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.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Biological PsychiatryAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- The costs of depression.Psychiatr Clin North Am. 2012; 35: 1-14
- The state of US health, 1990–2010: Burden of diseases, injuries, and risk factors.JAMA. 2013; 310: 591-608
- Synaptic plasticity and depression: New insights from stress and rapid-acting antidepressants.Nat Med. 2016; 22: 238-249
- Integrating neuroimmune systems in the neurobiology of depression.Nat Rev Neurosci. 2016; 17: 497-511
- Structural and synaptic plasticity in stress-related disorders.Rev Neurosci. 2011; 22: 535-549
- REDD1 is essential for stress-induced synaptic loss and depressive behavior.Nat Med. 2014; 20: 531-535
- mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists.Science. 2010; 329: 959-964
- Decreased expression of synapse-related genes and loss of synapses in major depressive disorder.Nat Med. 2012; 18: 1413-1417
- Depression as a microglial disease.Trends Neurosci. 2015; 38: 637-658
- Acute and chronic stress-induced disturbances of microglial plasticity, phenotype and function.Curr Drug Targets. 2013; 14: 1262-1276
- Microglia: Dynamic mediators of synapse development and plasticity.Trends Immunol. 2015; 36: 605-613
- The role of microglia in the healthy brain.J Neurosci. 2011; 31: 16064-16069
- Stress signalling pathways that impair prefrontal cortex structure and function.Nat Rev Neurosci. 2009; 10: 410-422
- Stress blunts serotonin- and hypocretin-evoked EPSCs in prefrontal cortex: Role of corticosterone-mediated apical dendritic atrophy.Proc Natl Acad Sci U S A. 2008; 105: 359-364
- Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain.Neuron. 2014; 82: 380-397
- The soluble isoform of CX3CL1 is necessary for neuroprotection in a mouse model of Parkinson’s disease.J Neurosci. 2012; 32: 14592-14601
- Identification of a unique TGF-β-dependent molecular and functional signature in microglia.Nat Neurosci. 2014; 17: 131-143
- Colony-stimulating factor 1 receptor (CSF1R) signaling in injured neurons facilitates protection and survival.J Exp Med. 2013; 210: 157-172
- Injured sensory neuron-derived CSF1 induces microglial proliferation and DAP12-dependent pain.Nat Neurosci. 2016; 19: 94-101
- Psychological stress activates the inflammasome via release of adenosine triphosphate and stimulation of the purinergic type 2X7 receptor.Biol Psychiatry. 2016; 80: 12-22
- Antidepressant effects of fibroblast growth factor-2 in behavioral and cellular models of depression.Biol Psychiatry. 2012; 72: 258-265
- GABA interneurons mediate the rapid antidepressant-like effects of scopolamine.J Clin Invest. 2016; 126: 2482-2494
- Peripheral innate immune challenge exaggerated microglia activation, increased the number of inflammatory CNS macrophages, and prolonged social withdrawal in socially defeated mice.Psychoneuroendocrinology. 2012; 37: 1491-1505
- β-Adrenergic receptor antagonism prevents anxiety-like behavior and microglial reactivity induced by repeated social defeat.J Neurosci. 2011; 31: 6277-6288
- Rational siRNA design for RNA interference.Nat Biotechnol. 2004; 22: 326-330
- Local gene knockdown in the brain using viral-mediated RNA interference.Nat Med. 2003; 9: 1539-1544
- The Mouse Brain in Stereotaxic Coordinates.2nd ed. Academic Press, San Diego2001
- GLYX-13 produces rapid antidepressant responses with key synaptic and behavioral effects distinct from ketamine.Neuropsychopharmacology. 2017; 42: 1231-1242
- Automated three-dimensional detection and shape classification of dendritic spines from fluorescence microscopy images.PLoS One. 2008; 3: e1997
- Dynamic structural remodelling of microglia in health and disease: A review of the models, the signals and the mechanisms.Brain Behav Immun. 2014; 37: 1-14
- Fractalkine receptor deficiency impairs microglial and neuronal responsiveness to chronic stress.Brain Behav Immun. 2016; 55: 114-125
- Linking molecules to mood: New insight into the biology of depression.Am J Psychiatry. 2010; 167: 1305-1320
- The molecular neurobiology of depression.Nature. 2008; 455: 894-902
- New insights on the role of microglia in synaptic pruning in health and disease.Curr Opin Neurobiol. 2016; 36: 128-134
- Emerging roles for CSF-1 receptor and its ligands in the nervous system.Trends Neurosci. 2016; 39: 378-393
- Impaired glutamate recycling and GluN2B-mediated neuronal calcium overload in mice lacking TGF-β1 in the CNS.Glia. 2013; 61: 985-1002
- Environment drives selection and function of enhancers controlling tissue-specific macrophage identities.Cell. 2014; 159: 1327-1340
- IL-1beta is an essential mediator of the antineurogenic and anhedonic effects of stress.Proc Natl Acad Sci U S A. 2008; 105: 751-756
- Divergent responses of inflammatory mediators within the amygdala and medial prefrontal cortex to acute psychological stress.Brain Behav Immun. 2016; 51: 70-91
- Microglia in neuronal plasticity: Influence of stress.Neuropharmacology. 2015; 96: 19-28
- Microglial brain region-dependent diversity and selective regional sensitivities to aging.Nat Neurosci. 2016; 19: 504-516
- Microglial interactions with synapses are modulated by visual experience.PLoS Biol. 2010; 8: e1000527
- Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner.Neuron. 2012; 74: 691-705
- Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals.J Neurosci. 2009; 29: 3974-3980
- Complement and microglia mediate early synapse loss in Alzheimer mouse models.Science. 2016; 352: 712-716
- Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis.Cell Stem Cell. 2010; 7: 483-495
- Microglia: Architects of the developing nervous system.Trends Cell Biol. 2016; 26: 587-597
- Knockdown of interleukin-1 receptor type-1 on endothelial cells attenuated stress-induced neuroinflammation and prevented anxiety-like behavior.J Neurosci. 2014; 34: 2583-2591
- Microglial recruitment of IL-1β-producing monocytes to brain endothelium causes stress-induced anxiety.Mol Psychiatry. 2017; ([published online ahead of print Apr 04])
- Monocyte trafficking to the brain with stress and inflammation: A novel axis of immune-to-brain communication that influences mood and behavior.Front Neurosci. 2015; 8: 447
- Spine synapse remodeling in the pathophysiology and treatment of depression.Neurosci Lett. 2015; 601: 20-29
- Estrogen protects against the detrimental effects of repeated stress on glutamatergic transmission and cognition.Mol Psychiatry. 2014; 19: 588-598
- Chronic stress effects on dendritic morphology in medial prefrontal cortex: Sex differences and estrogen dependence.Neuroscience. 2009; 162: 195-207
- Ovarian hormones, but not fluoxetine, impart resilience within a chronic unpredictable stress model in middle-aged female rats.Neuropharmacology. 2016; 107: 278-293
- Differential effects of stress on microglial cell activation in male and female medial prefrontal cortex.Brain Behav Immun. 2016; 52: 88-97
- Gender differences in depression severity and symptoms across depressive sub-types.J Affect Disord. 2014; 167: 351-357
- Gender differences in depression: Findings from the STAR*D study.J Affect Disord. 2005; 87: 141-150
- Epidemiology of women and depression.J Affect Disord. 2003; 74: 5-13
- Hormones and mood: From menarche to menopause and beyond.J Affect Disord. 2003; 74: 67-83
- Not all depression is created equal: Sex interacts with disease to precipitate depression.Biol Sex Differ. 2013; 4: 8
- Stress-induced elevation of glucocorticoids increases microglia proliferation through NMDA receptor activation.J Neuroimmunol. 2006; 171: 72-85
- Chronic stress alters the density and morphology of microglia in a subset of stress-responsive brain regions.Brain Behav Immun. 2010; 24: 1058-1068
- Evidence that microglia mediate the neurobiological effects of chronic psychological stress on the medial prefrontal cortex.Cereb Cortex. 2012; 22: 1442-1454
- Tissue-resident macrophages.Nat Immunol. 2013; 14: 986-995
- Neuron–microglia interactions in mental health disorders: “For better, and for worse.”.Front Immunol. 2016; 7: 544
Article Info
Publication History
Published online: June 14, 2017
Accepted:
May 31,
2017
Received in revised form:
May 30,
2017
Received:
December 30,
2016
Identification
Copyright
© 2017 Society of Biological Psychiatry.
