A prefrontal–bed nucleus pathway controls aversive memory specificity independently of glucocorticoids
Abstract
Adaptive memory requires balancing generalization to avoid similar threats with discrimination to recognize safety. The prevailing view is that stress-induced increases in glucocorticoids underlie the enhancement of memory consolidation, strengthening memories and promoting their generalization—referred to here as the standard model. However, circuits that drive memory consolidation often also regulate glucocorticoid release, confounding whether their effects on memory are circuit-driven or hormonally mediated. Here we identify a prefrontal pathway that controls memory specificity independently of glucocorticoids. Using optogenetic manipulations in male rats, we found that post-training inhibition of the rostral prelimbic cortex (rPL) to anteroventral bed nuclei of the stria terminalis (avBST) pathway promoted contextual generalization in an inhibitory avoidance discrimination task without affecting memory strength. Although this manipulation further elevated corticosterone, it produced generalization even in adrenalectomized rats, demonstrating glucocorticoid independence. Conversely, post-training pathway excitation enhanced contextual discrimination. Recordings of calcium signals revealed context-specific engagement of both avBST and avBST-projecting rPL neurons during memory retrieval, with greater responses in the neutral than the aversive context. These findings reveal glucocorticoid-independent circuit control of memory specificity, setting boundary conditions on the standard model and demonstrating mechanistic heterogeneity that may inform stress-related disorders where memory generalization is a core feature.
Related
- Independently tunable subcortical oscillators enable prefrontal control of cortical coupling
- Calmodulin controls spatial and temporal specificity of calcium-induced calcium release
- Toward welfare indicators: leg condition and aversive stimuli modulate defensive behavior in Opilones
- Lasting aversive consequences of a single dose of 4-hydroxytamoxifen
- DNA Methylation Alterations in Patients with Moderate-to-Severe Thyroid Eye Disease Treated with Intravenous Glucocorticoids
BibTeX
@article{lingg2026prefrontalbed,
title = {{A prefrontal–bed nucleus pathway controls aversive memory specificity independently of glucocorticoids}},
author = {Ryan T. Lingg and Shane B. Johnson and Dalton C. Hinz and Abdullahi A. Mohamed and Timothy D. Skog and Manuela Lizarazu and Sara A. Romig-Martin and Ryan T. LaLumiere and Nandakumar S. Narayanan and Jason J. Radley},
journal = {Nature Communications},
year = {2026},
month = oct,
doi = {10.1038/s41467-026-78719-y},
url = {https://www.nature.com/articles/s41467-026-78719-y},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - A prefrontal–bed nucleus pathway controls aversive memory specificity independently of glucocorticoids
AU - Ryan T. Lingg
AU - Shane B. Johnson
AU - Dalton C. Hinz
AU - Abdullahi A. Mohamed
AU - Timothy D. Skog
AU - Manuela Lizarazu
AU - Sara A. Romig-Martin
AU - Ryan T. LaLumiere
AU - Nandakumar S. Narayanan
AU - Jason J. Radley
PY - 2026
DA - 2026/10/20
JO - Nature Communications
DO - 10.1038/s41467-026-78719-y
UR - https://www.nature.com/articles/s41467-026-78719-y
AB - Adaptive memory requires balancing generalization to avoid similar threats with discrimination to recognize safety. The prevailing view is that stress-induced increases in glucocorticoids underlie the enhancement of memory consolidation, strengthening memories and promoting their generalization—referred to here as the standard model. However, circuits that drive memory consolidation often also regulate glucocorticoid release, confounding whether their effects on memory are circuit-driven or hormonally mediated. Here we identify a prefrontal pathway that controls memory specificity independently of glucocorticoids. Using optogenetic manipulations in male rats, we found that post-training inhibition of the rostral prelimbic cortex (rPL) to anteroventral bed nuclei of the stria terminalis (avBST) pathway promoted contextual generalization in an inhibitory avoidance discrimination task without affecting memory strength. Although this manipulation further elevated corticosterone, it produced generalization even in adrenalectomized rats, demonstrating glucocorticoid independence. Conversely, post-training pathway excitation enhanced contextual discrimination. Recordings of calcium signals revealed context-specific engagement of both avBST and avBST-projecting rPL neurons during memory retrieval, with greater responses in the neutral than the aversive context. These findings reveal glucocorticoid-independent circuit control of memory specificity, setting boundary conditions on the standard model and demonstrating mechanistic heterogeneity that may inform stress-related disorders where memory generalization is a core feature.
SN - 2041-1723
ER -