Skip to main content
×
Home
    • Aa
    • Aa

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

  • Benjamin D. Sachs (a1), Ramona M. Rodriguiz (a2), William B. Siesser (a1), Alexander Kenan (a1), Elizabeth L. Royer (a1), Jacob P. R. Jacobsen (a1), William C. Wetsel (a2) (a3) and Marc G. Caron (a1) (a2) (a3)...
Abstract
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.

Copyright
Corresponding author
Address for correspondence: Dr M. G. Caron, Duke University Medical Center, 487 CARL Building, Box 3287, Durham, NC 27710, USA. Tel: 919 684 5433Fax: 919 681 8641Email: m.caron@cellbio.duke.edu
Linked references
Hide All

This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

M Angoa-Perez , MJ Kane , DI Briggs , CE Sykes , MR Shah , DM Francescutti , DR Rosenberg , DM Thomas , DM Kuhn (2012) Genetic depletion of brain 5HT reveals a common molecular pathway mediating compulsivity and impulsivity. J Neurochem 121:974984.

MS Ansorge , M Zhou , A Lira , R Hen , JA Gingrich (2004) Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice. Science 306:879881.

JM Beaulieu , X Zhang , RM Rodriguiz , TD Sotnikova , MJ Cools , WC Wetsel , RR Gainetdinov , MG Caron (2008) Role of GSK3 beta in behavioral abnormalities induced by serotonin deficiency. Proc Natl Acad Sci USA 105:13331338.

L Bevilacqua , S Doly , J Kaprio , Q Yuan , R Tikkanen , T Paunio , Z Zhou , J Wedenoja , L Maroteaux , S Diaz , A Belmer , CA Hodgkinson , L Dell'osso , J Suvisaari , E Coccaro , RJ Rose , L Peltonen , M Virkkunen , D Goldman (2010) A population-specific HTR2B stop codon predisposes to severe impulsivity. Nature 468:10611066.

DA Brent , BA Johnson , J Perper , J Connolly , J Bridge , S Bartle , C Rather (1994) Personality disorder, personality traits, impulsive violence, and completed suicide in adolescents. J Am Acad Child Adolesc Psychiatry 33:10801086.

D Brunner , R Hen (1997) Insights into the neurobiology of impulsive behavior from serotonin receptor knockout mice. Ann N Y Acad Sci 836:81105.

RN Cardinal , DR Pennicott , CL Sugathapala , TW Robbins , BJ Everitt (2001) Impulsive choice induced in rats by lesions of the nucleus accumbens core. Science 292:24992501.

V Carola , G Frazzetto , T Pascucci , E Audero , S Puglisi-Allegra , S Cabib , KP Lesch , C Gross (2008) Identifying molecular substrates in a mouse model of the serotonin transporter × environment risk factor for anxiety and depression. Biol Psychiatry 63:840846.

A Caspi , K Sugden , TE Moffitt , A Taylor , IW Craig , H Harrington , J McClay , J Mill , J Martin , A Braithwaite , R Poulton (2003) Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301:386389.

CA Denny , NS Burghardt , DM Schachter , R Hen , MR Drew (2011) 4- to 6-week-old adult-born hippocampal neurons influence novelty-evoked exploration and contextual fear conditioning. Hippocampus 22:11881201.

RS Duman , GK Aghajanian (2012) Synaptic dysfunction in depression: potential therapeutic targets. Science 338:6872.

K Dzirasa , S Kumar , BD Sachs , MG Caron , M Nicolelis (2013) Cortical-amygdalar circuit dysfunction in a genetic mouse model of serotonin deficiency. J Neurosci 33:45054513.

AJ Eisch , D Petrik (2012) Depression and hippocampal neurogenesis: a road to remission? Science 338:7275.

DM Fergusson , LJ Woodward , LJ Horwood (2000) Risk factors and life processes associated with the onset of suicidal behaviour during adolescence and early adulthood. Psychol Med 30:2339.

SP Fernandez , P Gaspar (2011) Investigating anxiety and depressive-like phenotypes in genetic mouse models of serotonin depletion. Neuropharmacology 62:144154.

M Fukui , RM Rodriguiz , J Zhou , SX Jiang , LE Phillips , MG Caron , WC Wetsel (2007) Vmat2 heterozygous mutant mice display a depressive-like phenotype. J Neurosci 27:1052010529.

SL Hays , RJ McPherson , SE Juul , G Wallace , AG Schindler , C Chavkin , CA Gleason (2012) Long-term effects of neonatal stress on adult conditioned place preference (CPP) and hippocampal neurogenesis. Behav Brain Res 227:711.

C Heim , CB Nemeroff (2001) The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies. Biol Psychiatry 49:10231039.

RL Huot , KV Thrivikraman , MJ Meaney , PM Plotsky (2001) Development of adult ethanol preference and anxiety as a consequence of neonatal maternal separation in Long Evans rats and reversal with antidepressant treatment. Psychopharmacology 158:366373.

SA Irwin , A Iglewicz (2010) Oral ketamine for the rapid treatment of depression and anxiety in patients receiving hospice care. J Palliat Med 13:903908.

S Ishikawa , Y Saito , Y Yanagawa , S Otani , S Hiraide , K Shimamura , M Matsumoto , H Togashi (2012) Early postnatal stress alters extracellular signal-regulated kinase signaling in the corticolimbic system modulating emotional circuitry in adult rats. Eur J Neurosci 35:135145.

JP Jacobsen , WB Siesser , BD Sachs , S Peterson , MJ Cools , V Setola , JH Folgering , G Flik , MG Caron (2012) Deficient serotonin neurotransmission and depression-like serotonin biomarker alterations in tryptophan hydroxylase 2 (Tph2) loss-of-function mice. Mol Psychiatry 17:694704.

T Kikusui , S Ichikawa , Y Mori (2009) Maternal deprivation by early weaning increases corticosterone and decreases hippocampal BDNF and neurogenesis in mice. Psychoneuroendocrinology 34:762772.

YK Kim , HJ Lee , JC Yang , JA Hwang , HK Yoon (2009) A tryptophan hydroxylase 2 gene polymorphism is associated with panic disorder. Behav Genet 39:170175.

C Kinoshita , K Miyazaki , N Ishida (2012) Chronic stress affects PERIOD2 expression through glycogen synthase kinase-3beta phosphorylation in the central clock. Neuroreport 23:98102.

T Kitamura , Y Saitoh , N Takashima , A Murayama , Y Niibori , H Ageta , M Sekiguchi , H Sugiyama , K Inokuchi (2009) Adult neurogenesis modulates the hippocampus-dependent period of associative fear memory. Cell 139:814827.

MJ Kruesi , JL Rapoport , S Hamburger , E Hibbs , WZ Potter , M Lenane , GL Brown (1990) Cerebrospinal fluid monoamine metabolites, aggression, and impulsivity in disruptive behavior disorders of children and adolescents. Arch Gen Psychiatry 47:419426.

N Lajud , A Roque , M Cajero , G Gutierrez-Ospina , L Torner (2012) Periodic maternal separation decreases hippocampal neurogenesis without affecting basal corticosterone during the stress hyporesponsive period, but alters HPA axis and coping behavior in adulthood. Psychoneuroendocrinology 37:410420.

KP Lesch , D Bengel , A Heils , SZ Sabol , BD Greenberg , S Petri , J Benjamin , CR Muller , DH Hamer , DL Murphy (1996) Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274:15271531.

AT Leslie , KG Akers , AD Krakowski , SS Stone , M Sakaguchi , M Arruda-Carvalho , PW Frankland (2011) Impact of early adverse experience on complexity of adult-generated neurons. Transl Psychiatry 1:e35.

Y Matsuoka , T Furuyashiki , K Yamada , T Nagai , H Bito , Y Tanaka , S Kitaoka , F Ushikubi , T Nabeshima , S Narumiya (2005) Prostaglandin E receptor EP1 controls impulsive behavior under stress. Proc Natl Acad Sci USA 102:1606616071.

LD Matzel , J Babiarz , DA Townsend , HC Grossman , M Grumet (2008) Neuronal cell adhesion molecule deletion induces a cognitive and behavioral phenotype reflective of impulsivity. Genes Brain Behav 7:470480.

RA Millstein , A Holmes (2007) Effects of repeated maternal separation on anxiety- and depression-related phenotypes in different mouse strains. Neurosci Biobehav Rev 31:317.

MA Mines , CJ Yuskaitis , MK King , E Beurel , RS Jope (2010) GSK3 influences social preference and anxiety-related behaviors during social interaction in a mouse model of fragile X syndrome and autism. PLoS ONE 5:e9706.

C Mirescu , JD Peters , E Gould (2004) Early life experience alters response of adult neurogenesis to stress. Nat Neurosci 7:841846.

V Mosienko , B Bert , D Beis , S Matthes , H Fink , M Bader , N Alenina (2012) Exaggerated aggression and decreased anxiety in mice deficient in brain serotonin. Transl Psychiatry 2:e122.

C Murgatroyd , AV Patchev , Y Wu , V Micale , Y Bockmuhl , D Fischer , F Holsboer , CT Wotjak , OF Almeida , D Spengler (2009) Dynamic DNA methylation programs persistent adverse effects of early-life stress. Nat Neurosci 12:15591566.

DB Parfitt , JR Walton , EA Corriveau , DL Helmreich (2007) Early life stress effects on adult stress-induced corticosterone secretion and anxiety-like behavior in the C57BL/6 mouse are not as robust as initially thought. Horm Behav 52:417426.

MM Perez-Rodriguez , S Weinstein , AS New , L Bevilacqua , Q Yuan , Z Zhou , C Hodgkinson , M Goodman , HW Koenigsberg , D Goldman , LJ Siever (2010) Tryptophan-hydroxylase 2 haplotype association with borderline personality disorder and aggression in a sample of patients with personality disorders and healthy controls. J Psychiatr Res 44:10751081.

VF Prado (2006) Mice deficient for the vesicular acetylcholine transporter are myasthenic and have deficits in object and social recognition. Neuron 51:601612.

JM Revest , D Dupret , M Koehl , C Funk-Reiter , N Grosjean , PV Piazza , DN Abrous (2009) Adult hippocampal neurogenesis is involved in anxiety-related behaviors. Mol Psychiatry 14:959967.

J Rioja , LJ Santin , M Garcia , A Dona , L De Pablos , MI Cuadrado , FJ Alcalde , S Gonzalez-Baron , JA Aguirre (2004) 5-HT1A receptor activation before acute stress counteracted the induced long-term behavioral effects. Ann N Y Acad Sci 1018:333338.

M Roceri , W Hendriks , G Racagni , BA Ellenbroek , MA Riva (2002) Early maternal deprivation reduces the expression of BDNF and NMDA receptor subunits in rat hippocampus. Mol Psychiatry 7:609616.

RD Romeo , A Mueller , HM Sisti , S Ogawa , BS McEwen , WG Brake (2003) Anxiety and fear behaviors in adult male and female C57BL/6 mice are modulated by maternal separation. Horm Behav 43:561567.

A Sah , C Schmuckermair , SB Sartori , S Gaburro , M Kandasamy , R Irschick , L Klimaschewski , R Landgraf , L Aigner , N Singewald (2012) Anxiety- rather than depression-like behavior is associated with adult neurogenesis in a female mouse model of higher trait anxiety- and comorbid depression-like behavior. Transl Psychiatry 2:e171.

L Santarelli , M Saxe , C Gross , A Surget , F Battaglia , S Dulawa , N Weisstaub , J Lee , R Duman , O Arancio , C Belzung , R Hen (2003) Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301:805809.

HM Savignac , TG Dinan , JF Cryan (2011) Resistance to early-life stress in mice: effects of genetic background and stress duration. Front Behav Neurosci 5:13.

P Schipper , LJ Nonkes , P Karel , AJ Kiliaan , JR Homberg (2011) Serotonin transporter genotype × construction stress interaction in rats. Behav Brain Res 223:169175.

R Schmalzigaug , RM Rodriguiz , PE Bonner , CE Davidson , WC Wetsel , RT Premont (2009) Impaired fear response in mice lacking GIT1. Neurosci Let 458:7983.

DM Shaw , FE Camps , EG Eccleston (1967) 5-Hydroxytryptamine in the hind-brain of depressive suicides. Br J Psychiatry 113:14071411.

JK Shepherd , SS Grewal , A Fletcher , DJ Bill , CT Dourish (1994) Behavioural and pharmacological characterisation of the elevated ‘zero-maze’ as an animal model of anxiety. Psychopharmacology 116:5664.

D Treit , M Fundytus (1988) Thigmotaxis as a test for anxiolytic activity in rats. Pharmacol Biochem Behav 31:959962.

DL van den Hove , SB Jakob , KG Schraut , G Kenis , AG Schmitt , S Kneitz , CJ Scholz , V Wiescholleck , G Ortega , J Prickaerts , H Steinbusch , KP Lesch (2011) Differential effects of prenatal stress in 5-Htt deficient mice: towards molecular mechanisms of gene × environment interactions. PLoS ONE 6:e22715.

CA Winstanley , DE Theobald , RN Cardinal , TW Robbins (2004) Contrasting roles of basolateral amygdala and orbitofrontal cortex in impulsive choice. J Neurosci 24:47184722.

CA Zarate Jr., JB Singh , PJ Carlson , NE Brutsche , R Ameli , DA Luckenbaugh , DS Charney , HK Manji (2006) A randomized trial of an N-methyl-d-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 63:856864.

X Zhang , RR Gainetdinov , JM Beaulieu , TD Sotnikova , LH Burch , RB Williams , DA Schwartz , KR Krishnan , MG Caron (2005) Loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression. Neuron 45:1116.

Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

The International Journal of Neuropsychopharmacology
  • ISSN: 1461-1457
  • EISSN: 1469-5111
  • URL: /core/journals/the-international-journal-of-neuropsychopharmacology
Please enter your name
Please enter a valid email address
Who would you like to send this to? *
×

Keywords:

Type Description Title
UNKNOWN
Supplementary Materials

Sachs Supplementary Material
Figure S1

 Unknown (2.1 MB)
2.1 MB
UNKNOWN
Supplementary Materials

Sachs Supplementary Material
Figure S2

 Unknown (42 KB)
42 KB
WORD
Supplementary Materials

Sachs Supplementary Material
Figure S1-S2 and Table S1

 Word (1.9 MB)
1.9 MB