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Cited by 130Cannabis and Cannabinoid ResearchNeurogenesis and neuroplasticity mechanismsNeuroendocrine regulation and behavior

Sex difference in cell proliferation in developing rat amygdala mediated by endocannabinoids has implications for social behavior

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Krebs-Kraft, Desiree L., Hill, Matthew N., Hillard, Cecilia J., McCarthy, Margaret M.·2010·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1005003107PMC PMC2996668
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Abstract

The amygdala is a sexually dimorphic brain region critical for the regulation of social, cognitive, and emotional behaviors, but both the nature and the source of sex differences in the amygdala are largely unknown. We have identified a unique sex difference in the developing rat medial amygdala (MeA) that is regulated by cannabinoids. Newborn females had higher rates of cell proliferation than males. Treatment of neonates with the cannabinoid receptor agonist, WIN 55,212-2 (WIN), reduced cell proliferation in females to that of males and a wide range of WIN doses had no effect on cell proliferation in males. The effect of WIN on cell proliferation in the MeA was prevented by coinfusions of a CB2 but not CB1 receptor antagonist. Females had higher amygdala content of the endocannabinoid degradation enzymes, fatty acid amid hydrolase, and monoacylglycerol lipase than males, and lower amounts of the endocannabinoids 2-arachidonoylglycerol and N-arachidonylethanolamide (anandamide). Inhibition of the degradation of 2-arachidonoylglycerol in females occluded the sex difference in cell proliferation. Analyses of cell fate revealed that females had significantly more newly generated glial cells but not more newly generated neurons than males, and treatment with WIN significantly decreased glial cell genesis in females but not males. Finally, early exposure to cannabinoids masculinized juvenile play behavior in females but did not alter this behavior in males. Collectively, our findings suggest that sex differences in endocannabinoids mediate a sex difference in glial cell genesis in the developing MeA that impacts sex-specific behaviors in adolescence.

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  • Females have higher levels of neurogenesis within the newborn amygdala.

    “Previous research has shown that females have higher levels of neurogenesis within the newborn amygdala (30)”

    From Puberty Blocker, Leuprolide, Reduces Sex Differences in Rough-and-Tumble Play and Anxiety-like Behavior in Juvenile Rats (2024) · cites this paper as [30]

    The Discussion says neonatal females had more new amygdala cells, but attributes the difference to astrocyte genesis and explicitly reports no sex difference in neurogenesis. The Abstract likewise says females had more newly generated glial cells, not neurons. (LLM, conf=0.95)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • The sex difference in newborn cells is driven by a sex difference in endocannabinoids.

    “The sex difference in newborn cells is driven by a sex difference in a class of signaling molecules that are essential to brain development: endocannabinoids (Krebs-Kraft et al., 2010).”

    From Developmental origins of sex differences in the neural circuitry of play (2020) · cites this paper as Krebs-Kraft et al., 2010

    The Abstract reports more newly generated cells in neonatal female rat amygdala and shows that inhibiting endocannabinoid degradation eliminated the proliferation difference. The Discussion says the data support the hypothesis that endocannabinoid/CB2 signaling underlies that difference. Calling it definitively “driven by” endocannabinoids is stronger than the paper’s qualified conclusion; the copy also describes their influence on brain development but does not establish that they are essential to it. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • The sex difference in play emergence in weanling rats is opposite to that typically reported for older juvenile rats.

    “Unexpectedly, play emerged more rapidly in weanling-aged females than in males, resulting in a sex difference opposite of that typically reported for older, juvenile rats.”

    From Sexually dimorphic role for vasopressin in the development of social play (2014) · cites this paper as Krebs-Kraft et al., 2010

  • Previous findings have reported that peak GH levels at PD 30 and 90 are higher in males compared with females.

    “While GH is released in pulses and varies depending on time of day, previous findings have reported that peak levels at PD 30 and 90 are higher in males compared with females (30).”

    From Puberty Blocker, Leuprolide, Reduces Sex Differences in Rough-and-Tumble Play and Anxiety-like Behavior in Juvenile Rats (2024) · cites this paper as [30]

    The Results discuss sex differences in amygdala cell proliferation and endocannabinoid levels, not growth hormone. Searches for GH, growth hormone, pulsatile secretion, and peak levels at postnatal days 30 and 90 found no passage addressing the cited claim in our copy. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

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Cited by

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Authors
Krebs-Kraft, D. L., Hill, M. N., Hillard, C. J., & McCarthy, M. M.
Affiliations
  • Departments of aPhysiology and
  • Rockefeller University (US)
  • Medical College of Wisconsin (US)
  • University of Maryland, Baltimore (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2010-11-08
Volume
107
Issue
47
Pages
20535-20540
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1005003107
PMC
PMC2996668
OpenAlex
W2084663855
Cited by
130
References
3
Citations by year
2026: 5 · 2025: 5 · 2024: 12 · 2023: 6 · 2022: 9 · 2021: 11 · 2020: 16 · 2019: 8 · 2018: 9 · 2017: 10 · 2016: 6 · 2015: 4 · 2014: 8 · 2013: 8 · 2012: 4
FWCI
4.95
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • Canadian Institutes of Health Research
  • National Institute of Mental Health (R01MH052716)
  • National Institute on Drug Abuse (R21DA022439)
  • National Institute of Neurological Disorders and Stroke (T32 NS07375, T32NS007375)
Topics
  • Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
Keywords
sex differences, amygdala, cell proliferation, endocannabinoids, WIN 55,212-2, CB2 receptor, CB1 receptor, monoacylglycerol lipase, 2-arachidonoylglycerol, anandamide, social behavior, adolescent development, masculinization
MeSH terms
Fatty Acid Amide Hydrolases, Amidohydrolases, Amygdala, Analysis of Variance, Animals, Animals, Newborn, Female, Fluorescent Antibody Technique, Immunohistochemistry, Male, Monoacylglycerol Lipases, Morpholines, Naphthalenes, Neuroglia, Sex Characteristics, Social Behavior, Blotting, Western, Microscopy, Confocal, Benzoxazines, Cell Proliferation, Rats, Neurogenesis, Cannabinoid Receptor Modulators, Cannabinoid Receptor Agonists, Endocannabinoids

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