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Cited by 20Neurotransmitter Receptor Influence on BehaviorNeuroendocrine regulation and behaviorNeuroscience and Neuropharmacology Research

Crystallin Mu in Medial Amygdala Mediates the Effect of Social Experience on Cocaine Seeking in Males but Not in Females

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Walker, Deena M., Zhou, Xianxiao, Cunningham, Ashley M., Ramakrishnan, Aarthi, Cates, Hannah M., Lardner, Casey K., Peña, Catherine J., Bagot, Rosemary C. +12 more·2022·Biological Psychiatry
DOI 10.1016/j.biopsych.2022.06.026PMC PMC9828478
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Abstract

Background Social experiences influence susceptibility to substance use disorder. The adolescent period is associated with the development of social reward and is exceptionally sensitive to disruptions to reward-associated behaviors by social experiences. Social isolation (SI) during adolescence alters anxiety- and reward-related behaviors in adult males, but little is known about females. The medial amygdala (meA) is a likely candidate for the modulation of social influence on drug reward because it regulates social reward, develops during adolescence, and is sensitive to social stress. However, little is known regarding how the meA responds to drugs of abuse. Methods We used adolescent SI coupled with RNA sequencing to better understand the molecular mechanisms underlying meA regulation of social influence on reward. Results We show that SI in adolescence, a well-established preclinical model for addiction susceptibility, enhances preference for cocaine in male but not in female mice and alters cocaine-induced protein and transcriptional profiles within the adult meA particularly in males. To determine whether transcriptional mechanisms within the meA are important for these behavioral effects, we manipulated Crym expression, a sex-specific key driver gene identified through differential gene expression and coexpression network analyses, specifically in meA neurons. Overexpression of Crym, but not another key driver that did not meet our sex-specific criteria, recapitulated the behavioral and transcriptional effects of adolescent SI. Conclusions These results show that the meA is essential for modulating the sex-specific effects of social experience on drug reward and establish Crym as a critical mediator of sex-specific behavioral and transcriptional plasticity.

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Authors
Walker, D. M., Zhou, X., Cunningham, A. M., Ramakrishnan, A., Cates, H. M., Lardner, C. K., Peña, C. J., Bagot, R. C., Issler, O., Van der Zee, Y., Lipschultz, A. P., Godino, A., Browne, C. J., Hodes, G. E., Parise, E. M., Torres-Berrio, A., Kennedy, P. J., Shen, L., Zhang, B., & Nestler, E. J.
Affiliations
  • Icahn School of Medicine at Mount Sinai (US)
  • University of California, Los Angeles (US)
Corresponding author
Nestler, Eric J.
ORCID
Venue
Biological Psychiatry
Publisher
Elsevier BV
Published
2022-12
Volume
92
Issue
11
Pages
895-906
ISSN
0006-3223 (ISSN-L)
DOI
10.1016/j.biopsych.2022.06.026
PMC
PMC9828478
OpenAlex
W4283759775
Cited by
20
References
18
Citations by year
2026: 3 · 2025: 6 · 2024: 7 · 2023: 4
FWCI
1.88
Type
journal article
Language
en
Open access
Licence
Locations
  • Biological Psychiatry (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • VTechWorks (Virginia Tech) (submittedVersion, public-domain)
Funders
  • Alberta Precision Laboratories
  • National Institutes of Health (R01DA007359, K99DA042100, P01DA0047233, RF1AG054014, U01AG046170, R01MH051399)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
medial amygdala, CRYM, cocaine seeking, social isolation, adolescent social isolation, sex differences, drug reward, social reward, addiction vulnerability, transcriptional plasticity, gene expression profiling, sex-specific gene expression
MeSH terms
mu-Crystallins, Amygdala, Animals, Cocaine, Female, Male, Neurons, Reward, Mice

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