Prenatal Stress Impairs Postnatal Learning and Memory Development via Disturbance of the cGMP–PKG Pathway and Oxidative Phosphorylation in the Hippocampus of Rats

Abstract

Clinical and animal studies have found that prenatal stress can lead to pathological changes in embryos and fetuses. However, the mechanisms through which this occurs have not been made clear. In the present study, pregnant rats were subjected to chronic psychological stress during gestational days using an improved communication box system, and the changes in behavioral performance and proteins in the hippocampus of offspring were analyzed. It was found that prenatal stress caused postnatal growth retardation and impairment in spatial learning and memory. Furthermore, in isobaric tags for relative and absolute quantitation-based proteomics analyses, 158 significantly differentially expressed proteins (DEPs) were found between the two groups. Further analyses showed that these DEPs are involved in different molecular function categories and participate in several biological processes, such as energy metabolism, learning or memory, and synaptic plasticity. Moreover, the enrichment of pathways showed that the learning and memory impairment was primarily connected with the cyclic guanosine monophosphate-protein kinase G (cGMP-PKG) pathway and oxidative phosphorylation. At the same time, the cGMP level and the expression of PKG protein were significantly decreased, and the neuronal mitochondria appeared to have a swollen and irregular shape in the hippocampus of offspring of stressed rats. These results suggest that the chronic psychological stress that pregnant rats were subjected to during gestational days may have impaired the spatial learning and memory of offspring. This affected the hippocampal oxidative phosphorylation and inhibited the cGMP-PKG pathway.

Identification of potential key circular RNAs related to cognitive impairment after chronic constriction injury of the sciatic nerve

“…Meanwhile, the KEGG enrichment analysis indicated that the upregulated circRNAs were mainly enriched in the MAPK, cGMP-PKG and Wnt signaling pathways, and the downregulated circRNAs were primarily enriched in the PI3K-Akt, MAPK and AMPK signaling pathways. These signaling pathways have been validated to be closely related to inflammation and apoptosis ( Suo et al, 2018 ; Chen et al, 2019 ; Gabbouj et al, 2019 ; Sun Q. Y. et al, 2019 ; Li et al, 2020 ; Yue and Lopez, 2020 ; Liu X. Y. et al, 2021 ), further indicating that neuroinflammation and apoptosis might play vital roles in the development of cognitive deficits after CCI. Additionally, the miRNAs and targeted genes associated with the typical upregulated and downregulated circRNAs were further identified.…”

“…The downregulated circRNAs were mainly enriched in the PI3K-Akt, MAPK, AMPK, and Jak-STAT signaling pathways ( Figure 2E ). Of note, these processes and pathways were reported to be associated with inflammation and apoptosis in the development of cognitive deficits ( Suo et al, 2018 ; Chen et al, 2019 ; Sun Q. Y. et al, 2019 ; Feng et al, 2020 ; Li et al, 2020 ; Liu X. Y. et al, 2021 ).…”

Preclinical animal models of mental illnesses to translate findings from the bench to the bedside: Molecular brain mechanisms and peripheral biomarkers associated to early life stress or immune challenges

“…To understand the negative effects of PNS on the offspring's learning and memory behavioral deficits, Li and collaborators have recently analyzed the hippocampal protein profiles of offspring whose mothers were exposed to PNS, in terms of chronic fear stress during pregnancy, compared to control animals (Li et al, 2020).…”

Revisiting the sigma-1 receptor as a biological target to treat affective and cognitive disorders

“…All mentioned animal models cause memory deficits that differ in severity and memory type affected (for more information on animal models of memory deficits please see Gallagher, 1997 ; Götz and Götz, 2009 ; More et al, 2016 ; van der Staay et al, 2011 ). They may be a result of impaired cholinergic (scopolamine), glutamatergic (dizocilpine, phencyclidine) or serotonergic neurotransmission (para-chlorophenylalanine), neurons death ( β -amyloid(25–35)-peptide, 192 IgG-saporin, trimethyltin, ibotenic acid, carbon monoxide (CO), brain ischemia, olfactory bulbectomy), oxidative stress (cocaine) or oxidative phosphorylation (prenatal stress) (for more information on animal models of cognitive impairments please see Beraki et al, 2009 ; Cheng et al, 2012 ; Deryabina et al, 2020 ; Li et al, 2020 ; Muriach et al, 2010 ; Nakajima et al, 2007 ; Pepeu, 2004 ; van der Staay et al, 2011 ).…”