Social stress increases anxiety by GluA1-dependent synaptic strengthening of ventral tegmental area inputs to the basolateral amygdala.
Biological Psychiatry. 2025-04-01; :
DOI: 10.1016/j.biopsych.2025.04.007
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Contesse T(1), Gomes-Ribeiro J(1), Royon L(1), Fofo H(1), Braine A(2), Glangetas C(2), Zhang S(3), Barbano MF(4), Soiza-Reilly M(5), Georges F(2), Barik J(6), Fernandez SP(7).
Author information:
(1)Université Côte d’Azur, Nice, France; Institut de Pharmacologie Moléculaire &
Cellulaire, CNRS UMR7275, Valbonne, France; Inserm U1323.
(2)Université de Bordeaux, CNRS, IMN, UMR 5293, F-33000 Bordeaux, France.
(3)Confocal and Electron Microscopy Core, National Institute on Drug Abuse,
National Institutes of Health, Baltimore, MD, 21224, USA.
(4)Integrative Neuroscience Research Branch, National Institute on Drug Abuse,
National Institutes of Health, Baltimore, MD 21224, USA.
(5)Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE),
Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad
de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos
AiresC1428EGA, Argentina.
(6)Université Côte d’Azur, Nice, France; Institut de Pharmacologie Moléculaire &
Cellulaire, CNRS UMR7275, Valbonne, France; Inserm U1323. Electronic address:
.
(7)Université Côte d’Azur, Nice, France; Institut de Pharmacologie Moléculaire &
Cellulaire, CNRS UMR7275, Valbonne, France; Inserm U1323. Electronic address:
.
BACKGROUND: Brain defensive mechanisms evolved to maintain low levels of state
anxiety. However, risk factors such as stress exposure shifts activity within
defensive circuits, resulting in increased anxiety. The amygdala is a crucial
node for maintaining adaptive anxiety levels, and amygdala hyperactivity can
lead to pathological anxiety through mechanisms that are not well understood.
METHODS: We used chronic social defeat stress (CSD) in mice. We combined
anatomical tracing methods, patch-clamp recordings and optogenetics to probe how
synaptic inputs from the ventral tegmental area (VTA) to the basolateral
amygdala (BLA) are affected by CSD. We performed in vivo fiber photometry
recordings to track inputs onto basolateral amygdala. Array tomography and
electron microscopy were used to unravel the structural composition of VTA-BLA
synapses.
RESULTS: We identified the VTA as a source of glutamatergic inputs to the BLA
potentiated by stress. In turn, inputs from mPFC were not potentiated.
BLA-projecting VTA glutamatergic neurons are activated by social stress,
increasing their excitability and synaptic strength. In vivo potentiation of VTA
glutamatergic inputs in the BLA is sufficient to increase anxiety. We showed
that stress-induced synaptic strengthening is mediated by insertion of
GluA1-containing AMPA receptors. Impeding GluA1 subunit trafficking in BLA
neurons with VTA upstream inputs prevents stress-induced increase in synaptic
firing and anxiety.
CONCLUSIONS: Potentiation of VTA inputs increases synaptic integration,
enhancing amygdala activity and promoting maladaptive anxiety. Understanding the
impact of amygdala hyperactivity could lead to targeted therapies, restoring
circuit balance and offering new precision medicine approaches for anxiety
disorders.
Copyright © 2025. Published by Elsevier Inc.
DOI: 10.1016/j.biopsych.2025.04.007
PMID: 40245975