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Neuron. 2016 Jul 20;91(2):439-52. doi: 10.1016/j.neuron.2016.05.038. Epub 2016 Jun 23.

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

Author information

1
Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA.
2
Department of Statistics and Data Science, University of Texas at Austin, Austin, TX 78712, USA.
3
Department of Electrical and Computer Engineering, Duke University, Durham, NC 22208, USA.
4
Department of Statistical Sciences, Duke University, Durham, NC 22208, USA.
5
Departments of Bioengineering and Psychiatry and Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA.
6
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.

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.

KEYWORDS:

chronic stress; major depressive disorder; neural networks; oscillations; synchrony

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PMID:
27346529
PMCID:
PMC4986697
DOI:
10.1016/j.neuron.2016.05.038
[Indexed for MEDLINE]
Free PMC Article

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