Eric S Wohleb1, Rosemarie Terwilliger2, Catharine H Duman2, Ronald S Duman2. 1. Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut; Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, Ohio. Electronic address: eric.wohleb@uc.edu. 2. Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.
Abstract
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.
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.
Authors: Sheila M Marcus; Elizabeth A Young; Kevin B Kerber; Susan Kornstein; Amy H Farabaugh; Jeff Mitchell; Stephen R Wisniewski; G K Balasubramani; Madhukar H Trivedi; A John Rush Journal: J Affect Disord Date: 2005-08 Impact factor: 4.839
Authors: Alfredo Rodriguez; Douglas B Ehlenberger; Dara L Dickstein; Patrick R Hof; Susan L Wearne Journal: PLoS One Date: 2008-04-23 Impact factor: 3.240
Authors: Rachel M Anderson; Shane B Johnson; Ryan T Lingg; Dalton C Hinz; Sara A Romig-Martin; Jason J Radley Journal: Cereb Cortex Date: 2020-01-10 Impact factor: 5.357
Authors: Michael D Weber; Daniel B McKim; Anzela Niraula; Kristina G Witcher; Wenyuan Yin; Carly G Sobol; Yufen Wang; Caroline M Sawicki; John F Sheridan; Jonathan P Godbout Journal: Biol Psychiatry Date: 2018-10-25 Impact factor: 13.382