Get Off to Sleep: Pubertal Depression Prevention by Metabolic Intervention

Abstract

Puberty and adolescence are periods of brain-driven physiological development that display increased incidences of depression development. Adolescents display significant alterations to their stress response signaling, sleep patterns, and metabolism when compared to pre-pubescents. Increased exposure to stress, sleep disturbances, and impaired energy acquisition is typical during puberty and adolescence and similarly increases the likelihood of developing depression. A promising avenue of limiting the deleterious effects of stress and sleep disruption on pubertal and adolescent depressive behaviour is the use of treatments that blunt underlying metabolic impairments associated with depression. Treatments that directly or indirectly increase availability of the glucose metabolite L-lactate are associated with depression reduction. The investigations included in this dissertation evaluate the usability of L-lactate treatments in reducing depression development in pubertal CD-1 male and female mice. This work first examines a previously proposed oral lactate solution, its effect on energy substrate concentration and drowsiness, and its efficacy as a safe oral L-lactate treatment (Chapter 2). Subsequent research aimed to identify a pubertal model of depression that would allow future testing of L-lactate antidepressant treatment. Pubertal male and female mice exposed to chronic sleep disruption were evaluated for stress reactivity and depressive behavior and were identified as a model for antidepressant testing (Chapter 3). In the final study, we evaluated the effects of chronic sleep disruption on the expression of energy metabolites like L-lactate and glucose within the brain, its effect on neurotransmitters associated with depression, and changes to sleep architecture in relation to depression behaviour. Sleep disrupted and depressed animal models were administered L-lactate producing probiotics and were evaluated for improvements to energy substrate concentration, neurotransmitter expression, sleep recovery, and depression reduction (Chapter 4). The present thesis provides groundwork for the use of L-lactate therapies in depressed pubertal and adolescent groups and provides initial evaluations of probiotic intervention as a prevention strategy for juvenile depression.