Abstract
Life stressors during critical periods are reported to trigger an immune dysfunction characterised by abnormal production of inflammatory cytokines. Despite the relationship between early stressors and schizophrenia is described, the evidence on inflammatory biomarkers remains limited. We aimed to investigate whether an imbalance between pro- and anti-inflammatory cytokines in the brain is reflected in the peripheral blood of rats submitted to post-weaning social isolation (pwSI), a model with validity to study schizophrenia. We evaluated pro- and anti-inflammatory cytokines (IL-6, TNF-α, and IL-10) simultaneously at blood, prefrontal cortex and hippocampal tissues (Milliplex MAP), including the respective cytokines gene expression (mRNA) (qRT-PCR TaqMan mastermix). We also performed a correlation matrix to explore significant correlations among cytokines (protein and mRNA) in blood and brain, as well as cytokines and total number of square crossings in the open field for isolated-reared animals. Male Wistar rats (n = 10/group) were kept isolated (n = 1/cage) or grouped (n = 3–4/cage) since weaning for 10 weeks. After this period, rats were assessed for locomotion and sacrificed for blood and brain cytokines measurements. Prolonged pwSI decreased IL-10 protein and mRNA in the blood, and IL-10 protein in the hippocampus, along with decreased IL-6 and its mRNA expression in the prefrontal cortex. Our results also showed that cytokines tend to correlate to one-another among the compartments investigated, although blood and brain correlations are far from perfect. IL-10 hippocampal levels were negatively correlated with hyperlocomotion in the open field. Despite the unexpected decrease in IL-6 and unchanged TNF-α levels contrast to the expected pro-inflammatory phenotype, this may suggest that reduced anti-inflammatory signalling may be critical for eliciting abnormal behaviour in adulthood. Altogether, these results suggest that prolonged early-life adverse events reduce the ability to build proper anti-inflammatory cytokine that is translated from blood-to-brain.
Highlights
Rearing rat pups in isolation since weaning significantly interferes with the morphological and neurochemical development of the early postnatal brain, contributing to long-term maladaptive behaviours in adulthood (Fone and Porkess, 2008; Jones et al, 2011)
We evaluated a possible imbalance between protein and gene expression of proand anti-inflammatory cytokines (IL-6, TNF-α, and IL-10) simultaneously at both blood and brain tissues of rats submitted to the post-weaning social isolation (pwSI) model
These results suggest that prolonged early-life adverse events reduce the anti-inflammatory cytokine IL-10 in blood and brain, and that the latter may contribute to the occurrence of abnormal behaviour in adulthood
Summary
Rearing rat pups in isolation since weaning significantly interferes with the morphological and neurochemical development of the early postnatal brain, contributing to long-term maladaptive behaviours in adulthood (Fone and Porkess, 2008; Jones et al, 2011). The behavioural, morphological and neurochemical alterations elicited by post-weaning social isolation (pwSI) have translational significance to several core features that seem to share the neurobiology implicated in the pathophysiology of schizophrenia. Several lines of evidence suggest impaired prefrontal cortexhippocampus connectivity as the neuroanatomical substrate involved in spontaneous hyperlocomotion in isolated reared rats. The prefrontal cortex and the hippocampus are critical brain areas of dysfunction in clinical schizophrenia (Glantz and Lewis, 2000; Lewis et al, 2003; Pantelis et al, 2005; Vita and de Peri, 2007), and lack of social stimulation would contribute to reduced volume, besides impaired neurogenesis, plasticity and connectivity in these two brain areas (Lu et al, 2003; Silva-Gómez et al, 2003; Harte et al, 2004; Day-Wilson et al, 2006; Pascual et al, 2007; Ibi et al, 2008; Schubert et al, 2009; Quan et al, 2010; Pereda-Pérez et al, 2013; Biro et al, 2017)
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