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Postsynaptic mechanisms underlying negative prediction error

Award Number: R21DA057073
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2024

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Postsynaptic mechanisms underlying negative prediction error - ABSTRACT The role of the dopamine system in reward has been well established. Whether dopaminergic mechanisms may underlie reinforcement learning or incentive motivation has been a central issue in the field. Evidence that supports the reinforcement learning hypothesis mostly come from recordings of dopamine neuron firing or dopamine release that are often temporally correlated with prediction error. In contrast, causal evidence that supports the incentive motivation hypothesis mostly come from pharmacological manipulations of dopaminergic signaling that often show altered motivation in reward seeking. One study that stands out is Roy Wise’s 1978 study that used dopamine antagonist and unambiguously demonstrated that decreased dopaminergic signaling is sufficient in causing extinction learning. It is often cited as one of the best causal evidence that supports reinforcement learning but not incentive motivation hypothesis. However, a number of questions remain unanswered. Is it dose dependent? Is it receptor specific? Is it post-synaptic signaling pathway specific? Does such manipulation represent negative prediction error? To address these questions, the present application will employ operant conditioning paradigms similar to what’s used in the Wise paper and test the following hypothesis: lack of dopaminergic signaling--> negative prediction error--> lack of dopamine D2 receptor activation-->lack of inhibition of adenylyl cyclase 5 (AC5) --> elevated cAMP in D2 striatal neurons-->extinction learning. In Aim 1, we will use D2 antagonist and use Gs DREADD expressed in D2 striatal neurons to cause extinction (to test sufficiency). We will also use AC5 knockout mice, AC5 inhibitor and Gi DREADD expressed in D2 striatal neurons to prevent extinction (to test necessity). The objective of Aim 1 is to establish that “D2-AC5-cAMP elevation” is indeed necessary and sufficient in causing extinction learning using natural reward. However, those studies will not demonstrate if this pathway is in fact processing the negative prediction error signal in causing extinction learning. Aim 2 studies will use experimentally generated phasic dip in dopamine release to test this hypothesis. In addition, we will use light induced phasic dopamine neuron firing during no reward condition. We will test if such a manipulation will be able to prevent extinction caused by lack of reward.


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 = -$10,030 )
2025	2023	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Drug Use and Addiction Research Programs	001	2	6/5/2025	NON-COMPETING CONTINUATION	-$1,846
2025	2023	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Drug Use and Addiction Research Programs	000	2	5/5/2025	NON-COMPETING CONTINUATION	-$8,184
														Subtotal = -$10,030

Issue Date FY: 2023 ( Subtotal = $197,576 )
2023	2023	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Drug Use and Addiction Research Programs	000	2	7/12/2023	NON-COMPETING CONTINUATION	$197,576
														Subtotal = $197,576

Issue Date FY: 2022 ( Subtotal = $238,576 )
2022	2022	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Drug Use and Addiction Research Programs	000	1	8/11/2022	NEW	$238,576
														Subtotal = $238,576

Grand Total All Awards = $426,122

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Postsynaptic mechanisms underlying negative prediction error

Award Number: R21DA057073

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2024

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