Mom matters: Expound the influence of the interaction between maternal 5-HTT genotype and maternal care on offspring’s individual neurodevelopment

Project Information

PARENT

Grant agreement ID: 101105971

DOI

10.3030/101105971

Project closed

EC signature date 15 March 2023

Start date 15 April 2023

End date 14 April 2025

Funded under

• Marie Skłodowska-Curie Actions (MSCA)

Total cost

No data

EU contribution

€ 203 464,32

Coordinated by

STICHTING RADBOUD UNIVERSITAIR MEDISCH CENTRUM
Netherlands

Periodic Reporting for period 1 - PARENT (Mom matters: Expound the influence of the interaction between maternal 5-HTT genotype and maternal care on offspring’s individual neurodevelopment)

Reporting period: 2023-04-15 to 2025-04-14

Summary of the context and overall objectives of the project

Serotonin (5-HT), partially regulated by the 5-HT transporter (5-HTT), acts as both a neurotransmitter and a neurotrophic factor. In humans, the low-activity allelic variant of the 5-HTT-linked polymorphic region (5-HTTLPR s-allele) is associated with elevated 5-HT levels, which are linked to increased anxiety and heightened sensitivity to environmental stimuli. This allele is present in approximately 15% to 19% of the human population and is of particular interest due to its influence on stress reactivity and susceptibility to mental health conditions such as anxiety disorders and neurodevelopmental disorders (NDDs).

Emerging evidence suggests that maternal 5-HT levels can affect offspring neurodevelopment not only through genetic inheritance but also through environmental pathways. These include prenatal exposure via the placenta and postnatal influences through maternal behavior. While genetic predispositions cannot be changed, maternal care is a modifiable factor. This makes it a promising target for early-life interventions aimed at improving developmental outcomes and reducing the risk of NDDs.

This project aims to investigate whether environmental enrichment can improve maternal care and, in turn, promote better neurodevelopment in offspring, particularly in the context of altered serotonin levels.
In this study, the well-established 5-HTT knockout (5-HTT−/−) rats are used to model humans with the HTTLPR s-allele. I examined how offspring were affected by maternal genotypes (5-HTT+/+ vs. 5-HTT-/-) and housing conditions (standard vs. enriched). Behavioral assessments, including ultrasonic vocalization (USV) analysis, are conducted from infancy through adulthood to capture developmental trajectories.

Preliminary findings suggest that elevated 5-HT levels impair motor function in early life and contribute to increased anxiety and altered cognitive function in later developmental stages, such as young adulthood. Importantly, maternal care plays a key role in shaping these outcomes in a sex-dependent manner. Ongoing analyses seek to determine whether environmental enrichment can mitigate genotype-related deficits in maternal care and serve as a non-pharmacological intervention to support offspring development.

This project highlights the importance of gene–environment interactions and modifiable early-life conditions in shaping lifelong mental health trajectories, and ultimately contributes to the growing emphasis on preventive and personalized interventions that support maternal and child well-being.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

This project investigated how maternal 5-HTT genotype, maternal behavior, and environmental enrichment influence offspring neurodevelopment using a well-established rat model.

Maternal care behaviors were recorded in mothers with different 5-HTT genotypes (5-HTT+/+ and 5-HTT−/−) housed under standard and enriched cages. Clear genotype-dependent differences were observed: 5-HTT+/+ mothers displayed more active communicative behaviors such as licking and grooming, whereas 5-HTT−/− mothers spent more time nursing.

Offspring development was carefully assessed from infancy to adulthood across both housing conditions. Early sensorimotor and reflex tests demonstrated developmental delays in 5-HTT−/− pups. Environmental enrichment improved outcomes for 5-HTT+/+ and 5-HTT+/− pups but had limited benefits for 5-HTT−/− animals. To examine early communicative behavior, maternal separation-induced ultrasonic vocalizations (USVs), a key communicative behavior for pup survival, were recorded at critical early developmental stages to evaluate altered communication patterns linked to genotype and environment.

Anxiety-like, exploratory, social communication, and memory functions were measured during the juvenile and adult stages. As expected, 5-HTT−/− offspring showed higher anxiety levels. In 5-HTT+/− pups, their emotional responses were influenced by maternal genotype, especially in females. Cognitive testing indicated enhanced short-term memory and exploration in 5-HTT−/− offspring. Further effects of environmental enrichment are still being analyzed.

Overall, these results highlight complex interactions between genes, environment, and maternal care. Environmental enrichment can mitigate or exacerbate developmental trajectories depending on genotype and sex.

In addition, brain samples were collected from offspring following behavioral testing to investigate the neural basis associated with these neurodevelopmental changes. These samples are prepared for future analysis using advanced imaging and molecular approaches to map brain-wide neuronal activation linked to genotype, behavior, and environment.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

This project has advanced our understanding of how neurodevelopment is shaped by the interplay between maternal genetics, caring behavior, and environmental conditions. Using a rat model, it investigated how variations in the 5-HTT in mothers, along with differences in maternal care and environmental enrichment, influence the emotional, communicative, and cognitive trajectories of offspring.

The findings revealed clear genotype-dependent differences in maternal behavior, which had significant effects on offspring outcomes. Offspring exposed to altered maternal care showed increased anxiety and changes in exploratory and cognitive behaviors. Environmental enrichment generally promoted positive developmental outcomes, especially in certain genotypes, sexes, and stages, but its effects were not universally beneficial. Offspring with some genetic backgrounds did not experience the same improvements, at least in the early developmental stage.

These results reveal that the interactions of maternal genotypes, maternal care, and environments are more complex than previously assumed. Rather than being uniformly beneficial, enrichment or caregiving may interact with genetic predispositions in complex ways. This underscores the need for more precise and personalized approaches to early-life support, particularly for those at high risk due to genetic or environmental factors.

The project challenges simplified views of enrichment or caregiving as universally beneficial, highlighting the importance of tailoring developmental support based on individual profiles. These insights go beyond the current state of the art by emphasizing the conditional nature of developmental influences and the need for individualized perspectives in both research and intervention. They are highly relevant to public health and child development strategies, contributing to European objectives related to mental health, resilience, and early-life support.