上田 壮志

Rapid eye movement (REM) sleep is primarily regulated by the brainstem pons. In particular, the sublaterodorsal tegmentum (SubLDT) in the dorsal pons contains neurons whose activity is selective to REM sleep. Elucidation of the precise identities of these neurons and their roles in REM sleep regulation is challenging, however, due to the functional and molecular heterogeneity of the SubLDT. A recent study revealed that corticotropin-releasing hormone-binding protein (Crhbp)-positive neurons in the SubLDT projecting to the medulla play a crucial role in REM sleep regulation and that loss of these Crhbp-positive neurons underlies sleep deficits observed in Parkinson's disease. The firing patterns of these neurons during sleep/wake, however, remained unknown. Here, we used an opto-tagging method and conducted cell-type-specific recordings from Crhbp-positive neurons using a glass pipette microelectrode in unanesthetized male mice. We recorded 58 Crhbp-positive neurons and found that many of these neurons are REM sleep-active neurons (41.4%) and that the remaining neurons are mostly either wake-active, wake/REM sleep-active, or NREM sleep-active. In addition, projection-specific recordings revealed that the medulla-projecting Crhbp-positive neurons are mostly REM sleep-active neurons (75.0%). Based on clustering analysis and spike waveform analysis, REM sleep-active Crhbp-positive neurons can be further divided into different subtypes according to their electrophysiological properties, suggesting that Crhbp-positive neurons play diverse roles in REM sleep regulation.Significance statement Reduced REM sleep is a risk for dementia and mortality, suggesting it has critical roles in health. The mechanisms and functions of REM sleep, however, remain largely elusive. Classical electrophysiological studies identified neurons in the pons that are active during REM sleep, and a recent study revealed that Crhbp-positive neurons within the same area contribute to REM sleep regulation. The relationship between the neurons identified in each study, however, remained unknown. Loss of Crhbp-positive neurons underlies sleep deficits in Parkinson's disease, underscoring the importance of characterizing these neurons. Our study revealed that many of the Crhbp-positive neurons are REM sleep-active and comprise distinct subtypes in regard to firing patterns, suggesting their diverse roles in REM sleep regulation.

Summary The neural mechanisms regulating sequential transitions of male sexual behaviors, such as mounting, intromission, and ejaculation, in the brain remain unclear. Here, we report that dopamine (DA) and acetylcholine (ACh) dynamics in the ventral shell of the nucleus accumbens (vsNAc) closely aligns with serial transitions of sexual behaviors in male mice. During intromission, the vsNAc exhibits dual ACh-DA rhythms generated by reciprocal regulation between ACh and DA signaling via nicotinic acetylcholine (nAChR) and dopamine D2 (D2R) receptors. Knockdown of choline acetyl transferase (ChAT) or D2R in the vsNAc diminished the likelihood of intromission and ejaculation. Optogenetic manipulations reveal that DA signaling sustains male sexual behaviors by suppressing activities of D2R^vsNAcneurons. Moreover, ACh signaling promotes the initiation of mounting and intromission, but also induces the intromission-to-ejaculation transition by triggering a slowdown of DA rhythm. Therefore, dual ACh-DA dynamics harmonize in the vsNAc to drive sequential transitions of male mating behaviors.

Abstract Despite the importance of sleep to the cerebral cortex, how much sleep changes cortical neuronal firing remains unclear due to complicated firing behaviors. Here we quantified firing of cortical neurons using Hawkes process modeling that can model sequential random events exhibiting temporal clusters. “Intensity” is a parameter of Hawkes process that defines the probability of an event occurring. We defined the appearance of repetitive firing as the firing intensity corresponding to “intensity” in Hawkes process. Firing patterns were quantified by the magnitude of firing intensity, the time constant of firing intensity, and the background firing intensity. The higher the magnitude of firing intensity, the higher the likelihood that the spike will continue. The larger the time constant of firing intensity, the longer the repetitive firing lasts. The higher the background firing intensity, the more likely neurons fire randomly. The magnitude of firing intensity was inversely proportional to the time constant of firing intensity, and non-REM sleep increased the magnitude of firing intensity and decreased the time constant of firing intensity. The background firing intensity was not affected by the sleep/wake state. Our findings suggest that the cortex is organized such that neurons with a higher probability of repetitive firing have shorter repetitive firing periods. In addition, our results suggest that repetitive firing is ordered to become high frequency and short term during non-REM sleep, while unregulated components of firing are independent of the sleep/wake state in the cortex. Hawkes process modeling of firing will reveal novel properties of the brain.