Early life adversity shapes neural circuit function during sensitive postnatal developmental periods

Abstract

Early life adversity (ELA) is a major risk factor for mental illness, but the neurobiological mechanisms by which ELA increases the risk for future psychopathology are still poorly understood. Brain development is particularly malleable during prenatal and early postnatal life, when complex neural circuits are being formed and refined through an interplay of excitatory and inhibitory neural input, synaptogenesis, synaptic pruning, myelination, and neurogenesis. Adversity that influences these processes during sensitive periods of development can thus have long-lasting and pervasive effects on neural circuit maturation. In this review, we will discuss clinical and preclinical evidence for the impact of ELA on neural circuit formation with a focus on the early postnatal period, and how long-lasting impairments in these circuits can affect future behavior. We provide converging evidence from human and animal studies on how ELA alters the functional development of brain regions, neural circuits, and neurotransmitter systems that are crucial for cognition and affective behavior, including the hippocampus, the hypothalamus-pituitary-adrenal (HPA) axis, neural networks of fear responses and cognition, and the serotonin (5-HT) system. We also discuss how gene-by-environment (GxE) interactions can determine individual differences in susceptibility and resilience to ELA, as well as molecular pathways by which ELA regulates neural circuit development, for which we emphasize epigenetic mechanisms. Understanding the molecular and neurobiological mechanisms underlying ELA effects on brain function and psychopathology during early postnatal sensitive periods may have great potential to advance strategies to better treat or prevent psychiatric disorders that have their origin early in life.

Fig. 1. Behavioral, neurobiological, and physiological outcomes of postnatal ELA exposure in adolescence and adulthood.

A ELA outcomes in humans and non-human primates. Dotted lines indicate the range of time ELA can occur. B ELA outcomes in rodents. The effects of different types of ELA models and the time period during which they are generally applied are indicated during P0–21. Adolescence and adulthood outcomes are listed for each species and model.

Fig. 2. Plasticity of neural developmental processes throughout life.

A Schematic showing the development of inhibitory interneurons (blue; adapted from [204]), synaptogenesis (red), neurogenesis (orange), and 5-HTergic input (green; adapted from [89]) from the prenatal period to adulthood. Solid lines indicate normal development, dotted lines indicate the effects of postnatal ELA. Childhood, adolescence, and adulthood correlate to peak time periods of synapse formation, synaptic pruning, and spine maintenance, respectively. The time windows for sensitive periods are indicated below for hippocampus (before age 13), amygdala (most pronounced volume changes during childhood), PFC (before age 2), and HPA axis (before age 2). The extended sensitive period for hippocampus development is determined by the continued neurogenesis in this region in adulthood (orange line). B–F Schematic depiction of ELA effects on neuroplasticity processes. B Synaptic pruning for normal reared individuals showing activated microglia engulfing weak synapses. ELA reduces microglia engulfment of synapses leading to less refined connections. Excitatory action potentials are indicated in blue, inhibitory action potentials are indicated in red. C ELA increases CRH levels resulting in poor dendritic branching. D ELA reduces myelination resulting in less conductance. E ELA reduces adult hippocampal neurogenesis, thereby potentially decreasing neurogenesis-mediated inhibition of the mature dentate gyrus granule neurons. F ELA decreases GR expression and impairs HPA axis feedback, subsequently increasing CORT release.

Fig. 3. ELA effects on neural circuitry.

Shown are postnatal ELA effects on brain regions and neural circuits commonly implicated in psychopathology, such as the hippocampus, mPFC, OFC, amygdala, the HPA axis, and serotonergic signaling from the raphe nuclei (DRN and MRN) to cortical and limbic regions. Colored boxes denote ELA effects on specific functions of each brain region related to cognition and affective behavior.