Dysregulation of Prefrontal Cortex-Mediated Slow-Evolving Limbic Dynamics Drives Stress-Induced Emotional Pathology

Rainbo Hultman; Stephen D Mague; Qiang Li; Brittany M Katz; Nadine Michel; Lizhen Lin; Joyce Wang; Lisa K David; Cameron Blount; Rithi Chandy; David Carlson; Kyle Ulrich; Lawrence Carin; David Dunson; Sunil Kumar; Karl Deisseroth; Scott D Moore; Kafui Dzirasa

doi:10.1016/j.neuron.2016.05.038

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Dysregulation of Prefrontal Cortex-Mediated Slow-Evolving Limbic Dynamics Drives Stress-Induced Emotional Pathology

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Dysregulation of Prefrontal Cortex-Mediated Slow-Evolving Limbic Dynamics Drives Stress-Induced Emotional Pathology

Rainbo Hultman, Stephen D Mague, Qiang Li, Brittany M Katz, Nadine Michel, Lizhen Lin, Joyce Wang, Lisa K David, Cameron Blount, Rithi Chandy, …

Neuron (Cambridge, Mass.), Vol.91(2), pp.439-452

07/20/2016

DOI: 10.1016/j.neuron.2016.05.038

PMCID: PMC4986697

PMID: 27346529

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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. •Prefrontal cortex (PFC) oscillations synchronize with ultraslow limbic dynamics•PFC unit firing signals the synchronization state of amygdala (AMY) and ventral tegmental area (VTA)•Chronic stress selectively disrupts PFC-dependent regulation of AMY-VTA synchrony•PFC to AMY circuit stimulation recovers normal network function and behavior The complex mechanisms whereby multiple brain regions coordinate emotion remain tenebrous. Hultman et al. show that the prefrontal cortex (PFC) directly regulates beta oscillatory connectivity between multiple limbic brain regions. Stress-induced disruption of this PFC-dependent function yields pathological emotional behavior.

Oscillations

chronic stress

major depressive disorder

synchrony

neural networks

Details

Title: Subtitle: Dysregulation of Prefrontal Cortex-Mediated Slow-Evolving Limbic Dynamics Drives Stress-Induced Emotional Pathology
Creators: Rainbo Hultman - Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA
Stephen D Mague - Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA
Qiang Li - Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA
Brittany M Katz - Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA
Nadine Michel - Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA
Lizhen Lin - Department of Statistics and Data Science, University of Texas at Austin, Austin, TX 78712, USA
Joyce Wang - Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA
Lisa K David - Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA
Cameron Blount - Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA
Rithi Chandy - Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA
David Carlson - Department of Electrical and Computer Engineering, Duke University, Durham, NC 22208, USA
Kyle Ulrich - Department of Electrical and Computer Engineering, Duke University, Durham, NC 22208, USA
Lawrence Carin - Department of Electrical and Computer Engineering, Duke University, Durham, NC 22208, USA
David Dunson - Department of Statistical Sciences, Duke University, Durham, NC 22208, USA
Sunil Kumar - Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA
Karl Deisseroth - Departments of Bioengineering and Psychiatry and Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA
Scott D Moore - Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA
Kafui Dzirasa - Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA
Resource Type: Journal article
Publication Details: Neuron (Cambridge, Mass.), Vol.91(2), pp.439-452
Publisher: Elsevier Inc
DOI: 10.1016/j.neuron.2016.05.038
PMID: 27346529
PMCID: PMC4986697
ISSN: 0896-6273
eISSN: 1097-4199
Language: English
Date published: 07/20/2016
Academic Unit: Molecular Physiology and Biophysics; Psychiatry; Iowa Neuroscience Institute
Record Identifier: 9984065854702771

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