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Trans-synaptic signaling complex in amygdala pain mechanisms

Award Number: R01NS118731
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: 08/01/2020
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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Trans-synaptic signaling complex in amygdala pain mechanisms - Summary: Pain is a serious clinical problem that affects more than 100 million Americans. The economic costs of pain have been estimated to be more than several hundred billion dollars including healthcare costs and lost productivity. Persistent pain may produce long-term disability and lead to precipitation of depression, anxiety and cognitive impairment. Currently used medications for chronic pain are not always effective and have limitations in terms of tolerance and abuse liability. Thus, identifying novel therapeutic targets is essential to address this clinical burden. Peripheral and central pathways that encode, transmit, and amplify or reduce pain signals have been identified, including the spinothalamic and spinoparabrachial pathways. Plasticity of glutamatergic synapses along key nodes in the spinoparabrachial-amygdala pathway plays an important role in pain modulation and in the transition from subacute to chronic pain. However, the mechanisms governing the development, maintenance and plasticity of this system and their role in persistence of pain behaviors remain poorly understood. The proposed research will advance the concept that the trans-synaptic signaling complex centered on glutamate delta 1 receptor regulates function of synapses in the laterocapsular region of central amygdala also known as “nociceptive amygdala” and contributes to persistent pain mechanisms. Specific Aim1 will define the cell type- and projection-specific distribution of these receptors and their role in regulating amygdala circuitry and nocifensive and averse-affective behavior under normal conditions. Specific Aim 2 will determine persistent/chronic pain-related changes in glutamate delta 1 signaling using inflammatory and neuropathic pain models and test the effect of a rescue strategy on synaptic neuroplasticity in pain models. Changes in ultrastructure of amygdala synapses in pain models will be evaluated using 3D-electron microscopy. Specific Aim 3 will determine the effect of restoring trans- synaptic signaling through the glutamate delta 1 receptor in mitigating nocifensive and averse-affective behaviors in pain models. Complementary experiments will address the effect of cell-type specific manipulation of central amygdala circuitry in mitigating pain. To accomplish these aims we will utilize a combination of brain slice electrophysiology, behavior, chemo- and opto-genetics, confocal and electron microscopy (immuno and 3D), and genetic approaches to determine the functional and structural mechanisms through which the glutamate delta 1 signaling complex regulates pain-related neuroplasticity and behaviors. This project is significant because it would identify a novel brain mechanism of pain that could be targeted for pain management. Scientific rigor of research design is established by the use of multiple methods and approaches, replication of experiments in independent laboratories, use of validated models and reagents, consideration of blinding, biological variables and sex in addition to other aspects of experimental design.


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 = $0 )
2025	2024	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	6	12/6/2024	NON-COMPETING CONTINUATION	$0
2025	2024	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	005	6	7/1/2025	NON-COMPETING CONTINUATION	$0
2025	2023	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	5	12/4/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$173,177
2025	2023	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	12/4/2024	NON-COMPETING CONTINUATION	-$137,354
2025	2023	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	5	12/10/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2025	2022	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	12/4/2024	NON-COMPETING CONTINUATION	-$35,823
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $527,810 )
2024	2024	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	6	8/12/2024	NON-COMPETING CONTINUATION	$527,810
2024	2023	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	6/27/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$392,974
2024	2023	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	6/27/2024	NON-COMPETING CONTINUATION	-$392,974
														Subtotal = $527,810

Issue Date FY: 2023 ( Subtotal = $530,328 )
2023	2023	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	8/8/2023	NON-COMPETING CONTINUATION	$530,328
														Subtotal = $530,328

Issue Date FY: 2022 ( Subtotal = $530,374 )
2022	2022	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	7/19/2022	NON-COMPETING CONTINUATION	$530,374
														Subtotal = $530,374

Issue Date FY: 2021 ( Subtotal = $530,421 )
2021	2021	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	7/22/2021	NON-COMPETING CONTINUATION	$530,421
														Subtotal = $530,421

Issue Date FY: 2020 ( Subtotal = $553,214 )
2020	2020	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	7/29/2020	NEW	$553,214
														Subtotal = $553,214

Grand Total All Awards = $2,672,147

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Trans-synaptic signaling complex in amygdala pain mechanisms

Award Number: R01NS118731

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: 08/01/2020

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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