Maternal Chronic Ultrasound Stress Provokes Immune Activation and Behavioral Deficits in the Offspring: A Mouse Model of Neurodevelopmental Pathology

Abstract

Neurodevelopmental disorders stemming from maternal immune activation can significantly affect a child’s life. A major limitation in pre-clinical studies is the scarcity of valid animal models that accurately mimic these challenges. Among the available models, administration of lipopolysaccharide (LPS) to pregnant females is a widely used paradigm. Previous studies have reported that a model of ‘emotional stress’, involving chronic exposure of rodents to ultrasonic frequencies, induces neuroinflammation, aberrant neuroplasticity, and behavioral deficits. In this study, we explored whether this model is a suitable paradigm for maternal stress and promotes neurodevelopmental abnormalities in the offspring of stressed females. Pregnant dams were exposed to ultrasound stress for 21 days. A separate group was injected with LPS on embryonic days E11.5 and E12.5 to mimic prenatal infection. The behavior of the dams and their female offspring was assessed using the sucrose test, open field test, and elevated plus maze. Additionally, the three-chamber sociability test and Barnes maze were used in the offspring groups. ELISA and qPCR were used to examine pro-inflammatory changes in the blood and hippocampus of adult females. Ultrasound-exposed adult females developed a depressive-like syndrome, hippocampal overexpression of GSK-3β, IL-1β, and IL-6 and increased serum concentrations of IL-1β, IL-6, IL-17, RANTES, and TNFα. The female offspring also displayed depressive-like behavior, as well as cognitive deficits. These abnormalities were comparable to the behavioral changes induced by LPS. The ultrasound stress model can be a promising animal paradigm of neurodevelopmental pathology associated with prenatal ‘emotional stress’.

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“…1 A). US-groups of mice were subjected to a 21-day exposure of ultrasound of unpredictably alternating frequencies as described elsewhere ( Gorlova et al, 2019 ; Pavlov et al, 2023 ; see below). Concomitantly with US-exposure, mice assigned to FS-treated groups were housed on a custom-made diet containing FS, or on custom-made diet containing vehicle.…”

“…US procedure was carried out as described elsewhere ( Strekalova et al, 2018 ; Pavlov et al, 2019 , 2023 ). For a 21-day period, ultrasound radiation of average intensity of 50 ± 5 dB and variable frequencies in a 20–45 Hz range was constantly delivered within a laboratory environment to experimental groups of mice using a random schedule of alternating frequencies via a commercially available device (Weitech, Wavre, Belgium).…”

“…All samples were run in triplicate. Data were normalized to GAPDH mRNA expression and calculated as relative-fold changes compared to control vehicle-treated mice, as described elsewhere ( Gorlova et al, 2019 ; Pavlov et al, 2019 , 2023 ).…”

“…For example, mice emit sounds in the range of 20–25 kHz in life-threatening situations, such as maternal separation, predation, social defeat, or pain (reviewed in Gorlova et al, 2023 ). Our previous studies have shown that adult mice exposed to this frequency range (20–25 kHz) exhibited depressive-like and anxiety-like behaviors, in addition to physiological, hormonal and molecular changes, including neuroinflammation and oxidative stress ( Strekalova et al, 2018 ; Gorlova et al, 2019 , 2023 ; Pavlov et al, 2019 , 2023 ; Sambon et al, 2020 ; de Munter et al, 2021 ). More specifically, exposure to artificially generated ultrasound (20–25 kHz) in male mice was associated with upregulated corticosterone levels ( Pavlov et al, 2019 ), activated hippocampal microglia, upregulated IL-1β and IL-6 production locally in the hippocampus and within the systemic circulation ( Costa-Nunes et al, 2020 ; de Munter et al, 2021 ; Pavlov et al, 2023 ), and increased content of protein carbonyl in limbic structures, which is a marker of oxidative stress ( Gorlova et al, 2019 ; Sambon et al, 2020 ).…”

“…Our previous studies have shown that adult mice exposed to this frequency range (20–25 kHz) exhibited depressive-like and anxiety-like behaviors, in addition to physiological, hormonal and molecular changes, including neuroinflammation and oxidative stress ( Strekalova et al, 2018 ; Gorlova et al, 2019 , 2023 ; Pavlov et al, 2019 , 2023 ; Sambon et al, 2020 ; de Munter et al, 2021 ). More specifically, exposure to artificially generated ultrasound (20–25 kHz) in male mice was associated with upregulated corticosterone levels ( Pavlov et al, 2019 ), activated hippocampal microglia, upregulated IL-1β and IL-6 production locally in the hippocampus and within the systemic circulation ( Costa-Nunes et al, 2020 ; de Munter et al, 2021 ; Pavlov et al, 2023 ), and increased content of protein carbonyl in limbic structures, which is a marker of oxidative stress ( Gorlova et al, 2019 ; Sambon et al, 2020 ). Notably, ultrasound (US)-exposed male mice developed prominent depressive-like and anxiety-like behavioral changes ( Strekalova et al, 2018 ; Sambon et al, 2020 ; de Munter et al, 2021 ) that were counteracted by long-term administration of the classic antidepressant fluoxetine ( Morozova et al, 2016 ) and by treatments with antioxidants ( Sambon et al, 2020 ; Costa-Nunes et al, 2020 ; de Munter et al, 2021 ).Thus, US provides a closer analogy to human emotional stressors and recapitulates the key features of MDD and their pharmacological sensitivity in adult rodents.…”