Brain Circuits of Migraine Pain

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Summary Migraine is a prevalent neurological disorder affecting millions of people worldwide. The underlying pathophysiology of migraine likely involves diverse mechanisms within the trigeminal pain pathways and pain- related structures in the brain. Recently introduced medications targeting CGRP mechanisms including antibodies and small molecule CGRP receptor antagonists appear to act outside of the blood brain barrier. These medications are effective as preventive treatment in some patients implicating the role of meningeal CGRP in migraine pathology. However, many patients do not respond to these therapies and even those that do often experience “breakthrough migraines” suggesting the existence of non-CGRP peripheral migraine mechanisms. The brain circuits mediating migraine pain remain understudied. Cephalic nociceptive pathways involve activation of trigeminal afferents and transmission of the nociceptive signal through the second order cells in the trigeminocervical complex (TCC) to multiple brain regions. Human neuroimaging studies during a migraine attack have demonstrated activations in the amygdala and dorsal pons, encompassing the parabrachial nucleus (PBN). The PBN receives both exteroceptive and interoceptive sensory inputs and projects to multiple sites including the central nucleus of the amygdala (CeA), an area mediating emotional aspects of pain. Our preclinical studies using pharmacological and optogenetic activation of dural afferents, neuronal tracing and behavior suggest a functional pathway from the dura mater to TCC, PBN and CeA that may promote migraine-like pain. In this proposal, we will use opto/chemo-genetic methods, microscopy with immunostaining and RNAscope, CRISPR-Cas9 (i.e., CRISPR) genetic manipulations, electrophysiology, calcium imaging and pain behavior to investigate if, and how, the PBN→CeA pathway may promote migraine-like pain elicited by activation of dural afferents using several different approaches in male and female mice. Aim 1 will measure the effects on markers of neural activation in brain networks (microscopy) and consequences on pain behavior; Aim 2 will use brain slice electrophysiology and calcium imaging with pharmacological, CRISPR or opto/chemo-genetic manipulations of PBN outputs to evaluate plasticity of CeA cell types; Aim 3 will use chemogenetic inhibition of PBN outputs or CRISPR deletions in the CeA to evaluate possible inhibition of migraine pain behaviors. Our studies aim to address significant gaps in our knowledge of central pathways of migraine pain. We will determine the potential relevance of the central PBN→CeA circuit as a common pathway of migraine pain that can be engaged by CGRP-dependent and CGRP-independent peripheral mechanisms.