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Probing spike initiation properties of primary somatosensory neurons using optogenetics

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Neurons use action potentials, or spikes, to encode information. Abnormal coding of somatosensory input can cause chronic pain. Indeed, pathological changes in excitability in primary somatosensory neurons are necessary and sufficient for many forms of chronic pain. Our goal is to understand normal excitability and the causes and consequences of its pathological disruption. This understanding will help treat chronic pain by pinpointing precisely where and how to therapeutically intervene to restore normal excitability.

Spike initiation (SI) – the basis for excitability – reflects how ion channels interact based on their mutual sensitivity to voltage. Nonlinear interactions dictate whether SI is primarily sensitive to total depolarization or to its rate of change. Subtle changes in ion channel expression/function can qualitatively alter those interactions and the coding properties they convey.

Somatosensory evoked spikes originate in peripheral axon terminals (Fig 1) but the SI properties of primary somatosensory neurons have been studied almost exclusively in the cell body, or soma. This is because axons are prohibitively difficult to record intracellularly. This technical barrier has significantly impeded efforts to study somatosensation and its disruption in chronic pain. We have developed an innovative solution to overcome this barrier. OPTEx – OptoPhysiological Testing of Excitability – uses optogenetics to photoactivate axons. By applying precisely controlled photostimulus waveforms while recording evoked spikes electrophysiologically or with GCaMP-based calcium imaging, we can derive the SI properties of the photostimulated region. Combining our computational expertise with the OPTEx method, we will study SI properties and their pathological disruption at key loci in primary somatosensory neurons (Fig 1).

Aim 1– To determine the SI properties of peripheral axon terminals and their role in mechanosensation. By using photostimulation to bypass the mechanotransduction step, we will test if the SI step differs between functionally distinct cell types. We will also isolate the effects of inflammation on transduction and SI.

Aim 2– To determine the SI properties of central axon terminals and their role in GABA-evoked spiking. We will test our prediction that depolarization of central axon terminals by GABAergic input evokes antidromic spiking only if pathological conditions cause a combined change in chloride reversal potential and SI properties.

Aim 3– To measure changes in SI relative to the site of axonal damage and their role in ectopic spiking. We will measure how axonal SI properties change after nerve injury, and specifically whether changes differ between cell types and location relative to the site of injury (neuroma).

The proposed experiments leverage our successful development of the OPTEx method to test predictions arising from our computer simulations and somatic recordings. Based on our track record of synergistically combining experiments and simulations to study SI mechanisms, and with the necessary equipment and transgenic mice already in place, we are uniquely positioned to push the study of SI past existing barriers. The results will provide invaluable insight into how primary somatosensory neurons normally encode information and how that coding goes awry in pathological conditions. That information will in turn help guide the strategic development of therapies to alleviate chronic pain by manipulating the SI process at critical locations along the axon.

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