The interplay of early-life stress, nutrition, and immune activation programs adult hippocampal structure and function Hoeijmakers, L.; Lucassen, P.J.; Korosi, A. Published in: Frontiers in Molecular Neuroscience DOI: 10.3389/fnmol.2014.00103 Link to publication Citation for published version (APA): Hoeijmakers, L., Lucassen, P. J., & Korosi, A. (2014). The interplay of early-life stress, nutrition, and immune activation programs adult hippocampal structure and function. Frontiers in Molecular Neuroscience, 7, 103. https://doi.org/10.3389/fnmol.2014.00103 General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. Early-life adversity increases the vulnerability to develop psychopathologies and cognitive decline later in life. This association is supported by clinical and preclinical studies. Remarkably, experiences of stress during this sensitive period, in the form of abuse or neglect but also early malnutrition or an early immune challenge elicit very similar long-term effects on brain structure and function. During early-life, both exogenous factors like nutrition and maternal care, as well as endogenous modulators, including stress hormones and mediator of immunological activity affect brain development. The interplay of these key elements and their underlying molecular mechanisms are not fully understood. We discuss here the hypothesis that exposure to early-life adversity (specifically stress, under/malnutrition and infection) leads to life-long alterations in hippocampal-related cognitive functions, at least partly via changes in hippocampal neurogenesis. We further discuss how these different key elements of the early-life environment interact and affect one another and suggest that it is a synergistic action of these elements that shapes cognition throughout life. Finally, we consider different intervention studies aiming to prevent these early-life adversity induced consequences. The emerging evidence for the intriguing interplay of stress, nutrition, and immune activity in the early-life programming calls for a more in depth understanding of the interaction of these elements and the underlying mechanisms. This knowledge will help to develop intervention strategies that will converge on a more complete set of changes induced by early-life adversity. Keywords: hippocampus, neurogenesis, cognition, early-life stress, early-life nutrition, early-life neuroimmune activation, early-life infection INTRODUCTION Clinical studies have provided evidence that cognition in later life is strongly influenced by experiences occurring during the sensitive period of early development and adolescence. Indeed, adverse early-life events, e.g., social deprivation or abuse, are associated with an increased vulnerability to develop psychiatric disorders Different lines of work further illustrate the relation between cognitive functions and postnatal immune system activity. For example, maternal inflammatory responses during pregnancy The early postnatal environment encompasses many essential elements, which are key and determinant for proper brain development, many of which are largely transmitted via the mother-child interaction. A child is generally dependent on maternal care during the first weeks of life, encompassing tactile stimulation, Early-life adversity programs hippocampal functions nutritional provision, as well as transfer of antibodies and maternal warmth. As is evident from the above examples, an adverse early-life environment may affect the stress hormones, nutrition, or inflammatory modulators, all elements that can strongly interact and affect one another There is, e.g., increasing evidence that early-life maltreatment is associated with an increase in the pro-inflammatory markers of the immune system in adulthood The focus of this review will be on the essential elements present in the early postnatal environment and their involvement in the lasting effects on cognitive functioning. In particular we will discuss how the various elements during the early postnatal period (i.e., sensory stimuli, nutrition, stress hormones, and inflammatory molecules) interact, affect each other and ultimately how they may synergistically affect brain structure, and function on the long term. We focus on the consequences for hippocampal structure and related cognitive functioning and on a unique form of hippocampal plasticity, adult neurogenesis. The hippocampus is one of the key brain regions important for cognitive functions and this form of plasticity is very important for learning and memory processes and highly modulated by (early) environmental factors, i.e., stress The fact that the hippocampus is particularly susceptible to influences of the early-life environment and in particular stressful stimuli is easily understood when considering the important developmental processes that take place in this brain region during this sensitive developmental period. Indeed, hippocampal and dentate gyrus (DG) development in particular starts during late gestation and continues during the first 2 weeks after birth In the following sections we discuss the effects of early-life stress, nutrition, and central immune activity on hippocampal function and adult neurogenesis and thereafter discuss how to implement in these findings that (1) these elements affect one another and (2) they act synergistically to exert their function. MODULATION OF HIPPOCAMPAL FUNCTION AND NEUROGENESIS BY EARLY-LIFE STRESS Early-life stress exposure is strongly associated with cognitive impairments later in life Stress in the postnatal period can be induced using several rodent paradigms. The most widely studied models to induce early-life stress involve either naturally occurring variation or artificial modulation of maternal care In support of this notion, it has been demonstrated that a natural variation in maternal care The role of stress-related hormones (corticosterone; CORT) and neuropeptides (e.g., corticotropin releasing hormone, CRH) in the modulation of early-life stress effects on the hippocampus has been studied extensively. When the HPA axis is activated by a stressor this leads to HPA axis activation, which in turn leads to the initial release of CRH from the hypothalamic paraventricular nucleus (PVN), stimulation of pituitary adrenocorticotropic hormone (ACTH) secretion into the blood, and the subsequent release of glucocorticoids from the adrenal glands: CORT in rodents and cortisol in humans. Negative feedback takes place when glucocorticoids bind to GRs in the hippocampus, PVN, prefrontal cortex and pituitary and thereby inhibit release of CRH and ACTH In fact, exposure to stress during the postnatal early-life period programs the basal and stress-induced activation of the HPA axis and the behavioral responses to stress throughout life While glucocorticoid exposure during early-life evoked cognitive impairments in adulthood Because CRH expression is permanently altered after early stress in various models in the hypothalamus EARLY NUTRITIONAL FACTORS DETERMINE ADULT HIPPOCAMPAL STRUCTURE AND FUNCTION As mentioned in the introduction, early nutritional insults have lasting consequences for brain development and function later in life The offspring is during this critical developmental period fully dependent on the nutrition provided by the mother. Most preclinical models are based upon altering maternal nutrition during gestation and/or lactation. Indeed, micronutrient composition of the maternal diet during gestation and lactation determine the balancing of fatty acid (FA) levels in the brain of the offspring, as maternal micronutrients Various models are used to study how early malnourishment affects brain development and cognitive functions, e.g., through dietary restriction, overnutrition, or malnutrition by limitation of different key elements during gestation and/or lactation. For instance, protein restriction, global dietary restriction to 50% or high-fat, and modulation of essential macro-and micronutrients that need to be obtained from the diet are commonly used approaches The lipid content during early-life is essential for the composition of maternal milk during lactation and development of the pup brain. For instance, polyunsaturated fatty acids (PUFAs), including the omega-3 FA docosahexaenoic acid (DHA) and omega-6 FA arachidonic acid (AA), are structural components of the brain that promote healthy neuronal growth, repair, and myelination These functional changes following FA deficiency are furthermore associated with structural changes in the brain. Maternal omega-3 FA deficiency during gestation leads to underdevelopment of the primordial hippocampus in fetal rats at the last days of gestation Summarizing, evidently the nutritional composition during critical developmental periods (pre and postnatal) of life is essential for the proper development, structure and function of the hippocampus. Similar to the cognitive impairments induced by early-life stress, early-life malnutrition evokes such deficits as well. Another important element known to play a key role in modulating brain development and function is the neuroimmune system, which will be discussed in the next section. EARLY-IMMUNE RESPONSE ACTIVATION PROGRAMMING THE LATER-LIFE HIPPOCAMPUS Activation of the peripheral and/or central immune system in early-life is associated with psychopathologies in adulthood, including cognitive dysfunction Activity of the microglia is controlled by immune response regulating effector molecules, like pro-inflammatory (e.g., IL-1β, IL-6, and TNFα) and anti-inflammatory (e.g., IL-4 and IL-10) cytokines or chemokines In the following part, we will discuss the pre-clinical evidence in support of a direct role of postnatal immune challenges in the persistent modulation of hippocampal structure and function. Most studies of postnatal infection have focused on stimulation by bacteria like Escherichia coli or the Gram-negative bacteria component lipopolysaccharide (LPS). We will here address the hippocampus dependent cognitive functions following early-life neuroimmune stress from two different angles. Firstly, activation of the peripheral neuroimmune system and its immediate and lasting effects on central neuroimmune system function and brain function. Secondly, the consequences of central neuroimmune system activity without a prior peripheral immune challenge, for instance via activation of central viral infection or proinflammatory factors, on hippocampal function and neurogenesis in adulthood. A peripheral immune challenge with LPS (P1) or E. coli (P4) in the rat pup elicits an elevation of pro-inflammatory cytokines and CORT in the first few hours after the challenge in blood serum Early-life adversity programs hippocampal functions Interestingly, the pro-inflammatory response in the hippocampus following peripheral infection is accompanied by a direct effect on developmental hippocampal neurogenesis and structural changes in adulthood. E. coli infection at P4 immediately suppresses gene expression of neurotropic factor BDNF in the CA1 and CA3 Interestingly, these cognitive impairments in response to a second immune challenge appear in accordance with reduced newborn cell survival in the early-infected rats Neuroimmune system activation is not solely induced by peripheral bacterial components. The consequences of direct modulation of central cytokines and/or central induction of innate immune cells on the hippocampus are moderately studied. An example is TNFα injection at P3 and P5, increasing anxietylike behaviors in male mice Altogether, early-life peripheral infection immediately increases pro-inflammatory cytokines in the hippocampus and exerts lasting effects on hippocampal structure, but evokes only subtle alterations in hippocampal neurogenesis and functionality under basal condition. After exposure to a second immunological challenge in adulthood, however, a history of early-life infection has aversive effects on cognitive function related to an exaggerated pro-inflammatory response in the hippocampus. On the other hand, viral infection that induces a central stimulation of the immune system leaves detrimental effects on the DG, affecting adult hippocampal neurogenesis and cognitive functions. The lasting effect of early-life infection on hippocampal microglia suggests that a programming effect of peripheral and ultimately central immune system activity plays an important role in the lasting effects of hippocampal structure and cognitive functions. THE INTERPLAY OF THE DIFFERENT ELEMENTS IN THE EARLY-LIFE ENVIRONMENT The discussed consequences of early-life stress, nutrition, and immune activation can all be considered forms of early-life adversity. Although limited studies have examined the integrated role of these elements, the presented evidence in the above sections clearly points to the fact that challenges, even when very different in nature (disruption of maternal care, malnutrition, or immune), lead to strikingly similar outcomes of disrupted hippocampal structure and plasticity later in life as well as cognitive impairments. Knowing that these systems are tightly related and that they affect each other, it is reasonable to assume that the current models of early-life stress, malnutrition and infections discussed up to now elicit effects on all these different levels Early-life adversity programs hippocampal functions FIGURE 1 | Schematic representation of the interrelated role of different early-life elements for the consequences of early-life adversity. Early-life adversities in the form of early-life stress, under/malnutrition and infection are known to modulate hippocampal development and altogether determine hippocampal structure and function in adulthood with adverse effects on learning and memory. During the early sensitive period of development the offspring is fully dependent on the mother. Maternal care encompasses several elements (sensory stimuli, transfer of nutrition, hormones, and antibodies). In fact it is mostly via disruption of maternal care (with exception of early-life infection which can directly act upon the offspring) that early adversities will elicit disruptions in hormonal, (neuro)inflammatory and nutritional profiles in the offspring. Because these elements affect one another, they will ultimately act synergistically to modulate hippocampal structure and function throughout life. tight interaction and possible synergistic effects of stress and nutrition on neurocognitive development has been recently reviewed and discussed both prenatally WHAT IS THE EVIDENCE FOR AN INTERACTION BETWEEN EARLY-LIFE IMMUNE ACTIVATION AND EARLY-LIFE ADVERSITY? Early-life adversities like stress and malnutrition not only lead to the previously described effects on cognitive and hippocampal function but also to changes in adult immunological function. The stress and immune systems have a strong interactive profile, illustrated by, e.g., the immune-suppressive effect of corticosteroids Next to the evident programming effects of early-life stress on neuroimmune functions, possible lasting effects of inflammatory challenges during early-life on HPA axis activity need to be considered as well. Early-life infection generally leads to a direct elevation of circulating glucocorticoids in early-life WHAT IS THE EVIDENCE FOR AN INTERACTION BETWEEN EARLY-LIFE MALNUTRITION AND NEUROIMMUNE ACTIVATION? Next to early-life stress, also early-life nutritional insults can affect the neuroimmune system. For example, there are indications for a strong association between circulating leptin levels and the suppression of lymphoproliferative responses and pro-inflammatory cytokine secretion in protein malnourished infants, both before and after recovery following refeeding One of the possible mediators of the interaction between nutritional intake and immune system is leptin, which is secreted by white adipose tissue Although not extensively studied during early-life, current evidence on the dietary supply of methyl donors modulating the present levels of homocysteine in the (developing) brain Exciting new evidence further supports a strong interaction between nutrition and immune system in the programming of hippocampal structure and function. A recent paper by In the previous section we have highlighted some of the key elements of the early-life environment that might play an important role in the programming of cognitive functions by early-life adversity. As evident from the studies that we discussed these elements clearly do not act alone but rather in a synergistic manner. We discussed some of the possible mechanisms that could mediate the effects of early-life stress, malnutrition, and infection and discussed the evidence for their interactive profile. However clearly our discussion is not exhaustive and other equally important paths and mediators responsible for the final programming effect could be considered. For example, next to leptin, ghrelin a pancreatic hormone released upon hunger can influence not only eating behavior but stress, immune function as well as cognition EARLY-LIFE ADVERSITY; OPPORTUNITIES FOR INTERVENTION LATER IN LIFE Adversities in the early-life period provoke thus immediate and programmed effects on different levels with lasting consequences for hippocampal function. Identification of these consequences and the different systems at play during early-life is essential to design optimal intervention studies to counteract the more complete set of consequences following early-life adversity. In recent years, multiple intervention studies have been performed to counteract either the lack of nutritional components, the consequences of early-life stress or the pro-inflammatory state after early-life infections. For instance, clinical research revealed the potential of high levels of maternal warmth (regarded as a positive experience) to overcome the programmed effects of the aversive low socioeconomic status on the immune system during early-life . However, considering the evidence presented in this review that these systems interact and affect each other so tightly and that they might thus act synergistically to program brain structure and function for life, the question arises as to which consequences of early-life adversity to target and whether there is a crucial time window for these interventions for optimal beneficial effects of these interventions. Here, we will discuss a few examples of potential intervention studies. Because changes of HPA axis modulators are suggested as potential regulators of the lasting changes following early-life stress, suppression of these modulators has been investigated as a possible intervention in later life. For example, selective blockage of CRF receptor 1 immediately after the first week after chronic early-life stress exposure from postnatal day 10-17 in rats prevents hippocampal impairments in cognitive functioning and long-term potentiation Enriching the later life environment, a manipulation that is known to stimulate hippocampal neurogenesis and improve performance of hippocampus related spatial behavioral tasks in adulthood A final manner to intervene with the consequences of earlylife stress is modulation at the level of the epigenome. Early-life stress and early-life nutrition program later life function through alterations in chromatin structure and gene expression as became evident from clinical and animal studies. There is indeed increasing evidence that epigenetic mechanisms might be responsible for the early-life adversity induced life-long alterations in gene expression. Early-life adversity programs hippocampal functions choline modified some of these effects on the neural progenitor cells FINAL CONCLUSION Well-known factors such as genetic vulnerability, gender, life style, and aging contribute to disorder vulnerability. In addition, earlylife adversity further determines brain susceptibility to develop adult-onset psychopathologies and cognitive impairments later in life. Multiple elements (including stress, nutrition, and infections) in the early-life environment are crucial for proper hippocampal development, and structure and function in adulthood. Thus there is growing evidence that disruption of either of these elements has detrimental effects on cognitive functions, hippocampal structure, neurogenesis and the activity of neuroimmune cells in the hippocampus. Here, we have focused on how these different elements might interplay during early-life adversity and elicit similar effects on hippocampal neurogenesis and cognition in adulthood. Even though the interplay of these three elements is generally not considered in depth, the ultimate consequences are probably a synergistic effect and combination of these elements. Considering the intense cross talk between these elements and how they, together, program hippocampal structure and function, will provide important insights and con
