A conceptual revolution in the relationships between the brain and immunity

Schwartz, Michal; Kipnis, Jonathan

doi:10.1016/j.bbi.2010.12.015

Cited by 61 publications

(34 citation statements)

References 46 publications

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“…For instance, the modules enriched for cellular for stress response genes (Indianred4) and chromatin-modification genes (Mediumpurple2) ranked the highest for peripheral white blood cell measurements, whose association with the striatum is unknown. Some evidence suggests that the peripheral immune system plays an important role in stress resilience, cognition, and other central nervous system functions (Cohen et al, 2006; Kipnis et al, 2012; Schwartz and Kipnis, 2011), and our unbiased analyses support this link by showing that serological measurements of the peripheral immune system correlate with striatal transcriptional networks that are also associated with stress-related behavioral and sleep phenotypes. The precise relationship between the striatum and peripheral immune system is beyond the scope of this study, but this analysis can serve as complementary evidence for future investigations regarding the interactions between the functions of multiple organ systems involved in stress and sleep.…”

Section: Discussionsupporting

confidence: 70%

A Systems Approach Identifies Networks and Genes Linking Sleep and Stress: Implications for Neuropsychiatric Disorders

et al. 2015

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SUMMARY Sleep dysfunction and stress susceptibility are co-morbid complex traits, which often precede and predispose patients to a variety of neuropsychiatric diseases. Here, we demonstrate multi-level organizations of genetic landscape, candidate genes, and molecular networks associated with 328 stress and sleep traits in a chronically stressed population of 338 (C57BL/6J×A/J) F2 mice. We constructed striatal gene co-expression networks, revealing functionally and cell-type specific gene co-regulations important for stress and sleep. Using a composite ranking system, we identified network modules most relevant for 15 independent phenotypic categories, highlighting a mitochondria/synaptic module that links sleep and stress. The key network regulators of this module are overrepresented with genes implicated in neuropsychiatric diseases. Our work suggests the interplay between sleep, stress, and neuropathology emerge from genetic influences on gene expression and their collective organization through complex molecular networks, providing a framework to interrogate the mechanisms underlying sleep, stress susceptibility, and related neuropsychiatric disorders.

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Section: Discussionsupporting

confidence: 70%

A Systems Approach Identifies Networks and Genes Linking Sleep and Stress: Implications for Neuropsychiatric Disorders

et al. 2015

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“…In other work using transplantation of GFP-labeled bone marrow cells, the migration of these cells into the CNS was demonstrated; nearly all of the infiltrated cells had a highly ramified morphology expressing microglial markers with the AP being a region with consistently high infiltration of GFP-positive cells [35]. Nowadays, there is a tendency to explain monocyte-macrophage CNS infiltration as a prerequisite for healing of damaged brain when activated microglia are less effective in damage control [36,37]. These last three findings are consistent with our results in the AP under chronic psychological distress and may support the idea that in damaged CNS, the AP is the site for monocyte recruitment in order to assist microglia in the repair process.…”

Section: Discussionmentioning

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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“…However, cognitive deficits have been observed among youth with PHIV compared to typically developing peers [1]. HIV affects central nervous system functioning, largely indirectly through damaging cytokines produced as a result of immune activation and inflammation [2, 3]. During replication, HIV destroys and leads to decreases in CD4+ immune T cells [4], a major indicator of disease severity.…”

Section: Introductionmentioning

confidence: 99%

White matter microstructure among youth with perinatally acquired HIV is associated with disease severity

Uban

Herting

Williams

et al. 2015

Aids

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Objectives We investigated whether HIV disease severity was associated with alterations in structural brain connectivity, and whether those alterations in turn were associated with cognitive deficits in youth with perinatally-acquired HIV (PHIV). Design PHIV youth (n=40) from the Pediatric HIV/AIDS Cohort Study (PHACS) (mean age: 16±2 yrs) were included to evaluate how current and past disease severity measures (recent/nadir CD4%; peak viral load) relate to white matter (WM) microstructure within PHIV youth. PHIV youth were compared to 314 controls from the Pediatric Imaging, Neurocognition, and Genetics (PING) study. Methods Diffusion tensor imaging and tractography were utilized to assess WM microstructure. Mediation analyses were conducted to examine whether microstructure alterations contributed to relationships between higher disease severity and specific cognitive domains in PHIV youth. Results Whole brain fractional anisotropy (FA) was reduced, but radial (RD) and mean (MD) diffusivity were increased, in PHIV compared to control youth. Within PHIV youth, more severe past HIV disease was associated with reduced FA of the right inferior fronto-occipital (IFO) and left uncinate tracts; elevated MD of the F minor; and increased streamlines comprising the left inferior longitudinal fasciculus (ILF). Associations of higher peak viral load with lower working memory performance were partly mediated by reductions in right IFO FA levels. Conclusion Our findings suggest that PHIV youth have higher risk of alterations in WM microstructure compared to typically developing youth, and certain alterations are related to past disease severity. Further, WM alterations potentially mediate associations between HIV disease and working memory.

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A conceptual revolution in the relationships between the brain and immunity

Cited by 61 publications

References 46 publications

A Systems Approach Identifies Networks and Genes Linking Sleep and Stress: Implications for Neuropsychiatric Disorders

A Systems Approach Identifies Networks and Genes Linking Sleep and Stress: Implications for Neuropsychiatric Disorders

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

White matter microstructure among youth with perinatally acquired HIV is associated with disease severity

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