In the elderly, peripheral infection is associated with higher incidence of depressive complications, but the mechanisms underlying these complications are unknown. In this proposal, we present novel data that indicates that microglia of aged mice become hyperactive following peripheral lipopolysaccharide (LPS) challenge, exhibiting exaggerated induction of interleukin (IL)-12 and indoleamine 2,3 dioxygenase (IDO). Moreover, this amplified microglial response in aged mice is paralleled by prolonged sickness and depressive- like behaviors. Excessive microglia-specific IDO induction may be a pivotal event as recent studies indicate that IDO is central to inflammatory-mediated depression. The IDO pathway metabolizes tryptophan into several reactive intermediates and glutamate receptor agonists that can impact behavior as well as influence neuronal restructuring. In support of this premise, we show preliminary evidence of decreased apical dendrite length in hippocampus of aged mice at a time corresponding with depressive-like behavior. Taken together, these findings underscore the importance of understanding how microglia activation is dysregulated in the aged brain. One significant mechanism for microglia regulation is the fractalkine (FKN) system. Complementary expression of FKN on neurons and FKN receptor (FKNR) on microglia establishes a unique system whereby neuron-derived FKN restrains/modulates microglia activation. In this proposal, we provide evidence that impaired microglia regulation by FKN may be the basis for this LPS-induced microglial hyperactivation in the aged brain. For example, FKN mRNA levels are decreased in the brain of aged mice. In addition, peripheral LPS injection causes a greater microglia-specific reduction in FKNR mRNA in aged mice than adults. The objective of this 5 year project is to test one major hypothesis: When FKN regulation of microglia activation is impaired, peripheral innate immune challenge elicits microglial hyperactivity (excessive cytokine production and IDO activation) that causes prolonged depressive-like behavior and hippocampal dendritic atrophy. To address these issues, we propose three specific aims using a BALB/c mouse model of aging and a FNKR-/- transgenic mouse model of impaired microglia regulation. In the first aim we will determine the degree to extent to which impaired fractalkine (FKN/FKNR) interactions are associated with microglial hyperactivity in aged mice. In the second aim we will ascertain the degree to which peripheral immune challenge causes microglial hyperactivity and depressive-like behavior in mice with or without functional FKNR. In the final aim, we will determine the extent to which attenuation of microglia hyperactivation blocks prolonged depressive-like behavior and hippocampal dendritic atrophy in aged mice after peripheral LPS challenge. Addressing these aims is relevant to understanding age-associated changes in microglia regulation and is potentially important in developing interventions to protect against prolonged neuroinflammatory responses that contribute to long- lasting neurobehavioral complications.

Public Health Relevance

In the elderly, peripheral infection is associated with higher incidence of cognitive and behavioral complications but the mechanisms involved are not well understood. We propose that these inflammatory-related complications are caused by impaired regulation of microglia activation in the aged brain. In this application, we will use two mouse models, one of aging and one of impaired fractalkine (FKN)-dependent microglial regulation, to test one major hypothesis: When FKN regulation of microglia activation is impaired, peripheral innate immune challenge elicits microglial hyperactivity (excessive cytokine production and IDO activation) that causes prolonged depressive-like behavior and hippocampal dendritic atrophy. Thus, microglial hyperactivity with prolonged IDO activation may underlie inflammatory-related depression in the elderly.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG033028-02
Application #
7939870
Study Section
Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
Program Officer
Wise, Bradley C
Project Start
2009-09-30
Project End
2014-08-31
Budget Start
2010-09-01
Budget End
2011-08-31
Support Year
2
Fiscal Year
2010
Total Cost
$309,499
Indirect Cost
Name
Ohio State University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Niraula, Anzela; Wang, Yufen; Godbout, Jonathan P et al. (2018) Corticosterone Production during Repeated Social Defeat Causes Monocyte Mobilization from the Bone Marrow, Glucocorticoid Resistance, and Neurovascular Adhesion Molecule Expression. J Neurosci 38:2328-2340
Niraula, Anzela; Sheridan, John F; Godbout, Jonathan P (2017) Microglia Priming with Aging and Stress. Neuropsychopharmacology 42:318-333
Weber, Michael D; Godbout, Jonathan P; Sheridan, John F (2017) Repeated Social Defeat, Neuroinflammation, and Behavior: Monocytes Carry the Signal. Neuropsychopharmacology 42:46-61
McKim, Daniel B; Niraula, Anzela; Tarr, Andrew J et al. (2016) Neuroinflammatory Dynamics Underlie Memory Impairments after Repeated Social Defeat. J Neurosci 36:2590-604
Norden, Diana M; Trojanowski, Paige J; Walker, Frederick R et al. (2016) Insensitivity of astrocytes to interleukin 10 signaling following peripheral immune challenge results in prolonged microglial activation in the aged brain. Neurobiol Aging 44:22-41
DiSabato, Damon J; Quan, Ning; Godbout, Jonathan P (2016) Neuroinflammation: the devil is in the details. J Neurochem 139 Suppl 2:136-153
Muccigrosso, Megan M; Ford, Joni; Benner, Brooke et al. (2016) Cognitive deficits develop 1month after diffuse brain injury and are exaggerated by microglia-associated reactivity to peripheral immune challenge. Brain Behav Immun 54:95-109
Norden, Diana M; Trojanowski, Paige J; Villanueva, Emmanuel et al. (2016) Sequential activation of microglia and astrocyte cytokine expression precedes increased Iba-1 or GFAP immunoreactivity following systemic immune challenge. Glia 64:300-16
Norden, Diana M; Muccigrosso, Megan M; Godbout, Jonathan P (2015) Microglial priming and enhanced reactivity to secondary insult in aging, and traumatic CNS injury, and neurodegenerative disease. Neuropharmacology 96:29-41
Norden, Diana M; Bicer, Sabahattin; Clark, Yvonne et al. (2015) Tumor growth increases neuroinflammation, fatigue and depressive-like behavior prior to alterations in muscle function. Brain Behav Immun 43:76-85

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