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Salehzadeh Moghadami, Melody

University of British Columbia

Immune activation during early development has long-term effects on health, increasing the risk for neuropsychiatric disorders (e.g., mood disorders, schizophrenia, autism) and immune disorders (e.g. autoimmune disease, asthma, allergies). However, the mechanisms underlying the programming effects of early-life immune activation on the brain and immune system are unknown. Glucocorticoids (GCs) are steroid hormones regulated by the hypothalamic-pituitary-adrenal (HPA) axis and modulate the stress and immune responses. GCs are produced by the adrenal glands and also by the brain and lymphoid organs (i.e., bone marrow, thymus, spleen). Tight regulation of GC levels is critical for proper development, and high GC levels can have lasting implications for health and disease. In this dissertation, I present a series of studies examining GC regulation in the brain and lymphoid organs of neonatal and adult mice in response to an acute lipopolysaccharide (LPS) challenge. LPS is a widely used endotoxin that stimulates the innate immune response and HPA axis. I report that 1) LPS increases GC levels acutely in the blood, brain, bone marrow, thymus, and spleen of post-natal day (PND) 5 and 90 mice, 2) GC levels show tissue and regional variations in response to LPS at PND5 but not at PND90, and 3) LPS administered in the neonatal period (PND4 and 6) affects GC levels in lymphoid organs, but not in blood, of adult animals. Further, I report that transcripts for key steroidogenic enzymes are present in discrete brain regions, and transcript levels change in response to LPS in the neonatal brain. Additionally, transcripts for key steroidogenic enzymes, GC receptors, and HPA axis components are present in lymphoid organs, and transcript levels change in response to LPS primarily in the spleen. These data suggest that in mice, GCs are locally regulated within the brain, bone marrow, thymus, and spleen, all of which are affected by LPS in an age- and tissue-specific manner. These data provide possible mechanisms for how early-life immune activation can produce brain- and lymphoid organ-specific programming effects.

Text

2024-08-22

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/89007

Zoology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/