A Brainstem-Thalamic-Cortex Glutamatergic Neuron Pathway Modulates Propofol Anesthesia

Background: The precise mechanisms underlying the modulation and transformation of consciousness during propofol anesthesia remain inadequately understood. Both the paraventricular thalamus (PVT)-medial prefrontal cortex (mPFC) pathway and the parabrachial nucleus (PB) are implicated in the regulation of sleep-wake cycles. Consequently, this study aimed to explore whether projections from the PB to the PVT-mPFC pathway are involved in the effects of propofol anesthesia. Methods: Anterograde and retrograde viral tracing techniques were employed to map the projections from the PB to the PVT and from the PVT to the mPFC. The activity within this pathway was monitored using fiber photometry during propofol anesthesia. The study further examined the role of this pathway during the induction and emergence phases of propofol anesthesia through optogenetic modulation in conjunction with cortical electroencephalography (EEG) recordings. Results: Glutamatergic neurons in the PB exhibit dense projections to the PVT, and in turn, PVT glutamatergic neurons project densely to the mPFC. Administration of propofol resulted in a reduction of calcium signals in the parabrachial glutamatergic nucleus to paraventricular thalamus (PB Glu -PVT) pathway. Moreover, it has been observed that optogenetic activation of the PB Glu -PVT pathway significantly enhances cortical activation during propofol anesthesia, whereas optogenetic inhibition of this pathway yields the opposite effect. Additionally, optogenetic stimulation of the PVT Glu -mPFC pathway accelerates the induction of propofol anesthesia but prolongs the emergence time. Conversely, inhibition of the PVT Glu -mPFC pathway facilitates cortical activation under propofol anesthesia. Conclusion: Collectively, this study provides supportive evidence for the involvement of a brainstem-thalamic-cortical glutamatergic circuit in propofol anesthesia. The findings offer a preliminary perspective on how propofol may modulate consciousness and highlight potential pathways worthy of further investigation. Keywords: propofol, optogenetics, paraventricular thalamus, parabrachial nucleus, medial prefrontal cortex, glutamatergic neurons