Somatosensory input to the central nervous system is complexly regulated at the primary afferent synaptic relay onto target neurons within the spinal cord dorsal horn. The local neural circuits and processes that integrate and gate sensory information are still poorly understood. The most thoroughly studied mechanism of presynaptic inhibitory control at this site is afferent-evoked primary afferent depolarization (PAD), wherein depolarization of the afferent terminal is linked to depressed signaling, or paradoxically to hyper excitable states that instigate chronic pain conditions. This spinal mechanism has the capacity to dynamically limit or magnify somatic sensation, so clarifying how PAD circuits or circuit subtypes are engaged could go a long way to dissecting adaptive versus diseased sensory processing. PAD/PSI is historically described as multisynaptic and GABAergic. However we have compelling evidence that cholinergic primary afferents may release ACh and generate PAD directly as well as produce synaptic actions on spinal interneurons. To date, acetylcholine release from primary afferent central terminals has never been unambiguously demonstrated in mammals. Intriguingly, a subpopulation of primary afferents expresses a recently described form of the acetylcholine synthesis enzyme that is specific to the peripheral nervous system. This population has been difficult to study, and little is known about their functionality. Nicotinc receptors signaling is implicated in modulating sensory processing, including pain, so signaling from this sensory pathway may uniquely influence bodily sensation. This proposal will directly test the capacity of a putatively cholinergic primary afferents to release ACh as a modulatory transmitter. I have identified a ChAT-Cre driver line that may genetically target this afferent population, enabling transgenic approaches that will allow me to characterize fundamental properties of their synaptic pathway. In order to accomplish this I have designed strategies for selective activation and anatomical characterization of this uncharacterized afferent population. In studying presynaptic afferent control in particular, introducing optogenetic strategies should bring a new level of experimental control to identifying the mechanisms controlling afferents via presynaptic ionotropic receptors by allowing individual neuronal elements to be isolated. If some pChAT afferents are shown to presynaptically control others, a completely new view on the mechanisms governing afferent control provides this afferent class a unique neuromodulatory role insomatosensation.
Presynaptic inhibition of primary afferents by terminal depolarization gates somatosensory inflow to the CNS, but may underlie diseased sensory states. We propose to undertake studies of the fundamental properties of an uncharacterized population of sensory fibers that may have a direct role in these processes via unconventional mechanisms of synaptic transmission.