Merkel Cell - Insular Cortex - Fear Signaling Pathway

On June 7, 2025, Tracy L. Bale from the University of Colorado published a study in Neuropsychopharmacology titled: "Merkel cell stimulation in fear and sensory signaling." This research reveals the stimulatory role of Merkel cells in fear and sensory signal transmission.

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Overview

Stress and traumatic experiences can have significant and lasting effects on the sensory system. Researchers recently found unique protein expression in circulating extracellular vesicles of adult women who experienced sexual trauma during adolescence. These proteins were linked to epidermal skin cells (keratinocytes) and mechanosensory Merkel cells (MC), biologically connecting trauma exposure to a type of skin cell with neuron-like characteristics.

In this study, the authors aimed to develop and validate a preclinical mouse model that uses chemogenetics to activate Merkel cell populations. After chemogenetic stimulation of Merkel cells, significant neuronal activation was observed in the brain's insular cortex (IC), a region closely associated with integrating somatosensory information and emotional value.

When given the CNO drug, mice in their home cages showed a significant increase in nest grooming behavior. Furthermore, in a conditioned place preference experiment, Merkel cell stimulation triggered a noticeable avoidance response, and this effect was more pronounced in female mice.

Overall, these findings validate this preclinical model for further exploring the mechanosensory system and its potential role in post-traumatic stress disorder (PTSD) symptoms and therapeutic interventions. Ongoing research will focus on key developmental stages of Merkel cell development and related sex differences, how these factors influence an individual's susceptibility to trauma, and explore potential sensory-based treatment options for PTSD-related symptoms.

Fig.1 Validation of the Merkel cell-enriched keratinocyte population.¹

Findings of the Study

In summary, existing research indicates that female rodents exhibit stronger fear-related responses, mirroring the higher risk of PTSD in women. Multiple meta-analyses highlight significant sex differences not only in PTSD susceptibility but also in how traumatic events are experienced and the patterns of neural activation triggered by stimuli with positive and negative emotional valence. Furthermore, biological differences in fear responses may be influenced by sex hormones and could relate to evolutionary adaptations to stress or trauma.

Current research needs to focus more on the underlying mechanisms to reveal the neural and biological basis of Merkel cell (MC) function in perceiving emotional valence and in conditioned fear, especially mechanisms related to sex differences. Finally, since Merkel cells complete their maturation during adolescence—a critical developmental window when individuals are also more sensitive to trauma—future studies can use preclinical models to specifically investigate the impact of stress and MC activation during this developmental stage. These lines of research offer potential for exploring sensory-based therapeutic strategies for anxiety and PTSD-related symptoms using preclinical models.

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Reference

1. Korgan, Austin C et al. "Merkel cell stimulation in fear and sensory signaling." Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 10.1038/s41386-025-02144-w. 7 Jun. 2025, doi:10.1038/s41386-025-02144-w. Distributed under Open Access license CC BY 4.0, without modification.