Experience-induced transgenerational (re-)programming of neuronal structure and functions: Impact of stress prior and during pregnancy

Highlights

• Prenatal and preconception stress affect neuronal and behavioral development.

• Epigenetic mechanism mediate neuronal (mal)adaptations.

• Preconception stress is a promising model to investigate transgenerational inheritance.

• Strategies for prevention or therapeutic intervention of PS-induced psychopathologies should be developed.

Abstract

This review focuses on the inter- and transgenerational effects of stress experience prior to and during gestation. We provide an overview of findings from studies in humans as well as in animal models on brain structural and physiological functions and on the development of cognitive and executive functions. We also discuss the concept of stress-induced (re-)programming in more detail by highlighting epigenetic mechanisms and particularly those affecting the development of monoaminergic transmitter systems, which constitute the braińs reward system. As the majority of studies have focused on male individuals we will emphasize sex-specific differences in stress vulnerability and resilience. Finally, we offer some perspectives on the development of protective and therapeutic interventions in cognitive and emotional disturbances resulting from pre-conception and prenatal stress.

Introduction

Considerable evidence indicates that neurological disorders are often triggered during the fetal phase of life. Animal studies confirm observations in humans, which indicate that early life experience has a profound impact on adult behavior. One problem which is encountered while screening the current literature is the diversity of findings, which hinders the emergence of unifying and testable concepts and hypotheses. The diversity of paradigms, which are used to investigate prenatal stress (PS) in animal models, as well as the different definitions of stress or early life adversity and different stress assessment tools used in clinical studies, may contribute to the diversity of the observed changes in the prenatally stressed offspring, ranging from resilience and adaptive stress coping (concept of stress-inoculation), to learned helplessness and depressive behavior, posttraumatic stress disorder (PTSD), schizophrenia and even neurodegenerative diseases (Fig. 1).

While there is an increasing number of studies on human reactions to adult stressful experience, there is still a paucity of information on the predictability of such a reaction, based on genetic predisposition and early life experience. We will examine this variability in reactivity on the basis of what is currently known about early life experience, with focus on early life stress and the pathological outcomes. Furthermore, it is apparent that there is no single dimension to the resilience-vulnerability axis in the buildup of reactivity to stress, as it was shown that different brain areas may react differently along this scale. Most investigations of the effects of early life stress in humans are restricted to the analysis on the behavioral and macroscopic level, and with respect to genetic predisposition and epigenetic alterations human studies are confined to investigations in peripheral tissues. Animal models allow to mimic stress experience prior to and during different phases of gestation under strictly controlled experimental conditions, which is essential to disentangle brain (-region) specific mechanisms on the physiologic, brain structural, cellular and molecular level.

Several recent reviews have addressed the impact of prenatal stress on adult emotional development and susceptibility to psychiatric disorders, and most studies have emphasized the critical role of endocrine functions and PS-induced (re)programming of HPA axis functions (reviews by Bock et al., 2014, Daskalakis et al., 2013, Lodge and Grace, 2011, McEwen, 1999, Weinstock, 2008, Weinstock, 2011). In the present review we will focus on the long lasting effects of stress experienced prior to or during gestation, specifically on neuronal, synaptic and physiological development related to cognitive and executive functions in both, clinical studies and experimental approaches in animal models. We will compare the type of stressor, the possible long lasting molecular and epigenetic mechanisms mediating the effects of the stressor and the impact on different cognitive functions in the juvenile/adult brain. We will compare different brain areas, including, but not limited to the hippocampus, amygdala and prefrontal cortex.

Prenatal and preconception stress can be dissected along several dimensions, including the genetic background, type of stressor (physical stress, infection, nutrition, hormonal, drug intake, psychological stress), the timing of exposure of the organism to the stressful stimulation (preconception, pre/early/late gestational periods, neonatal) and the intensity/duration of the stressful experience (Mychasiuk et al., 2011a), all of which can determine the behavioral (and brain functional/structural) outcome in the offspring (Fig. 1). With respect to experimental prenatal stress paradigms the experiments range from applying the same stressor (e.g. restraint) to the pregnant dam for several days during the last trimester (predictable stressor) to applying random variable stressors (unpredictable stressors). Moreover, stressors of different “flavors” (e.g. mental, physical or chemical) and severity are applied, including restraint, exposure to a cold environment (4 °C) for up to 6 h, food deprivation, prevention of sleep during the light (inactive) phase of the daily cycle, swim stress, social stress induced by overcrowded housing conditions, loud noise, exposure to a dominant male, induction of immune challenge and “indirect” or “bystander” stress, i.e. stressing a cage mate (Mychasiuk et al., 2011b, Mychasiuk et al., 2011c). Also, the timing of assessment of behavioral and brain functional consequences in the PS offspring is critical, as it can range from delivery day to adulthood with different effects along postnatal growth.

In addition to environmental influences, genetic predisposition, including ethnicity, species, strain and gender, are additional factors, which contribute to the vulnerability/resilience towards preconception and prenatal stress exposure (Fig. 1). Finally, evidence is accumulating on the inter- and transgenerational transmission of early life adversity. We will summarize some of these studies with focus on stress experienced prior to gestation and its impact on the next generation.