A Role For Tachykinin 1 Preoptic Neurons In Natural And Anesthetic-Induced Arousal State Regulation
The role of the hypothalamic preoptic area (POA) in arousal state regulation has been studied since the early 20th century. Since then, the POA has been shown to modulate arousal in both natural (sleep and wake) as well as drug-induced (anesthetic-induced unconsciousness) states. While the POA is most known for its role in sleep promotion, populations of wake-promoting neurons within the region have also been identified. However, the complexity and molecular heterogeneity of the POA has made distinguishing these two populations difficult. Though multiple lines of evidence demonstrate that general anesthetics modulate the activity of the POA, the region’s heterogeneity has also made it challenging to determine whether the same neurons involved in sleep/wake regulation also modulate arousal in response to general anesthetics. While a number of studies show that sleep-promoting POA neurons are activated by various anesthetics, recent work suggests this is not universal to all arousal-regulating POA neurons. We hypothesized that the POA’s broad neuronal diversity could mask convergent roles of a subset of neurons in regulating both arousal and anesthesia.
In this dissertation, we utilize a neuropeptide, tachykinin 1 (Tac1), as a molecular marker for arousal state-regulating POA neurons and show using EEG/EMG recordings that chemogenetic activation of these POA Tac1 neurons strongly promotes wakefulness over both NREM and REM sleep, consolidating the wake state for hours. Additionally, actigraphy and video recordings demonstrate that POA Tac1 activation increases locomotor activity, with no evidence of enhanced anxiety. We also show that activation of this same population stabilizes the wake state against both isoflurane- and sevoflurane-induced unconsciousness, producing a partial resistance to entering isoflurane anesthesia and a more pronounced ability to exit both isoflurane and sevoflurane hypnosis. Furthermore, activation of POA Tac1 neurons promotes resistance throughout prolonged exposures to isoflurane on both the population and individual level, further supporting their arousal-promoting role. Together, these results demonstrate that POA Tac1 neurons can potently reinforce arousal against both endogenous and drug-induced states of unconsciousness, identifying a subpopulation within the POA that may be shared between the circuits regulating sleep/wake and anesthesia.