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Prenatal Hypoxia-Induced Adverse Reaction to Mild Stress is Associated with Depressive-Like Changes in the Glucocorticoid System of Rats

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Abstract

The effects of prenatal hypoxia on neurodevelopment are predominantly associated with impaired maternal glucocorticoid stimulation of the fetus, which is "imprinted" in altered sensitivity of glucocorticoid reception in brain structures of offspring and can affect brain plasticity during lifespan. This study aimed to investigate response of the brain glucocorticoid system to mild stress (MS) in adult rats that survived prenatal severe hypoxia (PSH) on embryonic days 14-16. In response to MS the control (but not PSH) rats demonstrate increased corticosterone levels, a decrease in exploratory activity and increased anxiety. In the raphe nuclei of adult PSH rats the expression of glucocorticoid receptors (GR) is increased without changes in serotonin levels in comparison with the control. MS induces a decrease in GR expression accompanied by up-regulation of tryptophan hydroxylase 2 (tph2) and down-regulation of monoamine oxidase A (maoa) transcription in the raphe nuclei of both control and PSH groups. PSH also causes significant deviations in GR expression and GR-dependent transcription in the hippocampus, the medial prefrontal cortex, but not in the amygdala of rats. However, in response to MS, PSH rats demonstrate mild changes in their activity, while in control animals the MS-induced activity of the glucocorticoid system in these brain structures is similar to intact PSH animals. Impaired activity of the glucocorticoid system in the extrahypothalamic brain structures of PSH rats is accompanied by increase in the hypothalamic corticotropin-releasing hormone (CRH) levels in comparison with the control regardless of MS. Synthesis of proopiomelanocortin (POMC) and release of adrenocorticotropic hormone (ACTH) into the blood are decreased in response to MS in the pituitary of control rats, which demonstrates a negative glucocorticoid feedback mechanism. Meanwhile, in the pituitary of PSH rats reduced POMC levels were found regardless of MS. Thus, prenatal hypoxia causes depression-like patterns in the brain glucocorticoid system with adverse reaction to mild stressors.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Abbreviations

ACTH:

Adrenocorticotropic hormone

AMG:

Amygdala

CHRNA7:

Cholinergic receptor nicotinic alpha 7 Subunit

CRH:

Corticotropin-releasing hormone

CRHR1:

Corticotropin-releasing hormone receptor 1

GR (NR3C1):

Glucocorticoid receptor (nuclear receptor subfamily 3, group C, member 1)

CS:

Corticosterone

HPAA:

Hypothalamic–pituitary–adrenal axis

HPC:

Hippocampus

HT:

Hypothalamus

MAOA:

Monoamine oxidase A

MS:

Mild stress

PFC:

Prefrontal cortex (medial)

POMC:

Proopiomelanocortin

PSH:

Prenatal severe hypoxia

PT:

Pituitary

RN:

Raphe nuclei (dorsal)

TPH2:

Tryptophan hydroxylase 2

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Acknowledgements

iBright™ FL1500 Imaging System was kindly provided by Scientific Park of the Russian department of the Thermo Scientific Company. The authors are deeply grateful to Mrs. Elena Axenova for her excellent technical assistance in experiments on animal models.

Funding

The work has been supported by the Ministry of Education and Science of the Russian Federation (Agreement no. 075-15-2020-921 of 13.11.2020) in the framework of the Project of World-class research center Pavlov Center “Integrative Physiology to Medicine, High-Tech Healthcare and Technologies of Stress Resistance”, section “Biological and Social Basis of Inclusion”. OV received support from the Russian Science Foundation, grant No. 22-75-00003 (RT PCR experiments).

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Authors and Affiliations

  1. Laboratory of Regulation of Brain Neuronal Functions, Pavlov Institute of Physiology, Russian Academy of Sciences, Makarova Emb. 6, 199034, Saint-Petersburg, Russia

    Oleg Vetrovoy, Viktor Stratilov & Ekaterina Tyulkova

  2. Department of Biochemistry, Faculty of Biology, Saint Petersburg State University, Universitetskaya Emb. 7-9, 199034, Saint- Petersburg, Russia

    Oleg Vetrovoy

  3. Group of Molecular Genetics of Tumor Cells, Institute of Cytology, Russian Academy of Sciences, Tihoretsky Pr. 4, 194064, Saint-Petersburg, Russia

    Ekaterina Lomert

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OV—designed experiments; OV, VS, EL, ET—performed experiments; OV, VS—analyzed data; OV, VS, ET—wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Oleg Vetrovoy.

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Animal experiments were carried out according to The Guidelines for Reporting Animal Research [31]. Experimental protocols were approved by the local ethical committee at the Pavlov Institute of Physiology.

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Vetrovoy, O., Stratilov, V., Lomert, E. et al. Prenatal Hypoxia-Induced Adverse Reaction to Mild Stress is Associated with Depressive-Like Changes in the Glucocorticoid System of Rats. Neurochem Res 48, 1455–1467 (2023). https://doi.org/10.1007/s11064-022-03837-0

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