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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    700—Adult Neurogenesis: Environmental and Pharmacological Regulation

    Wednesday, November 13, 2013, 8:00 am - 12:00 noon

    700.19: Altered adult neurogenesis, mRNA expression, and depressive-like behaviors induced by perinatal arsenic exposure are rescued by chronic fluoxetine treatment

    Location: Halls B-H

    *C. R. TYLER, A. M. ALLAN;
    Neurosciences, Univ. of New Mexico, Albuquerque, NM

    Abstract Body: Arsenic is a common and pervasive environmental contaminant found in drinking water. Epidemiological studies have shown a strong correlation between arsenic exposure and cognitive deficits and mood disorders, including depression. While the Environmental Protection Agency (EPA) standard for the allotment of arsenic in drinking water is in the parts-per-billion range, our lab has shown that a low concentration of 50 ppb arsenic exposure during development in mice has far-reaching consequences into adulthood, including deficits in learning and memory and increased depressive-like behaviors, both of which have been linked to reduced adult neurogenesis. Given that the morphological impact of developmental arsenic exposure on the hippocampus is not known, we investigated the affects of 50 ppb arsenic exposure throughout the perinatal period in adult mice using a BrdU pulse-chase assay. Adult hippocampal neurogenesis, as measured by BrdU colocalization with DCX and NeuN, was significantly reduced by 41% in animals exposed to arsenic compared to controls, (p<.05). Brief interval exposure to enrichment or chronic treatment with 20 mg/kg/day fluoxetine (Prozac) restored neurogenesis, (p<.05). Behavior alterations correlated with morphological hippocampal changes: adult males treated with chronic fluoxetine improved in the learned helplessness and the forced swim tasks, both of which are common tests used to assess depressive-like behavior in mice. Additionally, expression levels of 31% of neurogenesis-related genes including those involved in Alzheimer’s disease, apoptosis, axonogenesis, growth, Notch signaling, and transcription factors were altered after arsenic exposure and restored after exposure to enrichment, as measured using a qRT-PCR microarray. Thus, using a concentration previously considered safe by the EPA, we show that perinatal arsenic exposure alters hippocampal morphology and gene expression and induces depressive-like behaviors, but does not inhibit the cellular neurogenic response to treatment either by exposure to enrichment or chronic administration of fluoxetine. It is likely that behavioral deficits in learning and memory tasks and depressive-like symptoms observed during adulthood in animals developmentally exposed to arsenic derive from aberrant neurogenesis gene expression and morphology.

    Lay Language Summary: Epidemiological human studies have shown a correlation between arsenic levels in the body and mood disorders; higher levels of arsenic correspond to increased depression, anxiety, and cognitive decline in adulthood. Arsenic is found ubiquitously in our environment: it’s contained in pesticides, used as an antifungal agent in grain to feed cattle, and a byproduct of coal fired power plants. Arsenic is not only found in our air and food, but also in our water. While the government controls how much is allowed in water, many Americans living in rural communities use well water with arsenic levels exceeding the EPA standard. High concentrations of arsenic are known to cause cancer, yet it’s unclear what lower concentrations, like those found in our environment, can do to the brain.
    Our research suggests that arsenic in a mother’s drinking water affects the developing fetus and leads to cognitive damage lasting into adulthood. Our study is the first to demonstrate that pregnant mothers exposed to low concentrations of arsenic have offspring with impaired neurogenesis (growth of new neurons in the brain), associated gene activity, and altered mood, which can be restored with Prozac treatment.
    Depression is the most common mood disorder and affects several million people worldwide, including an estimated 1 in 10 Americans. Despite the plethora of drugs on the market for mood disorders, only 1 in 3 depressed patients report feeling better. Thus, understanding the mechanisms of depression, such as how it develops, what makes one person more susceptible than another, and the effects of genetics and the environment, is of great importance to the neuroscientific community.
    We report that arsenic induces changes in adult neurogenesis in the brain, which is an important component of learning and memory and can be decreased in individuals with mood disorders. To determine whether or not arsenic-induced cognitive damage is treatable, we gave four weeks of Prozac treatment to mice that were exposed to arsenic during their fetal development. We used the learned helplessness task, which measures how long it takes a mouse to escape a shock to test depressive symptoms. The arsenic-exposed animals showed greater learned helplessness_they took longer to escape the shock_indicative of depressive behavior. After treatment with Prozac, the arsenic-exposed animals behaved more like the control animals, indicating that Prozac restored normal behavior.
    We also found that Prozac fixed some, but not all, of the genes that were altered after arsenic exposure. Gene expression is important for brain function because certain genes have to be turned on and off for proper learning, memory, and other mental processes. In the case of arsenic-exposed animals, the genes responsible for neurogenesis were altered, which could be responsible for the deficits we observed in adult neurogenesis and the induced depression. Additionally, deficits in adult neurogenesis were also normalized by treatment with Prozac, which has been shown before.
    The next step is to determine how arsenic impacts gene expression so that we can develop better drugs to combat depression. Epigenetics, or the study of gene regulation by environmental factors (as opposed to genetics, which is purely hereditary and not influenced by environmental factors), has been shown to be important for many diseases, including depression. Thus, our next goal will be to determine how arsenic impacts the epigenetic mechanisms in the brain that control depressive behaviors. We hope that not only will our research provide more information about depression, leading to better treatments in the future, but that it will reveal more generally how environmental exposures during fetal development can lead to long-lasting changes in adulthood.