Adaptive immunity affects learning behavior in mice

Laboratory of NeuroImmune Regulation, Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5800, USA.
Brain Behavior and Immunity (Impact Factor: 5.89). 09/2008; 22(6):861-9. DOI: 10.1016/j.bbi.2007.12.008
Source: PubMed


Regulation of neuronal plasticity by the immune system is an evolving field of modern neuroscience. Here we employ immune deficient mice to examine the role of the immune system in learning behavior of mice in a variety of cognitive tasks. While no motivation or motor function deficits are evident in severe combined immune deficient (scid) mice, there was significant impairment in acquisition of cognitive tasks as compared to wild-type (WT) control mice. Moreover, acute depletion of adaptive immunity in adult WT mice significantly impaired learning behavior. Passive transfer of autologous T cells into WT mice following ablation of adaptive immunity restored previously impaired cognitive function. These results suggest that throughout lifetime, immune system supports cognitive function and may therefore have far-reaching therapeutic implications for cognitive disorders.

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    • "Recently, schizophrenia has increasingly been associated with progressive neurodegeneration, and one of the predominant underlying mechanisms appears to be immuno-inflammatory processes (Durrenberger et al. 2014; Pasternak et al. 2012; Pérez-Neri et al. 2006). Further to this, animal studies have established beneficial roles of T cells in cognition and behaviour ; for example, T cell replenishment restored cognitive impairment caused by systemic immune deficiency (Brynskikh et al. 2008; Kipnis et al. 2004; Wolf et al. 2009; Ziv et al. 2006). Herein, the relevance of T cells in schizophrenia, more specifically the implications of T cells in the etiology, course and treatment have been highlighted. "
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    ABSTRACT: Schizophrenia is a severe and highly complex neurodevelopmental disorder with an unknown etiopathology. Recently, immunopathogenesis has emerged as one of the most compelling etiological models of schizophrenia. Over the past few years considerable research has been devoted to the role of innate immune responses in schizophrenia. The findings of such studies have helped to conceptualize schizophrenia as a chronic low-grade inflammatory disorder. Although the contribution of adaptive immune responses has also been emphasized, however, the precise role of T cells in the underlying neurobiological pathways of schizophrenia is yet to be ascertained comprehensively. T cells have the ability to infiltrate brain and mediate neuro-immune cross-talk. Conversely, the central nervous system and the neurotransmitters are capable of regulating the immune system. Neurotransmitter like dopamine, implicated widely in schizophrenia risk and progression can modulate the proliferation, trafficking and functions of T cells. Within brain, T cells activate microglia, induce production of pro-inflammatory cytokines as well as reactive oxygen species and subsequently lead to neuroinflammation. Importantly, such processes contribute to neuronal injury/death and are gradually being implicated as mediators of neuroprogressive changes in schizophrenia. Antipsychotic drugs, commonly used to treat schizophrenia are also known to affect adaptive immune system; interfere with the differentiation and functions of T cells. This understanding suggests a pivotal role of T cells in the etiology, course and treatment of schizophrenia and forms the basis of this review.
    Journal of Neuroimmune Pharmacology 07/2015; DOI:10.1007/s11481-015-9626-9 · 4.11 Impact Factor
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    • "In these tests, first we observed behavioral differences between SCID and C57BL/6 (B6) mice, and next we asked whether splenocyte transfer to SCID pups could rescue social deficits. Importantly, in all previous behavioral studies of behavior in SCID mice, SCID and B6 dams reared their own litters (Brynskikh et al., 2008; Derecki et al., 2010). This design fails to take differences in maternal behavior into account, an important factor that influences offspring behaviors (Champagne, Francis, Mar, & Meaney, 2003; Schwendener, Meyer, & Feldon, 2009; Zimmerberg & Sageser, 2011). "
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    ABSTRACT: Mice with severe combined immunodeficiency (SCID) lack functional T and B lymphocytes, and have impaired cognitive abilities. We assessed social behaviors in male SCID and C57BL/6 (B6) juvenile mice. In a social preference task, SCID mice spent more time than B6 mice investigating a novel adult male mouse. In a social recognition task, SCID mice habituated to a novel ovariectomized mouse, but failed to show dishabituation when presented with an unfamiliar individual. We hypothesized that partial immune restoration could normalize behaviors. SCID pups (postnatal Day 7) received either saline or splenocytes from normal donors. Splenocyte-replaced SCID mice spent less time interacting with a novel mouse than saline-injected SCID or B6 control mice. Again, control SCID mice failed to dishabituate to a novel mouse, but splenocyte-replaced SCID mice showed dishabituation. In both of these studies, B6 and SCID pairs were used to produce offspring that remained with their dams until weaning. There are no studies of maternal behavior in SCID dams; therefore to investigate the potential role for this factor, we quantified maternal behavior in SCID and B6 dams; several significant differences were found. To control for differences in maternal care, we mated heterozygous SCIDs to produce offspring. These homozygous SCID and wild-type offspring reared by dams of the same genotypes displayed similar responses to a novel mouse; however, in the social recognition task, SCID males did not display dishabituation to a novel mouse. Taken together, our data indicate that Gene × Environment interactions influence social interactions in immune deficient mice. (PsycINFO Database Record (c) 2015 APA, all rights reserved).
    Behavioral Neuroscience 06/2015; 129(3):331-338. DOI:10.1037/bne0000053 · 2.73 Impact Factor
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    • "In fact, it has been postulated that CD4+ T-cells may have a physiological role in maintenance of memory and learning. Impairment in CD4+ T-cells, either by genetic manipulation or immunological depletion, results in decreased hippocampal neurogenesis and significant impairment in performance on memory tests [17], [18], [19], [20], suggesting that peripheral immune cells and mediators may play a role in maintaining cognitive function under physiological conditions [16]. "
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    ABSTRACT: The ability of neural stem/progenitor cells (NSCs) to self-renew, migrate to damaged sites, and differentiate into neurons has renewed interest in using them in therapies for neurodegenerative disorders. Neurological diseases, including viral infections of the brain, are often accompanied by chronic inflammation, whose impact on NSC function remains unexplored. We have previously shown that chronic neuroinflammation, a hallmark of experimental herpes simplex encephalitis (HSE) in mice, is dominated by brain-infiltrating activated CD8 T-cells. In the present study, activated CD8 lymphocytes were found to suppress NSC proliferation profoundly. Luciferase positive (luc+) NSCs co-cultured with activated, MHC-matched, CD8+ lymphocytes (luc-) showed two- to five-fold lower luminescence than co-cultures with un-stimulated lymphocytes. On the other hand, similarly activated CD4+ lymphocytes did not suppress NSC growth. This differential lymphocyte effect on proliferation was confirmed by decreased BrdU uptake by NSC cultured with activated CD8 T-cells. Interestingly, neutralizing antibodies to interferon-gamma (IFN-γ) reversed the impact of CD8 lymphocytes on NSCs. Antibodies specific to the IFN-γ receptor-1 subunit complex abrogated the inhibitory effects of both CD8 lymphocytes and IFN-γ, indicating that the inhibitory effect of these cells was mediated by IFN-γ in a receptor-specific manner. In addition, activated CD8 lymphocytes decreased levels of nestin and Sox2 expression in NSCs while increasing GFAP expression, suggesting possible induction of an altered differentiation state. Furthermore, NSCs obtained from IFN-γ receptor-1 knock-out embryos were refractory to the inhibitory effects of activated CD8+ T lymphocytes on cell proliferation and Sox2 expression. Taken together, the studies presented here demonstrate a role for activated CD8 T-cells in regulating NSC function mediated through the production of IFN-γ. This cytokine may influence neuro-restorative processes and ultimately contribute to the long-term sequelae commonly seen following herpes encephalitis.
    PLoS ONE 08/2014; 9(8):e105219. DOI:10.1371/journal.pone.0105219 · 3.23 Impact Factor
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