title: Serotonin deficiency alters susceptibility to the long-term consequences of adverse early life experience.
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.
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, United States.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Sachs
authors.affiliation: 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.
authors.forename: Ramona M
authors.initials: RM
authors.lastname: Rodriguiz
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, United States.
authors.forename: Ha L
authors.initials: HL
authors.lastname: Tran
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, United States.
authors.forename: Akshita
authors.initials: A
authors.lastname: Iyer
authors.affiliation: Department 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.
authors.forename: William C
authors.initials: WC
authors.lastname: Wetsel
authors.affiliation: Department 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: marc.caron@dm.duke.edu.
authors.forename: Marc G
authors.initials: MG
authors.lastname: Caron
mesh_terms: D000679:Amygdala / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal; D019052:Depression, Postpartum / Q000378:metabolism* / Q000523:psychology; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D005260:Female; D055879:Gene Knock-In Techniques; D006380:Helplessness, Learned; D006624:Hippocampus / Q000378:metabolism; D008426:Maternal Deprivation; D051379:Mice; D009154:Mutation; D055495:Neurogenesis / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000378:metabolism; D012021:Reflex, Abnormal; D013216:Reflex, Startle; D012701:Serotonin / Q000172:deficiency*; D013315:Stress, Psychological / Q000378:metabolism* / Q000523:psychology; D014365:Tryptophan Hydroxylase / Q000235:genetics
chemical_list: D012333:RNA, Messenger; D044402:Receptor, Serotonin, 5-HT2A; D018161:Receptors, Mineralocorticoid; D012701:Serotonin; C487802:Tph2 protein, mouse; D014365:Tryptophan Hydroxylase
keywords: Anxiety; Early life stress; Neurogenesis; Serotonin