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Early-Life Stress Reprograms Stress-Coping Abilities in Male and Female Juvenile Rats

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Abstract

Prenatal stress (PS) is a major risk factor for the development of emotional disorders in adulthood that may be mediated by an altered hypothalamic–pituitary–adrenal axis response to stress. Although the early onset of stress-related disorders is recognized as a major public health problem, to date, there are relatively few studies that have examined the incidence of early-life stressors in younger individuals. In this study, we assessed PS impact on the stress-coping response of juvenile offspring in behavioral tests and in the induced molecular changes in the hippocampus. Furthermore, we assessed if pregnancy stress could be driving changes in patterns of maternal behavior during early lactation. We found that PS modified stress-coping abilities of both sex offspring. In the hippocampus, PS increased the expression of bdnf-IV and crfr1 and induced sex difference changes on glucocorticoids and BDNF mRNA receptor levels. PS changed the hippocampal epigenetic landscape mainly in male offspring. Stress during pregnancy enhanced pup-directed behavior of stressed dams. Our study indicates that exposure to PS, in addition to enhanced maternal behavior, induces dynamic neurobehavioral variations at juvenile ages of the offspring that should be considered adaptive or maladaptive, depending on the characteristics of the confronting environment. Our present results highlight the importance to further explore risk factors that appear early in life that will be important to allow timely prevention strategies to later vulnerability to stress-related disorders.

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Data Availability

The data support the findings of this research are available from the corresponding author (mpallares@fmed.uba.ar) upon reasonable request. The authors will take the responsibility for maintaining availability.

Abbreviations

5-hmC:

5-Hydroxymethylcytosine

5-mC:

5-Methylcytosine

ANOVA:

Analysis of variance

BDNF:

Brain-derived neurotrophic factor

C:

Control group

CRF:

Corticotrophin-releasing factor

CRFR1:

Corticotrophin-releasing factor receptor 1

DNMT:

DNA methyl transferase

EPM:

Elevated plus maze behavioral test

FI:

Fragmentation index for maternal behavior assessment

FST:

Forced swimming behavioral test

GR:

Glucocorticoid receptor

HPA:

Hypothalamic-pituitary-adrenal axis

LDB:

Light-dark box behavioral test

MR:

Mineralocorticoid receptor

p75-NTR:

P75 neurotrophin receptor

PND:

Postnatal day

PS:

Prenatal stress group

qPCR:

Polymerase chain reaction

RA:

Risk assessment

SHRP:

Stress hypo-responsive period

SEM:

Standard error of the mean

TET:

Ten-eleven translocation proteins

TrkB:

Neurotrophic receptor tyrosine kinase 2

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Acknowledgements

The authors greatly appreciate the technical assistance of Ms. Susana Buglione, Ms. Mercedes Imsem, and Dr. Silvia Billi for technical assistance. M.E.P., M.C.M., V.P., A.A., M.A.B., and M.C.A. are researchers from CONICET. J.G.B. is an undergraduate student from Universidad de Buenos Aires.

Funding

This research was financially supported by the Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT, PICT 2015/BID 2469 to MEP), by CONICET (grant PIP 0249/12 and 0717/2015 to MCA) and by the UNSAM (Grants 2014- 2015 to MAB).

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Authors and Affiliations

  1. Laboratorio de Neuroprogramación Perinatal del Neurodesarrollo, Instituto de Biología Celular Y Neurociencias “Prof. Eduardo De Robertis” (IBCN)- Facultad de Medicina, Universidad de Buenos Aires, 2155 Paraguay St. CABA, C1121ABG, Buenos Aires, Argentina

    María Eugenia Pallarés, Verónica Pastor, Jazmín Grillo Balboa & Marta Cristina Antonelli

  2. Instituto de Investigaciones Biotecnológicas (IIB), Universidad Nacional de San Martín, Buenos Aires, Argentina

    Melisa Carolina Monteleone & Marcela Adriana Brocco

  3. Instituto Multidisciplinario de Biología Celular, Universidad Nacional de La Plata, Buenos Aires, Argentina

    Ana Alzamendi

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  1. María Eugenia Pallarés
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  2. Melisa Carolina Monteleone
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Contributions

M.E.P. designed, performed, analyzed all the experiments, and wrote the manuscript. M.C.M. helped with the development of real-time qPCR and chromatin remodeling experiments. V.P. helped with the development of prenatal stress protocol. J.G.B. analyzed behavioral data from maternal behavior. A.A. performed RIA analyses to detect corticosterone levels in serum. M.A.B. supervised the design, development, and analyses of molecular experiments. M.C.A. supervised the whole study design, development, and data analyses. M.C.A. also contributed to the final version of the paper. All authors made manuscript revisions and approved the submitted version.

Corresponding author

Correspondence to María Eugenia Pallarés.

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This research was performed in accordance with the standards for the care of laboratory animals as outlined in the NIH Guide for the Care and Use of Laboratory Animals (NIG Publications No. 8023, revised 1978). All protocols were approved by the Institutional Animal Care and Use Committee (CICUAL), Facultad de Medicina (School of Medicine), Universidad de Buenos Aires.

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Pallarés, M.E., Monteleone, M.C., Pastor, V. et al. Early-Life Stress Reprograms Stress-Coping Abilities in Male and Female Juvenile Rats. Mol Neurobiol 58, 5837–5856 (2021). https://doi.org/10.1007/s12035-021-02527-2

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  • DOI: https://doi.org/10.1007/s12035-021-02527-2

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