Prenatal Immune and Endocrine Modulators of Offspring's Brain Development and Cognitive Functions Later in Life

Abstract

Milestones of brain development in mammals are completed before birth, which provide the prerequisite for cognitive and intellectual performances of the offspring. Prenatal challenges, such as maternal stress experience or infections, have been linked to impaired cognitive development, poor intellectual performances as well as neurodevelopmental and psychiatric disorders in the offspring later in life. Fetal microglial cells may be the target of such challenges and could be functionally modified by maternal markers. Maternal markers can cross the placenta and reach the fetus, a phenomenon commonly referred to as “vertical transfer.” These maternal markers include hormones, such as glucocorticoids, and also maternal immune cells and cytokines, all of which can be altered in response to prenatal challenges. Whilst it is difficult to discriminate between the maternal or fetal origin of glucocorticoids and cytokines in the offspring, immune cells of maternal origin—although low in frequency—can be clearly set apart from offspring's cells in the fetal and adult brain. To date, insights into the functional role of these cells are limited, but it is emergingly recognized that these maternal microchimeric cells may affect fetal brain development, as well as post-natal cognitive performances and behavior. Moreover, the inheritance of vertically transferred cells across generations has been proposed, yielding to the presence of a microchiome in individuals. Hence, it will be one of the scientific challenges in the field of neuroimmunology to identify the functional role of maternal microchimeric cells as well as the brain microchiome. Maternal microchimeric cells, along with hormones and cytokines, may induce epigenetic changes in the fetal brain. Recent data underpin that brain development in response to prenatal stress challenges can be altered across several generations, independent of a genetic predisposition, supporting an epigenetic inheritance. We here discuss how fetal brain development and offspring's cognitive functions later in life is modulated in the turnstile of prenatal challenges by introducing novel and recently emerging pathway, involving maternal hormones and immune markers.

Risk of cognitive impairment in children after maternal exposure to the 1998 Yangtze River flood during pregnancy: analysis of data from China's second National Sample Survey on Disability

“…19 Vertical transfer of maternal stress hormones such as glucocorticoids via the placenta might also affect the development of the fetal brain, as well as postnatal cognitive performance and behaviour. 20 Epigenetic changes, such as DNA methyla tion, resulting from prenatal maternal stress are also crucial mechanisms that could increase the risk of developmental disabilities in children. 21 The interaction between altered maternal health behaviours and a compromised maternal immune system or intestinal microbiota, or both, as well as compromised placental functioning are also potential underlying mechanisms.…”

Synaptic Formation, Neural Circuits and Neurodevelopmental Disorders Controlled by Signaling, Translation, and Epigenetic Regulation

“…Environmental factors influence neuronal development and activity, and they have a considerable impact on neurodevelopmental disorders. Serious infection and exposure to psychoactive or addictive drugs during early development are two well-known environmental factors highly relevant to neuropsychiatric disorders (Frank et al, 2001;Patterson, 2011;Boulanger-Bertolus et al, 2018;Mueller et al, 2018;Schepanski et al, 2018). Maternal immune activation increases the likelihood of offspring developing schizophrenia and ASD via both innate and adaptive immune responses (Choi et al, 2016;Filiano et al, 2016;Kugelberg, 2016;Wu et al, 2017).…”

Associations between autistic-like traits and polymorphisms in NFKBIL1

“…This also means that the developing brain is highly sensitive to both endogenous and exogenous signals. Experiences during the pre-and postnatal period, including nutrition, trauma, stress and infection, have been strongly connected to alterations in neural circuits and associated behavioural outcomes [30][31][32][33] .…”

“…However, these changes can also be more subtle, leading to neurodevelopmental disorders that are noted early in life, as well as mood disorders such as depression that may not be apparent until adulthood. An increasing body of evidence is connecting maternal immune activation with a broad spectrum of CNS disorders in humans 31,32,62 . Possibly, it is not the specific pathogen causing an infection that determines the neurological and cognitive outcome in the offspring; the diversity of causes associated with increased risks of mental disorders suggests that general immune activation during gestation, rather than the type of pathogen, is associated with disturbances of fetal brain development causing debilitating effects later in life.…”

“…Maternal risk factors such as infection 62 , psychosocial stress 63 , genetic predisposition 64 and autoimmunity 65 can cause immune activation and changes in expression of cytokines, auto-antibodies against fetal proteins and/or other immune-related genes. This may lead to increased amounts of maternal markers crossing the placenta, including cytokines, immune cells, and stress hormones 31 , possibly causing effects on the fetus such as aberrant development of the immune, neurotransmitter, and endocrine systems (e.g. altered stress response).…”