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Neural mechanisms enabling caudal ventral preoptic area control of pain aversion

Award Number: R56NS115747
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: 12/01/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Neural mechanisms enabling caudal ventral preoptic area control of pain aversion - PROJECT SUMMARY Pain is the number one reason patients seek health care and greater than 20% of the US population is affected by chronic pain. Existing therapeutics have limited efficacy and a narrow therapeutic period, while also evoking deleterious side effects. It is therefore vital to understand pain processing in order to develop novel therapeutics to address this pressing health care crisis. According to the International Association for the Study of Pain (IASP) pain is “an unpleasant sensory and emotional experience associated with actual or potential tissue damage”. Intrinsic to the unpleasantness elicited by pain perception is the attribution of aversiveness to painful stimuli. This is normally advantageous as it drives self-protective behavior. Dysregulation of aversive circuits may contribute to the suffering associated with chronic pain conditions. Understanding how the brain encodes aversion is of vital importance as manipulation of the circuits encoding aversion could be an avenue for therapeutic intervention. Larval zebrafish provide an attractive model system for inquiries into the biology of pain processing. They are fully functioning animals, which must hunt for prey and assign appropriate valence to salient stimuli in order to survive. As such they have an intact nervous system that allows them to perceive and respond robustly to sensory stimuli. They robustly avoid painful stimuli and known analgesics are effective in blocking nociception in multiple assays that model nociception. Their small size and optical clarity allow for high throughput behavioral phenotypic screening and CNS-wide quantification of neuronal activity, allowing for holistic inquiry into the neurobiology of pain/nociception. Importantly the peripheral, spinal, subcortical, cortical structures and neuromodulatory systems that underpin pain sensation and the assignment of negative affect that drives the aversion evoked by painful stimuli are conserved in larval zebrafish. Despite these findings, outside of a strong conservation between primary nociceptor function, very little is known about if and how these structures and systems contribute to nociception and its behavioral outputs, which hinders the use of this species to model pain. Through a series of ablation studies, we found that the hypothalamic ventral caudal preoptic area (POvc) is required for behavioral aversion to painful stimuli. As the development and organization of the hypothalamus is highly conserved between zebrafish and mammals, findings from these studies will provide insight into how the hypothalamus encodes pain aversion. We hypothesize that the POvc is necessary for aversion to painful stimuli and acts upstream of locomotor pathways that enable escape. We will make use of the unique advantages of the zebrafish model system to test these hypotheses. In Aim 1, we will interrogate the contributions of POvc neurons to pain-evoked behavioral aversion. In Aim 2, we will characterize POvc neuronal activity in response to painful stimuli and interrogate the contributions of POvc neuronal subtypes to POvc neuronal activity. In Aim 3, we will examine the downstream targets of the POvc.


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 = $544,250 )
2026	2026	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	9/17/2026	COMPETING CONTINUATION	$544,250
														Subtotal = $544,250

Grand Total All Awards = $544,250

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Neural mechanisms enabling caudal ventral preoptic area control of pain aversion

Award Number: R56NS115747

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: 12/01/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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