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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article number109074
JournalCell Reports
Volume35
Issue number5
DOIs
StatePublished - May 4 2021

Keywords

  • PFC
  • VTA
  • dopamine
  • early-life stress
  • excitatory synapse
  • inhibitory synapse
  • synaptic plasticity
  • two-photon microscopy

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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