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Excitatory and Metabotopic Regulation of PKA in Stress and Resilience

Award Number: R01MH116896
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/06/2019
PERIOD OF PERFORMANCE END DATE: 05/31/2024

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Excitatory and Metabotopic Regulation of PKA in Stress and Resilience - STRIATAL EXCITATORY AND METABOTROPIC PKA REGULATION IN STRESS AND RESILIENCE Mental disorders such as anxiety and depression are major health concerns that contribute unabated to a large portion of all morbidity and mortality. These complex disorders may be viewed as mal- adaptations that arise in brain circuitry. In order to achieve more effective treatments, better mechanistic understanding of brain circuitry integration is needed. Normally, motivated behaviors and executive functions require processing of sensory-triggered excitatory neurotransmission and assignment of emotional context. This occurs in the striatum where cortical glutamatergic and midbrain dopaminergic inputs converge to mediate brain functions such as reward and stress responses. Striatal dysfunction is broadly implicated in the etiology of many mental illnesses. For example, stress-induced alterations in the activity of reward-related brain regions, such as the nucleus accumbens (NAc), are linked to the pathophysiology of depression. Insight into the mechanisms by which glutamate and dopamine neurotransmission are integrated within the NAc may shed light on some causes of mental illness, or implicate new drug targets and treatment strategies. Here, we introduce a new signaling mechanism which we hypothesize is controlled by striatal glutamatergic and dopaminergic signaling to allow concerted regulation of PKA activity. Specifically, our preliminary data indicates that glutamate controls constitutive phosphorylation of the RII-beta (RIIb) regulatory subunit by Cdk5, which then directly affects PKA activation by D1-type dopamine receptors via a second PKA-dependent auto-phosphorylation mechanism. We hypothesize that this unique mechanism mediates striatal plasticity and behavioral responses to stress and that chronic stress can cause mal-adaptations in this mechanism so that glutamate and dopamine signaling are uncoupled and PKA signaling is dysregulated. We further hypothesize that this mechanism may be targeted to improve striatal plasticity and behavioral resilience. To pursue this novel premise, we propose to 1) study the regulation of RIIb/PKA and explore downstream effectors in vitro and in vivo; 2) study the role of RIIb/PKA phosphorylation in ventral striatal neuronal excitability and synaptic plasticity and 3) study the regulation of this mechanism by acute and chronic stress, and determine how it contributes to behavioral responses to stress. These studies will yield important information on the mechanisms that integrate brain circuitry and how they are affected by stress. Thus, we will better understand some of the basis by which stress may contribute to complex mental disorders such as anxiety and depression and how they may be more effectively treated.


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 = -$84,197 )
2025	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Mental Health Research Grants	000	4	10/8/2024	NON-COMPETING CONTINUATION	-$45,798
2025	2022	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Mental Health Research Grants	001	5	10/15/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$38,399
														Subtotal = -$84,197

Issue Date FY: 2023 ( Subtotal = $5,686 )
2023	2022	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Mental Health Research Grants	001	5	9/19/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$314,095
2023	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Mental Health Research Grants	000	4	9/19/2023	NON-COMPETING CONTINUATION	-$308,409
														Subtotal = $5,686

Issue Date FY: 2022 ( Subtotal = $371,250 )
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Mental Health Research Grants	000	4	5/17/2022	NON-COMPETING CONTINUATION	$371,250
														Subtotal = $371,250

Issue Date FY: 2021 ( Subtotal = $371,250 )
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Mental Health Research Grants	000	3	4/26/2021	NON-COMPETING CONTINUATION	$371,250
														Subtotal = $371,250

Issue Date FY: 2020 ( Subtotal = $445,144 )
2020	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Mental Health Research Grants	001	2	5/27/2020	NON-COMPETING CONTINUATION	$371,250
2020	2019	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Mental Health Research Grants	000	1	5/6/2020	NEW	$73,894
														Subtotal = $445,144

Issue Date FY: 2019 ( Subtotal = $371,250 )
2019	2019	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Mental Health Research Grants	000	1	5/29/2019	NEW	$371,250
														Subtotal = $371,250

Grand Total All Awards = $1,480,383

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Excitatory and Metabotopic Regulation of PKA in Stress and Resilience

Award Number: R01MH116896

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/06/2019

PERIOD OF PERFORMANCE END DATE: 05/31/2024

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