The International Journal of Neuropsychopharmacology

Research Article

The effects of brain serotonin deficiency on behavioural disinhibition and anxiety-like behaviour following mild early life stress

Benjamin D. Sachsa1, Ramona M. Rodriguiza2, William B. Siessera1, Alexander Kenana1, Elizabeth L. Royera1, Jacob P. R. Jacobsena1, William C. Wetsela2a3 and Marc G. Carona1a2a3 c1

a1 Department of Cell Biology, Duke University, Durham, NC, USA

a2 Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA

a3 Department of Neurobiology, Duke University Medical Center, Durham, NC, USA


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.

(Received November 25 2012)

(Reviewed December 27 2012)

(Revised February 26 2013)

(Accepted March 12 2013)

(Online publication May 14 2013)

Key words

  • Animal models;
  • anxiety;
  • behavioural science;
  • early life stress;
  • impulsivity;
  • serotonin;
  • tryptophan hydroxylase


c1 Address for correspondence: Dr M. G. Caron, Duke University Medical Center, 487 CARL Building, Box 3287, Durham, NC 27710, USA. Tel: 919 684 5433 Fax: 919 681 8641 Email: