title: Dysregulation of Prefrontal Cortex-Mediated Slow-Evolving Limbic Dynamics Drives Stress-Induced Emotional Pathology.
abstract: 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.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Rainbo
authors.initials: R
authors.lastname: Hultman
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Mague
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Brittany M
authors.initials: BM
authors.lastname: Katz
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Nadine
authors.initials: N
authors.lastname: Michel
authors.affiliation: Department of Statistics and Data Science, University of Texas at Austin, Austin, TX 78712, USA.
authors.forename: Lizhen
authors.initials: L
authors.lastname: Lin
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Joyce
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Lisa K
authors.initials: LK
authors.lastname: David
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Cameron
authors.initials: C
authors.lastname: Blount
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Rithi
authors.initials: R
authors.lastname: Chandy
authors.affiliation: Department of Electrical and Computer Engineering, Duke University, Durham, NC 22208, USA.
authors.forename: David
authors.initials: D
authors.lastname: Carlson
authors.affiliation: Department of Electrical and Computer Engineering, Duke University, Durham, NC 22208, USA.
authors.forename: Kyle
authors.initials: K
authors.lastname: Ulrich
authors.affiliation: Department of Electrical and Computer Engineering, Duke University, Durham, NC 22208, USA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Carin
authors.affiliation: Department of Statistical Sciences, Duke University, Durham, NC 22208, USA.
authors.forename: David
authors.initials: D
authors.lastname: Dunson
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Sunil
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Departments of Bioengineering and Psychiatry and Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA.
authors.forename: Karl
authors.initials: K
authors.lastname: Deisseroth
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Moore
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA; Center for Neuroengineering, Duke University Medical Center, Durham, NC 27710, USA; Duke Institute for Brain Sciences, Duke University Medical Center, Durham, NC 27710, USA; Departments of Biomedical Engineering and Neurobiology, Duke University, Durham, NC 22208, USA. Electronic address: kafui.dzirasa@duke.edu.
authors.forename: Kafui
authors.initials: K
authors.lastname: Dzirasa
mesh_terms: D000679:Amygdala / Q000503:physiopathology*; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D003865:Major Depressive Disorder / Q000503:physiopathology; D004644:Emotions / Q000502:physiology*; D008810:Mice, Inbred C57BL; D017397:Prefrontal Cortex / Q000473:pathology / Q000503:physiopathology*; D013315:Stress, Psychological / Q000473:pathology*
keywords: chronic stress; major depressive disorder; neural networks; oscillations; synchrony