Nucleus Accumbens Circuits underlying Fear Extinction Learning

• Applicant: Dr. Sevil Duvarci
• Subject Area: Cognitive, Systems and Behavioural Neurobiology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 456771156

In order to survive, animals must detect and respond appropriately to cues and situations that signal danger in their surroundings. However, it is also crucial to adapt behavior when those stimuli no longer represent a threat. One classic example of this is fear extinction learning, during which the repeated presentation of a stimulus (conditioned stimulus, CS) that no longer predicts an aversive outcome (unconditioned stimulus, US) leads to a gradual decrease in learned fear responses. Deficits in fear extinction learning are a hallmark of anxiety disorders, and thus understanding the neural mechanisms underlying fear extinction has high clinical significance. Fear extinction represents new learning in which the association between the CS and an unexpected safe outcome is learned. This kind of associative learning is driven by prediction errors (PE) that signal the discrepancy between expected and actual outcomes. We have previously demonstrated for the first time that a subset of dopamine (DA) neurons signal the absence of the expected aversive outcome and this extinction prediction error (EPE) signal is both necessary for and sufficient to accelerate fear extinction learning (Salinas-Hernandez et al., 2018). Our findings from the first funding period revealed that the EPE-encoding DA neurons project to a restricted subregion within the medial nucleus accumbens (mNAc), specifically the anterior end of mNAc (amNAc; Salinas-Hernandez et al., 2023). However, how and through which neural circuits DAergic EPE signaling in NAc mediates initiation of extinction learning and ultimately leads to the formation of extinction memories is an open question that remains to be investigated. The first step in addressing this question is to understand the role of different components of the amNAc circuitry in fear extinction learning. In the NAc circuitry, the primary projection neurons comprise two distinct subtypes of medium spiny neurons (MSNs): DA D1-receptor and DA D2-receptor expressing neurons, known as D1-MSNs and D2-MSNs, respectively. In this proposal, our major goal will be to investigate the distinct contribution of D1- and D2-MSNs of amNAc in mediating fear extinction. To this end, we will first examine the activity of D1- and D2-MSNs by performing cell type-specific calcium imaging with miniscopes. Bidirectional optogenetic manipulations will further be performed to reveal the causal contribution of D1- and D2-MSNs in driving fear extinction learning. Next, we will investigate the impact of DA input on the activity of amNAc neurons during fear extinction learning. Finally, we will perform comprehensive anatomical analysis to uncover the unique monosynaptic inputs as well as the projection targets of D1- and D2-MSNs. Taken together, the proposed experiments will yield crucial insights into how the NAc circuitry mediates the EPE signaling and drives fear extinction learning.

• DFG Programme: Research Grants