TRPV1-TRPA1 Modulate Central Encoding of Somatosensory Information and Perception

Abstract

To effectively interact with the environment, sensory systems must extract and represent meaningful information from external stimuli. This process begins peripherally, where sensory neurons transduce environmental cues into neural activity. Among the key molecular mediators of this transduction are the Transient Receptor Potential (TRP) channels, particularly TRP Vanilloid 1 (TRPV1) and TRP Ankyrin 1 (TRPA1), which are polymodal channels well-characterised for their roles in detecting noxious stimuli, such as heat, chemical irritants and inflammatory agents. While their contributions to the peripheral nervous system are well known, their roles within the central nervous system are still not well understood.

Centrally, neuromodulatory systems such as the cholinergic and noradrenergic pathways are recognised as key regulators of cortical excitability and sensory processing. These systems dynamically modulate the gain of the neuronal response function and thus shape the representation of incoming sensory information, and in turn determine the animal's perception and behaviour in a context-dependent manner. Despite extensive research into such classical neuromodulators, the potential involvement of TRP channels in modulating sensory processing has received little attention. This thesis addresses this gap by investigating the contributions of TRPV1 and TRPA1 within the vibrissal primary somatosensory cortex (vS1) of mice, a well-established model system for tactile sensory processing. Through an integrative approach combining behavioural assays, in vivo two-photon calcium imaging, whole-cell patch-clamp recording and high-density Neuropixels electrophysiology, I examine how TRPV1 and TRPA1 modulate cortical activity and contribute to the encoding of sensory signals.

First, I demonstrate that TRPV1 activation in vS1 enhances perceptual sensitivity to whisker vibrations and increases sensory evoked cortical responses, while TRPV1 inhibition produces the opposite effect. Calcium imaging further reveals that TRPV1 enhances stimulus gain, increases the proportion of stimulus-selective neurons and improves the discrimination of near-threshold stimuli. At the cellular level, whole-cell recordings from layer 2/3 pyramidal neurons reveal that TRPV1 activation enhances intrinsic excitability. Crucially, these effects depend on TRPA1, as they are abolished in TRPA1 knockout mice or when TRPA1 is pharmacologically inhibited. Conversely, TRPA1 increases excitability independently of TRPV1, revealing a unidirectional interaction in which TRPV1 acts via TRPA1 to influence cortical function.

Finally, using Neuropixels recordings during whisker stimulation, I show that TRPV1-TRPA1 interactions enhance both single-neuron and population-level coding. TRPV1 activation amplifies stimulus-response functions, improves the discriminability of stimuli and increases the decoding accuracy of stimulus identity. On a population level, TRPV1 activity decreases positive noise correlations and increases negative correlations, thereby improving the efficiency of sensory coding. Blocking TRPA1 diminishes these effects, confirming its role in TRPV1-mediated modulation.

In summary, this thesis establishes TRPV1 as a central modulator of cortical sensory processing, acting through TRPA1 to enhance neuronal excitability, sharpen sensory representations and improve perceptual sensitivity. These findings expand the role of TRP channels beyond their known peripheral functions, positioning them as key contributors to cortical neuromodulation. Show more