Neural mechanisms of affective processing in prefrontal-limbic circuits

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Project summary Anhedonia is a defining symptom of mood disorders and anxiety disorders and is characterized by a loss of positive affect from rewarding experiences. Current theories of anhedonia emphasize that it consists of two distinct components: one is related to the expectation of reward, the other to the pleasure from receiving rewards. Understanding how the brain processes expected and received rewards at the level of single neurons is therefore a key challenge for basic neuroscience. Imaging studies indicate that one part of the prefrontal cortex, the subcallosal anterior cingulate cortex (ACC) is active when rewards are expected and is altered in individuals with anhedonia. Corroborating this finding, data from studies of monkeys with lesions of the subcallosal ACC indicate that this area is important for behavior related to the expectation, but not the receipt of rewards. However, no approach to date has been able to provide a circuit-level understanding of how the subcallosal ACC influences reward expectation. This level of understanding is important as deep brain stimulation of subcallosal ACC and nearby white matter pathways alleviates anhedonia in some patients. This intervention is hypothesized to work by altering functional interaction between subcallosal ACC and either amygdala or ventral striatum. Which pathway is more important for controlling behavior related to reward expectation or the requisite activity patterns is unknown. Our goal here is to determine the neural mechanisms engaged in the subcallosal ACC-amygdala-VS circuit when rewards are expected and then received. We hypothesize that the role of the subcallosal ACC is to modulate reward encoding within ventral striatum and amygdala during reward expectation, but not receipt. To test our hypothesis we will use an innovative combination of single-neuron recordings, field potential recordings, electrical stimulation, diffusion imaging methods, and chemogenetics analyzing the timing of reward-related neural responses and LFP coherence among the three sites under normal physiological conditions, when neurons in subcallosal ACC are chronically activated using chemogenetic methods, and when acute electrical stimulation is applied both under normal conditions and when the area is chronically activated. Completing these aims will fundamentally advance our understanding of the neural circuits and activity patterns that control reward-related behavioral and neural activity in primates as well as providing a circuit level understanding of how subcallosal ACC influences expected reward processing. This level of understanding has the potential to inform and help refine pathway- specific interventions for all disorders characterized by a loss pleasure from reward, such as depression as well as schizophrenia.