Study finds that a low protein diet during pregnancy causes changes in gene expression patterns in offspring that result in lasting impact on dopamine production in the brain. This dopamine imbalance can contribute to behavioural problems in adolescence and may have implications for susceptibility to conditions such as ADHD, schizophrenia, and addiction.
Diet during pregnancy can impact behaviour and mental health during adolescence and beyond, according to a study that examined the impact of a low protein diet during pregnancy on gene expression, brain development, and behaviour in mouse offspring. The research, conducted as a cross-collaboration between four groups in the MRC Laboratory of Medical Sciences (LMS), examined the impact of maternal diet on the expression of the Cdkn1c gene in offspring and found an increase in dopamine-producing neurons that lasted into adulthood. The findings highlight the importance of maternal nutrition during pregnancy and suggest links to conditions including schizophrenia, ADHD and addiction later in life.
Read the article in Scientific Reports: https://www.nature.com/articles/s41598-024-59083-7
The importance of healthy eating begins before we’re even born. It is no surprise that diet during pregnancy can have profound impacts on a child’s health, but the genetic and molecular mechanisms underpinning those impacts, and the extent of the lasting effects as a person ages, are complex and far from fully understood.
An LMS study, led by Dr Chiara Prodani with contributions from four labs (Epigenetic Memory, Lymphocyte Development, Metabolic Signalling, and Psychiatric Imaging), is helping to unpick some of the details. “The overall goal of the project was to understand how early life adversity – specifically dietary challenges during pregnancy – can have an impact on offspring at both a brain development level and a behaviour level,” she said. “We looked at the impact a low protein diet would have on particular epigenetic mechanisms, specifically imprinting, on one gene we knew was responsive to these diets from previous work.”
Epigenetics refers to factors that change how genes are expressed without altering the DNA sequence itself. Those epigenetic changes resulting from the diet caused both anatomical changes to the brain and behavioural changes in the offspring.
“We looked at behaviour at two different time points: in adolescence and later on in life,” said Dr Prodani. “We saw that there were some behavioural challenges in the juvenile mice, such as motor function, coordination and activity levels, but they mostly resolved with time. A few traits seemed to persist into adulthood, and these had to do with dopamine.”
Mice born from mothers subject to the low protein diet had increased numbers of dopaminergic neurons – neurons that produce dopamine, a chemical messenger fundamental to a wide range of brain functions. This disruption to baseline dopamine levels likely played a major role in the abnormal behaviour of adolescents, and though behaviour levelled out with age, the anatomical changes in the brain persisted.
Short term changes, long term impact
“It is a very short window in which the offspring were exposed to the low protein diet in the womb,” said study co-author Dr Andrew Dimond, “but a very important developmental window. It’s striking that it is enough to cause changes that last well into adulthood. That has big health implications.”
“We think there are short term changes that lead to an overabundance of particular cell types which are then locked in. Altering the expression of Cdkn1c alone could be sufficient to have some of these effects, but it is likely that there are more changes than just deregulation of this gene.”
Dopamine and mental health
Although behaviour of the adult mice was normal, the underlying dopamine system was compromised. This became clear when the system was stress tested with cocaine, a drug commonly used to interrogate dopamine function in experiments. When the adult mice were given the drug, the differences in baseline dopamine levels in the two groups of mice was clearly visible. “By adulthood many of the behavioural changes were not so clear,” said Dr Prodani. “But the moment you give those mice cocaine, the behaviours we saw were vastly different between normal mice and the low protein diet exposed mice. It visualized what we hypothesized might be happening as a result of the increased number of dopamine-producing neurons.”
This hypersensitivity in the mice has a clear potential correlation to risk of addiction in people, and the fundamental increase in dopamine levels in the system has analogies in human health conditions. “Elevated dopamine synthesis has been observed in people at risk of schizophrenia and similarly in people with ADHD, who have higher dopamine levels in the prefrontal cortex,” said Dr Dimond. “We’re not saying diet is definitely linked to these disorders, but we do see that low protein diet creates elevated baseline dopamine levels, and so it could be interesting to explore how this relates to the wider picture of raised dopamine levels in the brains of schizophrenia and ADHD patients.”
Making the link between a study in a mouse model centred on one particular form of epigenetic gene regulation and complex human mental health conditions is speculative. However, said Dr Prodani, there are clear parallels: “There is evidence from studies in people who were in their mothers’ womb during famine periods who had heightened risks of diseases like schizophrenia. This is a useful mouse model to study these environmental challenges and replicate some aspects of human conditions.” Although a public health message reinforcing that a healthy diet is important during pregnancy is a safe conclusion, there is a long way to go to unravel the full molecular systems at play in even this controlled scenario.
Going further “We have only scratched the surface of the molecular level of activity,” said Dr Prodani, “and it would be interesting to investigate broader gene expression impacts. There’s also the question of mitigation; there’s some evidence that supplementing the diet with folate might counter some of the disruption in Cdkn1c imprinting. Could it help recover some of those unusual behaviours as well?”
Beyond the findings themselves, the study forms part of a cohort of recent work from the LMS refining and proving the value of a new set of techniques which could be used very widely.
Immunofluorescence of tyrosine hydroxylase (TH) (an enzyme key to dopamine production, used as a marker of dopaminergic neurons) positive cells (green) in representative midbrain tissue sections of juvenile and adult mice (4–5 and 9–10 weeks of age, respectively) exposed to the control diet or low protein dietin utero. There were more of these cells in the brains of mice which had been exposed to low protein diet.
“The bioluminescent reporter aspect of the gene disruption is potentially also a great tool for others to use,” said Dr Dimond. The team linked a firefly bioluminescence gene to those they were studying, allowing them to see the expression levels of that gene across the life course. “When the subjects were exposed to a low protein diet,” continued Dr Dimond, “this gene, which is normally silent so doesn’t show up much, was activated abnormally. You can visualize that very clearly by bioluminescence.” Crucially this approach allows epigenetic disruption to be tracked in living mice and followed in offspring and even in subsequent generations.
With findings that hint at significant long-term health implications, and a set of experimental tools that could be turned to any number of future investigations, this work from across the LMS ecosystem is just the start.
