Acute and Enduring Sex-Dependent Effects of Pubertal Antimicrobial and Lipopolysaccharide Treatments on Cellular Mechanisms and Behaviours Associated With Neurodegeneration

Abstract

Puberty is a critical period of development accompanied by the maturation of various fundamental systems such as the central nervous system (CNS), immune system, and hypothalamic-pituitary-adrenal axis. The maturation of these systems renders puberty particularly sensitive to stressors, potentially increasing susceptibility to neurodegenerative disorders later in life. The gut microbiome may be a possible mechanism through which pubertal stress exposure could increase vulnerability to neurodegeneration. The gut microbiota communicates with the brain via enteric and autonomic neuroimmune and neuroendocrine pathways referred to as the “gut-brain” axis. Alterations to gut microbiota result in ‘gut dysbiosis’ and may negatively affect this bidirectional communication between the gut and the CNS, potentially influencing the development of neurodegenerative disorders. As such, we hypothesized that altering microbial composition through pubertal lipopolysaccharide (LPS) and antimicrobial treatments could influence behaviours and cellular mechanisms associated with neurodegeneration. The current thesis examined the sex-specific effects of pubertal LPS and antimicrobial treatment on acute cellular mechanisms associated with neurodegeneration (Article 1). Next, we examined the enduring sex-specific effects of pubertal LPS and antimicrobial treatments on behaviours and cellular mechanisms associated with neurodegeneration (Article 2). Lastly, we examined the sex-specific effects of pubertal LPS and antimicrobial treatment on the blood-brain barrier and intestinal permeability, a potential mechanism underlying the effects of the gut on the CNS and the development of neurodegenerative disorders. We also further examined the effects of pubertal LPS and antimicrobial treatment on gross motor coordination, heart rate, and core body temperature through the use of the G2 HR E-Mitter telemetry system (Article 3). Taken together, the current dissertation addresses whether pubertal LPS and antimicrobial treatments can increase vulnerability to neurodegeneration later in life, in a sexually dimorphic manner.