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Neuromodulatory regulation of synaptic plasticity in spinal nociceptive circuits

Award Number: R37NS122141
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2022
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Neuromodulatory regulation of synaptic plasticity in spinal nociceptive circuits - Project Summary/Abstract Long-term potentiation (LTP) of primary afferent synapses onto spinal projection neurons (PNs) has been linked to increased pain sensitivity. The timing rules controlling the generation of LTP in adult PNs can be persistently relaxed by neonatal tissue damage, which likely contributes to the ability of early life injury to ‘prime’ nociceptive circuits and thereby exacerbate pain after subsequent insult. In the brain, the temporal window governing this spike timing-dependent plasticity (STDP) is strongly regulated by G protein-coupled receptor (GPCR) signaling evoked by neuromodulators such as dopamine (DA). This raises the possibility that neonatal injury facilitates LTP at primary afferent synapses onto adult PNs, and thereby promotes persistent pain, via long-term changes in spinal neuromodulatory signaling. Unfortunately, it remains unknown how GPCRs influence STDP at sensory synapses onto PNs. As a result, the cellular and molecular mechanisms underlying the increased amplification of ascending nociceptive transmission by the adult dorsal horn during the primed state are poorly understood. The objective of this application is to identify the neuromodulatory signals that promote the activity-dependent strengthening of sensory synapses onto the key output neurons of the spinal nociceptive circuit and contribute to the priming of developing pain pathways after early life injury. The central hypothesis is that ‘non-Hebbian’ LTP at sensory synapses onto spinal PNs is enabled by D1-like (i.e. D1/D5) dopamine receptor activation, occurring in concert with mGluR5-dependent intracellular Ca2+ release and extracellular signal-regulated kinase (ERK) signaling, which is essential for neonatal priming. The rationale of the proposed research is that these studies will identify novel molecular strategies to reduce the signaling gain of the spinal nociceptive network. Guided by strong preliminary data, the central hypothesis will be tested by pursuing the following specific aims: (1) Elucidate how DA receptor activation shapes STDP in PNs; (2) Identify the signaling pathways which cooperate with DA receptors to facilitate LTP in PNs; and (3) Identify the neuromodulators which mediate the priming of spinal nociceptive circuits following neonatal tissue damage. These aims will be accomplished by using a multidisciplinary experimental approach that includes electrophysiological characterization of STDP in PNs combined with both reflexive and non-reflexive behavioral measures of pain. The proposed work is innovative because it will be the first to demonstrate that DA signaling dictates the timing rules governing the plasticity of sensory synapses onto spinal PNs. The outcome of these investigations will be the identification of new spinal mechanisms that augment nociceptive transmission to the brain, and the demonstration that aberrant neuromodulation contributes to the persistent sensitization of spinal nociceptive circuits after early tissue damage. Thus the proposed research is significant because it will provide knowledge needed to design novel interventional strategies to disrupt spinal LTP as a means to alleviate chronic pain and to minimize the long-term consequences of neonatal tissue injury for the developing CNS.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $536,380 )
2025	2025	CINCINNATI UNIV OF	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	3/19/2025	NON-COMPETING CONTINUATION	$536,380
														Subtotal = $536,380

Issue Date FY: 2024 ( Subtotal = $575,744 )
2024	2024	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	4/8/2024	NON-COMPETING CONTINUATION	$575,744
														Subtotal = $575,744

Issue Date FY: 2023 ( Subtotal = $606,669 )
2023	2023	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	3/21/2023	NON-COMPETING CONTINUATION	$606,669
														Subtotal = $606,669

Issue Date FY: 2022 ( Subtotal = $461,894 )
2022	2022	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/10/2022	NEW	$461,894
														Subtotal = $461,894

Grand Total All Awards = $2,180,687

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Neuromodulatory regulation of synaptic plasticity in spinal nociceptive circuits

Award Number: R37NS122141

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/2022

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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