Mouse models of immune dysfunction: their neuroanatomical differences reflect their anxiety-behavioural phenotype

Abstract

Extensive evidence supports the role of the immune system in modulating brain function and behaviour. However, past studies have revealed striking heterogeneity in behavioural phenotypes produced from immune system dysfunction. Using magnetic resonance imaging, we studied the neuroanatomical differences among 11 distinct genetically modified mouse lines (n = 371), each deficient in a different element of the immune system. We found a significant and heterogeneous effect of immune dysfunction on the brains of both male and female mice. However, by imaging the whole brain and using Bayesian hierarchical modelling, we were able to identify patterns within the heterogeneous phenotype. Certain structures—such as the corpus callosum, midbrain, and thalamus—were more likely to be affected by immune dysfunction. A notable brain–behaviour relationship was identified with neuroanatomy endophenotypes across mouse models clustering according to anxiety-like behaviour phenotypes reported in literature, such as altered volume in brains regions associated with promoting fear response (e.g., the lateral septum and cerebellum). Interestingly, genes with preferential spatial expression in the most commonly affected regions are also associated with multiple sclerosis and other immune-mediated diseases. In total, our data suggest that the immune system modulates anxiety behaviour through well-established brain networks.

The missing hallmark of health: psychosocial adaptation

“…Disruption and mimicry of this reflex may exacerbate or suppress inflammation and depression [ 167 ]. Genetic models of immunodeficiency have supported the link between the cellular immune system and anxiety-like behaviors [ 168 ]. T cells can affect behavior in multiple ways.…”

Transplantation of Human Stem Cell-Derived GABAergic Neurons into the Early Postnatal Mouse Hippocampus to Mitigate Neurodevelopmental Disorders

“…However, the administration of immunosuppressive drugs, such as cyclosporine A, causes renal toxicity after chronic administration, is labor-intensive because of the need for daily intraperitoneal injections to achieve stable systemic concentrations, causing animal stress 17 , and has off-target effects that can interact with pathology 18 . In addition, compromising the immune system has been shown to change behavioral phenotypes 19 , with alterations in the corresponding neuroanatomical regions 20 .…”