Persistent priming of hypothalamic microglia is associated with sensitization of the hypothalamic-pituitary-adrenal axis to acute stress, hyperactivity and behavioral response disruption in male rats.

Authors

Ana León-Rodríguez, María Del Mar Fernández-Arjona, Carmen Pedraza, Manuel F López-Aranda, Rick Visser, María D López-Ávalos

Published in

Frontiers in immunology. Volume 17. Pages 1828445. Epub Jun 30, 2026.

Abstract

Central and peripheral inflammation are under intense investigation because of their increasing relationship with neuropsychiatric disorders and neurodegeneration. Microglia, the main component of the innate immune system within the brain, coordinate neuroinflammatory processes, so they are a major focus of attention. Recent research has highlighted the capacity of microglia to acquire immunological memory from previous inflammatory events, similarly to macrophages. Thus, primed microglia are sensitized cells capable of developing exacerbated inflammatory responses with potential deleterious outcomes.
This study investigated the long-term consequences of a single acute neuroinflammatory event on hypothalamic sensitization of the stress response, underscoring microglial involvement.
Neuroinflammation was provoked in rats by a single intracerebroventricular injection of microbial neuraminidase (NA). Three months later, they were exposed to acute stress consisting of forced swimming. Hypothalamic inflammatory activation and hypothalamic-pituitary-adrenal (HPA) axis response were assessed, along with rats´ behavior.
Acute stress provoked a heightened corticosterone response in rats that had undergone neuroinflammation compared to saline-injected rats, indicating HPA axis sensitization. In the hypothalamus of NA-injected rats examined 12 and 48 hours after stress, gene expression of neuropeptides CRH and AVP was decreased, while glucocorticoid receptor expression was increased. CRH protein stores also increased, as did enzymes involved in endocannabinoid synthesis. These results suggest molecular signs of altered HPA-axis feedback regulation. In parallel, gene expression of inflammation-related genes revealed a moderate enhancement of inflammation after acute stress, which was more evident in the amygdala than in hypothalamus and was still detected 48 hours after stress. Moreover, comprehensive morphological analysis of microglia located in paraventricular nucleus and basolateral amygdala revealed a more reactive microglial profile, consistent with priming. Open field evaluation revealed disorganized behavior characterized by hyperactivity, disinhibition, increased arousal, stress reactivity, and impaired risk assessment.
A past acute neuroinflammatory event sensitizes the HPA axis, leading to augmented corticosterone response, molecular signs of altered HPA axis feedback regulation, and a complex behavioral response characterized by hyperactivity and increased arousal, all of which depict maladaptive stress reactivity. Long-lasting priming of microglial cells located in the hypothalamus, displaying an enhanced activation upon stress exposure, could contribute to those alterations.

PMID:
42454063
Bibliographic data and abstract were imported from PubMed on 15 Jul 2026.

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