The Role of Dorsal Raphe Neuron Subtypes in Fear Extinction Learning

• Applicant: Dr. Sevil Duvarci
• Subject Area: Cognitive, Systems and Behavioural Neurobiology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 575649874

The ability to learn which stimuli predict danger is crucial for survival but it is equally important to adapt behavior when those stimuli no longer represent a threat.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. Many anxiety disorders, such as post-traumatic stress disorder, are characterized by impaired fear extinction and thus understanding the neural mechanisms of this form of safety learning has high clinical significance. Fear extinction represents new learning in which the association between the CS and safety (the absence of the US) 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 recent findings further 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). Importantly, input from the dorsal raphe (DR) to amNAc-projecting DA neurons is crucial for EPE signaling and fear extinction learning (Salinas-Hernandez et al., 2023). However, DR is a brain region that is composed of several different subtypes of neurons such as serotonergic, glutamatergic, GABAergic neurons. Which subtype of DR neurons mediate EPE signaling to drive extinction learning is currently unknown. Based on our recent findings, we hypothesize that EPE signaling is mediated by DR glutamatergic neurons and their projections to amNAc-projecting DA neurons. To address this, we will first examine the dynamics of glutamate release onto amNAc-projecting DA neurons during fear extinction. We will next investigate the activity of glutamatergic DR inputs to these DA neurons by performing projection-specific activity-dependent calcium recordings. Projection- and cell type-specific bidirectional optogenetic manipulations will further be performed to reveal the causal contribution of glutamatergic DR neurons in driving fear extinction learning. Finally, we will investigate the unique monosynaptic inputs to glutamatergic DR neurons that potentially provide the critical information related to fear extinction and EPE-signaling. Taken together, the proposed experiments will yield crucial insights into the role of glutamatergic DR neurons in EPE signaling and fear extinction learning.

• DFG Programme: Research Grants