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Points of divergence on a bumpy road: early development of brain and immune threat processing systems following postnatal adversity

Abstract

Lifelong indices of maladaptive behavior or illness often stem from early physiological aberrations during periods of dynamic development. This is especially true when dysfunction is attributable to early life adversity (ELA), when the environment itself is unsuitable to support development of healthy behavior. Exposure to ELA is strongly associated with atypical sensitivity and responsivity to potential threats—a characteristic that could be adaptive in situations where early adversity prepares individuals for lifelong danger, but which often manifests in difficulties with emotion regulation and social relationships. By synthesizing findings from animal research, this review will consider threat sensitivity through the lenses of associated corticolimbic brain circuitry and immune mechanisms, both of which are immature early in life to maximize adaptation for protection against environmental challenges to an individual’s well-being. The forces that drive differential development of corticolimbic circuits include caretaking stimuli, physiological and psychological stressors, and sex, which influences developmental trajectories. These same forces direct developmental processes of the immune system, which bidirectionally communicates with sensory systems and emotion regulation circuits within the brain. Inflammatory signals offer a further force influencing the timing and nature of corticolimbic plasticity, while also regulating sensitivity to future threats from the environment (i.e., injury or pathogens). The early development of these systems programs threat sensitivity through juvenility and adolescence, carving paths for probable function throughout adulthood. To strategize prevention or management of maladaptive threat sensitivity in ELA-exposed populations, it is necessary to fully understand these early points of divergence.

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Fig. 1: Neural and immune influences on early life development of threat processing in males and females, conceptualized from the canalization perspective (inspired by Waddington [165], Gottleib [184], Blair and Raver [185], and McCarthy [186]).

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Acknowledgements

This work was partially funded by NIMH R01MH127850. The author thanks Dr. Laurel Gabard-Durnam for her invaluable editorial assistance with the manuscript. Artistic contribution from Jennifer Leigh at Creative Outlaw Design.

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Brenhouse, H.C. Points of divergence on a bumpy road: early development of brain and immune threat processing systems following postnatal adversity. Mol Psychiatry (2022). https://doi.org/10.1038/s41380-022-01658-9

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