Dysregulation of Prefrontal Cortex-Mediated Slow-Evolving Limbic Dynamics Drives Stress-Induced Emotional Pathology.
Circuits distributed across cortico-limbic brain regions compose the networks that mediate emotional behavior. The prefrontal cortex (PFC) regulates ultraslow (<1 Hz) dynamics across these networks, and PFC dysfunction is implicated in stress-related illnesses including major depressive disorder (MDD). To uncover the mechanism whereby stress-induced changes in PFC circuitry alter emotional networks to yield pathology, we used a multi-disciplinary approach including in vivo recordings in mice and chronic social defeat stress. Our network model, inferred using machine learning, linked stress-induced behavioral pathology to the capacity of PFC to synchronize amygdala and VTA activity. Direct stimulation of PFC-amygdala circuitry with DREADDs normalized PFC-dependent limbic synchrony in stress-susceptible animals and restored normal behavior. In addition to providing insights into MDD mechanisms, our findings demonstrate an interdisciplinary approach that can be used to identify the large-scale network changes that underlie complex emotional pathologies and the specific network nodes that can be used to develop targeted interventions.
Hultman, R; Mague, SD; Li, Q; Katz, BM; Michel, N; Lin, L; Wang, J; David, LK; Blount, C; Chandy, R; Carlson, D; Ulrich, K; Carin, L; Dunson, D; Kumar, S; Deisseroth, K; Moore, SD; Dzirasa, K
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