The role of dopamine neurons in the ventral tegmental area in anesthetic-emergence and cognitive recovery

• Applicant: Dr. David Obert
• Subject Area: Cognitive, Systems and Behavioural Neurobiology ; Anaesthesiology ; Human Cognitive and Systems Neuroscience
• Term: from 2023 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 517593652

Despite enormous research efforts the exact mechanisms underlying anesthetic-induced loss of consciousness (LOC) remain incompletely understood. The molecular targets of the various substances have been identified using in vitro studies, but the neural circuits mediating loss and return of consciousness are not fully elucidated. Since the emergence from general anesthesia seems to play an important role for the development of postoperative neurocognitive disorders (PNDs) there has been an increasing interest in the wake-up period over the last decade. Considering the demographic change and the fact that the incidence of PNDs is positively correlated with patient’s age, the optimization of the anesthetic management is crucial. In clinical practice, emergence is a slow process driven by anesthetic clearance. However, animal studies demonstrated that a stimulation of the dopaminergic system reduces the time to return of righting reflex (RORR). Especially, the neurons in the ventral tegmental area (VTA) with their projections to the nucleus accumbens (NAc) influenced the time to RORR significantly. However, RORR does not necessarily correlate with complete return of consciousness. For this reason, the neural circuits involved in cognitive recovery still remain elusive. Since the VTA also has projections to the prefrontal cortex (PFC), which is involved in attention and cognitive control, as well as to the hippocampus – a key player in memory consolidation – it seems very likely that the VTA has an important function in cognitive recovery. The aim of the present study is to characterize the role of the VTA during emergence from general anesthesia. To identify substance-specific mechanisms, GABAergic and non-GABAergic anesthetics will be used for induction. By manipulating the various projections separately, we will be able to discriminate the role of the connections to the NAc from the ones to PFC and hippocampus. The hypothesis is, that the NAc primarily mediates arousal whereas the projections to the PFC and hippocampus are involved in cognitive recovery. To test this hypothesis, we will use opto- and chemogenetics. These techniques will be combined with the implantation of local field potential electrodes. In addition, we will establish a central venous access since except for the volatile anesthetic sevoflurane the substances need to be injected intravenously. This project will help to elucidate the neural circuits involved in emergence from general anesthesia. Understanding these mechanisms will lead to new methods for rapid anesthetic reversal, and new treatments for common post-operative complications such as delirium and cognitive decline.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Ken Solt