Stress-Induced Neuronal Colony Stimulating Factor 1 Provokes Microglia-Mediated Neuronal Remodeling and Depressive-like Behavior

Biol Psychiatry. 2018 Jan 1;83(1):38-49. doi: 10.1016/j.biopsych.2017.05.026. Epub 2017 Jun 12.


Background: Chronic stress exposure causes neuronal atrophy and synaptic deficits in the medial prefrontal cortex (PFC), contributing to development of anxiety- and depressive-like behaviors. Concomitantly, microglia in the PFC undergo morphological and functional changes following stress exposure, suggesting that microglia contribute to synaptic deficits underlying behavioral consequences.

Methods: Male and female mice were exposed to chronic unpredictable stress (CUS) to examine the role of neuron-microglia interactions in the medial PFC during development of anxiety- and depressive-like behaviors. Thy1-GFP-M mice were used to assess microglia-mediated neuronal remodeling and dendritic spine density in the medial PFC. Viral-mediated knockdown of neuronal colony stimulating factor 1 (CSF1) was used to modulate microglia function and behavioral consequences after CUS.

Results: CUS promoted anxiety- and depressive-like behaviors that were associated with increased messenger RNA levels of CSF1 in the PFC. Increased CSF1 messenger RNA levels were also detected in the postmortem dorsolateral PFC of individuals with depression. Moreover, microglia isolated from the frontal cortex of mice exposed to CUS show elevated CSF1 receptor expression and increased phagocytosis of neuronal elements. Notably, functional alterations in microglia were more pronounced in male mice compared with female mice. These functional changes in microglia corresponded with reduced dendritic spine density on pyramidal neurons in layer 1 of the medial PFC. Viral-mediated knockdown of neuronal CSF1 in the medial PFC attenuated microglia-mediated neuronal remodeling and prevented behavioral deficits caused by CUS.

Conclusions: These findings revealed that stress-induced elevations in neuronal CSF1 provokes microglia-mediated neuronal remodeling in the medial PFC, contributing to synaptic deficits and development of anxiety- and depressive-like behavior.

Keywords: Colony stimulating factor 1; Depression; Microglia; Neuroimmune; Prefrontal cortex; Stress.

MeSH terms

  • Animals
  • Anxiety / metabolism
  • Anxiety / pathology
  • Chronic Disease
  • Depressive Disorder / metabolism*
  • Depressive Disorder / pathology
  • Disease Models, Animal
  • Female
  • Macrophage Colony-Stimulating Factor / genetics
  • Macrophage Colony-Stimulating Factor / metabolism*
  • Male
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microglia / metabolism*
  • Microglia / pathology
  • Neuronal Plasticity / physiology*
  • Neurons / metabolism*
  • Neurons / pathology
  • Phagocytosis / physiology
  • Prefrontal Cortex / metabolism
  • Prefrontal Cortex / pathology
  • RNA, Messenger / metabolism
  • Receptor, Macrophage Colony-Stimulating Factor / metabolism
  • Sex Characteristics
  • Stress, Psychological / metabolism*
  • Stress, Psychological / pathology
  • Uncertainty


  • RNA, Messenger
  • Macrophage Colony-Stimulating Factor
  • Receptor, Macrophage Colony-Stimulating Factor