TY - JOUR
T1 - Reactivation of Early-Life Stress-Sensitive Neuronal Ensembles Contributes to Lifelong Stress Hypersensitivity
AU - Balouek, Julie Anne
AU - McLain, Christabel A.
AU - Minerva, Adelaide R.
AU - Rashford, Rebekah L.
AU - Bennett, Shannon N.
AU - Rogers, Forrest D.
AU - Peña, Catherine Jensen
N1 - Funding Information: Received Jan. 3, 2023; revised June 1, 2023; accepted June 17, 2023. Author contributions: J.-A.B. and C.J.P. designed research; J.-A.B., C.A.M., A.R.M., R.L.R., S.N.B., F.D.R., and C.J.P. performed research; J.-A.B. and C.J.P. analyzed data; J.-A.B. and C.J.P. wrote the paper. This research was funded by National Institutes of Health Grants R00-MH-115096 (C.J.P.) and R01-MH-129643 (C.J.P.); PNI (Princeton Neuroscience Institute) Research Innovator Award (C.J.P.); and the New York Stem Cell Foundation (C.J.P.). C.J.P. is a New York Stem Cell Foundation Robertson Investigator. We thank Dr. Abigail Polter for helpful early discussion, and Tanzina Islam and Dana Waitman for their assistance with images. Parts of some figures were generated with BioRender.com. The authors declare no competing financial interests. Correspondence should be addressed to Catherine Jensen Peña at cpena@princeton.edu. https://doi.org/10.1523/JNEUROSCI.0016-23.2023 Copyright © 2023 the authors Publisher Copyright: Copyright © 2023 the authors.
PY - 2023/8/23
Y1 - 2023/8/23
N2 - Early-life stress (ELS) is one of the strongest lifetime risk factors for depression, anxiety, suicide, and other psychiatric disorders, particularly after facing additional stressful events later in life. Human and animal studies demonstrate that ELS sensitizes individuals to subsequent stress. However, the neurobiological basis of such stress sensitization remains largely unexplored. We hypothesized that ELS-induced stress sensitization would be detectable at the level of neuronal ensembles, such that cells activated by ELS would be more reactive to adult stress. To test this, we leveraged transgenic mice to genetically tag, track, and manipulate experience-activated neurons. We found that in both male and female mice, ELS-activated neurons within the nucleus accumbens (NAc), and to a lesser extent the medial prefrontal cortex, were preferentially reactivated by adult stress. To test whether reactivation of ELS-activated ensembles in the NAc contributes to stress hypersensitivity, we expressed hM4Dis receptor in control or ELS-activated neurons of pups and chemogenetically inhibited their activity during experience of adult stress. Inhibition of ELS-activated NAc neurons, but not control-tagged neurons, ameliorated social avoidance behavior following chronic social defeat stress in males. These data provide evidence that ELS-induced stress hypersensitivity is encoded at the level of corticolimbic neuronal ensembles.
AB - Early-life stress (ELS) is one of the strongest lifetime risk factors for depression, anxiety, suicide, and other psychiatric disorders, particularly after facing additional stressful events later in life. Human and animal studies demonstrate that ELS sensitizes individuals to subsequent stress. However, the neurobiological basis of such stress sensitization remains largely unexplored. We hypothesized that ELS-induced stress sensitization would be detectable at the level of neuronal ensembles, such that cells activated by ELS would be more reactive to adult stress. To test this, we leveraged transgenic mice to genetically tag, track, and manipulate experience-activated neurons. We found that in both male and female mice, ELS-activated neurons within the nucleus accumbens (NAc), and to a lesser extent the medial prefrontal cortex, were preferentially reactivated by adult stress. To test whether reactivation of ELS-activated ensembles in the NAc contributes to stress hypersensitivity, we expressed hM4Dis receptor in control or ELS-activated neurons of pups and chemogenetically inhibited their activity during experience of adult stress. Inhibition of ELS-activated NAc neurons, but not control-tagged neurons, ameliorated social avoidance behavior following chronic social defeat stress in males. These data provide evidence that ELS-induced stress hypersensitivity is encoded at the level of corticolimbic neuronal ensembles.
KW - DREADDs
KW - early life adversity
KW - early life stress
KW - engram
KW - nucleus accumbens (NAc)
KW - social defeat
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U2 - https://doi.org/10.1523/JNEUROSCI.0016-23.2023
DO - https://doi.org/10.1523/JNEUROSCI.0016-23.2023
M3 - Article
C2 - 37429717
SN - 0270-6474
VL - 43
SP - 5996
EP - 6009
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 34
ER -