A synaptic mechanism for encoding the learned value of action-derived safety
10 affiliations
- 1Section on the Neural Circuits of Emotion and Motivation, National Institute of Mental Health, Bethesda, MD, USA. [email protected]
- 2Section on the Neural Circuits of Emotion and Motivation, National Institute of Mental Health, Bethesda, MD 20892
- 3Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China
- 4Section on the Neural Circuits of Emotion and Motivation, National Institute of Mental Health, Bethesda, MD, USA
- 5Section on Neurobiology of Compulsive Behaviors, National Institute of Mental Health, Bethesda, MD 089
- 6Section on Neurobiology of Compulsive Behaviors, National Institute of Mental Health, Bethesda, MD, USA
- 7State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, China
- 8Laboratory of Neuropsychology, National Institute of Mental Health, Bethesda, MD 20892
- 9Laboratory of Neuropsychology, National Institute of Mental Health, Bethesda, MD, USA. [email protected]
- 10Section on the Neural Circuits of Emotion and Motivation, National Institute of Mental Health, Bethesda, MD, USA. [email protected]
Abstract
Motivated behavior is often framed in terms of biologically grounded outcomes, such as food or threat. Yet many motivated actions, like the pursuit of safety or agency, depend on outcomes that lack explicit sensory value and must instead be inferred from experience. Here, we identify a thalamostriatal circuit mechanism by which such internally constructed outcomes acquire motivational value. In mice performing an active avoidance task, neurons in the paraventricular thalamus (PVT) projecting to the nucleus accumbens (NAc) develop a safety-encoding signal that emerges following successful avoidance. This signal is experience-dependent and value-sensitive, diminishing upon devaluation of the instrumental contingency. Selective silencing of the PVT→NAc projection at safety onset disrupts avoidance persistence without impairing action-outcome learning, as confirmed by computational modeling of value updating based on prediction error. Mechanistically, PVT input recruits cholinergic interneurons (CINs) to modulate dopamine release and this influence depends on synaptic potentiation mediated by GluA2-lacking AMPA receptor insertion at PVT-CIN synapses. Disrupting this plasticity selectively impairs the avoidance response by blunting the motivational value of safety without affecting acquisition. These findings reveal how thalamic circuits assign value to abstract, internal outcomes, providing a framework for understanding how goals like safety are inferred, stabilized, and rendered behaviorally effective.
Related
- Differentiation protocol and maturation shape the axial identity and synaptic state in human iPSC-derived spinal motor neurons
- Antibacterial efficacy and mechanism of action of VTC3-knockout Saccharomyces cerevisiae against multidrug- resistant pathogenic bacteria
- Robust Identification of Drug Mechanism of Action Associated Genes Across Heterogeneous Drug Treated Datasets
- Colonization, growth-promoting effect, control efficacy against tobacco black shank, and mechanism of action of the tobacco endophyte Microbacterium foliorum 5SY32
- Pharmacologic modulation of orexin signaling: Impact on glucose–insulin homeostasis and potential mechanism of antidepressant action
BibTeX
@article{macdonald2026synaptic,
title = {{A synaptic mechanism for encoding the learned value of action-derived safety}},
author = {Emma E. Macdonald and Jun Ma and Di Liu and Kai Yu and Rachel A. Walker and Michael E. Authement and Yan Leng and Hannah C Goldbach and Guochuan Li and Yulong Li and Veronica A. Alvarez and Bruno B. Averbeck and Mario Alexander Penzo},
journal = {Nature Communications},
year = {2026},
month = jun,
doi = {10.1038/s41467-026-73906-3},
url = {https://doi.org/10.1038/s41467-026-73906-3},
note = {CC BY},
}
RIS
TY - JOUR
TI - A synaptic mechanism for encoding the learned value of action-derived safety
AU - Emma E. Macdonald
AU - Jun Ma
AU - Di Liu
AU - Kai Yu
AU - Rachel A. Walker
AU - Michael E. Authement
AU - Yan Leng
AU - Hannah C Goldbach
AU - Guochuan Li
AU - Yulong Li
AU - Veronica A. Alvarez
AU - Bruno B. Averbeck
AU - Mario Alexander Penzo
PY - 2026
DA - 2026/06/04
JO - Nature Communications
DO - 10.1038/s41467-026-73906-3
UR - https://doi.org/10.1038/s41467-026-73906-3
AB - Motivated behavior is often framed in terms of biologically grounded outcomes, such as food or threat. Yet many motivated actions, like the pursuit of safety or agency, depend on outcomes that lack explicit sensory value and must instead be inferred from experience. Here, we identify a thalamostriatal circuit mechanism by which such internally constructed outcomes acquire motivational value. In mice performing an active avoidance task, neurons in the paraventricular thalamus (PVT) projecting to the nucleus accumbens (NAc) develop a safety-encoding signal that emerges following successful avoidance. This signal is experience-dependent and value-sensitive, diminishing upon devaluation of the instrumental contingency. Selective silencing of the PVT→NAc projection at safety onset disrupts avoidance persistence without impairing action-outcome learning, as confirmed by computational modeling of value updating based on prediction error. Mechanistically, PVT input recruits cholinergic interneurons (CINs) to modulate dopamine release and this influence depends on synaptic potentiation mediated by GluA2-lacking AMPA receptor insertion at PVT-CIN synapses. Disrupting this plasticity selectively impairs the avoidance response by blunting the motivational value of safety without affecting acquisition. These findings reveal how thalamic circuits assign value to abstract, internal outcomes, providing a framework for understanding how goals like safety are inferred, stabilized, and rendered behaviorally effective.
SN - 2041-1723
ER -