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: Benjamin D Sachs, Ramona M Rodriguiz, Ha L Tran, Akshita Iyer, William C Wetsel, Marc G Caron
• Journal: Psychoneuroendocrinology (Psychoneuroendocrinology) Vol. 53 Pg. 69-81 (Mar 2015) ISSN: 1873-3360 [Electronic] England
• PMID: 25602134 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• RNA, Messenger
• Receptor, Serotonin, 5-HT2A
• Receptors, Mineralocorticoid
• Serotonin
• Tph2 protein, mouse
• Tryptophan Hydroxylase

Topics

• Amygdala (metabolism)
• Animals
• Animals, Newborn
• Behavior, Animal
• Depression, Postpartum (metabolism, psychology)
• Disease Models, Animal
• Disease Susceptibility
• Female
• Gene Knock-In Techniques
• Helplessness, Learned
• Hippocampus (metabolism)
• Maternal Deprivation
• Mice
• Mutation
• Neurogenesis (genetics)
• RNA, Messenger (metabolism)
• Receptor, Serotonin, 5-HT2A (genetics, metabolism)
• Receptors, Mineralocorticoid (genetics, metabolism)
• Reflex, Abnormal
• Reflex, Startle
• Serotonin (deficiency)
• Stress, Psychological (metabolism, psychology)
• Tryptophan Hydroxylase (genetics)