Traumatic stress history interacts with sex and chronic peripheral inflammation to alter mitochondrial function of synaptosomes.

BACKGROUND: Repeated exposures to chronic stress can lead to long lasting negative behavioral and metabolic outcomes. Here, we aim to determine the impact of chronic stress and chronic low-level inflammation on behavior and synaptosomal metabolism. METHODS: Male (n = 31) and female (n = 32) C57Bl/6 mice underwent chronic repeated predation stress or daily handling for two rounds of 15 consecutive days of exposure during the adolescent and early adult timeframes. Subsequently, mice were exposed to repeated lipopolysaccharide (LPS; 7.5 × 105 EU/kg) or saline injections every third day for eight weeks. Exploratory and social behaviors were assessed in the open field and social interaction tests prior to examination of learning and memory with the Barnes Maze. Mitochondrial function and morphology were assessed in synaptosomes post-mortem using the Cell Mito Stress test and Seahorse XFe24 analyzer, TEM, and western analysis, respectively. In addition, expression of TNF-α, IL-1ß, and ROMO1 were examined in the hippocampus and prefrontal cortex with Taqman qPCR. Circulating pro- and anti-inflammatory cytokines in the periphery were assessed using the MSD V-plex Proinflammatory Panel 1 following the first and last LPS injection as well as at the time of tissue collection. Circulating ROMO1 was assessed in terminal samples via ELISA. RESULTS: Exposure to repeated predatory stress increased time spent in the corners of the open field, suggestive of anxiety-like behavior, in both males and females. There were no significant group differences in the social interaction test and minimal effects were evident in the Barnes maze. A history of chronic stress interacted with chronic LPS in male mice to lead to a deficit in synaptosomal respiration. Female mice were more sensitive to both chronic stress and chronic LPS such that either a history of chronic stress or chronic LPS exposure was sufficient to disrupt synaptosomal respiration in females. Both stress and chronic LPS were sufficient to increase inflammation and reactive oxygen in males centrally and peripherally. Females had increased markers of peripheral inflammation following acute LPS but no evidence of peripheral or central increases in inflammatory factors or reactive oxygen following chronic exposures. CONCLUSION: Collectively, these data suggest that while metrics of inflammation and reactive oxygen are disrupted in males following chronic stress and chronic LPS, only the combined condition is sufficient to alter synaptosomal respiration. Conversely, although evidence of chronic inflammation or chronic elevation in reactive oxygen is absent, females demonstrate profound shifts in synaptosomal mitochondrial function with either a history of chronic stress or a history of chronic inflammation. These data highlight that different mechanisms are likely in play between the sexes and that sex differences in neural outcomes may be precipitated by sex-specific effects of life experiences on mitochondrial function in the synapse.

The economic cost of inadequate sleep.

Study Objectives: To estimate the economic cost (financial and nonfinancial) of inadequate sleep in Australia for the 2016-2017 financial year and relate this to likely costs in similar economies. Methods: Analysis was undertaken using prevalence, financial, and nonfinancial cost data derived from national surveys and databases. Costs considered included the following: (1) financial costs associated with health care, informal care provided outside healthcare sector, productivity losses, nonmedical work and vehicle accident costs, deadweight loss through inefficiencies relating to lost taxation revenue and welfare payments; and (2) nonfinancial costs of loss of well-being. They were expressed in US dollars ($). Results: The estimated overall cost of inadequate sleep in Australia in 2016-2017 (population: 24.8 million) was $45.21 billion. The financial cost component was $17.88 billion, comprised of as follows: direct health costs of $160 million for sleep disorders and $1.08 billion for associated conditions; productivity losses of $12.19 billion ($5.22 billion reduced employment, $0.61 billion premature death, $1.73 billion absenteeism, and $4.63 billion presenteeism); nonmedical accident costs of $2.48 billion; informal care costs of $0.41 billion; and deadweight loss of $1.56 billion. The nonfinancial cost of reduced well-being was $27.33 billion. Conclusions: The financial and nonfinancial costs associated with inadequate sleep are substantial. The estimated total financial cost of $17.88 billion represents 1.55 per cent of Australian gross domestic product. The estimated nonfinancial cost of $27.33 billion represents 4.6 per cent of the total Australian burden of disease for the year. These costs warrant substantial investment in preventive health measures to address the issue through education and regulation.