The interaction of perinatal organophosphate flame retardant exposure and adult chronic stress on cognitive processing

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Project Summary Abstract Mental disorders, including major depressive disorder, schizophrenia, and others, all share a central feature – cognitive impairment which results in individuals confronted with difficulty in memory, concentration, and decision-making. Emerging evidence points to two key factors contributing to cognitive decline beyond the underlying disease pathology - exposure to 1) environmental chemicals such as endocrine disrupting compounds (EDCs) during development and 2) chronic stress in adulthood. The interaction of chemical exposure and stress are unknown; but together may exacerbate cognitive impairment. First, EDCs exert their toxicity by disrupting nuclear receptor signaling during sensitive brain developmental periods. Numerous EDC studies have detected cognitive impairments in humans and animals. One group of understudied EDCs are organophosphate flame retardants (OPFRs) acting on nuclear and steroid receptors linked with cognition. The association between perinatal OPFR exposure and cognitive processing has not been explored. We previously identified an association between perinatal OPFR exposure on neonatal and juvenile hypothalamic gene expression and adult locomotor activity and approach/avoidance behaviors. Second, mental disorders share a common feature: exposure to stress, which contributes to cognitive dysfunction by exacerbating symptoms. A common paradigm to recapitulate chronic stressors in rodents is to apply mild stress for 6 weeks, known as chronic variable mild stress (CVMS). Using CVMS, the neural circuits underlying maladaptive effects of stress include corticotropin releasing factor (CRF) neurons. CRF is co-released with norepinephrine (NE), acetylcholine (ACh), and dopamine (DA), which control key brain regions (hippocampus, prefrontal cortex), and all are involved in cognition and mood. Based on our prior work and the literature, I hypothesize that perinatal OPFR exposure can disrupt cognition, alone or when combined with adult chronic stress exposure. My central hypothesis is that EDCs such as OPFRs influence the developing cognitive and stress neurocircuitry potentially inducing long-lasting functional deficits in cognitive processing and sensitize adults to exposure to chronic stress in mice. In Aim 1 (K99 phase), I will first determine if perinatal OPFR exposure disrupts adult cognition on the behavioral level and through alterations in ACh synaptic transmission using electrophysiology. In Aim 2 (K99), I will examine the effects of OPFR exposure on regional concentrations of NE and DA and CRF and associated gene expression in adults, and the role of hippocampal CRF neurons using optogenetics. Lastly, in Aim 3 (R00), I will combine my prior expertise in spine density analysis and immunohistochemistry, and new training in electrophysiology, high-performance liquid chromatography, and optogenetics to determine if the combination of perinatal OPFR exposure and adult CVMS alters cognition. The ultimate goal of my research program will be to determine the interactions of perinatal EDC exposure and adult chronic stressors on cognitive processing by influencing CRF and neurotransmitter signaling throughout the brain.