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VTA-specific noradrenergic regulation of motivational control

Final Report Summary - VTANORREGMOTCONTROL (VTA-specific noradrenergic regulation of motivational control)

An executive summary
Motivation is crucial for adaptive behaviors in order to choose actions to gain good things and to avoid the bad things. Disruption of motivational control leads to maladaptive behaviors and is one of the core symptoms in many central nervous system disorders including substance use disorder, anxiety disorders and depression. Dopamine (DA) system is crucial for motivational control. The central nervous noradrenaline (NA) system is well positioned to control DA system activity. Despite emerging role of NA activity regulating motivation, the field lacks a clear understanding of the exact nature of such control. Here we aimed to evaluate the role of NA system activity at the level of midbrain DA cell bodies in the ventral tegmental area (VTA) in motivational control. We used behavioral models of motivational control in combination with real-time dynamic optical stimulation of NA neurons terminals in the VTA, the region-specific pharmacology and electrophysiology to provide novel data on NA mechanisms of motivational processes. In addition, we have aimed at transferring optogenetics "know how" to the host Institution – Institute of Pharmacology PAS in Krakow, Poland.
Our study demonstrated that NA signaling in the VTA, arising from the phasic (but not tonic) activity of the NTS (but not the LC) regulates cocaine-induced associative learning. Interestingly, neither tonic nor phasic stimulation of NA axonal terminals in the VTA deriving from the LC and the NTS neurons had any reinforcing or aversive effects. Furthermore, we showed that NTS NA signaling in the VTA regulates anxiety-like behaviors. We further showed that the VTA NA signaling regulates cocaine-induced associated learning and anxiety via alpha1-adrenergic receptors leading to decreased dopamine and increased non-dopamine VTA neuronal activity.
In conclusion, NA signaling in the VTA, arising from the specific activity of the NTS neurons, acting via alpha1-adrenergic receptors regulate anxiety and DA mediated associative learning. Finally, our study is an example of successful international transfer of “know how” and implementation of optogenetics in behavioral research.