Role of the mesolimbic dopamine system in relief learning

Abstract

The relief from an aversive event is rewarding. Since organisms are able to learn which environmental cues can cease an aversive event, relief learning helps to better cope with future aversive events. Literature data suggest that relief learning is affected in various psychopathological conditions, such as anxiety disorders. Here, we investigated the role of the mesolimbic dopamine system in relief learning. Using a relief learning procedure in Sprague Dawley rats, we applied a combination of behavioral experiments with anatomical tracing, c-Fos immunohistochemistry, and local chemogenetic and pharmacological interventions to broadly characterize the role of the mesolimbic dopamine system. The present study shows that a specific part of the mesolimbic dopamine system, the projection from the posterior medial ventral tegmental area (pmVTA) to the nucleus accumbens shell (AcbSh), is activated by aversive electric stimuli. 6-OHDA lesions of the pmVTA blocked relief learning but fear learning and safety learning were not affected. Chemogenetic silencing of the pmVTA-AcbSh projection using the DREADD approach, as well as intra-AcbSh injections of the dopamine D2/3 receptor antagonist raclopride inhibited relief learning. Taken together, the present data demonstrate that the dopaminergic pmVTA-AcbSh projection is critical for relief learning but not for similar learning phenomena. This novel finding may have clinical implications since the processing of signals predicting relief and safety is often impaired in patients suffering from anxiety disorders. Furthermore, it may help to better understand psychological conditions like non-suicidal self-injury, which are associated with pain offset relief.

Adult social isolation leads to anxiety and spatial memory impairment: Brain activity pattern of COx and c-Fos

“…This could be explained by the fact that COx histochemistry is a technique that shows accumulated neuronal response. Therefore, the inconsistent performance of the IS group in the WM task (sometimes well-performed while others not) is not reflecting an endurable metabolic dysfunction in a brain structure known to be involved in rewarding responses [74]. Both PFC and VTA were impaired not only in c-Fos expression, but also at metabolic level.…”

Chronic inhibition of GABA synthesis in the infralimbic cortex facilitates conditioned safety memory and reduces contextual fear

“…The ASR is modulated by a number of factors, including the individual's arousal and affective state [1][2][3][4] . In rodents, ASR can be modified in response to emotional situations, with the startle magnitude being increased by fearful/threatening stimuli (also referred to as fear-potentiated startle (FPS)) 3,[5][6][7][8] and attenuated by threat-reducing or joyful/rewarding stimuli 3,7,[9][10][11] . Because these ASR modulations can be observed in both humans and rodents, the ASR provides an excellent translational research tool to investigate symptoms characterizing neuropsychiatric disorders 6,7,12,13 .…”

Modulating Dopamine Signaling and Behavior with Chemogenetics: Concepts, Progress, and Challenges

“…DA was also shown to play a crucial role in fear learning, and therefore anxiety disorders and posttraumatic stress disorder (Lee et al, 2016;Bouchet et al, 2018;Mayer et al, 2018). Yet how DAergic neurons modulate these processes is unclear.…”

“…Yet how DAergic neurons modulate these processes is unclear. Chemogenetic tools have facilitated investigations into this subject area, with hM4Di-mediated inhibition of a specific part of the mesolimbic system, projecting from the posterior medial VTA to the NAc shell, blocking relief learning following an aversive electrical stimulus cue (Mayer et al, 2018). There is ever growing data implicating the nigrostriatal pathway in this form of emotion since hM3Dq-mediated activation of SN DAergic neurons improved fear extinction memories and prevented future fear renewals (Bouchet et al, 2018).…”