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Vagus nerve stimulation targets fear pathways to enhance extinction of conditioned fear

Award Number: R01MH126516
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Vagus nerve stimulation targets fear pathways to enhance extinction of conditioned fear - PROJECT SUMMARY Emotionally traumatic experiences can lead to maladaptive memories that are enduring and intrusive. The goal of exposure-based therapies is to extinguish conditioned fears through repeated, unreinforced exposures to reminders of traumatic events. The extinction of conditioned fear depends upon the consolidation of new memories made during exposure to reminders. An impairment in extinction recall, observed in certain patient populations, can interfere with progress in exposure-based therapies, and the drive to avoid thoughts and reminders of the trauma can undermine compliance and increase dropout rate. Development of an effective adjunctive therapy would ideally improve the tolerability of therapy and/or improve the consolidation and maintenance of the extinction memory. We have recently demonstrated in rats that, compared to exposure alone, exposure paired with vagus nerve stimulation (VNS) enhances the extinction of fear-based memories. Under stressful conditions, the vagus nerve responds to elevations in epinephrine and signals the brain to facilitate the storage of new memories while, as part of the parasympathetic nervous system, it slows the sympathetic “fight-or-flight” response. We propose that stimulation of the left cervical vagus nerve during exposure to conditioned cues signals the brain to store new memories just as epinephrine or emotional arousal would do but bypasses the peripheral sympathetic response. In support of this hypothesis, we have found that VNS accelerates extinction, reverses extinction impairments, promotes generalization of extinction, and prevents reinstatement of conditioned fear in rats. VNS is thought to work by increasing the activity of neuromodulators throughout the brain, producing a synaptic state that is conducive to plasticity. In particular, the locus coruleus (LC) is thought to play a critical role in VNS efficacy by supplying noradrenergic input directly to multiple regions of the extinction network, including the prefrontal cortex (PFC), the basolateral amygdala (BLA), and the hippocampus (HIP). Here, we propose behavioral experiments designed to evaluate whether VNS produces more persistent and generalized extinction memories, which would provide important preclinical evidence that VNS could be an effective adjunct to exposure-based therapies. To elucidate the mechanisms by which VNS promotes its effects, we propose to optogenetically manipulate the LC, and to simultaneously record from PFC, BLA, and HIP during conditioning, extinction, and post-extinction behavioral testing. By increasing our understanding of the mechanisms by which VNS enhances extinction of conditioned fear, these studies will support treatment development for patients, and provide new fundamental insights into the neuromodulatory mechanisms of LC signaling on extinction-related plasticity.


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: 2026 ( Subtotal = $0 )
2026	2025	UNIVERSITY OF TEXAS AT DALLAS	800 WEST CAMPBELL RD.	RICHARDSON	TX	75080	DALLAS	USA	Mental Health Research Grants	000	4	1/7/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $536,947 )
2025	2025	UNIVERSITY OF TEXAS AT DALLAS	800 WEST CAMPBELL RD.	RICHARDSON	TX	75080	DALLAS	USA	Mental Health Research Grants	001	4	9/18/2025	NON-COMPETING CONTINUATION	$80,541
2025	2025	UNIVERSITY OF TEXAS AT DALLAS	800 WEST CAMPBELL RD.	RICHARDSON	TX	75080	DALLAS	USA	Mental Health Research Grants	000	4	2/13/2025	NON-COMPETING CONTINUATION	$456,406
														Subtotal = $536,947

Issue Date FY: 2024 ( Subtotal = $546,470 )
2024	2024	UNIVERSITY OF TEXAS AT DALLAS	800 WEST CAMPBELL RD.	RICHARDSON	TX	75080	DALLAS	USA	Mental Health Research Grants	001	3	2/15/2024	NON-COMPETING CONTINUATION	$483,253
2024	2024	UNIVERSITY OF TEXAS AT DALLAS	800 WEST CAMPBELL RD.	RICHARDSON	TX	75080	DALLAS	USA	Mental Health Research Grants	002	3	8/14/2024	NON-COMPETING CONTINUATION	$53,694
2024	2022	UNIVERSITY OF TEXAS AT DALLAS	800 WEST CAMPBELL RD.	RICHARDSON	TX	75080	DALLAS	USA	Mental Health Research Grants	000	1	1/19/2024	NEW	$9,523
														Subtotal = $546,470

Issue Date FY: 2023 ( Subtotal = $535,419 )
2023	2023	UNIVERSITY OF TEXAS AT DALLAS	800 WEST CAMPBELL RD.	RICHARDSON	TX	75080	DALLAS	USA	Mental Health Research Grants	000	2	3/7/2023	NON-COMPETING CONTINUATION	$535,419
														Subtotal = $535,419

Issue Date FY: 2022 ( Subtotal = $555,621 )
2022	2022	UNIVERSITY OF TEXAS AT DALLAS	800 W CAMPBELL RD	RICHARDSON	TX	75080	DALLAS	USA	Mental Health Research Grants	000	1	5/1/2022	NEW	$555,621
														Subtotal = $555,621

Grand Total All Awards = $2,174,457

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Vagus nerve stimulation targets fear pathways to enhance extinction of conditioned fear

Award Number: R01MH126516

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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