Re-establishment of Anxiety in Stress-Sensitized Mice Is Caused by Monocyte Trafficking from the Spleen to the Brain

Wohleb, Eric S.; McKim, Daniel B.; Shea, Daniel T.; Powell, Nicole D.; Tarr, A.J.; Sheridan, John F.; Godbout, Jonathan P.

doi:10.1016/j.biopsych.2013.11.029

Cited by 252 publications

(311 citation statements)

References 62 publications

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“…However, recent translational data indicate that during peripheral inflammation, activated monocytes/macrophages traffic to the brain in response to monocyte chemoattractant protein-1 (MCP-1), a chemokine produced by activated microglial cells in response to cytokine signaling in from the periphery (D'Mello et al, 2009;D'Mello et al, 2015). These monocytes/macrophages traffic primarily to perivascular and meningeal spaces, and have been shown to contribute to the behavioral changes in rodent models of stress-induced depressive and anxiety behaviors (Hodes et al, 2014;Wohleb et al, 2012;Wohleb et al, 2014). Interestingly, patterns of gene expression in the peripheral blood of patients with psychiatric disorders exhibit increased signatures consistent with proinflammatory 'M1' activation of monocyte/macrophages (Brambilla et al, 2014;Drago et al, 2015;Mostafavi et al, 2014).…”

Section: Peripheral and Central Immune Cell Activationmentioning

confidence: 99%

Inflammation Effects on Motivation and Motor Activity: Role of Dopamine

Felger

Treadway

2016

Neuropsychopharmacol

306

237

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Motivational and motor deficits are common in patients with depression and other psychiatric disorders, and are related to symptoms of anhedonia and motor retardation. These deficits in motivation and motor function are associated with alterations in corticostriatal neurocircuitry, which may reflect abnormalities in mesolimbic and mesostriatal dopamine (DA). One pathophysiologic pathway that may drive changes in DAergic corticostriatal circuitry is inflammation. Biomarkers of inflammation such as inflammatory cytokines and acute-phase proteins are reliably elevated in a significant proportion of psychiatric patients. A variety of inflammatory stimuli have been found to preferentially target basal ganglia function to lead to impaired motivation and motor activity. Findings have included inflammation-associated reductions in ventral striatal neural responses to reward anticipation, decreased DA and DA metabolites in cerebrospinal fluid, and decreased availability, and release of striatal DA, all of which correlated with symptoms of reduced motivation and/or motor retardation. Importantly, inflammation-associated symptoms are often difficult to treat, and evidence suggests that inflammation may decrease DA synthesis and availability, thus circumventing the efficacy of standard pharmacotherapies. This review will highlight the impact of administration of inflammatory stimuli on the brain in relation to motivation and motor function. Recent data demonstrating similar relationships between increased inflammation and altered DAergic corticostriatal circuitry and behavior in patients with major depressive disorder will also be presented. Finally, we will discuss the mechanisms by which inflammation affects DA neurotransmission and relevance to novel therapeutic strategies to treat reduced motivation and motor symptoms in patients with high inflammation.

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Section: Peripheral and Central Immune Cell Activationmentioning

confidence: 99%

Inflammation Effects on Motivation and Motor Activity: Role of Dopamine

Felger

Treadway

2016

Neuropsychopharmacol

306

237

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“…Few works have described the role of myeloid-derived cells recruited from the blood to the CNS under psychological distress conditions. Essentially, monocyte recruitment to the brain was found to be increased in response to social stress, which indicated an association of this event with the development of anxiety-like behavior [7,8]. …”

Section: Introductionmentioning

confidence: 99%

Chronic Psychological Distress as an Inducer of Microglial Activation and Leukocyte Recruitment into the Area Postrema

Vargas-Caraveo

Pérez-Ishiwara

Martínez‐Martínez

2015

Neuroimmunomodulation

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Background: Chronic psychological distress can cause neuroinflammation, but the involvement of leukocytes in this inflammatory response remains unclear. The area postrema (AP) is considered a neural-immune interface because it lacks a blood-brain barrier and a site for leukocyte recruitment in neuroinflammatory conditions induced by immunological insults, but its role in chronic psychological distress has not been explored. Objective: To determine leukocyte recruitment to the AP after chronic psychological distress. Methods: Rats were exposed to cat odor for 5 consecutive days to induce distress, and, on the 6th day, their brains were dissected to perform immunohistofluorescence studies of the AP. Immune cells were identified and quantified with CD45 and CD11b markers. The distribution of neurons and immune cells was determined using TrkA and CD45 markers, respectively. Results: Distress induced a significant increase in CD45⁺ and CD11b⁺ cells in the AP. Three immunophenotypes were determined in the control and distress groups: CD45⁺/CD11b^-, CD45⁺/CD11b⁺ and CD45^-/CD11b⁺. CD expression, morphology and fluorescence intensity enabled the identification of different immune cell types: starting from longitudinal ramified microglia (mainly in the control group) to amoeboid microglia, monocytes and lymphocytes (mostly in the distressed group). TrkA and CD45 expression in the AP revealed the proximity between soma neurons and leukocytes. Interestingly, some CD45⁺ cells expressed TrkA, with increased expression in the distressed group. Conclusions: The identification of microglial activation, leukocyte recruitment and the close proximity between neurons and leukocytes in the AP after chronic psychological distress exposure suggests the AP as a site for distress-induced immune responses and engraftment of leukocytes infiltrating the CNS.

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“…Interestingly, these deficits were transient, and no longer present 28 days after RSD. It is also important to highlight that the peripheral monocytes/macrophages that had trafficked into the brain are no longer detected 28 days after RSD [30].…”

Section: Discussionmentioning

confidence: 99%

“…Social avoidance was determined as previously described [30]. In the empty trial, an experimental mouse was placed into the arena with an empty wire mesh cage and activity was recorded for 2.5 minutes.…”

Section: Social Avoidancementioning

confidence: 99%

“…Because RSD-induced anxiety-like behavior persists for at least 8 days [33], it is possible that decreased time spent in the target quadrant of the Morris water maze is attributable to increased anxiety-like behavior or reduced encoding efficiency. In order to circumvent the possible anxiety-or encoding-related deficits, spatial memory was assessed in the Barnes maze.…”

Section: Rsd Impaired Spatial Recall But Not Acquisition In the Morrimentioning

confidence: 99%

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Repeated social defeat stress induces neuroinflammation and impairs hippocampal neurogenesis that differentially regulate mood and cognition

Niraula

McKim

Tarr

et al. 2015

Brain, Behavior, and Immunity

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Repeated social defeat (RSD) is a murine stressor that models several key physiological, immunological, and behavioral alterations observed in humans exposed to psychosocial stress.RSD induces prolonged anxiety-like behavior associated with myeloid cell trafficking into the brain, including the hippocampus. Because the hippocampus (HPC) is a key area involved in neuroplasticity, behavior, and cognition, the goal of this study was to investigate if the stressinduced monocyte trafficking affected hippocampal neurogenesis and cognitive function. Here, we show that RSD increased inflammatory mediators (IL-1β, TNFα and IL-6), enhanced microglia activation and monocyte trafficking (CD45hi) specifically in the caudal hippocampus.RSD also impaired spatial memory recall in the Barnes maze independent of anxiety-like behavior. RSD did not affect the number of proliferating neural progenitor cells and developing neurons when examined 14 hours post-RSD. Nonetheless there was a significant reduction in the number of young neurons and mature neurons in the HPC 10 days and 28 days post-RSD, respectively. Consistent with region-specific neuroinflammation, reduction in the number of mature neurons was greater in the caudal hippocampus of the RSD mice compared to controls.The RSD-induced spatial deficits, which are rostral hippocampus-mediated, were resolved by 28 days. Social avoidance which is caudal hippocampus-mediated still persisted 28 days after stress.Thus, stress-induced neuroinflammation is associated with reduced neuroplasticity, and the stress-induced affective and cognitive deficits are differentially associated with hippocampal neurogenesis.2

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Re-establishment of Anxiety in Stress-Sensitized Mice Is Caused by Monocyte Trafficking from the Spleen to the Brain

Cited by 252 publications

References 62 publications

Inflammation Effects on Motivation and Motor Activity: Role of Dopamine

Inflammation Effects on Motivation and Motor Activity: Role of Dopamine

Chronic Psychological Distress as an Inducer of Microglial Activation and Leukocyte Recruitment into the Area Postrema

Repeated social defeat stress induces neuroinflammation and impairs hippocampal neurogenesis that differentially regulate mood and cognition

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