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The Impact of Normative Aging and Alzheimers Disease on Fear based Disorders and Amygdala Dysfunction

Award Number: K99AG078400
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 08/15/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2023

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The Impact of Normative Aging and Alzheimers Disease on Fear based Disorders and Amygdala Dysfunction - Not only do fear-based disorders such as posttraumatic stress disorder (PTSD) quintuple the rate of suicide relative to those without these disorders, but they also increase the magnitude of age-related cognitive decline and double the risk for developing Alzheimer’s disease and other dementias in older adults. Fear-based disorders like PTSD are linked to fear memories. Due to the seemingly indelible and hyperactive properties of such fear memories, fear-based disorders can worsen with age. Although normative aging and Alzheimer’s disease have dissociable trajectories, one factor that negatively impacts cognitive aging and Alzheimer’s disease is the comorbidity of PTSD. Perturbations in the functional circuitry supporting fear memory extinction are also key neural mechanisms of PTSD. A critical anatomical structure within the neural circuitry underlying this dysfunctional processing is the basolateral amygdala (BLA), which is considered an integrative hub as it receives sensory and contextual information from the prefrontal cortex and hippocampus. While much of the current scientific focus on cognitive aging and Alzheimer’s disease centers on the prefrontal cortex and hippocampus, little is known about the underlying mechanisms of BLA dysfunction in aging, Alzheimer’s disease (AD), and the impact of co-occurring PTSD. One pathological process common to these disorders is underlying neuroinflammation. Importantly, ketogenic and ketone ester diets are known to ameliorate hyperactivity, inflammation, fear-based disorders, and show promise as treatments for the contributing factors to cognitive aging and AD. To date, no study has investigated how aging and AD act in concert to further impair the BLA’s role in extinguishing hyperactive fear memories (a central component of PTSD). To address the current gap in knowledge, this proposal will leverage the TgF344AD rat model of AD to understand the contribution of BLA inflammation, cellular dysfunction, and synaptic circuit impairment to underlying mechanisms of PTSD. Recent data from the lab suggests, relative to young wild type rats, aging and AD impairs fear extinction and recall, and furthermore, the BLA in aged and AD rats is hyperactive. As such, the overarching hypothesis of this proposal is that hyperactive fear memory, the core element of PTSD, increases with aging and is accelerated in AD due to progressive inflammatory-driven neurophysiological deficits in the BLA. In Specific Aim 1, this proposal will leverage a rodent fear conditioning protocol that models a critical component of PTSD (i.e., the inability to extinguish hyperactive fear memory) and assess how aging and Alzheimer’s disease contribute to BLA cellular dysfunction (both ex vivo and in vivo during fear extinction) and inflammation. Additionally, in Specific Aim 2, this proposal will determine if a ketone ester dietary intervention (known to have anti-epileptic and anti-inflammatory properties) or BLA inactivation can facilitate fear memory extinction and improve BLA hyperactivity and pathology in age and AD. The outcomes of this proposal will be critical to developing translational strategies to combat poor quality of life outcomes in older adults.


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: 2024 ( Subtotal = -$19,551 )
2024	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Aging Research	000	1	2/9/2024	NEW	-$19,551
														Subtotal = -$19,551

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Aging Research	000	1	7/21/2023	NEW	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $122,277 )
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Aging Research	001	1	9/14/2022	NEW	$19,323
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Aging Research	000	1	8/12/2022	NEW	$102,954
														Subtotal = $122,277

Grand Total All Awards = $102,726

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The Impact of Normative Aging and Alzheimers Disease on Fear based Disorders and Amygdala Dysfunction

Award Number: K99AG078400

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 08/15/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2023

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