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Fan Wang, Supervisor Uncovering a Monosynaptic Trigemino-parabrachial Circuit Facilitating Heightened Craniofacial Pain Perception by Erica Janet Rodriguez Department of Neurobiology Duke University Date:_______________________ Approved: ___________________________ Fan Wang, Supervisor ___________________________ Anne West ___________________________ Jorg Grandl ___________________________ Kevin Franks Dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Neurobiology in the Graduate School of Duke University 2017 ABSTRACT Uncovering a Monosynaptic Trigemino-parabrachial Circuit Facilitating Heightened Craniofacial Pain Perception by Erica Janet Rodriguez Department of Neurobiology Duke University Date:_______________________ Approved: ___________________________ Fan Wang, Supervisor ___________________________ Anne West ___________________________ Jorg Grandl ___________________________ Kevin Franks An abstract of a dissertation submitted in partial fulfillment of the requirements for the degree of Doctorof Philosophy in the Department of Neurobiology in the Graduate School of Duke University 2017 Copyright by Erica Janet Rodriguez 2017 iii Abstract Humans often rank craniofacial pain as more severe than body pain. Evidence suggests that a stimulus of the same intensity induces stronger pain in the face than in the body. However, the underlying neural circuitry for the differential processing of facial versus bodily pain remains unknown. Interestingly, the lateral parabrachial nucleus (PBL), a critical node in the affective pain circuit, is activated more strongly by noxious stimulation of the face than of the hindpaw. Using a novel activity-dependent technology called CANE developed in our laboratory, we identified and selectively labeled noxious-stimulus-activated PBL neurons and performed comprehensive anatomical input–output mapping. Surprisingly, we uncovered a hitherto uncharacterized monosynaptic connection between cranial sensory neurons and the PBL-nociceptive neurons. Optogenetic activation of this monosynaptic craniofacial-to- PBL projection induced robust escape and avoidance behaviors and stress calls, whereas optogenetic silencing specifically reduced facial nociception. The monosynaptic circuit revealed here provides a neural substrate for heightened craniofacial affective pain. iv Dedication This dissertation is dedicated to my grandparents, Ana and Jose Rodriguez, Leticia Campos, my parents, Myriam and Alberto Rodriguez, my sister, Amanda Rodriguez, and my fiancée, Tyler Gibson. v Table of Contents Abstract ......................................................................................................................................... iv Dedication ..................................................................................................................................... v Table of Contents ........................................................................................................................ vi Table of figures ........................................................................................................................... ix Acknowledgement ...................................................................................................................... xi 1. Introduction .............................................................................................................................. 1 1.1. Specific aims and hypothesis ................................................................................... 1 1.1.1. Test the hypothesis that PBL is more robustly activated by noxious craniofacial stimuli than by noxious bodily stimuli. ............................................................................ 3 1.1.2. Examine where noxious stimuli-activate PBL neurons project to and what their presynaptic inputs are. ............................................................................................... 5 1.1.3. Investigate the physiological and behavioral function of the direct trigemino- parabrachial circuit in noxious craniofacial perception. ................................................ 6 1.2. Background and Significance .................................................................................. 7 1.2.1. Differential perception of craniofacial nociception versus bodily nociception ............................................................................................................................ 9 1.2.2. Initial signaling of a noxious stimulus .................................................................. 12 1.2.3. Discriminative and affective pain pathways ........................................................ 14 1.2.4. The lateral parabrachial nucleus: a molecularly and physiologically diverse structure ............................................................................................................................... 16 1.2.5. PBL receives thermal nociceptive inputs ............................................................... 18 1.2.6. (C)apturing (A)ctivated (N)euronal (E)nsembles ................................................ 19 2. A craniofacial-specific monosynaptic circuit enables heightened affective pain. .... 21 2.2. Introduction ..................................................................................................................... 21 2.3. Materials and Methods .................................................................................................. 23 2.3.1. Animal Statement ..................................................................................................... 23 2.3.2. Animals ...................................................................................................................... 23 2.3.3. Viruses ....................................................................................................................... 25 2.3.4. Surgery ....................................................................................................................... 25 2.3.5. Immunohistochemistry ........................................................................................... 27 2.3.6. Floating section in situ hybridization .................................................................... 28 2.3.7. Image Acquisition and Quantification .................................................................. 29 2.3.8. Behavioral experiments for Fos immunostaining ............................................... 30 2.3.9. Behavioral experiments for capturing PBL-nociceptive neurons with CANE virus ...................................................................................................................................... 30 2.3.10. Electrophysiological recording in acute brainstem slices ................................ 32 vi 2.3.11. Optogenetic activation of TrpV1Cre::ChR2+ sensory afferent terminals in PBL in a real-time place escape/avoidance (PEA) test and in circular chamber for audio recording .............................................................................................................................. 34 2.3.12. Optogenetic activation of TrpV1Cre::ChR2+ sensory afferent terminals in PBL in a classical conditioned place aversion (CPA) test ..................................................... 36 2.3.13. Optogenetic silencing of TrpV1Cre::eArch+ sensory afferent terminals in PBL in von Frey tests and real-time place preference (RTPP) test ...................................... 37 2.3.14. Statistics ................................................................................................................... 40 2.4. Results and Discussion .................................................................................................. 41 2.4.1. Noxious facial stimuli activate the PBL more robustly and bilaterally compared to noxious bodily stimuli. ............................................................................... 42 2.4.2. PBL neurons activated by noxious facial stimuli are molecularly heterogeneous. .................................................................................................................... 46 2.4.3. CANE is efficient and selective in activity-dependent capturing of facial nociceptive relay PBL neurons. ......................................................................................... 47 2.4.4. PBL-nociceptive neurons project axons to multiple emotion- and instinct- related centers in the brain. ............................................................................................... 52 2.4.5. PBL-nociceptive neurons receive reciprocal inputs from emotion-related limbic regions and bilateral inputs from various reticular brainstem regions. ........ 53 2.4.6. CANE-captured PBL-nociceptive neurons receive direct input from primary sensory neurons in the ipsilateral trigeminal ganglion. ............................................... 55 3.4.1. TrpV1-Cre+ primary trigeminal sensory neurons provide functional monosynaptic excitatory input onto PBL-pain neurons. ............................................... 61 3.4.2. Activation of TrpV1-Cre+ axon terminals in PBL induces robust aversive behavior and audible vocalization. .................................................................................. 64 3.4.3. Silencing TrpV1-Cre+ axon terminals in PBL partially reduces mechanical allodynia in face but not in hindpaw after capsaicin injection .................................... 68 2.5. Conclusion ......................................................................................................................
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