Microbe-Immune-Stress Interactions Impact Behaviour during Postnatal Development.

Decades of research have established the role of microbiota-brain communication in behaviour and brain function. Studies have shown that microbiota composition and diversity are influenced by a variety of factors including host genetics, diet, and other environmental exposures, with implications for the immunological and neurobiological development of the host organism. To further understand early-life interactions between environment, genetic factors, the microbiome and the central nervous system, we investigated the impact of postnatal stress in C57Bl/6 wild type and T-cell deficient mice on microbe-brain interactions and behaviour. Mice were exposed to immune challenge with lipopolysaccharide (LPS) at postnatal day (P) 3 and maternal separation at P9 (16 h overnight). Behavioural assessment of growth and development as well as behaviour (righting reflex, ultrasonic vocalizations in response to brief maternal separation, open field, sociability, and grooming) was conducted. Microbiota diversity and composition of fecal samples collected at P24 revealed reduced alpha diversity in T-cell-deficient mice as well as genotype- and stress-related taxa. Notably, integrated analyses of microbiota and behaviour in the context of immunocompromise revealed key behavioural related taxa that may be important to brain development. These findings are important to determining the influence of genetic and environmental factors on gut microbiota and advances our understanding microbiome-brain signaling pathways on neurodevelopment and behaviour.

Loss of T cells influences sex differences in stress-related gene expression.

Deficiencies in the adaptive immune system have been linked to anxiety-like behaviours and stress reactivity. Mice lacking T lymphocytes through knockout of the T cell receptor (TCR) ß and δ chains were compared to wild type C57Bl/6 mice. Central stress circuitry gene expression was assessed following repeated restraint stress. TCRß-/-δ-/- mice showed an increased baseline plasma corticosterone and exaggerated changes in stress-related gene expression after repeated restraint stress. Sexual dimorphic stress responses were observed in wild-type C57Bl/6 mice but not in TCRß-/-δ-/- mice. These data suggest that T cell-brain interactions influence sex-differences in CNS stress circuitry and stress reactivity.

Loss of T cells influences sex differences in behavior and brain structure.

Clinical and animal studies demonstrate that immune-brain communication influences behavior and brain function. Mice lacking T cell receptor ß and δ chains were tested in the elevated plus maze, open field, and light-dark test and showed reduced anxiety-like behavior compared to wild type. Interestingly sex differences were observed in the behavioural phenotype of TCRß-/-δ- mice. Specifically, female TCRß-/-δ- mice spent more time in the light chamber compared to wild type females, whereas male TCRß-/-δ- spent more time in the center of the open field compared to wild type males. In addition, TCRß-/-δ- mice did not show sex differences in activity-related behaviors observed in WT mice. Ex vivo brain imaging (7 Tesla MRI) revealed volume changes in hippocampus, hypothalamus, amygdala, periaqueductal gray, and dorsal raphe and other brain regions between wild type and T cell receptor knockout mice. There was also a loss of sexual dimorphism in brain volume in the bed nucleus of the stria terminalis, normally the most sexually dimorphic region in the brain, in immune compromised mice. These data demonstrate the presence of T cells is important in the development of sex differences in CNS circuitry and behavior.