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.

Keywords: cytokines; epigenetic aberrations; fetal brain development; glucocorticoids (GC); maternal distress; maternal microchimeric cells; pregnancy; prenatal infection.

Figure 1

Milestones of brain development in mice and humans. In both species, brain development commences with neurulation, a process creating the neural tube. This provides the prerequisite for the subsequent production of neuron from neural stem cells, a process defined as neurogenesis. Early during human development, at gestation week 4, the anterior part of the neural tube begins to form into distinct regions. The forebrain, midbrain and hindbrain are defined as the anterior part; the spinal cord is located at the posterior part. Two weeks later, the neural tube can be clearly divided into the brain regions that are present at birth. Some of the previously produced neurons now start to migrate to distinct brain regions, a process that continues until approx. week 26. Earlier by week 11, the cerebrum has developed—more rapidly than other structures—and largely covers the entire brain, except cerebellum and medulla oblongata. Due to its progressive development within the cranium, the cerebrum is forced to convolve itself resulting in gyri and sulci (51). During the second trimester of pregnancy, several processes start to define brain connectivity. These include synaptogenesis, gliogenesis, and apoptosis. Simultaneously, microglial cells invasion begins. By mid-third trimester, the fine-tuning of neuronal connectivity starts with proliferation of myelin sheaths throughout the neurons of the central nervous system (52). Shortly after birth, the previously established neuronal connections are reduced based on neuronal activity, meaning a reduction of neuronal connections to the ones often used. Since murine gestation is much shorter compared to human pregnancy, some developmental steps continue to proceed after birth. In mice, neural development begins during mid-pregnancy, followed by neurulation and formation of the neural tube (53). Subsequently, production of neurons, their migration and the formation of synapses occur almost simultaneously. Also, yolk sac-derived microglial cells invade the fetus starting on day 9 of pregnancy (54). The developmental milestones underlying brain development in mice and humans are highly susceptible to challenges and can be modulated by maternal markers vertically transferred during pregnancy. Hereby, the time point and intensity of the challenges clearly determine the impact and damage they may cause.

Figure 2

Consequences of cytokine and glucocorticoid surges on distinct areas of the offspring's brain. Maternal cytokines and glucocorticoids can transplacentally cross into the fetus and differentially affect offspring's brain development by interfering with e.g., cell differentiation, axonal growth, and synaptic connectivity. The brain regions depicted here are of pivotal relevance for mental health due to their involvement in cognitive functions. Compared to physiological conditions, prenatal surges of maternal cytokines increase the number of neuronal connections in a subdivision of the prefrontal cortex, whereas glucocorticoids decreases them (105, 119). Additionally, prenatal glucocorticoid exposure decreases prefrontal cortical volume. In the hippocampus, an increase of cytokines is known to increase the number of microglial cells in the corn ammonis area 1 (CA1), whilst simultaneously reducing dendritic arborizations and neuronal complexity (111). Similarly, in the CA3 and dentate gyrus (DG) of the hippocampus, the microglia density increases after cytokine exposure. Also glucocorticoid surges deteriorate the neuronal complexity in CA1 and CA3 (109, 110) and have been shown to increases the number of microglia in DG. Both, cytokines and glucocorticoids can decrease total hippocampal volume, neurogenesis and synaptic connections. Prenatal cytokine surges can also decrease the amygdala volume, whereas glucocorticoids have been shown to increase the number of neurons and microglia. There is no evidence that the central nucleus (CN) of the amygdala is affected, but an increased microglia density after prenatal cytokine and glucocorticoid exposure has been detected in the lateral nucleus (LN) (120, 121). Contrarily, an increased number of neuronal connections and microglia was detectable upon glucocorticoid challenge in the basolateral nucleus (BLN).

Figure 3

Prenatal challenges and related alterations of immune and endocrine markers can prime postnatal neurodevelopmental disorders. Maternal well-being and health can be challenged during pregnancy, e.g., by distress or infection. This subsequently leads to increased cytokines and glucocorticoids levels and potentially to altered frequencies or phenotypes of maternal microchimeric cells in the offspring. Upon entering the fetal brain, such vertically transferred maternal modulators can significantly interfere with physiologically occurring brain development. A combination of genetic susceptibility and disturbed brain development can subsequently increase the risk for neurodevelopmental disorders in childhood. Subsequent postnatal environmental challenges —drug abuse, trauma, infection, others—may perpetuate such prenatally triggered risk for neurodevelopmental disorders, psychiatric and neurological diseases during adolescence and adulthood, which can also be passed on to the next generation.