Dentate Gyrus Microstructure Is Associated With Resilience After Exposure to Maternal Stress Across Two Human Cohorts

Milenna T. van Dijk; Ardesheer Talati; Pratik Kashyap; Karan Desai; Nora C. Kelsall; Marc J. Gameroff; Natalie Aw; Eyal Abraham; Breda Cullen; Jiook Cha; Christoph Anacker; Myrna M. Weissman; Jonathan Posner

doi:10.1016/j.biopsych.2023.06.026

Dentate Gyrus Microstructure Is Associated With Resilience After Exposure to Maternal Stress Across Two Human Cohorts

Milenna T. van Dijk, Ardesheer Talati, Pratik Kashyap, Karan Desai, Nora C. Kelsall, Marc J. Gameroff, Natalie Aw, Eyal Abraham, Breda Cullen, Jiook Cha, Christoph Anacker, Myrna M. Weissman, Jonathan Posner

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

Background: Maternal stress (MS) is a well-documented risk factor for impaired emotional development in offspring. Rodent models implicate the dentate gyrus (DG) of the hippocampus in the effects of MS on offspring depressive-like behaviors, but mechanisms in humans remain unclear. Here, we tested whether MS was associated with depressive symptoms and DG micro- and macrostructural alterations in offspring across 2 independent cohorts. Methods: We analyzed DG diffusion tensor imaging–derived mean diffusivity (DG-MD) and volume in a three-generation family risk for depression study (TGS; n = 69, mean age = 35.0 years) and in the Adolescent Brain Cognitive Development (ABCD) Study (n = 5196, mean age = 9.9 years) using generalized estimating equation models and mediation analysis. MS was assessed by the Parenting Stress Index (TGS) and a measure compiled from the Adult Response Survey from the ABCD Study. The Patient Health Questionnaire-9 and rumination scales (TGS) and the Child Behavior Checklist (ABCD Study) measured offspring depressive symptoms at follow-up. The Schedule for Affective Disorders and Schizophrenia–Lifetime interview was used to assign depression diagnoses. Results: Across cohorts, MS was associated with future symptoms and higher DG-MD (indicating disrupted microstructure) in offspring. Higher DG-MD was associated with higher symptom scores measured 5 years (in the TGS) and 1 year (in the ABCD Study) after magnetic resonance imaging. In the ABCD Study, DG-MD was increased in high-MS offspring who had depressive symptoms at follow-up, but not in offspring who remained resilient or whose mother had low MS. Conclusions: Converging results across 2 independent samples extend previous rodent studies and suggest a role for the DG in exposure to MS and offspring depression.

Original language	English
Pages (from-to)	27-36
Number of pages	10
Journal	Biological Psychiatry
Volume	95
Issue number	1
Early online date	29 Jun 2023
DOIs	https://doi.org/10.1016/j.biopsych.2023.06.026
State	Published - 1 Jan 2024
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2023 Society of Biological Psychiatry

Funding

This work was supported by the National Institute of Mental Health (Grant Nos. K99MH129611 [to MTvD], R01MH036197 [to MMW and JP], and R00MH108719 [to CA]), AFSP Young Investigator Award (Grant No. YIG-R-001-19 [to MTvD]), NARSAD Young Investigator Award from the Brain and Behavior Research Foundation (Grant No. P50MH090964 [to CA]), and Depression Center pilot awards from the Columbia University Department of Psychiatry (to AT and CA), and the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (Grant Nos. 2021R1C1C1006503 [to JC] and RS-2023-00265406 [to JC]), and by Creative-Pioneering Researchers Program through Seoul National University (Grant No. 200-20230058 [to JC]). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or any other sponsor. MTvD, AT, and MMW contributed to the conceptual design of the current manuscript; MMW along with JP and AT contributed to TGS conceptual design; MJG contributed to TGS data management; PK, KD, NA, and JC under the direction of JP contributed to the preprocessing of MRI data; MTvD, along with contributions from NCK for data cleaning, performed statistical analysis; MTvD, AT, MMW, JP, CA, BC, and EA contributed to the interpretation of the results; MTvD wrote the manuscript with contributions from AT, MMW, JP, PK, BC, CA, and EA; and MMW and JP directed and obtained research funding. Data used in the preparation of this article were obtained from the ABCD Study (https://abcdstudy.org), held in the National Institute of Mental Health Data Archive. This is a multisite longitudinal study designed to recruit more than 10,000 children ages 9 to 10 years and follow them over 10 years into early adulthood. The ABCD Study is supported by the National Institutes of Health and additional federal partners under award numbers U01DA041048, U01DA050989, U01DA051016, U01DA041022, U01DA051018, U01DA051037, U01DA050987, U01DA041174, U01DA041106, U01DA041117, U01DA041028, U01DA041134, U01DA050988, U01DA051039, U01DA041156, U01DA041025, U01DA041120, U01DA051038, U01DA041148, U01DA041093, U01DA041089, U24DA041123, and U24DA041147. A full list of supporters is available at https://abcdstudy.org/federal-partners.html. A listing of participating sites and a complete listing of the study investigators can be found at https://abcdstudy.org/consortium_members/. ABCD consortium investigators designed and implemented the study and/or provided data but did not necessarily participate in the analysis or writing of this report. This manuscript reflects the views of the authors and may not reflect the opinions or views of the National Institutes of Health or ABCD consortium investigators. The ABCD Study data repository grows and changes over time. The ABCD Study data used in this report came from DOI: 10.15154/pptr-qm29. In the past 3 years, MMW has received royalties from Oxford University Press, Perseus Books Group, American Psychiatric Association Publishing, and Multi-Health Systems. JP has received funding from Takeda (formerly Shire) and Aevi Genomics and was on an advisory board for Innovation Sciences. CA has received research funding from Sunovion Pharmaceuticals and consulted for Ono Pharmaceuticals. None of these present any conflict with the current work. All other authors report no biomedical financial interests or potential conflicts of interest. In the past 3 years, MMW has received royalties from Oxford University Press, Perseus Books Group, American Psychiatric Association Publishing, and Multi-Health Systems. JP has received funding from Takeda (formerly Shire) and Aevi Genomics and was on an advisory board for Innovation Sciences. CA has received research funding from Sunovion Pharmaceuticals and consulted for Ono Pharmaceuticals. None of these present any conflict with the current work. All other authors report no biomedical financial interests or potential conflicts of interest. Data used in the preparation of this article were obtained from the ABCD Study ( https://abcdstudy.org ), held in the National Institute of Mental Health Data Archive. This is a multisite longitudinal study designed to recruit more than 10,000 children ages 9 to 10 years and follow them over 10 years into early adulthood. The ABCD Study is supported by the National Institutes of Health and additional federal partners under award numbers U01DA041048, U01DA050989, U01DA051016, U01DA041022, U01DA051018, U01DA051037, U01DA050987, U01DA041174, U01DA041106, U01DA041117, U01DA041028, U01DA041134, U01DA050988, U01DA051039, U01DA041156, U01DA041025, U01DA041120, U01DA051038, U01DA041148, U01DA041093, U01DA041089, U24DA041123, and U24DA041147. A full list of supporters is available at https://abcdstudy.org/federal-partners.html . A listing of participating sites and a complete listing of the study investigators can be found at https://abcdstudy.org/consortium_members/ . ABCD consortium investigators designed and implemented the study and/or provided data but did not necessarily participate in the analysis or writing of this report. This manuscript reflects the views of the authors and may not reflect the opinions or views of the National Institutes of Health or ABCD consortium investigators. The ABCD Study data repository grows and changes over time. The ABCD Study data used in this report came from DOI: 10.15154/pptr-qm29 . This work was supported by the National Institute of Mental Health (Grant Nos. K99MH129611 [to MTvD], R01MH036197 [to MMW and JP], and R00MH108719 [to CA]), AFSP Young Investigator Award (Grant No. YIG-R-001-19 [to MTvD]), NARSAD Young Investigator Award from the Brain and Behavior Research Foundation (Grant No. P50MH090964 [to CA]), and Depression Center pilot awards from the Columbia University Department of Psychiatry (to AT and CA), and the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (Grant Nos. 2021R1C1C1006503 [to JC], and RS-2023-00265406 [to JC]), and by Creative-Pioneering Researchers Program through Seoul National University (Grant No. 200-20230058 [to JC]). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or any other sponsor.

Funders	Funder number
NCK
National Institutes of Health	U01DA051039, U01DA051016, U01DA051038, U01DA051018, U01DA051037, U01DA041106, U01DA041117, U01DA041028, U01DA041148, U24DA041147, U01DA041048, U01DA041025, U24DA041123, U01DA041134, U01DA041156, U01DA041089, U01DA041022, U01DA041120, U01DA041174, U01DA050987, U01DA050988, U01DA050989, U01DA041093
National Institute of Mental Health	R00MH108719, R01MH036197, K99MH129611
Brain and Behavior Research Foundation	P50MH090964
American Foundation for Suicide Prevention	YIG-R-001-19
Sunovion
National Alliance for Research on Schizophrenia and Depression
Department of Psychiatry, Columbia University
Seoul National University	200-20230058
Ministry of Science, ICT and Future Planning	RS-2023-00265406, 2021R1C1C1006503
National Research Foundation of Korea

Keywords

DTI
Dentate gyrus
Depression
Hippocampus
MRI
Maternal stress
Resilience
Susceptibility

Access to Document

10.1016/j.biopsych.2023.06.026

Cite this

van Dijk, M. T., Talati, A., Kashyap, P., Desai, K., Kelsall, N. C., Gameroff, M. J., Aw, N., Abraham, E., Cullen, B., Cha, J., Anacker, C., Weissman, M. M., & Posner, J. (2024). Dentate Gyrus Microstructure Is Associated With Resilience After Exposure to Maternal Stress Across Two Human Cohorts. Biological Psychiatry, 95(1), 27-36. https://doi.org/10.1016/j.biopsych.2023.06.026

@article{d6f74f33d4bf401fad443347883e968b,

title = "Dentate Gyrus Microstructure Is Associated With Resilience After Exposure to Maternal Stress Across Two Human Cohorts",

abstract = "Background: Maternal stress (MS) is a well-documented risk factor for impaired emotional development in offspring. Rodent models implicate the dentate gyrus (DG) of the hippocampus in the effects of MS on offspring depressive-like behaviors, but mechanisms in humans remain unclear. Here, we tested whether MS was associated with depressive symptoms and DG micro- and macrostructural alterations in offspring across 2 independent cohorts. Methods: We analyzed DG diffusion tensor imaging–derived mean diffusivity (DG-MD) and volume in a three-generation family risk for depression study (TGS; n = 69, mean age = 35.0 years) and in the Adolescent Brain Cognitive Development (ABCD) Study (n = 5196, mean age = 9.9 years) using generalized estimating equation models and mediation analysis. MS was assessed by the Parenting Stress Index (TGS) and a measure compiled from the Adult Response Survey from the ABCD Study. The Patient Health Questionnaire-9 and rumination scales (TGS) and the Child Behavior Checklist (ABCD Study) measured offspring depressive symptoms at follow-up. The Schedule for Affective Disorders and Schizophrenia–Lifetime interview was used to assign depression diagnoses. Results: Across cohorts, MS was associated with future symptoms and higher DG-MD (indicating disrupted microstructure) in offspring. Higher DG-MD was associated with higher symptom scores measured 5 years (in the TGS) and 1 year (in the ABCD Study) after magnetic resonance imaging. In the ABCD Study, DG-MD was increased in high-MS offspring who had depressive symptoms at follow-up, but not in offspring who remained resilient or whose mother had low MS. Conclusions: Converging results across 2 independent samples extend previous rodent studies and suggest a role for the DG in exposure to MS and offspring depression.",

keywords = "DTI, Dentate gyrus, Depression, Hippocampus, MRI, Maternal stress, Resilience, Susceptibility",

author = "{van Dijk}, {Milenna T.} and Ardesheer Talati and Pratik Kashyap and Karan Desai and Kelsall, {Nora C.} and Gameroff, {Marc J.} and Natalie Aw and Eyal Abraham and Breda Cullen and Jiook Cha and Christoph Anacker and Weissman, {Myrna M.} and Jonathan Posner",

note = "Publisher Copyright: {\textcopyright} 2023 Society of Biological Psychiatry",

year = "2024",

month = jan,

day = "1",

doi = "10.1016/j.biopsych.2023.06.026",

language = "אנגלית",

volume = "95",

pages = "27--36",

journal = "Biological Psychiatry",

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van Dijk, MT, Talati, A, Kashyap, P, Desai, K, Kelsall, NC, Gameroff, MJ, Aw, N, Abraham, E, Cullen, B, Cha, J, Anacker, C, Weissman, MM & Posner, J 2024, 'Dentate Gyrus Microstructure Is Associated With Resilience After Exposure to Maternal Stress Across Two Human Cohorts', Biological Psychiatry, vol. 95, no. 1, pp. 27-36. https://doi.org/10.1016/j.biopsych.2023.06.026

TY - JOUR

T1 - Dentate Gyrus Microstructure Is Associated With Resilience After Exposure to Maternal Stress Across Two Human Cohorts

AU - van Dijk, Milenna T.

AU - Talati, Ardesheer

AU - Kashyap, Pratik

AU - Desai, Karan

AU - Kelsall, Nora C.

AU - Gameroff, Marc J.

AU - Aw, Natalie

AU - Abraham, Eyal

AU - Cullen, Breda

AU - Cha, Jiook

AU - Anacker, Christoph

AU - Weissman, Myrna M.

AU - Posner, Jonathan

PY - 2024/1/1

Y1 - 2024/1/1

N2 - Background: Maternal stress (MS) is a well-documented risk factor for impaired emotional development in offspring. Rodent models implicate the dentate gyrus (DG) of the hippocampus in the effects of MS on offspring depressive-like behaviors, but mechanisms in humans remain unclear. Here, we tested whether MS was associated with depressive symptoms and DG micro- and macrostructural alterations in offspring across 2 independent cohorts. Methods: We analyzed DG diffusion tensor imaging–derived mean diffusivity (DG-MD) and volume in a three-generation family risk for depression study (TGS; n = 69, mean age = 35.0 years) and in the Adolescent Brain Cognitive Development (ABCD) Study (n = 5196, mean age = 9.9 years) using generalized estimating equation models and mediation analysis. MS was assessed by the Parenting Stress Index (TGS) and a measure compiled from the Adult Response Survey from the ABCD Study. The Patient Health Questionnaire-9 and rumination scales (TGS) and the Child Behavior Checklist (ABCD Study) measured offspring depressive symptoms at follow-up. The Schedule for Affective Disorders and Schizophrenia–Lifetime interview was used to assign depression diagnoses. Results: Across cohorts, MS was associated with future symptoms and higher DG-MD (indicating disrupted microstructure) in offspring. Higher DG-MD was associated with higher symptom scores measured 5 years (in the TGS) and 1 year (in the ABCD Study) after magnetic resonance imaging. In the ABCD Study, DG-MD was increased in high-MS offspring who had depressive symptoms at follow-up, but not in offspring who remained resilient or whose mother had low MS. Conclusions: Converging results across 2 independent samples extend previous rodent studies and suggest a role for the DG in exposure to MS and offspring depression.

AB - Background: Maternal stress (MS) is a well-documented risk factor for impaired emotional development in offspring. Rodent models implicate the dentate gyrus (DG) of the hippocampus in the effects of MS on offspring depressive-like behaviors, but mechanisms in humans remain unclear. Here, we tested whether MS was associated with depressive symptoms and DG micro- and macrostructural alterations in offspring across 2 independent cohorts. Methods: We analyzed DG diffusion tensor imaging–derived mean diffusivity (DG-MD) and volume in a three-generation family risk for depression study (TGS; n = 69, mean age = 35.0 years) and in the Adolescent Brain Cognitive Development (ABCD) Study (n = 5196, mean age = 9.9 years) using generalized estimating equation models and mediation analysis. MS was assessed by the Parenting Stress Index (TGS) and a measure compiled from the Adult Response Survey from the ABCD Study. The Patient Health Questionnaire-9 and rumination scales (TGS) and the Child Behavior Checklist (ABCD Study) measured offspring depressive symptoms at follow-up. The Schedule for Affective Disorders and Schizophrenia–Lifetime interview was used to assign depression diagnoses. Results: Across cohorts, MS was associated with future symptoms and higher DG-MD (indicating disrupted microstructure) in offspring. Higher DG-MD was associated with higher symptom scores measured 5 years (in the TGS) and 1 year (in the ABCD Study) after magnetic resonance imaging. In the ABCD Study, DG-MD was increased in high-MS offspring who had depressive symptoms at follow-up, but not in offspring who remained resilient or whose mother had low MS. Conclusions: Converging results across 2 independent samples extend previous rodent studies and suggest a role for the DG in exposure to MS and offspring depression.

KW - DTI

KW - Dentate gyrus

KW - Depression

KW - Hippocampus

KW - MRI

KW - Maternal stress

KW - Resilience

KW - Susceptibility

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Dentate Gyrus Microstructure Is Associated With Resilience After Exposure to Maternal Stress Across Two Human Cohorts

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