific behavioral outcomes. Neuron 84:1143-56
Rudebeck, Peter H; Putnam, Philip T; Daniels, Teresa E et al. (2014) A role for primate subgenual cingulate cortex in sustaining autonomic arousal. Proc Natl Acad Sci U S A 111:5391-6
Hadj-Bouziane, Fadila; Liu, Ning; Bell, Andrew H et al. (2012) Amygdala lesions disrupt modulation of functional MRI activity evoked by facial expression in the monkey inferior temporal cortex. Proc Natl Acad Sci U S A 109:E3640-8