The Role of Posterior Striatum Projecting Dopamine Neurons in Associative Fear Learning

• Applicant: Dr. Sevil Duvarci
• Subject Area: Cognitive, Systems and Behavioural Neurobiology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 470520017

Associative learning enables animals to learn from experience, and thus is essential for adaptive responding in an ever-changing environment. In particular, the ability to learn which stimuli predict danger is crucial for survival. In the laboratory, this kind of associative learning is modelled using classical fear conditioning where an initially neutral stimulus (conditioned stimulus, CS) comes to elicit fear responses after being paired in time with an aversive outcome (unconditioned stimulus, US). Notably, its clinical significance has made fear conditioning an intensively studied paradigm since much evidence indicates that anxiety disorders, such as the post-traumatic stress disorder (PTSD), result from dysregulation of brain circuits that mediate associative fear learning. Understanding neural mechanisms underlying fear learning is therefore crucial for a better understanding of the pathophysiology of anxiety disorders and can help develop new treatment strategies. Associative learning, such as fear conditioning, is driven by prediction errors (PE) which act as teaching signals to instruct new learning. It is well-established that dopamine (DA) neurons encode PE signals to drive associative reward learning. Importantly, recent evidence suggests that DA neurons encode prediction errors not only for rewards but also for aversive outcomes. Striatum constitutes the major projection target of DA neurons; however, whether DA neurons that project to the striatum, in particular a specific subregion of the striatum, are involved in associative fear learning has remained elusive. Recent studies have identified a unique subpopulation of DA neurons based on their input-output organization. These DA neurons project selectively to a distinct subdivision of the striatum, the posterior tail of the striatum (pTS), and are activated strongly by novel and high-intensity stimuli. Furthermore, they have been shown to reinforce threat avoidance. However, whether these DA neurons are required for associative fear learning is currently unknown. We hypothesize that pTS-projecting DA neurons encode an aversive PE signal which is necessary for acquisition of associative fear learning. Addressing this hypothesis will be the major goal of this proposal. To this end, we will perform projection-specific activity-dependent calcium recordings, temporally-precise optogenetic manipulations as well as measurement of DA release using a DA biosensor. These data will reveal for the first time the crucial role pTS-projecting DA neurons play in associative fear learning. In addition, we will further investigate the role of DA input on the activity of pTS neurons during associative fear learning to shed light on how DA modulates striatal activity and thus enables learning. Taken together, we expect that our results will identify a novel role for the pTS-projecting DA neurons and furthermore will suggest that a unique mesostriatal circuit is crucial for associative fear learning.

• DFG Programme: Research Grants