Neuroinflammation, Early-Life Adversity, and Brain Development

Abstract

The overarching objective is to review how early exposure to adversity interacts with inflammation to alter brain maturation. Both adversity and inflammation are significant risk factors for psychopathology. Literature relevant to the effects of adversity in children and adolescents on brain development is reviewed. These studies are supported by research in animals exposed to species-relevant stressors during development. While it is known that exposure to adversity at any age increases inflammation, the effects of inflammation are exacerbated at developmental stages when the immature brain is uniquely sensitive to experiences. Microglia play a vital role in this process, as they scavenge cellular debris and prune synapses to optimize performance. In essence, microglia modify the synapse to match environmental demands, which is necessary for someone with a history of adversity. Overall, by piecing together clinical and preclinical research areas, what emerges is a picture of how adversity uniquely sculpts the brain. Microglia interactions with the inhibitory neurotransmitter GABA (specifically, the subtype expressing parvalbumin) are discussed within contexts of development and adversity. A review of inflammation markers in individuals with a history of abuse is combined with preclinical studies to describe their effects on maturation. Inconsistencies within the literature are discussed, with a call for standardizing methodologies relating to the age of assessing adversity effects, measures to quantify stress and inflammation, and more brain-based measures of biochemistry. Preclinical studies pave the way for interventions using anti-inflammation-based agents (COX-2 inhibitors, CB2 agonists, meditation/yoga) by identifying where, when, and how the developmental trajectory goes awry.

Commentary: Improving the Effectiveness and Utility of the Helping to End Addiction Long-Term (HEAL) Prevention Cooperative: A Full Translational Framework

“…The HPC projects focus primarily on T2–T4. Modeling bio-behavioral mechanisms (e.g., levels of stress reactivity, neurocognitive functioning, inhibitory transmitter GABA, and neuroinflammation (Andersen, 2022 )) impacted by adverse social determinants of health and that may mediate intervention effects on pathways to OUD is strongly recommended …”

Cortisol and α-amylase awakening response in children and adolescents with functional neurological (conversion) disorder

“…Of particular interest with regard to aberrant neural network function is the growing understanding that ACEs interact with inflammation – the immune-inflammatory component of the stress system – to alter brain maturation and to increase vulnerability for a broad range of symptoms and psychiatric disorders (Andersen, 2022). In the field of FND, ACE-related neuroinflammatory changes are hypothesised to contribute to neural network dysregulation (Radmanesh et al, 2020; Sharma and Szaflarski, 2021).…”

“…Within paediatrics, the current understanding of FND is that stress system activation and dysregulation play a central role in generating these symptoms (Apazoglou et al, 2017; Kozlowska, 2017; Kozlowska et al, 2020; Sharma and Szaflarski, 2021). Of particular relevance in this context are the stress system components that are embedded within the brain and that modulate neural network function (Agorastos et al, 2019; Andersen, 2022; Apazoglou et al, 2017; Frank et al, 2016). Accordingly, in the Mind-Body Program at The Children’s Hospital at Westmead, we use a stress system model of FND to inform our clinical practice and guide our treatment of patients (Kozlowska, 2017; Kozlowska et al, 2020).…”

Early Adversity and Accelerated Brain Aging: A Mini-Review

“…Most studies examine consequences of early adversity in postnatal or adult life, and do not address the long-term consequences on neuroinflammation ( Delpech et al, 2016 ; Réus et al, 2019 ; Desplats et al, 2020 ; Dutcher et al, 2020 ; Reshetnikov et al, 2020 ; Kim et al, 2021 ). One of the reports indicates that MS increases microglial numbers/activation in 10 month old animals ( Criado-Marrero et al, 2020 ), but few studies have actually followed animals with a history of early adversity across the life-span, to address the temporal and circuit-specific emergence of neuroinflammatory signatures ( Ganguly and Brenhouse, 2015 ; Tay et al, 2018 ; Andersen, 2022 ). However, it is noteworthy that in some models of early stress (MIA), neuroinflammatory changes do not appear to contribute to synaptic atrophy and cognitive decline, with no changes reported in microglia or reactive astrocytes in 22 month old animals with a history of MIA ( Giovanoli et al, 2015 ).…”