Strain Differences in Stress Responsivity Are Associated with Divergent Amygdala Gene Expression and Glutamate-Mediated Neuronal Excitability
Open accessAbstract
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 (∼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.
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Strain-dependent responses to restraint or chronic mild stress have been shown, indicating complex genetics regulate risk and resilience to chronic stress.
“Strain–dependent responses to other physical stressors such as restraint or CMS have been shown, underscoring the role of complex genetics in regulating risk and resilience to chronic stress32–34.”
From Neurobiology of resilience (2012) · cites this paper as [33]
The amygdala exhibits profound functional changes as a result of chronic stress that are closely linked to attendant changes in anxiety.
“Moreover, the amygdala exhibits profound functional changes as a result of chronic stress that are closely linked to attendant changes in anxiety (5,6,9–12).”
From Chronic Stress Remodels Synapses in an Amygdala Circuit-Specific Manner (2019) · cites this paper as [12]
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References 69 · Cited by 226
- Authors
- Mozhui, K., Karlsson, R.-M., Kash, T. L., Ihne, J., Norcross, M., Patel, S., Farrell, M. R., Hill, E. E., Graybeal, C., Martin, K. P., Camp, M., Fitzgerald, P. J., Ciobanu, D. C., Sprengel, R., Mishina, M., Wellman, C. L., Winder, D. G., Williams, R. W., & Holmes, A.
- Affiliations
- University of Tennessee Health Science Center (US)
- National Institutes of Health (US)
- Vanderbilt University (US)
- Indiana University Bloomington (US)
- University of Nebraska–Lincoln (US)
- Max Planck Society (DE)
- The University of Tokyo (JP)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2010-04-14
- Volume
- 30
- Issue
- 15
- Pages
- 5357-5367
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2866495
- OpenAlex
- W2044220354
- Cited by
- 226
- References
- 69
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 10 · 2023: 12 · 2022: 5 · 2021: 17 · 2020: 14 · 2019: 18 · 2018: 10 · 2017: 11 · 2016: 21 · 2015: 13 · 2014: 18 · 2013: 15 · 2012: 24
- FWCI
- 8.73
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Lincoln (University of Nebraska) (submittedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- National Institutes of Health
- Japan Society for the Promotion of Science (21249012)
- National Institute on Alcohol Abuse and Alcoholism (U01AA013513, U01AA013499, U24AA13513, K99AA017668, Z01AA000411, R00AA017668, ZIAAA000411)
- National Institute of Mental Health (Z01MH002784)
- National Institute on Drug Abuse (P20DA021131)
- National Center for Research Resources (U24RR021760)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- stress responsivity, inbred mouse strains, DBA/2J, C57BL/6J mice, restraint stress, anxiety, depression, glutamate receptors, NMDA receptor, GRIN2A, AMPA receptors, metaplasticity, dendritic spines, corticolimbic circuitry
- MeSH terms
- Amygdala, Animals, Hippocampus, Male, Mice, Inbred C57BL, Mice, Inbred DBA, Synaptic Transmission, Neuronal Plasticity, Neurons, Restraint, Physical, Species Specificity, Stress, Psychological, Gene Expression, Receptors, N-Methyl-D-Aspartate, Prefrontal Cortex, Receptors, AMPA, Mice, Knockout, Glutamic Acid, Excitatory Postsynaptic Potentials, Dendritic Spines, Mice
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