Skin-brain axis signaling mediates behavioral changes after skin wounding

Abstract

Patients with chronic wounds often have associated cognitive dysfunction and depression with an as yet unknown mechanism for this association. To address the possible causality of skin wounding inducing these changes, behavior and cognitive functions of female C57BL/6 mice with an excisional skin wound were compared to unwounded animals. At six days post wounding, animals exhibited anxiety-like behaviors, impaired recognition memory, and impaired coping behavior. Wounded animals also had concomitant increased hippocampal expression of Tnfa, the pattern recognition receptor (PRR) Nod2, the glucocorticoid receptors GR/Nr3c1 and Nr3c2. Prefrontal cortex serotonin and dopamine turnover were increased on day six post-wounding. In contrast to the central nervous system (CNS) findings, day six post -wounding serum catecholamines did not differ between wounded and unwounded animals, nor did levels of the stress hormone corticosterone, TNFα, or TGFβ. Serum IL6 levels were, however elevated in the wounded animals. These findings provide evidence of skin-to-brain signaling, mediated either by elevated serum IL6 or a direct neuronal signaling from the periphery to the CNS, independent of systemic mediators. Wounding in the periphery is associated with an altered expression of inflammatory mediators and PRR genes in the hippocampus, which may be responsible for the observed behavioral deficits.

Quantifying innervation facilitated by deep learning in wound healing

“…Iodine and ethanol wipes were used to sterilely prep experimental mice. An 8 mm sterile skin biopsy punch instrument was used to create full-thickness wounds on the dorsal skin as described previously 7 , 31 . In this study we used splinted wound model to avoid wound contraction 32 , 33 .…”

“…During healing phases, a strong interaction between the nervous system and skin involving a variety of neuromodulators, cytokines, hormones, and other effector molecules has been reported 6 , 7 . The nervous system can be influenced both at the local and central levels by the stimuli at the skin and vice versa.…”

Quantifying innervation facilitated by deep learning in wound healing

“…Iodine and ethanol wipes were used to sterilely prep experimental mice. An 8 mm sterile skin biopsy punch instrument was used to create full-thickness wounds on the dorsal skin as described previously 7 , 29 . At the end of the experiment, mice were euthanized by cervical dislocation under 5% isoflurane, and skin samples were collected on days 3,7,10, and 15 post-wounding.…”

Human mini-brains for reconstituting central nervous system disorders

“…Skin-brain axis Psychological hyperstress can cause and aggravate neurogenic inflammation, which may further trigger skin diseases such as atopic dermatitis and psoriasis. 141 Meanwhile, the skin can also affect the brain through the transmission of hormones or cytokines to the brain region. 141,142 Given the correlation between the skin and brain, there is an increasing demand on the development of skin-brain axis on chips.…”

“…141 Meanwhile, the skin can also affect the brain through the transmission of hormones or cytokines to the brain region. 141,142 Given the correlation between the skin and brain, there is an increasing demand on the development of skin-brain axis on chips. Wufuer et al successfully developed a human skin-BBB chip on which human immortalized keratinocytes (HaCaT), fibroblasts, and human umbilical vein endothelial cells (HUVEC) were cultured (Fig.…”