IMPACT OF PERIPHERAL IMMUNE CELLS AND SIGNALS ON BRAIN AND BEHAVIOUR OUTCOMES

Abstract

Immune-brain communication is a critical component of the microbiome-gut-brain axis, and an important topic for today’s neuroscientists. Recent behavioural studies revealed that mice lacking the b and d chains of the T cell receptor (TCRb-/-d-/-) – which are functionally deficient in T cells – showed reduced anxiety-like behaviour on approach/avoidance tests. Therefore, in order to contribute to the knowledge of how the adaptive immune system participates in neurodevelopment, this thesis examines adaptive immune influence on the brain and behaviour: the impact of T cell deletion on microglia, myeloid cells in the blood, and behaviour, and of microbiota manipulation on neuroanatomy. The first study examined microglia number and density in adult TCRb-/- d-/- mice and showed increased numbers of microglia in the basolateral amygdala, and evidence of regional reductions in microglial density in TCRb-/-d-/- mice. Mice completely lacking microbiomes (Germ free - GF), are generally recognized to be deficient in mature lymphocytes. To determine how the microbiome impacts brain development, structural brain imaging was used to identify volume changes in neuroanatomy both globally, and regionally in stress circuitry. GF mice had smaller total brain volumes, and larger cortex but smaller hippocampus volumes, relative to total brain volume. Two models of recolonization indicate roles for the microbiome in postnatal brain volume development and contributed to identifying regional volumes that remain susceptible to postnatal microbiota influence. To understand how T cell deletion impacts peripheral immunophenotype, the final study investigated circulating myeloid cell numbers before and after puberty, alongside approach-avoidance behaviour tasks. Results indicate that TCRb-/-d-/- mice have higher monocyte and lower neutrophil v numbers compared to controls, and lack typical maturation of population heterogeneity and monocyte subtype observed in controls. Overall, this thesis demonstrates that the adaptive immune system is essential for typical neurodevelopment and contributes to efforts to identify the potential neuroimmune basis of neurodevelopmental disorders.