Dysregulation of the mesoprefrontal dopamine circuit mediates an early-life stress-induced synaptic imbalance in the prefrontal cortex
Won Chan Oh,
Gabriela Rodríguez,
Douglas Asede,
Kanghoon Jung,
In-Wook Hwang,
Roberto Ogelman,
McLean M. Bolton,
Hyung-Bae Kwon
Affiliations
Won Chan Oh
Max Planck Florida Institute for Neuroscience, Jupiter, FL 33458, USA; Department of Pharmacology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, USA; Corresponding author
Gabriela Rodríguez
Max Planck Florida Institute for Neuroscience, Jupiter, FL 33458, USA
Douglas Asede
Max Planck Florida Institute for Neuroscience, Jupiter, FL 33458, USA
Kanghoon Jung
Max Planck Florida Institute for Neuroscience, Jupiter, FL 33458, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
In-Wook Hwang
Department of Pharmacology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, USA
Roberto Ogelman
Department of Pharmacology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, USA
McLean M. Bolton
Max Planck Florida Institute for Neuroscience, Jupiter, FL 33458, USA
Hyung-Bae Kwon
Max Planck Florida Institute for Neuroscience, Jupiter, FL 33458, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Max Planck Institute of Neurobiology, Martinsried 82152, Germany; Corresponding author
Summary: Stress adversely affects an array of cognitive functions. Although stress-related disorders are often addressed in adulthood, far less is known about how early-life stress (ELS) affects the developing brain in early postnatal periods. Here we show that ELS, induced by maternal separation, leads to synaptic alteration of layer 2/3 pyramidal neurons in the prefrontal cortex (PFC) of mice. We find that layer 2/3 neurons show increased excitatory synapse numbers following ELS and that this is accompanied by hyperexcitability of PFC-projecting dopamine (DA) neurons in the ventral tegmental area. Notably, excitatory synaptic change requires local signaling through DA D2 receptors. In vivo pharmacological treatment with a D2 receptor agonist in the PFC of control mice mimics the effects of ELS on synaptic alterations. Our findings reveal a neuromodulatory mechanism underlying ELS-induced PFC dysfunction, and this mechanism may facilitate a more comprehensive understanding of how ELS leads to mental disorders.
