Developmental Stressors Induce Innate Immune Memory in Microglia and Contribute to Disease Risk

Abstract

Many types of stressors have an impact on brain development, function, and disease susceptibility including immune stressors, psychosocial stressors, and exposure to drugs of abuse. We propose that these diverse developmental stressors may utilize a common mechanism that underlies impaired cognitive function and neurodevelopmental disorders such as schizophrenia, autism, and mood disorders that can develop in later life as a result of developmental stressors. While these stressors are directed at critical developmental windows, their impacts are long-lasting. Immune activation is a shared pathophysiology across several different developmental stressors and may thus be a targetable treatment to mitigate the later behavioral deficits. In this review, we explore different types of prenatal and perinatal stressors and their contribution to disease risk and underlying molecular mechanisms. We highlight the impact of developmental stressors on microglia biology because of their early infiltration into the brain, their critical role in brain development and function, and their long-lived status in the brain throughout life. Furthermore, we introduce innate immune memory as a potential underlying mechanism for developmental stressors’ impact on disease. Finally, we highlight the molecular and epigenetic reprogramming that is known to underlie innate immune memory and explain how similar molecular mechanisms may be at work for cells to retain a long-term perturbation after exposure to developmental stressors.

A molecular framework for autistic experiences: Mitochondrial allostatic load as a mediator between autism and psychopathology

“…The neuroimmune system is the second established component of allostatic load that works in concert with HPA neuroendocrine signaling to modulate the stress response. Neuroimmune dysregulation is well-documented in clinical studies of neuropathology and is observed in response to ELS (74,204,205), and neurodevelopmental (206) and psychological (207-209) disorders. In fact, Bottaccioli et al (210) proposed that the "neuroendocrine-immune" network is a central molecular mediator between psychosocial stress and the psyche.…”

Gestational stress and perinatal SSRIs differentially impact the maternal and neonatal microbiome‐gut‐brain axis

“…When looking at the neonatal brain, we found that gestational stress decreases the density of microglia on postnatal day 2. We know that microglia have receptors that respond to stress hormones in early development 86,87 and on embryonic day 14 prenatal restraint stress results in increased microglia density in the embryonic neocortical primordium of mice 88 while during the early postnatal period prenatal stress reduces the number of immature microglia in the corpus callosum and internal capsule, and promotes an accelerated microglial differentiation in brain regions such as the entorhinal cortex, parietal lobe neocortex, thalamus and septum in the neonatal rat 89 . In addition, the impact of stress on microbiota could also impact microglia via the release of various metabolites such as short‐chain fatty acids (SCFAs) or aryl hydrocarbon receptor (AhR) ligands 90 .…”

A Molecular Framework for Autistic Experiences: Mitochondrial Allostatic Load as A Mediator between Autism and Psychopathology

“…The neuroimmune system is the second established component of allostatic load that works in concert with HPA neuroendocrine signaling to modulate the stress response. Neuroimmune dysregulation is well-documented in clinical studies of neuropathology and is observed in response to ELS (68,186,187), and neurodevelopmental (188) and psychological (189)(190)(191) disorders. In fact, Bottaccioli et al (2022) proposed that the "neuroendocrine-immune" network is a central molecular mediator between psychosocial stress and the psyche (192).…”