Impact of prenatal maternal cytokine exposure on sex
differences in brain circuitry regulating stress in offspring
45 years later

J 2021

Impact of prenatal maternal cytokine exposure on sex differences in brain circuitry regulating stress in offspring 45 years later

GOLDSTEIN, J.M., J.E. COHEN, Klára MAREČKOVÁ, L. HOLSEN, S. WHITFIELD-GABRIELI et. al.

Basic information

Original name

Impact of prenatal maternal cytokine exposure on sex differences in brain circuitry regulating stress in offspring 45 years later

Authors

GOLDSTEIN, J.M., J.E. COHEN, Klára MAREČKOVÁ (203 Czech Republic, guarantor, belonging to the institution), L. HOLSEN, S. WHITFIELD-GABRIELI, S.E. GILMAN, S.L. BUKA and M. HORNIG

Edition

Proceedings of the National Academy of Sciences of the United States of America, WASHINGTON, NATL ACAD SCIENCES, 2021, 0027-8424

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30103 Neurosciences

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 12.779

RIV identification code

RIV/00216224:14740/21:00124230

Organization unit

Central European Institute of Technology

DOI

http://dx.doi.org/10.1073/pnas.2014464118

UT WoS

000641176100005

Keywords in English

prenatal immune programming; prenatal stress; stress circuitry; sex; functional brain imaging

Abstract

V originále

Stress is associated with numerous chronic diseases, beginning in fetal development with in utero exposures (prenatal stress) impacting offspring's risk for disorders later in life. In previous studies, we demonstrated adverse maternal in utero immune activity on sex differences in offspring neurodevelopment at age seven and adult risk for major depression and psychoses. Here, we hypothesized that in utero exposure to maternal proinflammatory cytokines has sex-dependent effects on specific brain circuitry regulating stress and immune function in the offspring that are retained across the lifespan. Using a unique prenatal cohort, we tested this hypothesis in 80 adult offspring, equally divided by sex, followed from in utero development to midlife. Functional MRI results showed that exposure to proinflammatory cytokines in utero was significantly associated with sex differences in brain activity and connectivity during response to negative stressful stimuli 45 y later. Lower maternal TNF-a levels were significantly associated with higher hypothalamic activity in both sexes and higher functional connectivity between hypothalamus and anterior cingulate only in men. Higher prenatal levels of IL-6 were significantly associated with higher hippocampal activity in women alone. When examined in relation to the anti-inflammatory effects of IL-10, the ratio TNF-alpha:IL-10 was associated with sex-dependent effects on hippocampal activity and functional connectivity with the hypothalamus. Collectively, results suggested that adverse levels of maternal in utero proinflammatory cytokines and the balance of pro- to anti-inflammatory cytokines impact brain development of offspring in a sexually dimorphic manner that persists across the lifespan.

Links

EE2.3.30.0009, research and development project

Name: Zaměstnáním čerstvých absolventů doktorského studia k vědecké excelenci

Citovat

GOLDSTEIN, J.M., J.E. COHEN, Klára MAREČKOVÁ, L. HOLSEN, S. WHITFIELD-GABRIELI, S.E. GILMAN, S.L. BUKA and M. HORNIG. Impact of prenatal maternal cytokine exposure on sex differences in brain circuitry regulating stress in offspring 45 years later. Proceedings of the National Academy of Sciences of the United States of America. WASHINGTON: NATL ACAD SCIENCES, 2021, vol. 118, No 15, p. „e2014464118“, 8 pp. ISSN 0027-8424. Available from: https://dx.doi.org/10.1073/pnas.2014464118.

@article{1835898,
   author = {Goldstein, J.M. and Cohen, J.E. and Marečková, Klára and Holsen, L. and WhitfieldandGabrieli, S. and Gilman, S.E. and Buka, S.L. and Hornig, M.},
   article_location = {WASHINGTON},
   article_number = {15},
   doi = {http://dx.doi.org/10.1073/pnas.2014464118},
   keywords = {prenatal immune programming; prenatal stress; stress circuitry; sex; functional brain imaging},
   language = {eng},
   issn = {0027-8424},
   journal = {Proceedings of the National Academy of Sciences of the United States of America},
   title = {Impact of prenatal maternal cytokine exposure on sex differences in brain circuitry regulating stress in offspring 45 years later},
   url = {https://www.pnas.org/content/pnas/118/15/e2014464118.full.pdf},
   volume = {118},
   year = {2021}
}

TY  - JOUR
ID  - 1835898
AU  - Goldstein, J.M. - Cohen, J.E. - Marečková, Klára - Holsen, L. - Whitfield-Gabrieli, S. - Gilman, S.E. - Buka, S.L. - Hornig, M.
PY  - 2021
TI  - Impact of prenatal maternal cytokine exposure on sex differences in brain circuitry regulating stress in offspring 45 years later
JF  - Proceedings of the National Academy of Sciences of the United States of America
VL  - 118
IS  - 15
SP  - „e2014464118“
EP  - „e2014464118“
PB  - NATL ACAD SCIENCES
SN  - 00278424
KW  - prenatal immune programming
KW  - prenatal stress
KW  - stress circuitry
KW  - sex
KW  - functional brain imaging
UR  - https://www.pnas.org/content/pnas/118/15/e2014464118.full.pdf
N2  - Stress is associated with numerous chronic diseases, beginning in fetal development with in utero exposures (prenatal stress) impacting offspring's risk for disorders later in life. In previous studies, we demonstrated adverse maternal in utero immune activity on sex differences in offspring neurodevelopment at age seven and adult risk for major depression and psychoses. Here, we hypothesized that in utero exposure to maternal proinflammatory cytokines has sex-dependent effects on specific brain circuitry regulating stress and immune function in the offspring that are retained across the lifespan. Using a unique prenatal cohort, we tested this hypothesis in 80 adult offspring, equally divided by sex, followed from in utero development to midlife. Functional MRI results showed that exposure to proinflammatory cytokines in utero was significantly associated with sex differences in brain activity and connectivity during response to negative stressful stimuli 45 y later. Lower maternal TNF-a levels were significantly associated with higher hypothalamic activity in both sexes and higher functional connectivity between hypothalamus and anterior cingulate only in men. Higher prenatal levels of IL-6 were significantly associated with higher hippocampal activity in women alone. When examined in relation to the anti-inflammatory effects of IL-10, the ratio TNF-alpha:IL-10 was associated with sex-dependent effects on hippocampal activity and functional connectivity with the hypothalamus. Collectively, results suggested that adverse levels of maternal in utero proinflammatory cytokines and the balance of pro- to anti-inflammatory cytokines impact brain development of offspring in a sexually dimorphic manner that persists across the lifespan.
ER  -

GOLDSTEIN, J.M., J.E. COHEN, Klára MAREČKOVÁ, L. HOLSEN, S. WHITFIELD-GABRIELI, S.E. GILMAN, S.L. BUKA and M. HORNIG. Impact of prenatal maternal cytokine exposure on sex differences in brain circuitry regulating stress in offspring 45 years later. \textit{Proceedings of the National Academy of Sciences of the United States of America}. WASHINGTON: NATL ACAD SCIENCES, 2021, vol.~118, No~15, p.~„e2014464118“, 8 pp. ISSN~0027-8424. Available from: https://dx.doi.org/10.1073/pnas.2014464118.

Detailed Information on Publication Record