Seminars

Though most individuals are capable of maintaining psychological integrity in the face of stress, social stressors can instigate the onset of severe neuropsychiatric disorders, including depression. In rodents, chronic subordination stress is often followed by a long-lasting behavioral syndrome, which includes social avoidance, anhedonia, impaired coping responses to other environmental stressors, and anxiety-like behaviors. However, within the inbred C57BL/6J mouse line, the typical chronic stress-induced syndrome does not occur in all individuals, thereby allowing for measurements of resiliency. Vulnerabilities to stress are likely mediated by dysregulated signaling of descending prefrontal cortex (PFC) pathways. The current studies were designed to examine the role of histone modifications in PFC as key mechanisms linking an individual’s vulnerability to chronic stress. Indeed, repressive histone methylation in the medial PFC is significantly reduced in resilient animals, and this molecular event occurs with increased expression of the T-type calcium channel (Cav3.1), a key mediator of neural activity. Furthermore, direct infusion of HDAC inhibitors into the medial PFC promotes a robust antidepressant-like effect and increases Cav3.1 expression. Finally, multi-circuit in vivo recordings before stress in conjunction with experimental remote-control of circuit activity using optogenetics or designer receptors exclusively activated by designer drugs (DREADDs) were utilized to characterize the circuit based mechanisms that mediate resiliency in mice. The rationale underlying these studies is that individual variation in cortical circuits through their regulation of certain ion channels is ultimately controlled by epigenetic mechanisms. Indeed, patterns of neural activity clearly predict later stress responses, and direct modulation of these circuits alters resiliency to stress. Identifying such regulatory mechanisms will aid in the future development of treatment strategies for stress-related illnesses, such as depression and addiction.