136 - Effects of Timing of Early Life Stress on Depressive-like Phenotypes and Metabolic Dysfunction

Poster Board Number: 136
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Abstract Body : Introduction: Early life stress (ELS) is associated with the development of depression and metabolic dysfunction later in life. While several studies have established this link, the outcomes are variable, caused in part by differences in the severity and duration of ELS. The long-term effects of severe stress have been extensively studied, yet we have limited information on the effects of moderate stress. Timing of ELS may also contribute to this variation, as many developmental processes demonstrate critical periods during which time they are more susceptible to disruptions. Early prenatal and late juvenile timepoints represent two such critical windows, and we will investigate the effects of ELS during these periods using early, acute prenatal alcohol exposure (PAE) and sub-chronic unpredictable mild stress (SUMS), respectively. Both PAE and juvenile SUMS are common ELS that have been associated with later life depression and dysmetabolism. PAE can disrupt neurogenesis and induce intrauterine growth restriction, while juvenile SUMS can impair neuron organization and various metabolic pathways, increasing offspring risk of developing depression and dysmetabolism. While the effects of ELS at these two timepoints individually have been studied extensively, few studies have compared outcomes directly particularly using moderate ELS. Here, we address this gap in knowledge using a preclinical mouse model to compare depressive and metabolic outcomes among five experimental groups: vehicle control, 2-week mild SUMS, 2-week moderate SUMS, 4-week moderate SUMS, and PAE.
Materials and Methods: 8-week-old nulliparous pregnant C57BL/6 dams were administered 2 ml/100 g of water or 31.5% v/v ethanol via oral gavage on GD7.5, and their offspring formed our groups such that the PAE group received ethanol, and all other groups received water. At juvenile age (P21-27), offspring underwent depression testing using three behavioural assays that measure different depressive outcomes (U-shaped 2-choice Field (U-field), Tail Suspension Test, Forced Swim Test). Following juvenile testing, stress group mice were subjected to one of three juvenile SUMS regimens, varying in intensity and duration. Offspring will undergo depression testing again at adolescent (P56-62) and adult (P119-125) ages. Following adult depression testing, metabolic function will be tested using multiple metabolic measures (glucose tolerance test, blood insulin and lipids). Mean outcomes among groups were compared using a two-way ANOVA with treatment and sex as main effects. To determine differential depressive and metabolic outcomes among individuals, two-dimensional matrices were constructed.
Preliminary Results: As predicted, there were no differences in sociability as measured by the U-field between treatment groups at the juvenile timepoint. Interestingly, at the adolescent timepoint, only the 2-week moderate SUMS group exhibited significantly less sociability, an index of depression. No sex differences in sociability have been found at the juvenile or adolescent timepoints.
Significance and Implications: This study will help determine the effects of timing of ELS on specific depressive and metabolic outcomes to help identify individuals at risk and provide them with supports to mitigate the effects of these disorders.
Funding Sources: Children’s Health Foundation Award R5211A06 (KW).