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Principal Investigator: Isabel Bleimeister
Organization: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
Fiscal Year: 2024
Award: $48,974
Funding agency: National Institute of Neurological Disorders and Stroke
Project Summary/Abstract
Pain is a debilitating condition that severely impacts quality of life. Despite a growing need for new treatments,
an incomplete understanding of the neural circuitry underlying pain has limited the development of novel pain
therapeutics. Spinal projection neurons in the superficial dorsal horn channel pain signals from the spinal cord
into the brain. These neurons may represent a viable target for future pain management strategies. While virtually
all the spinal output neurons mediating nociception target the contralateral parabrachial nucleus, subsets of
these neurons also project to other supraspinal structures, such as the ipsilateral parabrachial nucleus (spino-
PBN neurons) or the contralateral periaqueductal gray (spino-PAG neurons). Given the distinct collateralization
patterns of these neurons, I hypothesize that the spino-PBN and spino-PAG neurons have distinct
nociceptive functions. I will test this hypothesis using anatomical (Aim 1), functional (Aim 2), and behavioral
(Aim 3) approaches. Aim 1 will characterize the projection patterns of the spino-PAG and spino-PBN neurons
through retrograde viral tracing, optical clearing, and ribbon scanning confocal microscopy. Aim 2 will determine
the functional response properties of the spino-PAG and spino-PBN neurons using two-photon calcium imaging
and natural stimuli applied to an ex vivo preparation. Aim 3 will uncover the role of the spino-PAG and spino-
PBN neurons in mediating nocifensive behavior using chemogenetics and behavioral assays of nociception. The
experiments described in this proposal have the potential to advance our basic understanding of the spinal output
circuitry mediating nociception and help determine the efficacy of spinal projection neurons as new targets for
clinical intervention. To complete this proposal, I will receive rigorous intellectual and technical training from a
team of expert scientist and clinician mentors. This training will enable me to become an independent
investigator, allowing me to accomplish my long-term goal of becoming a physician-scientist specializing in pain.
Terms: <2-photon><Affect><Affective><Anatomic Sites><Anatomic structures><Anatomy><Assay><Behavior><Behavior monitoring><Behavioral><Behavioral Assay><Bilateral><Bioassay><Biological Assay><Brain><Brain Nervous System><Calcium><Cell Communication and Signaling><Cell Nucleus><Cell Signaling><Clinical><Contralateral><DREADDs><Data><Development><Encephalon><Future><Genetic><Goals><Image><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Investigators><Ipsilateral><Knowledge><Laser Scanning Confocal Microscopy><Mediating><Medulla Spinalis><Mentors><Mesencephalic Central Gray><Midbrain Central Gray><Modeling><Nerve Cells><Nerve Impulse Transmission><Nerve Transmission><Nerve Unit><Neural Cell><Neurocyte><Neuronal Transmission><Neurons><Nociception><Nucleus><Optics><Output><Pain><Pain Control><Pain Therapy><Pain management><Painful><Pathway interactions><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Pattern><Periaqueductal Gray><Persons><Physicians><Play><Population><Preparation><Property><QOL><Quality of life><Research Personnel><Researchers><Role><Scientist><Side><Signal Transduction><Signal Transduction Systems><Signaling><Spinal><Spinal Cord><Stimulus><Structure><Technical Expertise><Testing><Thalamic structure><Thalamus><Therapeutic><Therapeutic Intervention><Training><Transmission><Viral><annulus of the aqueduct><axon signaling><axon-glial signaling><axonal signaling><behavior response><behavioral monitoring><behavioral response><biological signal transduction><career><cell type><cellular targeting><chronic pain><clinical research site><clinical site><confocal scanning microscopy><designer receptors exclusively activated by designer drugs><detector><determine efficacy><developmental><dorsal horn><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><evaluate efficacy><examine efficacy><experiment><experimental research><experimental study><experiments><gene manipulation><genetic manipulation><genetically manipulate><genetically perturb><glia signaling><glial signaling><imaging><improved outcome><intervention therapy><interventional strategy><midbrain central gray substance><nerve signaling><neural circuit><neural circuitry><neural signaling><neurocircuitry><neuronal><neuronal patterning><neuronal signaling><neurotransmission><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><nociceptive><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><optical><pain signal><pain treatment><parabrachial nucleus><pathway><patient oriented outcomes><periaqueductal gray matter><preparations><response><social role><somatosensory><synaptic circuit><synaptic circuitry><technical skills><thalamic><tool><transmission process><two-photon><virtual>