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Serotonin deficiency alters susceptibility to the long-term consequences of adverse early life experience.

Sachs BD1, Rodriguiz RM2, Tran HL1, Iyer A1, Wetsel WC3, Caron MG4.

Psychoneuroendocrinology. 2015 Mar;53:69-81.

1Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, United States.

2Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, United States; Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, NC 27710, United States.

3Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, United States; Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, United States; Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, NC 27710, United States; Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, United States.and

4Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, United States; Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, United States.

Electronic address: [email protected]

 

Abstract

Brain 5-HT deficiency has long been implicated in psychiatric disease, but the effects of 5-HT deficiency on stress susceptibility remain largely unknown. Early life stress (ELS) has been suggested to contribute to adult psychopathology, but efforts to study the long-term consequences of ELS have been limited by a lack of appropriate preclinical models. Here, we evaluated the effects of 5-HT deficiency on several long-term cellular, molecular, and behavioral responses of mice to a new model of ELS that combines early-life maternal separation (MS) of pups and postpartum learned helplessness (LH) training in dams. Our data demonstrate that this paradigm (LH/MS) induces depressive-like behavior and impairs pup retrieval in dams. In addition, we show that brain 5-HT deficiency exacerbates anxiety-like behavior induced by LH/MS and blunts the effects of LH/MS on acoustic startle responses in adult offspring. Although the mechanisms underlying these effects remain unclear, following LH/MS, 5-HT-deficient animals had significantly less mRNA expression of the mineralocorticoid receptor in the amygdala than wild-type animals. In addition, 5-HT-deficient mice exhibited reduced mRNA levels of the 5-HT2a receptor and p11 in the hippocampus regardless of stress. LH/MS decreased the number of doublecortin+ immature neurons in the hippocampus in both wild-type (WT) and 5-HT-deficient animals. Our data emphasize the importance of complex interactions between genetic factors and early life experience in mediating long-term changes in emotional behavior. These findings may have important implications for our understanding of the combinatorial roles of 5-HT deficiency, ELS, and postpartum depression in the development of neuropsychiatric disorders.

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