title: The effects of brain serotonin deficiency on behavioural disinhibition and anxiety-like behaviour following mild early life stress.
abstract: Aberrant serotonin (5-HT) signalling and exposure to early life stress have both been suggested to play a role in anxiety- and impulsivity-related behaviours. However, whether congenital 5-HT deficiency × early life stress interactions influence the development of anxiety- or impulsivity-like behaviour has not been established. Here, we examined the effects of early life maternal separation (MS) stress on anxiety-like behaviour and behavioural disinhibition, a type of impulsivity-like behaviour, in wild-type (WT) and tryptophan hydroxylase 2 (Tph2) knock-in (Tph2KI) mice, which exhibit ~60-80% reductions in the levels of brain 5-HT due to a R439H mutation in Tph2. We also investigated the effects of 5-HT deficiency and early life stress on adult hippocampal neurogenesis, plasma corticosterone levels and several signal transduction pathways in the amygdala. We demonstrate that MS slightly increases anxiety-like behaviour in WT mice and induces behavioural disinhibition in Tph2KI animals. We also demonstrate that MS leads to a slight decrease in cell proliferation within the hippocampus and potentiates corticosterone responses to acute stress, but these effects are not affected by brain 5-HT deficiency. However, we show that 5-HT deficiency leads to significant alterations in SGK-1 and GSK3β signalling and NMDA receptor expression in the amygdala in response to MS. Together, these findings support a potential role for 5-HT-dependent signalling in the amygdala in regulating the long-term effects of early life stress on anxiety-like behaviour and behavioural disinhibition.
authors.affiliation: Department of Cell Biology, Duke University, Durham, NC 27710, USA.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Sachs
authors.forename: Ramona M
authors.initials: RM
authors.lastname: Rodriguiz
authors.forename: William B
authors.initials: WB
authors.lastname: Siesser
authors.forename: Alexander
authors.initials: A
authors.lastname: Kenan
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Royer
authors.forename: Jacob P R
authors.initials: JP
authors.lastname: Jacobsen
authors.forename: William C
authors.initials: WC
authors.lastname: Wetsel
authors.forename: Marc G
authors.initials: MG
authors.lastname: Caron
mesh_terms: D000679:Amygdala / Q000378:metabolism; D000818:Animals; D001007:Anxiety / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000523:psychology; D001010:Anxiety, Separation / Q000150:complications / Q000523:psychology; D001522:Behavior, Animal; D001921:Brain / Q000254:growth & development / Q000378:metabolism* / Q000503:physiopathology; D003345:Corticosterone / Q000097:blood; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000254:growth & development / Q000378:metabolism; D017874:Immediate-Early Proteins / Q000378:metabolism; D007175:Impulsive Behavior / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000523:psychology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity; D055495:Neurogenesis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012701:Serotonin / Q000172:deficiency*; D015398:Signal Transduction; D013315:Stress, Psychological / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000523:psychology; D014365:Tryptophan Hydroxylase / Q000235:genetics / Q000378:metabolism; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D003345:Corticosterone; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D017874:Immediate-Early Proteins; D017346:Protein Serine-Threonine Kinases; D016194:Receptors, N-Methyl-D-Aspartate; D012701:Serotonin; D014365:Tryptophan Hydroxylase; D000099184:Serum-Glucocorticoid Regulated Kinases; C000605507:Gsk3b protein, mouse