TY - JOUR
T1 - Behavioural and dopaminergic signatures of resilience
AU - Willmore, Lindsay
AU - Cameron, Courtney
AU - Yang, John
AU - Witten, Ilana B.
AU - Falkner, Annegret L.
N1 - Funding Information:
We thank C. Peña, J. Shaevitz and members of the Witten and Falkner laboratories for useful discussions; R. Cho for comments on a previous version of the manuscript; A. Zhukovskaya and A. Minerva for assistance with rebuttal materials; and staff at the PNI Viral Core Facility for reagents and the PNI Brain Registration and Histology Core Facility for assistance with histology. Funding was from NIH T32MH065214 (to L.W.), NSF GRFP DGE-2039656 (to L.W.), NIMH DP2MH126375 (to A.L.F.), NIH R01MH126035 (to A.L.F.), ARO W911NF1710554 (to I.B.W.), NIH R01 DA047869 (to I.B.W.), NYSCF (to A.L.F. and I.B.W.), SCGB (to A.L.F. and I.B.W.), Klingenstein Foundation (to A.L.F.) and an Alfred P. Sloan Fellowship (to A.L.F.). A.L.F. and I.B.W. are New York Stem Cell Foundation Robertson Investigators.
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/11/3
Y1 - 2022/11/3
N2 - Chronic stress can have lasting adverse consequences in some individuals, yet others are resilient to the same stressor1,2. Susceptible and resilient individuals exhibit differences in the intrinsic properties of mesolimbic dopamine (DA) neurons after the stressful experience is over3–8. However, the causal links between DA, behaviour during stress and individual differences in resilience are unknown. Here we recorded behaviour in mice simultaneously with DA neuron activity in projections to the nucleus accumbens (NAc) (which signals reward9–12) and the tail striatum (TS) (which signals threat13–16) during social defeat. Supervised and unsupervised behavioural quantification revealed that during stress, resilient and susceptible mice use different behavioural strategies and have distinct activity patterns in DA terminals in the NAc (but not the TS). Neurally, resilient mice have greater activity near the aggressor, including at the onset of fighting back. Conversely, susceptible mice have greater activity at the offset of attacks and onset of fleeing. We also performed optogenetic stimulation of NAc-projecting DA neurons in open loop (randomly timed) during defeat or timed to specific behaviours using real-time behavioural classification. Both open-loop and fighting-back-timed activation promoted resilience and reorganized behaviour during defeat towards resilience-associated patterns. Together, these data provide a link between DA neural activity, resilience and resilience-associated behaviour during the experience of stress.
AB - Chronic stress can have lasting adverse consequences in some individuals, yet others are resilient to the same stressor1,2. Susceptible and resilient individuals exhibit differences in the intrinsic properties of mesolimbic dopamine (DA) neurons after the stressful experience is over3–8. However, the causal links between DA, behaviour during stress and individual differences in resilience are unknown. Here we recorded behaviour in mice simultaneously with DA neuron activity in projections to the nucleus accumbens (NAc) (which signals reward9–12) and the tail striatum (TS) (which signals threat13–16) during social defeat. Supervised and unsupervised behavioural quantification revealed that during stress, resilient and susceptible mice use different behavioural strategies and have distinct activity patterns in DA terminals in the NAc (but not the TS). Neurally, resilient mice have greater activity near the aggressor, including at the onset of fighting back. Conversely, susceptible mice have greater activity at the offset of attacks and onset of fleeing. We also performed optogenetic stimulation of NAc-projecting DA neurons in open loop (randomly timed) during defeat or timed to specific behaviours using real-time behavioural classification. Both open-loop and fighting-back-timed activation promoted resilience and reorganized behaviour during defeat towards resilience-associated patterns. Together, these data provide a link between DA neural activity, resilience and resilience-associated behaviour during the experience of stress.
UR - http://www.scopus.com/inward/record.url?scp=85140122169&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85140122169&partnerID=8YFLogxK
U2 - 10.1038/s41586-022-05328-2
DO - 10.1038/s41586-022-05328-2
M3 - Article
C2 - 36261520
AN - SCOPUS:85140122169
SN - 0028-0836
VL - 611
SP - 124
EP - 132
JO - Nature
JF - Nature
IS - 7934
ER -