Migraine-related plasticity at central synapses of TRPV1 trigeminal nociceptors

• Applicant: Dr. Bruno Pradier
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Cognitive, Systems and Behavioural Neurobiology
• Term: from 2016 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 327243506

Migraine is a disabling and episodic brain disorder with high prevalence and complex pathophysiology. Trigeminal nociceptors and the trigeminal nucleus caudalis (TNC) are key brain structures for the integration and processing of craniofacial pain. Animal models suggest that sensitization of this pathway plays a major role in the pathology of migraine, yet surprisingly little is known about long-term changes in trigeminal afferents or their synapses in the TNC. One potential mechanism of sensitization of the TNC could be changes in synaptic plasticity of nociceptive afferents. Given its importance in migraine and the small number of physiological studies of the TNC, this proposal aims at the detailed investigation of migraine-related plasticity at primary nociceptive afferent synapses onto second-order relay neurons within the TNC. To selectively stimulate primary nociceptive afferents I will employ an optogenetic mouse line to study sensitization of these fibers in vitro and in vivo. Aim 1: To characterize long-term depression at optogenetically isolated nociceptive trigeminal synapses. Our preliminary data show that migraine-inducing drugs (PACAP and nitric oxide (NO) -donor SNAP) depress nociceptive trigeminal synapses in acute TNC slices within minutes of local application. Similarly, low-frequency optical stimulation (LFS) of primary nociceptive afferents depresses synaptic activity. I will study the mechanisms by which these drugs as well as LFS cause persistent alterations at these synapses in acute TNC slices of TRPV1/Chr2 mice that could contribute to migraine pathophysiology.Aim 2: To characterize the role of TRPV1 nociceptive afferents in rodent models of migraine. Using the optogenetic TRPV1/ChR2 mouse line we plan to characterize in vivo the sensitization of dura-innervating primary nociceptors with two pharmacologically independent mouse models for migraine (PACAP, NO-donor NTG). I will also investigate whether prolonged, optogenetic, dural stimulation is sufficient to induce sensitization of the trigeminal pathway. These experiments will give us valuable information about sensitization of pathways mediating craniofacial pain in rodent models for migraine.Aim 3: To develop a novel in vitro model to investigate migraine-related synaptic plasticity. I am going to induce a migraine-like state in TRPV1/ChR2 animals by administration of PACAP or NTG. In brainstem slices of these mice, I will investigate TNC plasticity in vitro by measuring strength and activity of primary nociceptor synapses compared to saline-injected mice. The results will inform us about mechanisms of synaptic plasticity that are induced in vivo.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professorin Julie Kauer, Ph.D.