Community Research and Development Information Service - CORDIS

Periodic Report Summary 1 - DOPAPREDICT (Functional Analysis of Dopamine Prediction Error Circuits)

The ability to discriminate novel from familiar sensory stimuli is a fundamental feature of the central nervous system. When humans or animals detect novel stimuli in their environment, they respond with distinct orienting and exploratory behaviors. This behavioral novelty response also has an autonomic component which includes transient changes in skin conductance, heart and respiratory rates1. Novel stimuli familiarize after a few exposures suggesting a very rapid form of memory formation. Disturbances in novelty processing are associated with numerous human pathological conditions including schizophrenia5,49,50 and autism7,8,51, which highlights the clinical relevance of understanding the circuit mechanisms underlying novelty detection and learning.
A candidate circuit implicated in novelty processing resides in the two dopaminergic midbrain structures substantia nigra pars compacta (SNc) and ventral tegmental area (VTA). Human fMRI studies suggest activation of midbrain dopamine neurons by stimulus novelty11. Experiments in animals using voltammetry52 or microdialysis13 further demonstrate increased dopamine release in novel environments. Single-unit recordings show activation of dopamine neurons by stimuli that are novel but also physically salient15. Hence, dopamine single-units have yet to be systematically investigated under experimental conditions in which potentially confounding effects of novelty-unrelated stimulus saliency or novelty-induced locomotion are controlled for and in which stimulus novelty is manipulated selectively.
Moreover, it is currently unclear, how the novelty response of dopamine neurons, relate to dopamine’s well-established role in learning from reward and punishment. Lateral dopamine neurons, primarily of the SNc, are activated by unexpected rewards and sensory cues predicting rewards as well as by unexpected punishment and sensory cues predicting punishment21,53. Medial dopamine neurons, primarily of the VTA, are activated by unexpected rewards and rewarding cues but they are inhibited by punishment and aversive cues. Thus, VTA dopamine neurons encode the discrepancy between predicted and actual reward, also called reward prediction error. Based on formal theories of reinforcement learning, it has been shown that dopamine prediction errors act as a teaching signal to mediate learning from reward and punishment53,54.
Based on their different firing patterns in the reinforcement context, the subpopulation of SNc and VTA neurons have also been termed salience and valence neurons, respectively21. If salience, valence or both subpopulations respond to stimulus novelty remains controversial. Due to the intrinsic salience of novel stimuli, novelty-evoked responses could be mainly found in SNc. Human fMRI studies indirectly support this possibility11,22, but the limited resolution of the fMRI technique does not permit dissociating the source of novelty signals between SNc and VTA. On the other hand, the robust dopamine release in the nucleus accumbens, a major VTA projection target, upon entry of rats into a novel space indicates novelty responses among dopamine neurons in VTA52. Since dopamine neurons along the medial to lateral extent of the VTA and the adjacent SNc differ considerably in their projection targets and electrophysiological properties23, the answer to this question has profound implications for delineating the novelty circuits in the brain.
In this project, behavioral techniques combined with fiber photometry and optogenetics are used to study the role of dopamine in novelty processing in awake, behaving mice.

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