Strain Differences in Stress Responsivity Are Associated with Divergent Amygdala Gene Expression and Glutamate-mediated Neuronal Excitability

Overview

Journal J Neurosci

Specialty Neurology

Date 2010 Apr 16

PMID 20392957

Citations 126

Authors

Khyobeni Mozhui

Rose-Marie Karlsson

Thomas L Kash

Jessica Ihne

Maxine Norcross

Sachin Patel

Mollee R Farrell

Elizabeth E Hill

Carolyn Graybeal

Kathryn P Martin

Marguerite Camp

Paul J Fitzgerald

Daniel C Ciobanu

Rolf Sprengel

Masayoshi Mishina

Cara L Wellman

Danny G Winder

Robert W Williams

Andrew Holmes

Affiliations

Soon will be listed here.

Abstract

Stress is a major risk factor for numerous neuropsychiatric diseases. However, susceptibility to stress and the qualitative nature of stress effects on behavior differ markedly among individuals. This is partly because of the moderating influence of genetic factors. Inbred mouse strains provide a relatively stable and restricted range of genetic and environmental variability that is valuable for disentangling gene-stress interactions. Here, we screened a panel of inbred strains for anxiety- and depression-related phenotypes at baseline (trait) and after exposure to repeated restraint. Two strains, DBA/2J and C57BL/6J, differed in trait and restraint-induced anxiety-related behavior (dark/light exploration, elevated plus maze). Gene expression analysis of amygdala, medial prefrontal cortex, and hippocampus revealed divergent expression in DBA/2J and C57BL/6J both at baseline and after repeated restraint. Restraint produced strain-dependent expression alterations in various genes including glutamate receptors (e.g., Grin1, Grik1). To elucidate neuronal correlates of these strain differences, we performed ex vivo analysis of glutamate excitatory neurotransmission in amygdala principal neurons. Repeated restraint augmented amygdala excitatory postsynaptic signaling and altered metaplasticity (temporal summation of NMDA receptor currents) in DBA/2J but not C57BL/6J. Furthermore, we found that the C57BL/6J-like changes in anxiety-related behavior after restraint were absent in null mutants lacking the modulatory NMDA receptor subunit Grin2a, but not the AMPA receptor subunit Gria1. Grin2a null mutants exhibited significant ( approximately 30%) loss of dendritic spines on amygdala principal neurons under nonrestraint conditions. Collectively, our data support a model in which genetic variation in glutamatergic neuroplasticity in corticolimbic circuitry underlies phenotypic variation in responsivity to stress.

Citing Articles

Transcriptome dynamics in mouse amygdala under acute and chronic stress revealed by thiol-labeled RNA sequencing.

Zhao D, Zhang L, Yang Y Neurobiol Stress. 2024; 33:100688.

PMID: 39583745 PMC: 11582550. DOI: 10.1016/j.ynstr.2024.100688.

Sex Differences in Mouse Models of Voluntary Alcohol Drinking and Abstinence-Induced Negative Emotion.

Salazar A, Centanni S Alcohol. 2024; 121:45-57.

PMID: 39053705 PMC: 11637945. DOI: 10.1016/j.alcohol.2024.07.004.

Neurobiological basis of stress resilience.

Nestler E, Russo S Neuron. 2024; 112(12):1911-1929.

PMID: 38795707 PMC: 11189737. DOI: 10.1016/j.neuron.2024.05.001.

A brain-enriched circular RNA controls excitatory neurotransmission and restricts sensitivity to aversive stimuli.

Giusti S, Pino N, Pannunzio C, Ogando M, Armando N, Garrett L Sci Adv. 2024; 10(21):eadj8769.

PMID: 38787942 PMC: 11122670. DOI: 10.1126/sciadv.adj8769.

Effects of CB1 receptor negative allosteric modulator Org27569 on oxycodone withdrawal symptoms in mice.

Scicluna R, Everett N, Badolato C, Wilson B, Bowen M Psychopharmacology (Berl). 2024; 241(8):1705-1717.

PMID: 38676755 PMC: 11269377. DOI: 10.1007/s00213-024-06591-z.

References

Cohen H, Geva A, Matar M, Zohar J, Kaplan Z . Post-traumatic stress behavioural responses in inbred mouse strains: can genetic predisposition explain phenotypic vulnerability?. Int J Neuropsychopharmacol. 2007; 11(3):331-49. DOI: 10.1017/S1461145707007912. View

Caspi A, Hariri A, Holmes A, Uher R, Moffitt T . Genetic sensitivity to the environment: the case of the serotonin transporter gene and its implications for studying complex diseases and traits. Am J Psychiatry. 2010; 167(5):509-27. PMC: 2943341. DOI: 10.1176/appi.ajp.2010.09101452. View

Grice D, Reenila I, Mannisto P, Brooks A, Smith G, Golden G . Transcriptional profiling of C57 and DBA strains of mice in the absence and presence of morphine. BMC Genomics. 2007; 8:76. PMC: 1851712. DOI: 10.1186/1471-2164-8-76. View

Millstein R, Ralph R, Yang R, Holmes A . Effects of repeated maternal separation on prepulse inhibition of startle across inbred mouse strains. Genes Brain Behav. 2006; 5(4):346-54. DOI: 10.1111/j.1601-183X.2005.00172.x. View

Rojas P, Joodmardi E, Hong Y, Perlmann T, Ogren S . Adult mice with reduced Nurr1 expression: an animal model for schizophrenia. Mol Psychiatry. 2007; 12(8):756-66. DOI: 10.1038/sj.mp.4001993. View

Shansky R, Hamo C, Hof P, McEwen B, Morrison J . Stress-induced dendritic remodeling in the prefrontal cortex is circuit specific. Cereb Cortex. 2009; 19(10):2479-84. PMC: 2742599. DOI: 10.1093/cercor/bhp003. View

Pothion S, Bizot J, Trovero F, Belzung C . Strain differences in sucrose preference and in the consequences of unpredictable chronic mild stress. Behav Brain Res. 2004; 155(1):135-46. DOI: 10.1016/j.bbr.2004.04.008. View

Muigg P, Hoelzl U, Palfrader K, Neumann I, Wigger A, Landgraf R . Altered brain activation pattern associated with drug-induced attenuation of enhanced depression-like behavior in rats bred for high anxiety. Biol Psychiatry. 2007; 61(6):782-96. DOI: 10.1016/j.biopsych.2006.08.035. View

Berton O, Nestler E . New approaches to antidepressant drug discovery: beyond monoamines. Nat Rev Neurosci. 2006; 7(2):137-51. DOI: 10.1038/nrn1846. View

10.

Malenka R, Bear M . LTP and LTD: an embarrassment of riches. Neuron. 2004; 44(1):5-21. DOI: 10.1016/j.neuron.2004.09.012. View

11.

Nestler E, Barrot M, DiLeone R, Eisch A, Gold S, Monteggia L . Neurobiology of depression. Neuron. 2002; 34(1):13-25. DOI: 10.1016/s0896-6273(02)00653-0. View

12.

DuBois D, Perlegas A, Floyd D, Weiner J, McCool B . Distinct functional characteristics of the lateral/basolateral amygdala GABAergic system in C57BL/6J and DBA/2J mice. J Pharmacol Exp Ther. 2006; 318(2):629-40. DOI: 10.1124/jpet.105.100552. View

13.

Korostynski M, Kaminska-Chowaniec D, Piechota M, Przewlocki R . Gene expression profiling in the striatum of inbred mouse strains with distinct opioid-related phenotypes. BMC Genomics. 2006; 7:146. PMC: 1553451. DOI: 10.1186/1471-2164-7-146. View

14.

Strekalova T, Spanagel R, Bartsch D, Henn F, Gass P . Stress-induced anhedonia in mice is associated with deficits in forced swimming and exploration. Neuropsychopharmacology. 2004; 29(11):2007-17. DOI: 10.1038/sj.npp.1300532. View

15.

Schweizer M, Henniger M, Sillaber I . Chronic mild stress (CMS) in mice: of anhedonia, 'anomalous anxiolysis' and activity. PLoS One. 2009; 4(1):e4326. PMC: 2627902. DOI: 10.1371/journal.pone.0004326. View

16.

Millstein R, Holmes A . Effects of repeated maternal separation on anxiety- and depression-related phenotypes in different mouse strains. Neurosci Biobehav Rev. 2006; 31(1):3-17. DOI: 10.1016/j.neubiorev.2006.05.003. View

17.

Willner P, Moreau J, Nielsen C, Papp M, Sluzewska A . Decreased hedonic responsiveness following chronic mild stress is not secondary to loss of body weight. Physiol Behav. 1996; 60(1):129-34. DOI: 10.1016/0031-9384(95)02256-2. View

18.

Yalcin B, Willis-Owen S, Fullerton J, Meesaq A, Deacon R, Rawlins J . Genetic dissection of a behavioral quantitative trait locus shows that Rgs2 modulates anxiety in mice. Nat Genet. 2004; 36(11):1197-202. DOI: 10.1038/ng1450. View

19.

Peters A . The small pyramidal neuron of the rat cerebral cortex. The perikaryon, dendrites and spines. Am J Anat. 1970; 127(4):321-55. DOI: 10.1002/aja.1001270402. View

20.

Anisman H, Matheson K . Stress, depression, and anhedonia: caveats concerning animal models. Neurosci Biobehav Rev. 2005; 29(4-5):525-46. DOI: 10.1016/j.neubiorev.2005.03.007. View