Central amygdala CRF+ neurons tune defensive state stability during threat
Year: 2026
Type: article
Abstract: The central amygdala (CeA) is critical for mediating behavioral responses to threat, 1 1. Ciocchi, S. ∙ Herry, C. ∙ Grenier, F. ... Encoding of conditioned fear in central amygdala inhibitory circuits Nature. 2010; 468 :277-282 Crossref Scopus (782) PubMed Google Scholar , 2 2. Duvarci, S. ∙ Pare, D. Amygdala microcircuits controlling learned fear Neuron. 2014; 82 :966-980 Full Text Full Text (PDF) Scopus (641) PubMed Google Scholar including the coordination of competing freezing and mobile responses through distinct cell types. 3 3. Le, Q.E. ∙ Lardant, E. ∙ Siddiqui, Y. ... Corticotropin-releasing factor and somatostatin neurons in the central amygdala mediate dynamic defensive behaviors during fear extinction J. Neurosci. 2026; 46 , e1049252026 Crossref Scopus (0) Google Scholar , 4 4. Demaestri, C. ∙ Pisciotta, M. ∙ Altunkeser, N. ... Central amygdala CRF+ neurons promote heightened threat reactivity following early life adversity in mice Nat. Commun. 2024; 15 , 5522 Crossref Scopus (13) PubMed Google Scholar , 5 5. Fadok, J.P. ∙ Krabbe, S. ∙ Markovic, M. ... A competitive inhibitory circuit for selection of active and passive fear responses Nature. 2017; 542 :96-100 Crossref Scopus (344) PubMed Google Scholar , 6 6. Hartley, N.D. ∙ Gaulden, A.D. ∙ Báldi, R. ... Dynamic remodeling of a basolateral-to-central amygdala glutamatergic circuit across fear states Nat. Neurosci. 2019; 22 :2000-2012 Crossref Scopus (52) PubMed Google Scholar Defensive behavior must remain flexible as threat contingencies change, 7 7. Fanselow, M.S. Neural organization of the defensive behavior system responsible for fear Psychon. Bull. Rev. 1994; 1 :429-438 Crossref Scopus (867) PubMed Google Scholar , 8 8. LeDoux, J. ∙ Daw, N.D. Surviving threats: neural circuit and computational implications of a new taxonomy of defensive behaviour Nat. Rev. Neurosci. 2018; 19 :269-282 Crossref Scopus (315) PubMed Google Scholar yet the circuit mechanisms that regulate how threat is translated into appropriate defensive states remain unclear. Using a dual-threat conditioning paradigm, we found that divergence from an immobility-dominant passive phenotype during a temporally immediate threat (delay conditioned stimulus [CS]) toward a more active phenotype during a variable-trace threat (variable trace CS; vTrace) emerged specifically through increased disengagement from immobility. Chronic unpredictable stress (CUS) disrupted this transition-level phenotype in males, thereby promoting immobility persistence that generalized during the trace threat. To identify the circuit mechanisms underlying these effects, we manipulated CeA neurons expressing corticotropin-releasing factor (CeA CRF+) during threat recall using chemogenetics and blocked CRFR1 signaling via systemic administration of the antagonist antalarmin. Silencing CeA CRF+ neurons and CRFR1 antagonism reduced transitions out of immobility without impairing cue discrimination, thus phenocopying the transition-level deficit observed in CUS males. These findings suggest that stress-induced behavioral rigidity, particularly under temporal uncertainty of threat, may arise from impaired CRF-dependent destabilization of passive defensive states. Together, our findings indicate that CeA CRF+ neurons and CRFR1 signaling regulate threat responding by facilitating the transitions out of immobility during threat evaluation. This work identifies CRF signaling as a mechanism that enables defensive responding to adjust to temporal threat contingencies, which may be disrupted in fear-related pathology.
Source: Current Biology
Authors: Camila Demaestri, Yingchu He, Jamie L. Maguire
Institution: Tufts University
Language: English
Topic: Memory and Neural Mechanisms
Subfield: Cognitive Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $7,030
OpenAlex ID: W7212000790