Visualizing cold spots: TRPM8-expressing sensory neurons and their projections

Area of Science:

• Neuroscience
• Sensory Biology
• Molecular Biology

Background:

• Dorsal root ganglion (DRG) neurons sense environmental stimuli like temperature, but functional subpopulations lack clear molecular markers.
• Transient Receptor Potential (TRP) channels, including TRPM8, are temperature-gated ion channels involved in thermosensation.
• TRPM8 is activated by cooling, and its absence impairs cool sensation.

Purpose of the Study:

• To comprehensively investigate the anatomical and functional properties of TRPM8-expressing fibers.
• To characterize the unique population of DRG neurons expressing TRPM8.
• To explore the in vivo architecture and connectivity of cold-sensing fibers.

Main Methods:

• Utilized genetically engineered mice (TRPM8(EGFPf)) to track TRPM8-expressing neurons.
• Assessed cold and menthol responses in cultured DRG neurons from hemizygous and homozygous mice.
• Examined in vivo neuronal projections in the spinal cord and epidermis.
• Investigated co-expression with nociceptive markers and changes under inflammatory conditions.

Main Results:

• TRPM8(EGFPf) neurons in cultured DRGs responded robustly to cold and menthol.
• Homozygous TRPM8(EGFPf/EGFPf) DRGs showed severely reduced cold and absent menthol responses, confirming TRPM8's role.
• In vivo, TRPM8(EGFPf) neurons identified a distinct DRG subpopulation, mostly non-nociceptive.
• These neurons project to superficial spinal cord layers (Layer I) and form unique epidermal endings, including in mystacial pads.
• TRPM8 expression was unaffected by inflammation, unlike TRPV1.

Conclusions:

• TRPM8 expression is functionally linked to cold sensitivity in DRG neurons.
• This study provides the first detailed in vivo anatomical map of cold-sensing TRPM8+ fibers.
• TRPM8+ cold fibers possess a unique projection pattern distinct from peptidergic pain fibers.