The pathophysiological impact of stress on the dopamine system is dependent on the state of the critical period of vulnerability
Open accessAbstract
Unregulated stress during critical periods of development is proposed to drive deficits consistent with schizophrenia in adults. If accurate, reopening the critical period could make the adult susceptible to pathology. We evaluated the impact of early adolescent and adult stress exposure (combination of daily footshock for 10 days and 3 restraint sessions) on (1) midbrain dopamine (DA) neuron activity, (2) ventral hippocampal (vHipp) pyramidal neuron activity, and (3) the number of parvalbumin (PV) interneurons in the vHipp and their associated perineuronal nets (PNNs). Ventral tegmental area (VTA) DA neuron population activity and vHipp activity was increased 1-2 and 5-6 weeks post-adolescent stress, along with a decrease in the number of PV+, PNN+, PV + /PNN + cells in the vHipp, which are consistent with the MAM model of schizophrenia. In contrast, adult stress decreased VTA DA neuron population activity only at 1-2 weeks post stress, which is consistent with what has been observed in animal models of depression, without impacting vHipp activity and PV/PNN expression. Administration of valproate (VPA), which can re-instate the critical period of plasticity via histone deacetylase (HDAC) inhibition, caused adult stress to produce changes similar to those induced by adolescent stress, presumably by increasing stress vulnerability to early adolescent levels. Our findings indicate that timing of stress is a critical determinant of the pathology produced in the adult: adolescent stress led to circuit deficits that recapitulates schizophrenia, whereas adult stress induced a depression-like hypodopaminergic state. Reopening the critical period in the adult restores vulnerability to stress-induced pathology resembling schizophrenia.
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Differences in psychopathological phenotypes observed may depend on the timing of the stress exposure during youth.
“differences in the psychopathological phenotypes observed may depend on the timing of the stress exposure during youth [30]”
From Towards a youth mental health paradigm: a perspective and roadmap (2023) · cites this paper as [30]
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Towards a youth mental health paradigm: a perspective and roadmap
Uhlhaas, P. J., Davey, C. G., Mehta, U. M., Shah, J., Torous, J., Allen, N. B., Avenevoli, S., Bella-Awusah, T., Chanen, A., Chen, E. Y. H., et al. (2023) · Molecular Psychiatry · doi:10.1038/s41380-023-02202-z · Cited by 318 · see citing works
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- Authors
- Gomes, F. V., Zhu, X., & Grace, A. A.
- Affiliations
- University of Pittsburgh (US)
- Corresponding author
- Zhu, Xiyu
- Venue
- Molecular Psychiatry
- Published
- 2019-09-05
- Volume
- 25
- Issue
- 12
- Pages
- 3278-3291
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC7056584
- OpenAlex
- W2971431266
- Cited by
- 91
- References
- 62
- Citations by year
- 2026: 11 · 2025: 5 · 2024: 16 · 2023: 16 · 2022: 19 · 2021: 10 · 2020: 14
- FWCI
- 8.56
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-09-27)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (2r01mh057440-26a1, 5r01mh101180-05)
- National Institute of Mental Health (R01-MH101180, R01-MH057440, R37MH057440)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- stress, dopaminergic system, schizophrenia, ventral tegmental area, ventral hippocampus, parvalbumin interneurons, perineuronal nets, adolescent stress, adult stress, valproic acid, histone deacetylase inhibition, footshock, restraint stress, hypodopaminergic state, depression, neuroplasticity
- MeSH terms
- Animals, Dopamine, Interneurons, Parvalbumins, Schizophrenia, Ventral Tegmental Area
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