Sex-dependent differences in the genomic profile of lingual sensory neurons in naïve and tongue-tumor bearing mice

Abstract

Mechanisms of sex-dependent orofacial pain are widely understudied. A significant gap in knowledge exists about comprehensive regulation of tissue-specific trigeminal sensory neurons in diseased state of both sexes. Using RNA sequencing of FACS sorted retro-labeled sensory neurons innervating tongue tissue, we determined changes in transcriptomic profiles in males and female mice under naïve as well as tongue-tumor bearing conditions Our data revealed the following interesting findings: (1) FACS sorting obtained higher number of neurons from female trigeminal ganglia (TG) compared to males; (2) Naïve female neurons innervating the tongue expressed immune cell markers such as Csf1R, C1qa and others, that weren’t expressed in males. This was validated by Immunohistochemistry. (3) Accordingly, immune cell markers such as Csf1 exclusively sensitized TRPV1 responses in female TG neurons. (4) Male neurons were more tightly regulated than female neurons upon tumor growth and very few differentially expressed genes (DEGs) overlapped between the sexes, (5) Male DEGs contained higher number of transcription factors whereas female DEGs contained higher number of enzymes, cytokines and chemokines. Collectively, this is the first study to characterize the effect of sex as well as of tongue-tumor on global gene expression, pathways and molecular function of tongue-innervating sensory neurons.

Three‐dimensional topography of rat trigeminal ganglion neurons using a combination of retrograde labeling and tissue‐clearing techniques

“…The greater distribution of small thermosensitive ganglion neurons in the skin/mucosa, rather than in deep tissues, may be important for protection against burns from hot and cold temperatures in the external environment. Recently, it has been reported that not only differences in cell body size but also the expression patterns of chemical markers are characteristics in ganglion cells innervating different regions (Ambalavanar et al., 2003; Buchholtz et al., 2020; Hovhannisyan et al., 2023; Ibrahim et al., 2023; Leijon et al., 2019; Lindquist et al., 2021; Reid et al., 2011; Wu et al., 2018; Yang et al., 2022). In the future, the integration of data on chemical markers expressed by ganglion cells, axonal projection targets, and cell body localization within the trigeminal ganglion should provide a complete picture of trigeminal ganglion function.…”

“…We used 58 Sprague–Dawley rats (males n = 31, females n = 27; 250–350 g; Shizuoka Laboratory Animal Center, Shizuoka, Japan). Because previous studies have reported that there are no differences in the number and distribution of retrogradely labeled ganglion cells between male and female rats (Ambalavanar et al., 2003), both sexes were used (but see Ibraham et al., 2023). There was no apparent difference in the number of fast blue‐labeled cells between male and female rats (Supporting Information Figure S1).…”

Targeting TRPV1 for Cancer Pain Relief: Can It Work?

“…However, self-perceived pain in cancer patients shows individual differences [ 155 ], depending on both the ethnic background [ 156 ] and gender [ 157 ]. (Parenthetically, RNA sequencing of the trigeminal sensory neurons revealed distinct transcriptomic profiles between male and female mice under tongue-tumor bearing conditions [ 158 ].) Furthermore, cancer pain is often associated with anxiety and depression [ 159 ], and patients may even experience referred pain at sites not affected by the disease [ 13 ].…”